Distinct neural mechanisms for heading retrieval and context recognition in the hippocampus during spatial reorientation.

Reorientation, the process of regaining one's bearings after becoming lost, requires identification of a spatial context (context recognition) and recovery of facing direction within that context (heading retrieval). We previously showed that these processes rely on the use of features and geometry, respectively. Here, we examine reorientation behavior in a task that creates contextual ambiguity over a long timescale to demonstrate that male mice learn to combine both featural and geometric cues to recover heading. At the neural level, most CA1 neurons persistently align to geometry, and this alignment predicts heading behavior. However, a small subset of cells remaps coherently in a context-sensitive manner, which serves to predict context. Efficient heading retrieval and context recognition correlate with rate changes reflecting integration of featural and geometric information in the active ensemble. These data illustrate how context recognition and heading retrieval are coded in CA1 and how these processes change with experience.

Expert consensus: Profiling and management of advanced or metastatic epithelial ovarian cancer / Consenso de expertos basado en la evidencia: perfilamiento y manejo del carcinoma epitelial de ovario de alto grado avanzado.

Introduction and objective: The approach to patients with advanced or metastatic high-grade epithelial ovarian cancer (EOC) has evolved over time with the advent of new therapies and multimodal strategies. The objective of this consensus of experts is to generate national recommendations for the profiling and management of advanced or metastatic high-grade OEC, defined as stages III and IV of the "The International Federation of Gynecology and Obstetrics (FIGO) classification at the time of diagnosis to base on the literature review that included international evidence-based clinical practice guidelines (CPG). Material and methods: Eleven panelists (oncologists and gynecological oncologists) answered 8 questions about the profiling and management of advanced or metastatic ovarian epithelial carcinoma. The panelists were chosen for their academic profile and influence in national health institutions. Guidelines from the "ESMO Standardized Operating Procedures Consensus Conference" were used to develop the consensus. It was agreed that the level of agreement to accept a recommendation should be ≥ 80%. The document was peer reviewed. Results: Eight general recommendations are made, which are presented into five domains. Some of these recommendations are subdivided into specific recommendations. Initial treatment Recommendation 1.1 Complete primary cytoreduction (PCS) surgery is suggested as the initial therapy of choice for patients with high-grade or metastatic EOC, which should ideally be carried out in centers with experience, followed by adjuvant therapy. 1.2 Neoadjuvant chemotherapy followed by interval cytoreduction surgery (ICS) is suggested in those who are unlikely to achieve a complete cytoreduction in PCS either due to unresectable metastatic disease or who present unresectability criteria (imaging, laparoscopic and/or by laparotomy) and that have been defined by a gynecological oncologist and patients with poor functional status and comorbidities according to the criteria of the multidisciplinary team (clinical oncology, gynecological oncology, radiology, etc.). Recommendation 2. In patients with high-grade epithelial ovarian cancer (EOC), in stage III locally advanced or metastatic, who received neoadjuvant chemotherapy and achieved a complete or partial response (cytoreduction with tumor residue < 2.5 mm), the use of Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) could be considered as an alternative to standard platinum-based adjuvant intravenous chemotherapy during interval cytoreductive surgery, after discussion in a multidisciplinary tumor board, at a center experienced in treating this type of patients. Use of genetic testing. Recommendation 3. It is suggested at the time of diagnosis to offer molecular genetic testing to all patients with high-grade advanced or metastatic EOC regardless of family history. Recommendation 4. It is suggested to offer genetic counseling, by qualified personnel, to all patients with high-grade advanced or metastatic EOC who are ordered genetic testing. Recommendation 5. It is suggested that all patients with advanced or metastatic high-grade EOC undergo a germ panel that includes the Breast Cancer Susceptibility Genes 1/2 genes (BRCA 1/2) and the other susceptibility genes according to with institutional protocols and the availability of genetic testing panels; If it is negative, then somatic testing should be performed that includes the homologous recombination deficiency (HRD) status, regardless of family history. Adjuvant Therapy Recommendation 6. 6.1. It is suggested that all patients with advanced stage III/IV EOC, with PSC of (0-2), got adjuvant intravenous chemotherapy as standard treatment within six weeks after Prc. It is suggested paclitaxel/carboplatin. Recommendation 6.2. It is suggested to use standard chemotherapy base on platinum plus Bevacizumab as adjuvant chemotherapy to patients with high-risk disease (EOC stage IV or stage III with suboptimal tumor cytoreduction), following by bevacizumab as maintenance. The use of bevacizumab as maintenance therapy is not recommended if bevacizumab was not included in the first line of treatment. We suggested the dose used in GOG-0218 and ICON7 trials. Recommendation 6.3 It is suggested combined intravenous/intraperitoneal chemotherapy only for selected patients, with optimal cytoreduction (residual lesions < 1 cm), especially those without residual disease (R0) and who are evaluated in a multidisciplinary meeting. It is not considered standard treatment. Recommendation 6.4. 6.4.1 It is suggested to use Poly ADP ribose polymerase (PARP) inhibitors such as olaparib or niraparib as maintenance after receiving first-line chemotherapy in patients with stage III/IV BRCA1/2 positive EOC who received platinumbased chemotherapy and obtained complete response/partial response (CR/PR), 6.4.2 It is suggested to use olaparib alone or in combination with bevacizumab or niraparib in patients with stage III/IV BRCA1/2 positive EOC who received platinum-based chemotherapy plus bevacizumab and achieved CR/PR. 6.4.3 It is suggested to use niraparibin patients with stage III/IV BRCA1/2 negative or unknown EOC who received platinum-based chemotherapy and achieved CR/PR. 6.4.4 It is suggested to use bevacizumab or olaparib plus bevacizumab in patients with EOC stage III/IV BRCA1/2 negative or unknown (HRD positive) who received platinum-based chemotherapy plus bevacizumab and obtained CR/PR. Treatment of disease relapse Recommendation 7. Secondary cytoreductive surgery followed by chemotherapy is suggested for selected patients with high-grade advanced EOC in first relapse, platinum-sensitive (platinum-free interval ≥ 6 months), positive "Arbeitsgemeinschaft Gynäkologische Onkologie ­ AGO" score or "I-model" positive (< 4.7) with a potential resection to R0 in centers with access to optimal surgical and postoperative support. Note: Platinum-free interval and AGO score have only been developed as positive predictors of complete resection and not to exclude patients from surgery. Recommendation 8. 8.1 For patients with relapse advanced high-grade EOC platinum-sensitive, the following is suggested: Platinum-based combination chemotherapy: carboplatin/liposomal doxorubicin or carboplatin/paclitaxel or carboplatin/nab-paclitaxel or carboplatin/docetaxel or carboplatin/gemcitabine) for six cycles. If combination therapy is not tolerated, give carboplatin or cisplatin alone. Combination chemotherapy (carboplatin/gemcitabine or carboplatin/paclitaxel or carboplatin/doxorubicin liposomal) plus bevacizumab followed by bevacizumab as maintenance (until progression or toxicity). Recommendation 8.2 For patients with relapsed advanced high-grade EOC platinum-resistant, it is suggested: Sequential treatment with chemotherapy, preferably with a non-platinum single agent (weekly paclitaxel or pegylated liposomal doxorubicin or docetaxel or oral etoposide or gemcitabine or trabectidine or, topotecan). Weekly paclitaxel or pegylated liposomal doxorubicin or topotecan could be administrate with or without bevacizumab. Other agents are considered potentially active (capecitabine, cyclophosphamide, ifosfamide, irinotecan, oxaliplatin, pemetrexed, vinorelbine, cyclophosphamide) could be recommended for later lines. Hormone receptor-positive patients who do not tolerate or have no response to cytotoxic regimens may receive hormone therapy with tamoxifen or other agents, including aromatase inhibitors (anastrozole and letrozole) or leuprolide acetate, or megestrol acetate. Patients with a performance score ≥ 3 should be considered only for best supportive care. Recommendation 8.3 Maintenance therapy with PARP inhibitors: It is suggested in patients with relapse advanced high-grade EOC stage III/IV BRCA1/2 (positive, negative or unknown) who have received two or more lines of platinum-based chemotherapy and have achieved CR/PR, use olaparib, niraparib or rucaparib. Niraparib could be useful in BRCA 1/2 +/-/unknown patients, as rucaparib, however, the latter does not yet have approval from the regulatory office in Colombia. Conclusions: It is expected that the recommendations issued in this consensus will contribute to improving clinical care, oncological impact, and quality of life of these women.

Introducción y objetivo: el abordaje de pacientes con cáncer epitelial de ovario (CEO) de alto grado avanzado o metastásico ha ido evolucionando a través del tiempo con el advenimiento de nuevas terapias y estrategias multimodales. El objetivo de este consenso de expertos es generar recomendaciones nacionales para el perfilamiento y manejo del CEO de alto grado avanzado o metastásico, definido como estadios III y IV de la clasificación de la Federación Internacional de Ginecología y Obstetricia (FIGO) al momento del diagnóstico, a partir de la revisión de la literatura que incluyó guías de práctica clínica (GPC) internacionales basadas en la evidencia. Materiales y métodos: once panelistas (oncólogos y ginecólogos oncólogos) respondieron ocho preguntas sobre el perfilamiento y manejo del carcinoma epitelial de ovario avanzado o metastásico. Los panelistas fueron escogidos por su perfil académico e influencia en instituciones de salud nacionales. Para el desarrollo del consenso se utilizaron los lineamientos de la "Conferencia de consenso de procedimientos operativos estandarizados de ESMO". Se definió que el nivel de acuerdo para aceptar una recomendación debía ser ≥ 80%. El documento fue revisado por pares. Resultados: Se hacen 8 recomendaciones generales, presentadas en cinco dominios; algunas de ellas se subdividen en recomendaciones específicas. Tratamiento inicial Recomendación 1 1.1. Como terapia inicial de elección para pacientes con CEO de alto grado o metastásico se sugiere la cirugía de citorreducción primaria (Cpr) completa que, idealmente, debe realizarse en centros con experiencia, seguida de terapia adyuvante. 1.2. Se sugiere quimioterapia neoadyuvante seguida de cirugía de citorreducción de intervalo (Cint) en quienes sea improbable alcanzar una citorreducción completa en la Cpr, bien sea por enfermedad metastásica no resecable o que presenten criterios de irresecabilidad (imagenológicos, laparoscópicos o por laparotomía) que hayan sido definidos por un ginecólogo oncólogo. También en pacientes con un pobre estado funcional y comorbilidades de acuerdo con el criterio del equipo multidisciplinario (oncología clínica, ginecología oncológica, radiología, etc.). Recomendación 2. En pacientes con CEO de alto grado, en estadio III localmente avanzado o metastásico, que recibieron quimioterapia neoadyuvante y alcanzaron respuesta completa o parcial (citorreducción con residuo tumoral < 2,5 mm), se podría evaluar el uso de la quimioterapia intraperitoneal hipertérmica (Hyperthermic IntraPeritoneal Chemotherapy - HIPEC) como alternativa a la quimioterapia IV adyuvante estándar basada en platinos durante la Cint, previa discusión en junta multidisciplinaria, en un centro de experiencia en este tipo de pacientes. Uso de pruebas genéticas Recomendación 3. Al momento del diagnóstico, se sugiere ofrecer testeo molecular genético a toda paciente con CEO de alto grado avanzado o metastásico, independientemente de la historia familiar. Recomendación 4. Se sugiere ofrecer asesoramiento genético, por parte de personal calificado, a toda paciente con CEO de alto grado avanzado o metastásico a quien se le ordene un testeo genético. Recomendación 5. Se sugiere que a toda paciente con CEO de alto grado avanzado o metastásico se le realice panel germinal que incluya los genes de susceptibilidad al cáncer de mama 1/2 (BRCA 1/2) y los otros genes de susceptibilidad de acuerdo con los protocolos institucionales y la disponibilidad de paneles de testeo genético; si es negativo entonces se debería realizar testeo somático que incluya el estatus de deficiencia de la recombinación homóloga (homologous recombination deficiency - HRD), independientemente de la historia familiar. Terapia adyuvante Recomendación 6 6.1. Se sugiere que a toda paciente con CEO estadios III/IV avanzado o metastásico, con estatus de desempeño (performance score care - PSC) de 0-2 se le administre como tratamiento estándar quimioterapia intravenosa (IV) adyuvante dentro de las seis semanas posteriores a la Cpr. Se sugiere administrar paclitaxel/carboplatino. 6.2. Se sugiere utilizar quimioterapia estándar basada en platino más bevacizumab como adyuvancia en pacientes con enfermedad de alto riesgo (CEO estadios IV o III con citorreducción tumoral subóptima), continuando con bevacizumab como mantenimiento. No se recomienda el uso de bevacizumab como terapia de mantenimiento si no se incluyó en la primera línea de tratamiento. Se sugiere seguir los esquemas de los estudios Gynecologic Oncology Group Study (GOG-0218) e International Collaborative Ovarian Neoplasm (ICON7). 6.3. Se sugiere la quimioterapia combinada IV/intraperitoneal (IP) solo para pacientes seleccionadas, con una citorreducción óptima (lesiones residuales < 1 cm), en especial aquellas sin enfermedad residual (R0) y que sean evaluadas en junta multidisciplinaria. La quimioterapia combinada IV/IP no se considera como tratamiento estándar. 6.4. 6.4.1. Se sugiere utilizar inhibidores de poli(ADP-ribosa) polimerasa (PARP) tales como olaparib o niraparib como mantenimiento después de recibir una primera línea de quimioterapia en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino y obtuvieron respuesta completa/respuesta parcial (RC/RP). 6.4.2. Se sugiere utilizar olaparib solo o en combinación con bevacizumab o niraparib en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. 6.4.3. Se sugiere utilizar niraparib en pacientes con CEO estadio III/IV BRCA1/2 negativo o desconocido que recibieron quimioterapia basada en platino y obtuvieron RC/RP. 6.4.4. Se sugiere utilizar bevacizumab u olaparib más bevacizumab en pacientes con CEO estadios III/IV BRCA1/2 negativo o desconocido (HRD positivo) que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. Tratamiento de la recaída de la enfermedad Recomendación 7. Se sugiere la realización de la cirugía de citorreducción secundaria (Csec), seguida de quimioterapia, a pacientes seleccionadas con CEO de alto grado avanzado o metastásico en primera recaída, platino-sensibles (intervalo libre de platinos ≥ 6 meses), puntuación Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) positiva o Integrate model (I-Model) positivo (< 4,7), y con una potencial resección a R0, en centros con acceso a soporte quirúrgico y posoperatorio óptimo. Nota: el intervalo libre de tratamiento con platinos y la puntuación AGO solo se han desarrollado como predictores positivos de resección completa y no para excluir a las pacientes de la cirugía. Recomendación 8 8.1. Para pacientes con CEO de alto grado avanzado o metastásico en recaída platino-sensibles se sugiere: Quimioterapia combinada basada en platino: carboplatino/doxorrubicina liposomal o carboplatino/paclitaxel o carboplatino/ nab-paclitaxel o carboplatino/docetaxel o carboplatino/gemcitabina, por seis ciclos. Si no se tolera la terapia combinada, dar carboplatino o cisplatino solo. Quimioterapia combinada: carboplatino/gemcitabina o carboplatino/paclitaxel o carboplatino/doxorubicina liposomal, más bevacizumab, seguida de bevacizumab como mantenimiento (hasta progresión o toxicidad). 8.2. Para pacientes con CEO de alto grado avanzado o metastásico en recaída, platino-resistentes, se sugiere: Tratamiento secuencial con quimioterapia, preferiblemente con un agente único que no sea un platino (paclitaxel semanal o doxorrubicina liposomal pegilada o docetaxel o etopósido oral o gemcitabina o trabectidina o topotecan). El paclitaxel semanal o la doxorrubicina liposomal pegilada o el topotecan pueden ser administrados con o sin bevacizumab. Existen otros agentes que se consideran potencialmente act ivos (capecitabina, ciclofosfamida, ifosfamida, irinotecán, oxaliplatino, pemetrexed, vinorelbina, ciclofosfamida), que se podrían recomendar para líneas posteriores. Las pacientes con receptores hormonales positivos que no toleran o no tienen respuesta a los regímenes citotóxicos pueden recibir terapia hormonal con tamoxifeno u otros agentes, incluidos los inhibidores de la aromatasa (anastrozol y letrozol) o acetato de leuprolide o acetato de megestrol. Pacientes con PSC ≥ 3 deberían ser consideradas solo para el mejor cuidado de soporte. 8.3. Terapia de mantenimiento con inhibidores PARP. Para pacientes con CEO de alto grado avanzado o metastásico en recaída estadios III/IV BRCA1/2 (positivo, negativo o desconocido), que hayan recibido dos o más líneas de quimioterapia basada en platino y hayan alcanzado RC/RP, se sugiere utilizar olaparib, niraparib o rucaparib. El niraparib podría ser útil en pacientes BRCA 1/2 +/-/desconocido, al igual que el rucaparib, sin embargo, este último no tiene aún aprobación del ente regulador en Colombia. Conclusiones: se espera que las recomendaciones emitidas en este consenso contribuyan a mejorar la atención clínica, el impacto oncológico y la calidad de vida de estas mujeres.

Surgical Management of Iatrogenic Mercury Poisoning From Subcutaneous Injection Into the Arm.

BACKGROUND: Mercury, an element with threats of severe toxic insult to humans and no biological function, has a surprisingly extensive record of human exposure. Regardless of hesitancies toward its harmfulness, it has been historically identified with an almost supernatural power to provide protection from evil and sickness, give good fortune, lend aid in athletic undertakings, or even allow one to achieve immortality. Mercury poisoning is an iatrogenic disease even today as people attempt to achieve these effects through volitional injections into their body by practitioners. Although an uncommon practice in the United States, awareness of patient presentation after volitional injections of elemental mercury is necessary for appropriate treatment of these patients. We aim to increase awareness of the cultural practice of subcutaneous injections of mercury, as it is uncommonly seen in the United States, to contribute a broader understanding to the patient's medical presentation and describe an approach and the impact of medical and surgical intervention. METHODS: In this report, we describe a rare case of elemental mercury poisoning secondary to volitional subcutaneous injection to the arm. Initial management of care through chelation therapy and monitoring of renal and serum mercury levels in addition to symptoms of systemic spread was overseen by an internal medicine physician and poison control. Surgical intervention via full-thickness excision of the visible mercury to the right arm followed by local flap and skin grafting reconstruction was performed. CONCLUSIONS: Mercury poisoning from intentional subcutaneous administration is an uncommon patient presentation in the United States; however, knowledge of management of this rare condition is important for effective management of iatrogenic mercury toxicity.

Farm to Fork Stability of Phytochemicals and Micronutrients in Brassica oleracea and Allium Vegetables.

Brassica oleracea and Allium vegetables are known for their unique, family specific, water-soluble phytochemicals, glucosinolates, and S-alk(en)yl-l-cysteine sulfoxides, respectively. However, they are also important delivery systems of several other health-related compounds, such as carotenoids (lipid-soluble phytochemicals), vitamin C (water-soluble micronutrient), and vitamin K1 (lipid-soluble micronutrient). When all-year-round availability or transport over long distances is targeted for these often seasonal, locally grown vegetables, processing becomes indispensable. However, the vegetable processing chain, which consists of multiple steps (e.g., pretreatment, preservation, storage, preparation), can impact the nutritional quality of these vegetables corresponding to the nature of the health-related compounds and their susceptibility to (bio)chemical conversions. Since information about the impact of the vegetable processing chain is scattered per compound or processing step, this review targets an integration of the state of the art and discusses needs for future research. Starting with a discussion on substrate-enzyme location within the vegetable matrix, an overview is provided of the impact and potential of processing, encompassing a wide range of (nonenzymatic) conversions.

Demonstrating responsiveness of the pediatric cardiac quality of life inventory in children and adolescents undergoing arrhythmia ablation, heart transplantation, and valve surgery.

PURPOSE: Pediatric Cardiac Quality of Life Inventory (PCQLI) is a disease-specific pediatric cardiac health-related quality of life (HRQOL) instrument that is reliable, valid, and generalizable. We aim to demonstrate PCQLI responsiveness in children undergoing arrhythmia ablation, heart transplantation, and valve surgery before and after cardiac intervention. METHODS: Pediatric cardiac patients 8-18 years of age from 11 centers undergoing arrhythmia ablation, heart transplantation, or valve surgery were enrolled. Patient and parent-proxy PCQLI Total, Disease Impact and Psychosocial Impact subscale scores were assessed pre- and 3-12 months follow-up. Patient clinical status was assessed by a clinician post-procedure and dichotomized into markedly improved/improved and no change/worse/much worse. Paired t-tests examined change over time. RESULTS: We included 195 patient/parent-proxies: 12.6 ± 3.0 years of age; median follow-up time 6.7 (IQR = 5.3-8.2) months; procedural groups - 79 (41%) ablation, 28 (14%) heart transplantation, 88 (45%) valve surgery; clinical status - 164 (84%) markedly improved/improved, 31 (16%) no change/worse/much worse. PCQLI patient and parent-proxies Total scores increased (p ≤ 0.013) in each intervention group. All PCQLI scores were higher (p < 0.001) in the markedly improved/improved group and there were no clinically significant differences in the PCQLI scores in the no difference/worse/much worse group. CONCLUSION: The PCQLI is responsive in the pediatric cardiac population. Patients with improved clinical status and their parent-proxies reported increased HRQOL after the procedure. Patients with no improvement in clinical status and their parent-proxies reported no change in HRQOL. PCQLI may be used as a patient-reported outcome measure for longitudinal follow-up and interventional trials to assess HRQOL impact from patient and parent-proxy perspectives.

It is important to have quality of life (QOL) measures that are sensitive to change in QOL before and after procedures and to be sensitive to change over time. The Pediatric Cardiac Quality of Life Inventory (PCQLI) is a QOL measure specifically developed for children with cardiac disease. This study assessed the responsiveness of the PCQLI to detect change in QOL over time. QOL in Children and adolescents who were being treated for abnormal heart rhythms, heart transplantation, and aortic, pulmonary, or mitral valve surgery were assessed before and after their procedure. Children and adolescents with improved clinical status post-procedure, and their parents, reported better QOL after the procedure. Patients with no improvement from a cardiac standpoint and their parents reported no change in QOL after their procedure. The PCQLI may be used to assess QOL before and after cardiac procedures or medical treatment and follow QOL over time.

Variable effect of the post-partum menstrual cycle on aldosterone and renin in women with recent preeclampsia.

The purpose of the present study is to identify the impact of the postpartum menstrual cycle on aldosterone, renin, and their ratio of women with and without a preeclamptic pregnancy in the past. To this end, we analysed the data from 59 women with a history of preeclampsia and 39 healthy parous controls. Five to seven months post-partum, we measured aldosterone, renin, and the aldosterone-to-renin ratio during both the follicular and the luteal phase of the menstrual cycle. All measurements were taken in the supine position in the morning. Patients had maintained a standardized sodium diet in the week prior to the measurements. Our results show that in both post-partum women with recent preeclampsia and controls, average levels of renin and aldosterone are significantly elevated in the luteal phase as compared to the follicular phase. The aldosterone-to-renin ratio does not differ between the two phases in either group. Compared to controls, women with recent preeclampsia have significantly lower levels of renin, aldosterone, and aldosterone-to-renin ratio in the follicular phase. This remained consistent in the luteal phase, except for renin. A close correlation existed between the luteal and follicular aldosterone-to-renin ratio in the control group but not in the preeclampsia group. We conclude that both renin and aldosterone are significantly affected by the menstrual cycle whereas the resulting aldosterone-to-renin ratio is not. Post-partum women with recent preeclampsia tend to have lower values for aldosterone and the aldosterone-to-renin ratio than controls.

Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age.

BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).

Identification of a gene expression signature of vascular invasion and recurrence in stage I lung adenocarcinoma via bulk and spatial transcriptomics.

Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI+ compared with VI- tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42×10-6) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI- LUAD (HR=2.76; p=0.003). To determine our VI predictor's robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2×10-16) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.

Single-cell RNA-sequencing of human eosinophils in allergic inflammation in the esophagus.

BACKGROUND: Eosinophils are elusive cells involved in allergic inflammation. Single-cell RNA-sequencing (scRNA-seq) is an emerging approach to deeply characterize cellular properties, heterogeneity, and functionality. OBJECTIVES: We sought to comprehensively characterize the transcriptome and biological functions of human eosinophils at a site of severe allergic inflammation in the esophagus (ie, eosinophilic esophagitis [EoE]). METHODS: We employed a gravity-based scRNA-seq methodology to sequence blood eosinophils from patients with EoE and control individuals compared to a reanalyzed public scRNA-seq dataset of human esophageal eosinophils of EoE patients. We used flow cytometry, immunostaining, and a stimulation assay to verify mRNA findings. RESULTS: In total, scRNA-seq was obtained from 586 eosinophils (188 from blood [n = 6 individuals] and 398 from esophagus [n = 6 individuals]). The esophageal eosinophils were composed of a population of activated eosinophils (enriched in 659 genes compared with peripheral blood-associated eosinophils) and a small population of eosinophils resembling peripheral blood eosinophils (enriched in 62 genes compared with esophageal eosinophils). Esophageal eosinophils expressed genes involved in sensing and responding to diverse stimuli, most notably IFN-γ, IL-10, histamine and leukotrienes, and succinate. Esophageal eosinophils were most distinguished from other esophageal populations by gene expression of the receptors CCR3, HRH4, SUCNR1, and VSTM1; transcription factors CEBPE, OLIG1, and OLIG2; protease PRSS33; and the hallmark eosinophil gene CLC. A web of bidirectional eosinophil interactions with other esophageal populations was derived. Comparing esophageal eosinophils and mast cells revealed that esophageal eosinophils expressed genes involved in DNAX-activation protein-12 (also known as TYROBP) interactions, IgG receptor-triggered events, immunoregulation, and IL-10 signaling. CONCLUSIONS: In EoE, esophageal eosinophils exist as 2 populations, a minority population resembling blood eosinophils and the other population characterized by high de novo transcription of diverse sensing receptors and inflammatory mediators readying them to potentially intersect with diverse cell types.

Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis.

BACKGROUND: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear. METHODS: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24. RESULTS: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events. CONCLUSIONS: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).

Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection.

BACKGROUND: Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss. METHODS: A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities. RESULTS: Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters. CONCLUSIONS: This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.

Scope of practice of oculofacial plastic and reconstructive surgeons: a public perception survey.

PURPOSE: The purpose of this study is to determine the public's perception of the scope of practice for oculofacial plastic and reconstructive surgeons (OFPRS). METHODS: A 49-question survey was distributed by QualtricsⓇ to a panel similar to the US demographic composition. Responses collected underwent bivariate statistical analysis. RESULT: A total of 530 responses were obtained, with most respondents being white, female, over the age of 35, from the Midwest, and with at least a college education or above. Most respondents did not think ophthalmologists or optometrists were surgeons, and only 158 people (29.8%) knew the primary specialty of OFPRS was ophthalmology. Board certification was preferred by 98.87% of respondents, and 95.28% preferred ASOPRS-trained OFPRS. CONCLUSIONS: Our study highlights the gap in knowledge about OFPRS as a field, the qualifications and training required, and the scope of practice. Notably, even for OFPRS-specific procedures, PRS remained the leading subspecialist chosen for interventions such as orbital decompression (58.5% vs. 71.5%), orbital reconstruction (57.9% vs. 74.2%), enucleation/evisceration (48.1% vs. 53.4%), optic nerve-related surgery (39.8% vs. 43.4%), orbital cancer resection (42.8% vs. 46.8%), and tear duct surgery (41.9% vs. 52.5%). Additionally, most respondents did not feel that facial fillers, laser skin resurfacing, eyelid cancer removal, or cataract surgery were within the OFPRS scope of practice.

Eosinophil Specialization Is Regulated by Exposure to the Esophageal Epithelial Microenvironment.

Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis (EoE), are not well understood. Herein, we report an ex-vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant pro-inflammatory (IL-13) or pro-fibrotic (TGF-ß) cytokines. Compared with untreated cocultures, IL-13 increased expression of CD69 on eosinophils, whereas TGF-ß increased expression of CD81, CD62L, and CD25. Eosinophils from IL-13-treated cocultures demonstrated increased secretion of GRO-α, IL-8, and M-CSF and also generated increased extracellular peroxidase activity following activation. Eosinophils from TGF-ß-treated cocultures secreted increased IL-6 and exhibited increased chemotactic response to CCL11 compared with eosinophils from untreated or IL-13-treated coculture conditions. When eosinophils from TGF-ß-treated cocultures were cultured with fibroblasts, they upregulated SERPINE1 expression and fibronectin secretion by fibroblasts compared with eosinophils that were cultured with GM-CSF, alone. Translational studies revealed that CD62L was heterogeneously expressed by eosinophils in patient biopsies. Our results demonstrate that disease-relevant pro-inflammatory and pro-fibrotic signals present in the esophagus of EoE patients cause distinct profiles of eosinophil activation and gene expression.

Sex Differences in Youth with Chronic Tic Disorder and Tourette Syndrome: Evaluation of Tic Severity, Psychological Profiles, and Quality of Life.

Background: Tourette syndrome (TS) and Chronic Tic Disorder (CT) are neurodevelopmental conditions involving motor and/or phonic tics. Youth with tics may encounter feelings of isolation, diminished self-esteem and quality of life, and academic difficulties. A growing body of scientific literature suggests sex differences in youth with tics, but findings have been mixed so far. Because symptom severity peaks around puberty, understanding sex differences in tic manifestations and associated symptoms during this critical period is essential. Therefore, we aimed to assess sex differences related to tic symptoms, action planning styles, quality of life, and externalizing/internalizing symptoms in youth with tics. Methods: Our sample consisted of 66 youths with tics (19 girls) aged 7-14 (mean = 10 years). Youths were assessed with clinical interviews, as well as self- and parent-reported inventories evaluating tic symptoms, psychological profiles, and quality of life. Results: While no differences in tic symptoms were found, girls exhibited lower functional inflexibility, reduced overall functional planning effectiveness, and higher impairment in the psychological well-being subscale than boys. Additionally, girls had reduced general life satisfaction and social self-esteem. Boys reported more explosive outbursts, higher levels of hyperactivity, and more difficulties with self-concept. Conclusions: Our analyses suggested differences in several manifestations associated with tics. This introduces new perspectives that refine our understanding of sex differences. A better understanding of sex differences in tic disorders may eventually improve outcomes for all individuals living with these conditions.

Comparing the 'When' and the 'Where' of Electrocortical Activity in Patients with Tourette Syndrome, Body-Focused Repetitive Behaviors, and Obsessive Compulsive Disorder.

Background/Objectives: Tourette Syndrome (TS), Obsessive Compulsive Disorder (OCD), and Body-Focused Repetitive Behaviors (BFRB) are three disorders that share many similarities in terms of phenomenology, neuroanatomy, and functionality. However, despite the literature pointing toward a plausible spectrum of these disorders, only a few studies have compared them. Studying the neurocognitive processes using Event-Related Potentials (ERPs) offers the advantage of assessing brain activity with excellent temporal resolution. The ERP components can then reflect specific processes known to be potentially affected by these disorders. Our first goal is to characterize 'when' in the processing stream group differences are the most prominent. The second goal is to identify 'where' in the brain the group discrepancies could be. Methods: Participants with TS (n = 24), OCD (n = 18), and BFRB (n = 16) were matched to a control group (n = 59) and were recorded with 58 EEG electrodes during a visual counting oddball task. Three ERP components were extracted (i.e., P200, N200, and P300), and generating sources were modelized with Standardized Low-Resolution Electromagnetic Tomography. Results: We showed no group differences for the P200 and N200 when controlling for anxiety and depressive symptoms, suggesting that the early cognitive processes reflected by these components are relatively intact in these populations. Our results also showed a decrease in the later anterior P300 oddball effect for the TS and OCD groups, whereas an intact oddball effect was observed for the BFRB group. Source localization analyses with sLORETA revealed activations in the lingual and middle occipital gyrus for the OCD group, distinguishing it from the other two clinical groups and the controls. Conclusions: It seems that both TS and OCD groups share deficits in anterior P300 activation but reflect distinct brain-generating source activations.

Impacts of ADHD Symptomatology on the Response to Cognitive-Behavioural Therapy with Gilles de la Tourette Syndrome Patients.

(1) Background: Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Attention deficit and hyperactivity disorder (ADHD) is a common comorbidity of TS that adds further impairment. Cognitive-behavioural therapy (CBT) has shown efficacy in treating tics, yet its effectiveness in individuals with TS and comorbid ADHD remains unclear. Also, it is suggested that ADHD characteristics like executive dysfunction and inattention could hinder the response to CBT. This study aims to compare the response to CBT for tics and its maintenance six months post-therapy among TS individuals with and without ADHD symptoms. (2) Methods: In this study, 55 TS participants who completed 14-week CBT for tics were split into high (TS+) or low (TS-) ADHD symptomatology groups. Outcomes were evaluated using the Yale Global Tic Severity Scale (YGTSS) regarding global tic severity and motor and vocal tic frequency post-CBT and at a 6-month follow-up. (3) Results: No significant group difference was found regarding improvements post-CBT (n = 55), nor the maintenance six months later (n = 45). (4) Conclusions: ADHD symptoms may not hinder the response to CBT or its maintenance, suggesting that TS individuals with ADHD symptoms may not require specialized CBT interventions.

Transnasal Endoscopy Acquires Esophageal Biopsies Adequate for Comprehensive Pathology Evaluation in Patients With Eosinophilic Esophagitis.

BACKGROUND: Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS). METHODS: The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P ≤ .05 was considered significant. RESULTS: Median age (P = .82) or height (P = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm2) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P = .15), and non-eosinophil-related individual EoEHSS scores did not differ. CONCLUSIONS: TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE.

The Role of Surgery to Relieve Symptomatic Cutaneous T-Cell Lymphoma Refractory to Medical Treatments.

Background: Though mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), it has no curative treatment. The aim of current topical and systemic treatment is centered around relieving symptoms and optimizing disease-free time. The use of surgical management to achieve the same goals of symptomatic reduction is not well described in the current literature. Methods: We present a case of refractory MF that failed chemotherapy, radiotherapy, and UV light therapy. Despite medical management, the tumor burden progressed to significant compression neuropathy of the ulnar and median nerves. Results: To reduce tumor burden and attempt to provide symptomatic relief, a surgical plan was developed to include radical resection of the tumor of the left upper extremity (LUE) with release of the cubital tunnel, carpal tunnel, Guyon canal, and coverage with split-thickness skin graft. The patient reported decreased symptomatology interfering with her daily activities and, overall, a better quality of life postoperatively. Conclusion: Surgical intervention, in addition to established medical standards of care, for symptomatic relief of compression neuropathy from tumor mass effect for refractory CTCL should be considered to achieve quality of life goals for patients.