Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing.

We present an efficient approach for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to rapidly create a library of complex functional ionizable lipopolymers. We synthesized a diverse library of 155 polymers, formulated them into polyplexes to establish structure-activity relationships crucial for endosomal escape and efficient transfection. After discovering a lead structure, lipopolymer-lipid hybrid nanoparticles are introduced to preferentially deliver to and elicit effective mRNA transfection in lung endothelium and immune cells, including T cells with low in vivo toxicity. The lipopolymer-lipid hybrid nanoparticles showed 300-fold improvement in systemic mRNA delivery to the lung compared to in vivo -JetPEI ® . Lipopolymer-lipid hybrid nanoparticles demonstrated efficient delivery of mRNA-based therapeutics for treatment of two different disease models. Lewis Lung cancer progression was significantly delayed after treatment with loaded IL-12 mRNA in U155@lipids after repeated i.v. administration. Systemic delivery of human CFTR (hCFTR) mRNA resulted in production of functional form of CFTR protein in the lungs. The functionality of hCFTR protein was confirmed by restoration of CFTR- mediated chloride secretion in conductive airway epithelia in CFTR knockout mice after nasal instillation of hCFTR mRNA loaded U155@lipids. We further showed that, U155@lipids nanoparticles can deliver complex CRISPR-Cas9 based RNA cargo to the lung, achieving 5.6 ± 2.4 % gene editing in lung tissue. Moreover, we demonstrated successful PD-1 gene knockout of T cells in vivo . Our results highlight a versatile delivery platform for systemic delivering of mRNA of various sizes for gene therapy for a variety of therapeutics.

ICD-10 diagnosis codes in electronic health records do not adequately capture fracture complexity for proximal humerus fractures.

BACKGROUND: The ability to do comparative effectiveness research (CER) for proximal humerus fractures (PHF) using data in electronic health record (EHR) systems and administrative claims databases was enhanced by the 10th revision of the International Classification of Diseases (ICD-10), which expanded the diagnosis codes for PHF to describe fracture complexity including displacement and the number of fracture parts. However, these expanded codes only enhance secondary use of data for research if the codes selected and recorded correctly reflect the fracture complexity. The objective of this project was to assess the accuracy of ICD-10 diagnosis codes documented during routine clinical practice for secondary use of EHR data. METHODS: A sample of patients with PHFs treated by orthopedic providers across a large, regional health care system between January 1, 2016, and December 31, 2018, were retrospectively identified from the EHR. Four fellowship-trained orthopedic surgeons reviewed patient radiographs and recorded the Neer Classification characteristics of displacement, number of parts, and fracture location(s). The fracture characteristics were then reviewed by a trained coder, and the most clinically appropriate ICD-10 diagnosis code based on the number of fracture parts was assigned. We assessed congruence between ICD-10 codes documented in the EHR and radiograph-validated codes, and assessed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for EHR-documented ICD-10 codes. RESULTS: There were 761 patients with unilateral, closed PHF who met study inclusion criteria. On average, patients were 67 years of age and 77% were female. Based on radiograph review, 37% were 1-part fractures, 42% were 2-part, 11% were 3-part, and 10% were 4-part fractures. Of the EHR diagnosis codes recorded during clinical practice, 59% were "unspecified" fracture diagnosis codes that did not identify the number of fracture parts. Examination of fracture codes revealed PPV was highest for 1-part (PPV = 0.66, 95% confidence interval [CI] 0.60-0.72) and 4-part fractures (PPV = 0.67, 95% CI 0.13-1.00). CONCLUSIONS: Current diagnosis coding practices do not adequately capture the fracture complexity needed to conduct subgroup analysis for PHF. Conclusions drawn from population studies or large databases using ICD-10 codes for PHF classification should be interpreted within this limitation. Future studies are warranted to improve diagnostic coding to support large observational studies using EHR and administrative claims data.

Anthracyclines and Biomarkers of Myocardial Injury: The Effect of Remote Ischemic Conditioning.

Background: Remote ischemic conditioning (RIC) has been beneficial in laboratory studies of anthracycline cardiotoxicity, but its effects in patients is not established. Objectives: The authors studied the effect of RIC on cardiac biomarkers and function during and after anthracycline chemotherapy. Methods: The ERIC-Onc study (Effect of Remote Ischaemic Conditioning in Oncology Patients; NCT02471885) was a randomized, single-blind, sham-controlled study of RIC at each chemotherapy cycle. The primary endpoint was troponin T (TnT) during chemotherapy and up to 1 year. Secondary outcomes included cardiac function, major adverse cardiovascular events (MACE), and MACE or cancer death. Cardiac myosin-binding-protein C (cMyC) was investigated in parallel with TnT. Results: The study was prematurely halted after the evaluation of 55 patients (RIC n = 28, sham n = 27). Biomarkers increased from baseline to cycle 6 of chemotherapy for all patients (median TnT 6 [IQR: 4-9] ng/L to 33 [IQR: 16-36)] ng/L; P ≤ 0.001; cMyC 3 (IQR: 2-5) ng/L to 47 (IQR: 18-49) ng/L; P ≤ 0.001). Mixed-effects regression analysis for repeated measures showed no difference in TnT between the 2 groups (RIC vs sham, mean difference 3.15 ng/L; 95% CI: -0.04 to 6.33; P = 0.053), or cMyC (RIC vs sham, mean difference 4.17 ng/L; 95% CI: -0.12 to 8.45; P = 0.056). There were more MACE and cancer deaths in the RIC group (11 vs 3; HR: 0.25; 95% CI: 0.07-0.90; P = 0.034), with more cancer deaths (8 vs 1; HR: 0.21; 95% CI: 0.04-0.95; P = 0.043) at 1 year. Conclusions: TnT and cMyC significantly increased during anthracycline chemotherapy with 81% having a TnT ≥14 ng/L at cycle 6. RIC did not affect the rise in biomarkers, but there was a small increase in early cancer deaths, possibly related to the greater proportion of patients with metastatic disease randomized to the RIC group (54%vs 37%). (Effect of Remote Ischaemic Conditioning in Oncology Patients [ERIC-ONC]; NCT02471885).

Waterborne infections in haemato-oncology units - a narrative review.

Bone marrow transplant and haemato-oncology patients are at risk of healthcare-associated infections due to waterborne pathogens. We undertook a narrative review of waterborne outbreaks in haemato-oncology patients from 2000 to 2022. Databases searched included PubMed, DARE and CDSR, and were undertaken by two authors. We analysed the organisms implicated, sources identified and infection prevention and control strategies implemented. The most commonly implicated pathogens were Pseudomonas aeruginosa, non-tuberculous mycobacteria and Legionella pneumophila. Bloodstream infection was the most common clinical presentation. The majority of incidents employed multi-modal strategies to achieve control, addressing both the water source and routes of transmission. This review highlights the risk to haemato-oncology patients from waterborne pathogens and discusses future preventative strategies and the requirement for new UK guidance for haemato-oncology units.

Measurement of changes in uterine and fibroid volume during treatment of heavy menstrual bleeding (HMB).

STUDY QUESTION: Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)? SUMMARY ANSWER: Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids. WHAT IS KNOWN ALREADY: SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids. STUDY DESIGN SIZE DURATION: In a prospective clinical study (with no comparator), 19 women with HMB were treated over a period of 12 months with SPRM-UPA and uterine and fibroid size were assessed with high resolution structural MRI and stereology. PARTICIPANTS/MATERIALS SETTING METHODS: A cohort of 19 women aged 38-52 years (8 with and 11 without fibroids) were treated with three 12-week courses of 5 mg SPRM-UPA given daily, with four weeks off medication in-between treatment courses. Unbiased estimates of the volume of uterus and total volume of fibroids were obtained at baseline, and after 6 and 12 months of treatment, by using the Cavalieri method of modern design-based stereology in combination with magnetic resonance imaging (MRI). MAIN RESULTS AND THE ROLE OF CHANCE: Bland-Altman plots showed good intra-rater repeatability and good inter-rater reproducibility for measurement of the volume of both fibroids and the uterus. For the total patient cohort, two-way ANOVA did not show a significant reduction in the volume of the uterus after two or three treatment courses of SPRM-UPA (P = 0.51), which was also the case when the groups of women with and without fibroids were considered separately (P = 0.63). One-way ANOVA did not show a significant reduction in total fibroid volume in the eight patients with fibroids (P = 0.17). LIMITATIONS REASONS FOR CAUTION: The study has been performed in a relatively small cohort of women and simulations that have subsequently been performed using the acquired data have shown that for three time points and a group size of up to 50, with alpha (Type I Error) and beta (Type II Error) set to 95% significance and 80% power, respectively, at least 35 patients would need to be recruited in order for the null hypothesis (that there is no significant reduction in total fibroid volume) to be potentially rejected. WIDER IMPLICATIONS OF THE FINDINGS: The imaging protocol that we have developed represents a generic paradigm for measuring the volume of the uterus and uterine fibroids that can be readily incorporated in future studies of medical treatments of HMB. In the present study, SPRM-UPA failed to produce a significant reduction in the volume of the uterus or the total volume of fibroids (which were present in approximately half of the patients) after either two or three 12-week courses of treatment. This finding represents a new insight in respect of the management of HMB using treatment strategies that target hormone-dependence. STUDY FUNDING/COMPETING INTERESTS: The UPA Versus Conventional Management of HMB (UCON) trial was funded by the EME Programme (Medical Research Council (MRC) and National Institutes of Health Research (NIHR)) (12/206/52). The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care.Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. H.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (All paid to Institution) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., and Myovant Sciences GmbH. H.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. L.W. has received grant funding from Roche Diagnostics (Paid to Institution). All other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: The study reported here is an embedded mechanism of action study (no comparator) within the UCON clinical trial (registration ISRCTN: 20426843).

Genome-wide CRISPRi Screen in Human iNeurons to Identify Novel Focal Cortical Dysplasia Genes.

Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 12 new genes that significantly increase pS6 levels. Interestingly, positive hits were enriched for brain-specific genes, highlighting the effectiveness of using human iPSC-derived induced neurons (iNeurons) in our screen. We investigated the signaling pathways of six candidate genes: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. All six genes increased phosphorylation of S6. However, only two genes, PIK3R3 and HIP1, caused hyperphosphorylation more proximally in the AKT/mTOR/S6 signaling pathway. Importantly, these two genes have recently been found independently to be mutated in resected brain tissue from FCD patients, supporting the predictive validity of our screen. Knocking down each of the other four genes (LRRC4, EIF3A, TSN, and URI1) in iNeurons caused them to become resistant to the loss of growth factor signaling; without growth factor stimulation, pS6 levels were comparable to growth factor stimulated controls. Our data markedly expand the set of genes that are likely to regulate mTOR pathway signaling in neurons and provide additional targets for identifying somatic gene variants that cause FCD.

Rosette-induced separation of T cells by acoustophoresis.

Breakthrough cell therapies for the treatment of cancers require the separation of specific cells, such as T cells, from the patient's blood. Current cell therapy processes rely on magnetic separation, which adds clinical risk and requires elevated manufacturing controls due to the added foreign material that constitutes the magnetic beads. Acoustophoresis, a method that uses ultrasound for cell separation, has demonstrated label-free enrichment of T cells from blood, but residual other lymphocytes limit the ultimate purity of the output T cell product. Here, to increase the specificity of acoustophoresis, we use affinity reagents to conjugate red blood cells with undesired white blood cells, resulting in a cell-cell complex (rosette) of increased acoustic mobility. We achieve up to 99% purity of T cells from blood products, comparable to current standards of magnetic separation, yet without the addition of separation particles.

The Fall of the Nation's First Gender-Affirming Surgery Clinic.

Johns Hopkins Hospital established the first gender-affirming surgery (GAS) clinic in the United States in 1966. Operating for more than 13 years, the clinic was abruptly closed in 1979. According to the hospital, the decision was made in response to objective evidence claiming that GAS was ineffective. However, this evidence directly contradicted many contemporaneous studies and faced immediate criticism from the scientific community. Despite this resistance, it took the hospital nearly 40 years to resume performing GAS. Scientific evidence-imbued in scandal, bias, and moralism-was instrumentalized to serve broader institutional interests. The burgeoning field of plastic surgery tethered and then untethered GAS from its auspices in response to poor technical outcomes and transphobia. No longer serving surgeons' interests, the clinic was marginalized to "barely minimal facilities" in 1974, five years before GAS was formally banned. Over the next 5 years, the clinic co-inhabited space with the Department of Obstetrics and Gynecology. Simultaneously, the Department of Obstetrics and Gynecology navigated scandals related to reproductive technology (namely, the Dalkon Shield [A.H. Robins] controversy) until the clinic space was demolished in 1979. The study that informed the GAS ban was preferentially funded in keeping with the political economy of biomedical research. This article presents a spatial argument for how the closure of the nation's first GAS clinic was not based in empirical data alone but was manipulated to fuel political and institutional agendas.

A Systematic Review of Muscle Synergies during a Walking Gait to Define Optimal Donor-Recipient Pairings for Lower Extremity Functional Reconstruction.

Functional lower extremity reconstruction primarily aims to restore independent ambulation. We sought to define the synergies recruited during a walking gait to inform donor selection for various motor deficits. With these findings, we discuss the functional neuromuscular components of independent gait with the goal of informing lower extremity reconstruction. Methods: A systematic review was performed using MEDLINE for articles published between January 2000 and December 2020. Search terms included (1) "motor module(s)," "synergy," "motor pattern," or "motor primitive" and (2) "gait," "walking," "ambulation," or "locomotion." Abstracts/full texts were reviewed by two independent reviewers. Results: A total of 38 studies were selected. The average reported number of synergies and variance accounted for was 4.5 ± 0.9 and 88.6% ± 7.7%, respectively. Four motor modules were conserved across nearly all studies. Conclusions: Walking can be reduced to the sequential activation of four motor modules. Activities during the stance phase are critical for both standing stability and forward progression and should be prioritized for reconstruction with the goal of preserving efficient gait. Muscles recruited during swing, except those used for ankle dorsiflexion, are less prone to injury and benefit from greater redundancy, less often necessitating reconstruction. With the emphasis on stability during stance, several synergistic or sometimes even antagonistic tendons can be used to replace their counterparts and restore efficient, independent ambulation. With a finite supply of donor tissues, and in the absence of well-defined clinical outcomes data, this research allows us to effectively prioritize reconstructive goals and maximize patient outcomes.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Readability Analysis and Accessibility of Online Materials About Transgender Voice Care.

OBJECTIVE: To determine readability, understandability, and actionability of online health information related to transgender voice care. STUDY DESIGN: Review of online materials. SETTING: Academic medical center. METHODS: A Google search of "transgender voice care" was performed with the first 50 websites meeting inclusion criteria included. Readability was assessed using the Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), and the Simple Measure of Gobbledygook (SMOG). Understandability and actionability were measured by 2 independent reviewers using the Patient Education Materials Assessment Tool for Printable Materials (PEMAT-P). Unpaired t tests were used to compare clinician- and patient-oriented sites, surgical and nonsurgical sites, and sites that discuss nonbinary indications for voice care. Analysis of variance was used to compare sites that discuss voice feminization, masculinization, both, or neither. RESULTS: Average scores across the cohort for FRES, FKGL, and SMOG were 43.77 ± 13.52, 12.14 ± 2.66, and 11.30 ± 1.93, respectively, indicating materials were above a 12th-grade reading level. PEMAT-P scores for understandability and actionability were 64.95% ± 15.78% and 40.55% ± 23.86%, respectively. Patient-oriented sites were significantly more understandable and actionable than clinician-oriented sites (P < .02). Websites that discussed only voice feminization were significantly more readable according to objective metrics (FKGL, SMOG) than websites that discussed both feminization and masculinization or those that did not differentiate care types (P < .05). CONCLUSION: Online information written about transgender voice care is written at a level above what is recommended for patient education materials. Providers may improve accessibility of transgender voice care by enhancing readability of online materials.

Evaluación del olfato en pacientes operados por adenoma hipofisario con acceso transesfenoidal en el Instituto de Neurocirugía Dr. Asenjo / Olfactory evaluation in patients operated for pituitary adenoma with transsphenoidal access at the Instituto de Neurocirugía Dr. Asenjo

Introducción: El olfato tiene una gran importancia en la calidad de vida. Los accesos quirúrgicos selares pueden realizarse por vía transcraneal, transeptal y transnasal, y pueden generar hiposmia al incluir resecciones que afectan a la mucosa olfatoria. Objetivo: Determinar la existencia de alteración persistente en el olfato ocasionado por los accesos quirúrgicos transeptal y transnasal en pacientes operados por adenoma hipofisiario en el Instituto de Neurocirugía Dr. Asenjo. Material y Método: Estudio prospectivo de cohorte con comparación de resultados olfatorios ("sniffin' sticks" versión extendida) y encuesta SNOT-22 pre y poscirugía por adenoma hipofisiario por vía transeptal o transnasal. Se utilizaron medidas estadísticas de comparación de pruebas pareadas paramétricas y no paramétricas según las características de las variables evaluadas. Resultados: Se reclutaron 60 pacientes, completando el seguimiento 39. En 21 se realizó acceso transeptal y en 18 transnasal. Al analizar el total de pacientes y por cada técnica quirúrgica, no hubo diferencias significativas en los puntajes del "sniffin' sticks" versión extendida y tampoco en SNOT-22. Conclusión: La literatura describe incidencia de hiposmia posoperatoria muy variable, entre 0% y 88%, con mediciones subjetivas y objetivas. Existe una predilección por la técnica endoscópica a nivel internacional, por lo que cuenta con estudios de mejor calidad. A nivel nacional existen dos estudios previos que han encontrado tasas de hiposmia posoperatoria de 10% y 14%. En este estudio no hubo diferencias significativas en los puntajes obtenidos en la prueba de olfato entre el pre y posoperatorio.

Introduction: Olfaction is of great importance in quality of life. Surgical accesses to the sellar region can be performed by transcranial, transseptal, and transnasal routes, which can generate hyposmia when including resections that affect the olfactory mucosa. Aim: To determine the existence of persistent alteration in olfaction caused by transseptal and transnasal surgical accesses in patients operated for pituitary adenoma at the Instituto de Neurocirugía Dr. Asenjo. Material and Method: Prospective cohort study with comparison of olfactory results ("sniffin' sticks" extended version) and SNOT-22 survey pre and post transseptal or transnasal surgery for pituitary adenoma. Parametric and non-parametric paired test comparison statistics were used according to the characteristics of the variables evaluated. Results: 60 patients were recruited and 39 completed follow-up. 21 patients underwent transseptal access and 18 underwent transnasal access. When analyzing the total number of patients and for each surgical technique, there were no significant differences in the scores obtained in the "sniffin' sticks" extended version and neither for the SNOT-22. Conclusion: The literature describes a highly variable incidence of postoperative hyposmia, between 0% and 88%, with subjective and objective measurements. There is a predilection for the endoscopic technique at an international level, which is why it has better quality studies. At the national level there are two previous studies that have found postoperative hyposmia rates of 10% and 14%. In this study there were no significant differences in the scores obtained between pre and postoperative olfaction test.

Hiperacusia en trastornos del espectro autista: una revisión de la literatura / Hyperacusis in autism spectrum disorders: a review of the literature

Resumen La hiperacusia se define como la intolerancia a ciertos sonidos cotidianos que causa angustia y discapacidad significativas en las actividades sociales, ocupacionales, recreativas y otras actividades cotidianas. Los sonidos pueden percibirse como incómodamente fuertes, desagradables, atemorizantes o dolorosos. Se encuentra presente en aproximadamente un 3% población general, y aumenta significativamente en trastornos del espectro autista (TEA), alcanzando entre un 15% a 40%. Los mecanismos fisiopatológicos no son del todo claros, pero se ha propuesto, una alteración en el funcionamiento de mecanismos reflejos y de regulación, tanto a nivel de la vía auditiva periférica, como central, incluyendo estructuras no relacionadas directamente con la vía auditiva. El siguiente texto tiene como objetivo analizar la relación entre hiperacusia y TEA, enfatizando en la frecuencia en que se presentan como comorbilidades, en los posibles mecanismos fisiopatológicos, y en actualizaciones en el abordaje diagnóstico y terapéutico. Se realiza una revisión bibliográfica cualitativa en Pubmed con artículos entre los años 2008-2020 utilizando los términos: "hyperacusis autism", "sistema olivococlear", arrojando 39 artículos, de los cuales se seleccionaron en base a la temática de cada uno, evaluada por los autores. A pesar de una significativa relación entre hiperacusia y TEA, los mecanismos fisiopatológicos de ambas patologías siguen siendo un misterio. Existen estudios que sugieren pruebas de screening no invasivas que relacionan ambas patologías, pero debido a los sesgos de selección, todavía no son factibles de usar en forma universal. El abordaje terapéutico ha sido poco explorado, y no se dispone de fármacos que hayan demostrado su efectividad, por el contrario, algunos de ellos empeoran la sintomatología. Se recomienda al tratante, seguir un camino largo, en conjunto con el paciente, donde las terapias no farmacológicas como la terapia cognitivo conductual han mostrado tener buenos resultados.

Abstract Hyperacusis is defined as intolerance to certain sounds that causes significant distress and disability in social, occupational, recreational and other activities. Sounds can be perceived as uncomfortably loud, unpleasant, frightening, or painful. It is present in approximately 3% of the general population, and increases significantly in autism spectrum disorders (ASD), between 15% and 40%. The pathophysiological mechanisms are not entirely clear, but an alteration in the functioning of reflex and regulatory mechanisms has been proposed, both at the peripheral and central auditory pathways, including structures not directly related to the auditory pathway. The therapeutic approach has been little explored as there are no drugs that have demonstrated their effectiveness, on the contrary, some of them worsen the symptoms. The practitioner is recommended to follow a long path, in conjunction with the patient, where non-pharmacological therapies such as cognitive behavioral therapy have been shown to have good results. The following text shows a review of the literature with articles referring to the subject between the years 2008-2019.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Cuerpos extraños en otorrinolaringología: Experiencia en Clínica Santa María / Foreign bodies in otolaryngology: Experience at Clínica Santa María

Resumen Introducción: Los cuerpos extraños (CE) en oído, nariz y vía aéreodigestiva superior son el 30% de las urgencia en otorrinolaringología (ORL). No existen datos epidemiológicos nacionales que describan la casuística de CE. Objetivo: Describir la epidemiología de pacientes con diagnóstico de CE evaluados, entre el 2013-2018 en Clínica Santa María de Santiago, Chile. Describir las características de los CE, ubicación, método de extracción y complicaciones. Material y Método: Estudio descriptivo y retrospectivo, basado en revisión de fichas clínicas de pacientes con diagnóstico de CE, analizando variables epidemiológicas y clínicas. Resultados: Se revisaron 1.847 casos con diagnóstico de CE, confirmando 1.494. La mayoría de sexo masculino (53,3%), con un promedio de edad de 16,5 años (rango de 0-95 años). Los CE más prevalentes fueron ótico (52,9%) y nasal (27,9%). El síntoma asociado más frecuente fue la sensación de CE (18,1%). El diagnóstico fue principalmente por examen físico (84%), requiriéndose exámenes complementarios en 18,2%. La extracción fue ambulatoria en su mayoría (84,6%), requiriendo extracción en pabellón el 12,5%. El 5,5% presentó complicaciones, y la tasa de letalidad fue de 0,07%. Conclusión: Esta casuística, única a nivel nacional, nos permite conocer la epidemiología de los CE. Un bajo porcentaje de pacientes fue de riesgo vital, pero el manejo oportuno permite una baja tasa de complicaciones y letalidad.

Abstract Introduction: Foreign bodies (FB) in the ear, nose and upper airway-digestive tract are 30% of the emergencies in otolaryngology (ORL). There is no national epidemiological data that describes the FB casuistry. Aim: To describe the epidemiology of patients who have a diagnosis of a FB evaluated, between 2013-2018, at Santa María Clinic in Santiago, Chile. To describe the characteristics of FB, location, method of removal, and complications. Material and Method: A descriptive and retrospective study, based on review of clinical records of patients with the diagnosis of FB, analyzing epidemiological and clinical variables. Results: 1847 cases with a diagnosis of FB were reviewed, of which 1494 were confirmed. Most were male (53.3%), with an average age of 16.5 years (range 0-95 years). The most prevalent FB locations were otic (52.9%) and nasal (27.9%). The most frequent associated symptom was sensation of a FB (18.1%). The diagnosis was fundamentally based on physical examination (84%), requiring complementary tools in 18.2%. The extraction was mostly ambulatory (84.6%), requiring extraction in the operation room in 12.5%. 5.5% presented complications, and the fatality rate was 0.07%. Conclusion: This casuistry is unique at the national level, and allows us to know the epidemiology of FB. A low percentage of patients correspond to life-threatening locations, but timely management allows a low rate of complications and fatality.

Laparoscopic and robotic pyeloplasty as minimally invasive alternatives to the open approach for the treatment of uretero-pelvic junction obstruction in infants: a multi-institutional comparison of outcomes and learning curves.

BACKGROUND: Since the development of minimally invasive surgery (MIS), laparoscopic and robotic approaches have been widely adopted. However, little has been published detailing the learning curve of MIS, especially in infants. OBJECTIVE: To quantify the learning curve of laparoscopic (LP) and robot-assisted laparoscopic pyeloplasty (RAL-P) for treatment of uretero-pelvic junction obstruction (UPJO) in infants evidenced by number of cases, operative time, success and complications. PATIENTS AND METHODS: Between 2009 and 2017, we retrospectively reviewed pyeloplasty cases for treatment of UPJO in infants at three academic institutions. The primary outcome was success. Secondary outcomes were UPJO recurrence, complications, and operative time as a surrogate of skill acquisition. Continuous variables were analyzed by t test, Welch-test, and one-way ANOVA. Non-continuous variables were analyzed by Chi-squared test or Fisher's exact test. Learning curves (LC) were studied by r-to-z transformation and CUSUM. RESULTS: Thirty-nine OP, 26 LP, and 39 RAL-P had mean operative times (OT) of 106, 121, and 151 min, respectively. LCs showed plateau in OT after 18 and 13 cases for LP and RAL-P, respectively. RAL-P showed a second phase of further improvements after 37 cases. At 16 months follow-up, there were similar rates of success and complications between the three groups. CONCLUSIONS: Despite different duration of learning phases, proficiency was achieved in both LP and RAL-P as evidenced by stabilization of operative time and similar success rates and complications to OP. Before and after achievement of proficiency, LP and RAL-P can be safely learned and implemented for treatment of UPJO in infants.

Fibropapillomatosis and Chelonid Alphaherpesvirus 5 Infection in Kemp's Ridley Sea Turtles (Lepidochelys kempii).

Fibropapillomatosis (FP), a debilitating, infectious neoplastic disease, is rarely reported in endangered Kemp's ridley sea turtles (Lepidochelys kempii). With this study, we describe FP and the associated chelonid alphaherpesvirus 5 (ChHV5) in Kemp's ridley turtles encountered in the United States during 2006-2020. Analysis of 22 case reports of Kemp's ridley turtles with FP revealed that while the disease was mild in most cases, 54.5% were adult turtles, a reproductively valuable age class whose survival is a priority for population recovery. Of 51 blood samples from tumor-free turtles and 12 tumor samples from turtles with FP, 7.8% and 91.7%, respectively, tested positive for ChHV5 DNA via quantitative polymerase chain reaction (qPCR). Viral genome shotgun sequencing and phylogenetic analysis of six tumor samples show that ChHV5 sequences in Kemp's ridley turtles encountered in the Gulf of Mexico and northwestern Atlantic cluster with ChHV5 sequences identified in green (Chelonia mydas) and loggerhead (Caretta caretta) sea turtles from Hawaii, the southwestern Atlantic Ocean, and the Caribbean. Results suggest an interspecific, spatiotemporal spread of FP among Kemp's ridley turtles in regions where the disease is enzootic. Although FP is currently uncommon in this species, it remains a health concern due to its uncertain pathogenesis and potential relationship with habitat degradation.

Strategies to Identify Mesenchymal Stromal Cells in Minimally Manipulated Human Bone Marrow Aspirate Concentrate Lack Consensus.

BACKGROUND: There is a need to identify and quantify mesenchymal stromal cells (MSCs) in human bone marrow aspirate concentrate (BMAC) source tissues, but current methods to do so were established in cultured cell populations. Given that surface marker and gene expression change in cultured cells, it is doubtful that these strategies are valid to quantify MSCs in fresh BMAC. PURPOSE: To establish the presence, quantity, and heterogeneity of BMAC-derived MSCs in minimally manipulated BMAC using currently available strategies. STUDY DESIGN: Descriptive laboratory study. METHODS: Five published strategies to identify MSCs were compared for suitability and efficiency to quantify clinical-grade BMAC-MSCs and cultured MSCs at the single cell transcriptome level on BMAC samples being used clinically from 15 orthopaedic patients and on 1 cultured MSC sample. Strategies included (1) the guidelines by the International Society for Cellular Therapy (ISCT), (2) CD271 expression, (3) the Ghazanfari et al transcriptional profile, (4) the Jia et al transcriptional profile, and (5) the Silva et al transcriptional profile. RESULTS: ISCT guidelines did not identify any MSCs in BMAC at the transcriptional level and only 1 in 9 million cells at the protein level. Of 12,850 BMAC cells, 9 expressed the CD271 gene. Only 116 of 396 Ghazanfari genes were detected in BMAC, whereas no cells expressed all of them. No cells expressed all Jia genes, but 25 cells expressed at least 13 of 22. No cells expressed all Silva genes, but 19 cells expressed at least 8 of 23. Most importantly, the liberalized strategies tended to identify different cells and most of them clustered with immune cells. CONCLUSION: Currently available methods need to be liberalized to identify any MSCs in fresh human BMAC and lack consensus at the single cell transcriptome and protein expression levels. These different cells should be isolated and challenged to establish phenotypic differences. CLINICAL RELEVANCE: This study demonstrated that improved strategies to quantify MSC concentrations in BMAC for clinical applications are urgently needed. Until then, injected minimally manipulated MSC doses should be reported as rough estimates or as unknown.