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Abstract Purpose To compare CTVHR and OAR dimensions and inter-rater agreement between magnetic resonance (MR) and trans-rectal ultrasound (TRUS) images in IB cervical cancer patients. Methods IB cervical cancer patients treated with (chemo)radiotherapy plus MR-guided brachytherapy (BT) were prospectively enrolled in this study. Radiation oncologists contoured CTVHR and OARs in pre-BT MR images (MRI) and intra-operative TRUS images. These contours were subsequently compared in regard to volume and dimension. Contour inter-rater agreement analysis was also investigated using kappa index (KI). Stata 15.0 was used for statistical analysis and a p-value

Aedes albopictus mosquitoes are important vectors for a number of human pathogens including the Zika, dengue, and chikungunya viruses. Capable of displacing Aedes aegypti populations, this mosquito adapts to cooler environments which increases its geographical range and transmission potential. There are limited control strategies for Aedes albopictus mosquitoes which is likely attributed to the lack of comprehensive biological studies on this emerging vector. To fill this void, here using RNAseq we characterized Aedes albopictus mRNA expression profiles at 34 distinct time points throughout development providing the first high-resolution comprehensive view of the developmental transcriptome of this worldwide human disease vector. This enabled us to identify several patterns of shared gene expression among tissues as well as sex-specific expression patterns. To illuminate the similarities and differences with Aedes aegypti, a related human disease vector, we also performed a comparative analysis between the two developmental transcriptomes, identifying life stages where the two species exhibit similar and distinct gene expression patterns. These findings provide insights into the similarities and differences between Aedes albopictus and Aedes aegypti mosquito biology. In summary, the results generated from this study should form the basis for future investigations on the biology of Aedes albopictus and provide a gold mine resource for the development of transgene-based vector control strategies.

Abstract Objective: Methicillin-resistant Staphylococcus aureus (MRSA) infection is highly unlikely when nasal-swab results are negative. We evaluated the impact of an electronic prompt regarding MRSA nasal screening on the length of vancomycin therapy for respiratory indications. Design: Retrospective, single-center cohort study. Setting: Tertiary-care academic medical center (Mayo Clinic) in Jacksonville, Florida. Patients: Eligible patients received empiric treatment with vancomycin for suspected or confirmed respiratory infections from January through April 2019 (preimplementation cohort) and from October 2019 through January 2020 (postimplementation cohort). Intervention: The electronic health system software was modified to provide a best-practice advisory (BPA) prompt to the pharmacist upon order verification of vancomycin for patients with suspected or confirmed respiratory indications. Pharmacists were prompted to order a MRSA nasal swab if it was not already ordered by the provider. Methods: We reviewed patient records to determine the time from vancomycin prescription to de-escalation. The secondary end point was incidence of acute kidney injury. Results: The study included 120 patients (preimplementation, n = 61; postimplementation, n = 59). Median time to de-escalation was significantly shorter for the postimplementation cohort: 76 hours (interquartile range [IQR], 52–109) versus 42 hours (IQR, 37–61; P = .002). Acute kidney injury occurred in 11 patients (18%) in the preimplementation cohort and in 3 patients (5%) in the postimplementation cohort (P = .01; number needed to treat, 8). Conclusions: Implementation of a BPA notification for MRSA nasal screening helped decrease the time to de-escalation of vancomycin.

Purpose: Opioid addiction is a major public health concern. Chronic opioid use (COU) patterns after radiation for head and neck cancer (HNC) remain poorly understood. The aim of this study was to estimate the prevalence of COU and to identify its risk factors in patients with HNC undergoing curative-intent radiation therapy (RT) or chemoradiotherapy (CRT). Methods and Materials: We performed a systematic review and meta-analysis using the PubMed (Medline), EMBASE, and Cochrane Library databases, queried from dates of inception until January 2020. COU was defined as persistent use of opioids ≥ 3 months after treatment completion. Meta-analyses were performed using random effects models. Heterogeneity was assessed using the I2 value. Results: Seven retrospective studies, reporting on 1841 patients, met the inclusion criteria. Median age was 59.4 (range: 56.0-62.0) years with 1343 (72.9%) men and 498 (27.1%) women. Primary tumor locations included oropharynx (n = 891, 48.4%), oral cavity (n = 533, 29.0%), larynx (n = 93, 5.1%), hypopharynx (n = 32, 1.7%), and nasopharynx (n = 29, 1.6%). Eight hundred fifty-four (46.0%) patients had stage I/II and 952 (50.3%) had stage III-IV disease. Three hundred one (16.3%) patients had RT alone, 738 (40.1%) received CRT, and 594 (32.3%) underwent surgery followed by adjuvant RT/CRT. The proportion of patients with HNC who developed COU post-RT/CRT was 40.7% at 3 months (95% confidence interval [CI]: 22.6%-61.7%; I2 = 97.1%) and 15.5% at 6 months (95% CI: 7.3%-29.7%; I2 = 94.3%). Oropharyngeal malignancies had the highest rate of COU based on primary tumor location (46.6%; 95% CI: 30.8%-63.1%; P < .0001). High proportions of COU were found in patients with a history of psychiatric disorder(s) (61.7%), former/current alcohol abuse (53.9%), and opioid requirements before radiation treatment (51.6%; P = .035). Conclusions: A significant proportion of patients who undergo RT for HNC suffer from COU. High-risk factors for COU include an oropharyngeal primary, history of psychiatric disorder, former/current alcohol abuse, and pre-treatment opioid use. New strategies to mitigate COU are needed.

Although there are existing vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), new COVID-19 cases are increasing due to low immunization coverage and the emergence of new variants. For this reason, new drugs to treat and prevent severe COVID-19 are needed. Here, we provide four different FDA-approved drugs against SARS-CoV-2 proteins involved in the entry and replication process, aiming to identify potential drugs to treat COVID-19. We use the main protease (Mpro), the spike glycoprotein (S protein), and RNA-dependent RNA polymerase (RdRp) as protein targets for anti- SARS-CoV-2 drugs. In our constructed database, we selected different drugs against each target (Mpro, S protein, and RdRp) based on their common interactions with relevant residues involved in viral entry at the host cell and replication. Furthermore, their stability inside the binding pocket, as well as their predicted binding-free energy, allow us to provide new insight into the possible drug repurposing of viomycin (interacting with Mpro) due to its interactions with key residues, such as Asn 143, Glu 166, and Gln 189 at the same time as hesperidin (interacting with the S protein) is interacting with residues Tyr 449, Ser 494, and Thr 500, keeping inside the predicted binding pocket, as well as interacting with residues in different variants of concern. Finally, we also suggest nystatin and elvitegravir (interacting with RdRp) as possible drugs due to their stability within the predicted pocket along the simulation and their interaction with key residues, such as Asp 760, Asp 761, and Asp 618. Altogether our results provide new knowledge about the possible mechanism of the inhibition of viomycin, hesperidin, elvitegravir, and nystatin to inhibit the viral life cycle of SARS-CoV-2 and some of its variants of concern (VOC). Additionally, some iodide-based contrast agents were also found to bind the S protein strongly, i.e., iohexol (−58.99 Kcal/mol), iotrolan (−76.19 Kcal/mol), and ioxilan (−62.37 Kcal/mol). Despite the information we report here as the possible strong interaction between these contrast agents and the SARS-CoV-2′s S protein, Mpro, and RdRp, we believe that further investigation, including chemical modifications in their structures, are needed for COVID-19 treatment.

Abstract Background Sexually transmitted Human Papilloma Virus (HPV) infection is a known risk factor for cancer of the anal canal in both men and women. Case presentation We describe a report of synchronous carcinoma of the anal canal in a heterosexual couple. High risk type 16 HPV DNA was detected in both tumors. Conclusion Longstanding sexual partners may share risk of HPV-associated anal canal cancer.

Abstract Background Heart-sparing techniques are time and resource intensive, although not all patients require the use of these strategies. This study evaluates the performance of different distance metrics in predicting the need for breath-hold radiotherapy in left-sided breast cancer patients receiving adjuvant radiotherapy. Methods Fifty left-sided breast cancer patients treated with breast conserving surgery and adjuvant radiotherapy to the breast from a single institution were retrospectively studied. The left breast and organs at risk were contoured in accordance to guidelines and a plan with tangents was obtained using the free-breathing CT in supine position. Heart (mean heart dose (MHD), heart V25 Gy) and left anterior descending artery dosimetry were computed and compared against distance metrics under investigation (Contact Heart, 4th Arch and 5th Arch). Recursive partitioning analysis (RPA) was used to determine optimal cut-points for distance metrics for dosimetric end points. Receiver operating characteristic curves and Pearson correlation coefficients were used to evaluate the association between distance metrics and dosimetric endpoints. Univariable and multivariable logistic regression analysis was performed to identify significant predictors of dosimetric end points. Results The mean MHD and heart V25 Gy were 2.3 Gy and 10.4 cm3, respectively. With tangents, constraints for MHD (

Abstract Background To evaluate the dosimetric performance of multi-channel vaginal cylinder (MCVC) against interstitial brachytherapy (ISBT) for the treatment of vaginal tumors. Methods Vaginal tumors with extension of > 0.5 cm and ≤ 2 cm from the lateral vaginal wall and/or ≤ 1 cm in height above the vaginal vault were retrospectively selected from a ISBT registry trial database. The selected patients were treated with ISBT and targets included the intermediate (IRCTV) or high-risk (HRCTV) clinical target volumes. For technique comparison, a 35 mm MCVC was registered with the interstitial intra-vaginal cylinder. Bladder and rectum contours were transferred from the ISBT to the MCVC-BT plans. Vaginal mucosa was achieved by 3 mm uniform expansion from cylinder surface. Both the ISBT and MCVC-BT plans were optimized using the Inverse Planning Simulated Annealing optimization algorithm. After normalizing target D90 to 700 cGy, dose to organs at risk were measured and compared between ISBT and MCVC plans. Results Six interstitial patient plans met the inclusion criteria for this study. Four patients had vaginal primaries and two recurrent cancers in the vagina. Lower doses to bladder and rectum were seen with ISBT plans. In half of the MCVC plans, the rectal dose met the recommended constraints. For plans in which the rectal constraint was not met, the target volumes were abutting the rectum and had a cranial-caudal length ≥ 5 cm. Dose to vaginal mucosa was lower in ISBT plans directed to the HRCTVs, although no difference was seen in circumferential IRCTVs. Conclusions Overall, ISBT results in decreased dose to OARs as compared to MCVC. However, MCVC BT results in acceptable doses to OARs with possible improvement in vaginal doses for circumferential targets. Careful consideration to tumor geometry and location may help guide optimal techniques in vaginal tumor brachytherapy.

Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-mediated cytotoxicity (ADCC), a key effector function of human NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG antibodies. Though CD16A is a potent activating receptor, it is also a low affinity IgG Fc receptor (FcγR) that undergoes a rapid downregulation in expression by a proteolytic process involving ADAM17 upon NK cell activation. These regulatory processes are likely to limit the efficacy of tumor-targeting therapeutic mAbs in the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by engineering these cells with a recombinant FcγR consisting of the extracellular region of CD64, the highest affinity FcγR expressed by leukocytes, and the transmembrane and cytoplasmic regions of CD16A. This novel recombinant FcγR (CD64/16A) was expressed in the human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells were derived. CD64/16A lacked the ADAM17 cleavage region in CD16A and it was not rapidly downregulated in expression following NK cell activation during ADCC. CD64/16A on NK cells facilitated conjugation to antibody-treated tumor cells, ADCC, and cytokine production, demonstrating functional activity by its two components. Unlike NK cells expressing CD16A, CD64/16A captured soluble therapeutic mAbs and the modified NK cells mediated tumor cell killing. Hence, CD64/16A could potentially be used as a docking platform on engineered NK cells for therapeutic mAbs and IgG Fc chimeric proteins, allowing for switchable targeting elements and a novel cancer cellular therapy.

Objective: To present a case of a double ectopic thyroid gland in a 10-year old boy and discuss the pros and cons of the different management options that were available. Methods Design: Case Report Setting: Tertiary Hospital in Metro Manila Subject: One (1) Results: A 10-year-old boy presented with hoarseness and easy fatigability for 6 years. Rigid endoscopy and CT scan showed an infraglottic mass originating from the anterior tracheal wall causing obstruction. Biopsy revealed thyroid tissue with atypia. Thyroid scintigraphy showed uptake in the submental and midline anterior neck. Thyroid hormone levels were consistent with hypothyroidism. Levothyroxine returned hormone levels to normal and resulted in complete regression of the mass with no symptoms of dyspnea, stridor or bleeding. Conclusion: The management of ectopic thyroid presents a challenge as there are no guidelines for optimal treatment. Thyroid hormone insufficiency is a frequent occurrence, and emphasis must be given to its monitoring. Surgery in a critical airway lesion such as this may be reserved for cases where the patient experiences dyspnea and stridor or lack of response to thyroid hormone treatment. Keywords: Ectopic thyroid, direct laryngoscopy, thyroid hormone, levothyroxine

Con el fin de contribuir al conocimiento de su actividad a nivel celular, se evaluó el mecanismo de acción del aceite esencial de Eucalyptus citriodora (Fam. Myrtaceae) sobre la bioenergética mitocondrial, su efecto sobre la velocidad de consumo de oxígeno de mitocondrias energizadas (estados 3 y 4) y su coeficiente de control respiratorio (CCR). Además, se analizó la actividad de los complejos de la cadena respiratoria usando técnicas espectrofotométricas. Los resultados obtenidos indican que el aceite esencial de E. citriodora aumenta la velocidad del consumo de oxígeno en los estados 3 y 4, disminuye el CCR, desacopla la fosforilación oxidativa, aumenta la actividad de la citocromo c oxidasa y aumenta la actividad ATPasa en mitocondrias íntegras, a partir de la concentración de 10 μg/mL. Estos resultados sugieren que el aceite esencial o sus metabolitos afectan el funcionamiento normal del transporte de electrones de la cadena respiratoria y la síntesis de ATP.

El intervencionismo coronario a través de la vía de acceso radial ha generado un creciente interés, sobre todo, por la reducción de las complicaciones vasculares. En el Departamento de Cardiología Intervencionista del hospital Hermanos Ameijeiras el acceso radial ha comenzado a utilizarse de forma sistemática. Con el objetivo de establecer la efectividad del abordaje radial en el intervencionismo coronario percutáneo y estimar la supervivencia libre de eventos adversos mayores a corto plazo, se realizó un estudio observacional prospectivo, en el que se incluyeron 279 pacientes consecutivos sometidos a angioplastia coronaria en el período comprendido entre septiembre del 2009 a mayo del 2010. Se consideraron como eventos adversos mayores: la muerte, infarto del miocardio no fatal, necesidad urgente de nuevo proceder de revascularización y el sangramiento mayor. Las tasas de supervivencia fueron estimadas por el método de Kaplan Meier y comparadas mediante el test de Log Rank en función de la vía de acceso. Se utilizó la vía radial en el 68,46% de los pacientes, la tasa de éxito fue similar en comparación a la vía femoral (93,2% vs. 89,8%, p=0,325) y no hubo diferencias en cuanto al número de lesiones tratadas, stents implantados, tiempos de procedimiento y fluoroscopía. Los eventos adversos mayores fueron menos frecuentes cuando se utilizó el acceso radial (2,1% vs 6,8%, p=0,049). La sobrevivida libre de eventos a los 30 días en los pacientes abordados por vía radial fue 97,9% y de 93,18% por vía femoral (p=0,021). Se concluye que la vía radial resulta un acceso efectivo y seguro en el intervencionismo coronario con una supervivencia libre de eventos cardíacos mayores a corto plazo significativamente superior al acceso femoral. Palabras clave: Acceso radial; Acceso femoral; Intervencionismo coronario percutáneo.

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.

Canonical Wnt/β-catenin signaling has been suggested to promote self-renewal of pluripotent mouse and human embryonic stem cells. Here, we show that SB-216763, a glycogen synthase kinase-3 (GSK3) inhibitor, can maintain mouse embryonic stem cells (mESCs) in a pluripotent state in the absence of exogenous leukemia inhibitory factor (LIF) when cultured on mouse embryonic fibroblasts (MEFs). MESCs maintained with SB-216763 for one month were morphologically indistinguishable from LIF-treated mESCs and expressed pluripotent-specific genes Oct4, Sox2, and Nanog. Furthermore, Nanog immunostaining was more homogenous in SB-216763-treated colonies compared to LIF. Embryoid bodies (EBs) prepared from these mESCs expressed early-stage markers for all three germ layers, and could efficiently differentiate into cardiac-like cells and MAP2-immunoreactive neurons. To our knowledge, SB-216763 is the first GSK3 inhibitor that can promote self-renewal of mESC co-cultured with MEFs for more than two months.

Plasma lipoproteins of d < 1.063 g/ml from rabbits fed a diet containing 1% cholesterol for 4 days showed changes in concentration and rates of flotation as determined by analytical ultracentrifugation. A marked increase in cholesteryl ester content of lipoprotein with d < 1.019 g/ml was the most prominent change in rabbits fed the diet for 21 days. Gel electrophoresis and immunochemical procedures demonstrated that in control and hypercholesterolemic rabbits there were some common apolipoproteins found in all lipoproteins with density < 1.063 g/ml. In control rabbits, there were also apolipoproteins specific to the lipoprotein fraction with d < 1.019 and to the fraction with d 1.019–1.063 g/ml. However, in rabbits fed the hypercholesterolemic diet for 21 days, the apolipoproteins characteristic of fraction 1.019–1.063 were the most abundant in the fraction with d < 1.019 g/ml. Liver slices from rabbits fed the high cholesterol diet for 7 and 21 days incorporated more l-[14C]leucine into very low density and low density lipoproteins than controls.The results suggest that cholesterol feeding leads to an increase in biosynthesis of lipoproteins with d < 1.063 g/ml. The newly synthesized lipoprotein contains apolipoproteins similar to those found in controls but with a higher lipid-to-protein ratio. Fram the apoprotein composition, it is concluded that the very low density fraction present in cholesterol-fed animals is more structurally related to low density lipoproteins than to the very low density lipoproteins isolated from control animals.

Introduction: Interventions to treat speech-language difficulties in primary progressive aphasia (PPA) often use word accuracy as a highly comparable outcome. However, there are more constructs of importance to people with PPA that have received less attention., Methods: Following Core Outcome Set Standards for Development Recommendations (COSSTAD), this study comprised: Stage 1 - systematic review to identify measures; Stage 2 - consensus groups to identify important outcome constructs for people with PPA (n = 82) and care partners (n = 91); Stage 3 - e-Delphi consensus with 57 researchers., Results: The systematic review identified 84 Outcome Measurement Instruments. Core outcome constructs identified included: (1) Participate in conversations with family and friends, (2) get words out, (3) be more fluent, (4) convey a message by any means, and (5) understand what others are saying. Researchers were unable to reach a consensus on measurement instruments., Discussion: Further work is required to develop appropriate measurement instruments that address all core outcome constructs important to key stakeholders., Highlights: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Precision medicine represents a paradigm shift in oncology. Access to genetic testing and targeted therapies is frequently limited. Assays based on DNA sequencing can miss druggable alterations. We aimed to determine the impact of a free access program to RNA tests in patient management., Methods: We designed a multicenter prospective observational study within the Spanish National Group for Translational Oncology and Rare and Orphan Tumors (GETTHI). Eligible patients were adults with solid cancers that had progressed on standard therapies. Tumor samples were analyzed using two RNA sequencing assays (Trailblaze Pharos TM and Archer FusionPlex Solid Tumor TM ). A central committee evaluated the actionability of genetic alterations and reported the findings to attending physicians, who made the final clinical management decisions., Results: Between November 2016 and April 2019, 395 patients with 41 different tumors across 30 hospitals were included. Molecular analysis revealed actionable genetic alterations in 57 individuals (14.4%). Targeted therapies were advised for 23 and seven received a matched targeted therapy: two lung cancers (EML4-ALK and CD74-ROS1 fusion), three glioblastomas (EGFR point mutations), one oligodendroglioma (FGFR3-TACC3 fusion) and a prostate cancer (SND1-BRAF fusion). The outcomes included two tumor responses, one disease stabilization, one early withdrawal due to toxicity, one progression, and one unknown., Conclusion: Despite the growing knowledge of cancer biology and its translation to drug development, the overall impact of personalized treatments remains low. Access to comprehensive molecular tests covering properly all known actionable alterations and programs for a wide access to targeted therapies seem to be critical steps., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Competing Interests: Disclosures: Disclosure forms are available with the article online.

Objective: To compare the quality of urinary incontinence (UI) care for women in the safety-net and nonsafety-net settings prior to referral to a specialist., Methods: We performed a retrospective review of 200 women from two nonsafety-net hospitals and 188 women from two safety-net hospitals who were referred to Urogynecology and Reconstructive Surgery specialists for bothersome UI between March 2017 and March 2020. We evaluated the care that women received 12 months prior to referral, by measuring adherence to a set of previously developed quality indicators (QIs), for example, the performance of a urinalysis or pelvic exam., Results: Women seen in safety-net hospitals were more likely to receive QI-compliant care than women in the nonsafety-net hospitals prior to referral, with 55.53% of appropriate care given in the safety-net vs 40.3% in the nonsafety-net setting (P <.01). Clinicians in the safety-net hospitals were more likely to adhere to QIs in patients with general, stress, and urgency incontinence., Conclusion: Women were more likely to receive timely, quality-based UI care in the safety net compared to the nonsafety-net setting. This may be in part due to aspects unique to the safety-net system, including an eConsult referral system, which guides referring clinicians in appropriate management steps that should be taken prior to the specialist visit, as well as women's health-focused primary care clinics., Competing Interests: Declaration of Competing Interest Jennifer Anger was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) R56DK117261 for this work. The other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objetive . Decoding speech from brain activity can enable communication for individuals with speech disorders. Deep neural networks (DNNs) have shown great potential for speech decoding applications. However, the limited availability of large datasets containing neural recordings from speech-impaired subjects poses a challenge. Leveraging data from healthy participants can mitigate this limitation and expedite the development of speech neuroprostheses while minimizing the need for patient-specific training data. Approach . In this study, we collected a substantial dataset consisting of recordings from 56 healthy participants using 64 EEG channels. Multiple neural networks were trained to classify perceived sentences in the Spanish language using subject-independent, mixed-subjects, and fine-tuning approaches. The dataset has been made publicly available to foster further research in this area. Main results . Our results demonstrate a remarkable level of accuracy in distinguishing sentence identity across 30 classes, showcasing the feasibility of training DNNs to decode sentence identity from perceived speech using EEG. Notably, the subject-independent approach rendered accuracy comparable to the mixed-subjects approach, although with higher variability among subjects. Additionally, our fine-tuning approach yielded even higher accuracy, indicating an improved capability to adapt to individual subject characteristics, which enhances performance. This suggests that DNNs have effectively learned to decode universal features of brain activity across individuals while also being adaptable to specific participant data. Furthermore, our analyses indicate that EEGNet and DeepConvNet exhibit comparable performance, outperforming ShallowConvNet for sentence identity decoding. Finally, our Grad-CAM visualization analysis identifies key areas influencing the network's predictions, offering valuable insights into the neural processes underlying language perception and comprehension. Significance . These findings advance our understanding of EEG-based speech perception decoding and hold promise for the development of speech neuroprostheses, particularly in scenarios where subjects cannot provide their own training data., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background/objectives: Functional MRI (fMRI) is widely used to assess language lateralization, but its application in patients with brain tumors can be hindered by cognitive impairments, compensatory neuroplasticity, and artifacts due to patient movement or severe aphasia. Gray matter volume (GMV) analysis via voxel-based morphometry (VBM) in language-related brain regions may offer a stable complementary approach. This study investigates the relationship between GMV and fMRI-derived language lateralization in healthy individuals and patients with left-hemisphere brain tumors, aiming to enhance accuracy in complex cases., Methods: The MRI data from 22 healthy participants and 28 individuals with left-hemisphere brain tumors were analyzed. Structural T1-weighted and functional images were obtained during three language tasks. Language lateralization was assessed based on activation in predefined regions of interest (ROIs), categorized as typical (left) or atypical (right or bilateral). The GMV in these ROIs was measured using VBM. Linear regressions explored GMV-lateralization associations, and logistic regressions predicted the lateralization based on the GMV., Results: In the healthy participants, typical left-hemispheric language dominance correlated with higher GMV in the left pars opercularis of the inferior frontal gyrus. The brain tumor participants with atypical lateralization showed increased GMV in six right-hemisphere ROIs. The GMV in the language ROIs predicted the fMRI language lateralization, with AUCs from 80.1% to 94.2% in the healthy participants and 78.3% to 92.6% in the tumor patients., Conclusions: GMV analysis in language-related ROIs effectively complements fMRI for assessing language dominance, particularly when fMRI is challenging. It correlates with language lateralization in both healthy individuals and brain tumor patients, highlighting its potential in preoperative language mapping. Further research with larger samples is needed to refine its clinical utility.

Background: There is conflicting data regarding the optimal abductor mechanism (AM) repair technique after resection of proximal femur tumors. We sought to compare functional outcomes following tumor resection and reconstruction with proximal femoral replacement based on the AM repair technique utilized., Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We established two study groups based on AM repair technique as follows: soft-tissue reattachment (STr) and greater trochanter preservation (GTp). In the STr group, the gluteus medius and minimus muscles were reattached to the endoprosthesis, whereas in the GTp group, the greater trochanter and gluteal tendons were preserved. The STr group was further subdivided into direct and indirect reattachments. Weighted means adjusting for sample size were calculated., Results: A total of 658 patients from 12 articles were included. Patients who had STr displayed higher Musculoskeletal Tumor Society scores (75 versus 67.3%, P < 0.001), lower rates of Trendelenburg gait (33.9 versus 52.4%, P < 0.01), and ambulation with assistive devices (30.4 versus 54.9%, P < 0.001) compared to the GTp group. Within the STr group, indirect reattachment was associated with higher Musculoskeletal Tumor Society scores (87.2 versus 70.1%, P < 0.001) and lower rates of Trendelenburg gait (3.8 versus 36.3%, P < 0.001) and ambulation with assistive devices (0 versus 42.4%, P < 0.001) compared to direct reattachment. The reattachment hardware failure rate in GTp was 15%., Conclusion: A STr provided superior functional outcomes compared to GTp in tumor-related proximal femoral replacement. From a functional outcome perspective, the use of indirect STr was better compared to direct STr., Level of Evidence: III., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The focus of therapeutic tools in glaucoma has been mainly to control of intraocular pressure. Recently there has been a growing interest in investigating the relationship of vascular risk factors in the development of glaucoma. The aim of this study was to assess the association between systemic arterial hypertension, diabetes mellitus and hypercholesterolemia, and peripapillary vascularization measured by Optical Coherence Tomography Angiography (OCTA) in glaucoma and healthy subjects., Methods: In this unicenter, observational, cross-sectional study, 212 subjects, 118 glaucoma patients and 94 controls were consecutively recruited. Of these, 86 participants were excluded due to poor OCTA image quality. Therefore, 146 subjects were included in the final analysis, 74 glaucoma patients and 72 controls. Using a linear regression model, with 95% confidence and 80% statistical power, the effect of vascular risk factors on OCTA parameters in the 146 subjects included in the final analysis was studied., Results: No significant impact of vascular risk factors on OCTA measurements was found. Diabetic patients tended to show a lower peripapillary perfusion vascular density than subjects without diabetes (β 0.016, 95%CI 0.003;0.030, p 0.016). Similarly, hypercholesterolemia patients appeared to show less peripapillary flow index than non-hypercholesterolaemic patients (β 0.029, 95%CI 0.013;0.046, p 0.001). Glaucoma patients had 0.02% lower peripapillary perfusion vascular density (β 0.020, 95% CI 0.011;0.029, p < 0.001), 0.04% lower peripapillary flow index (β 0.036, 95%CI 0.022;0.051, p < 0.001) and 9.62% thinner retinal nerve fibre layer (β 9.619, 95%CI 5.495;13.744, p < 0.001)., Conclusions: In conclusion glaucoma has greater effect on peripapillary vascular density parameters than any of the vascular risk factors analyzed., Key Messages: What is known: • Vascular disfunction plays an important role in the development of glaucoma. • Optical coherence tomography angiography makes it possible to assess the retinal microvasculature and the role that its alterations could have in the development of glaucoma., What Is New: • Decrease of the peripapillary microcirculation seems to be more related to the increase in intraocular pressure and the glaucoma itself than to the presence of cardiovascular risk factors. • The effect of having diabetes, systemic arterial hypertension or hypercholesterolaemia on vascular parameters or nerve fibre layer thickness was low. • There was also no relevant impact of the systemic medication used for these diseases on the peripapillary vascular parameters studied or on nerve fibre layer thickness., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Nailfold Videocapillaroscopy (NVC) is a valuable tool in the differential diagnosis of Raynaud's phenomenon (RP), present in certain Rheumatic diseases (RD). Knowing that many people have cardiovascular risk factors (CVRF), the main objective was to demonstrate that CVRF and carotid plaques produce NVC alterations., Methods: Cross-sectional unicentric study carried out from 2020 to 2023. Four groups were formed: subjects with RD and RP, participants with RD without RP, subjects with RP without RD and finally participants without RP or RD (study group). Each subject exhibiting CVRF presented only a single risk factor. The variables collected were: sociodemographic, CVRF (diabetes, tobacco, alcohol (ALC), obesity (OBE), dyslipidemia and arterial hypertension (AH)), diseases, RP, treatments, tortuosities and NVC alterations (ramified capillaries, enlarged capillaries, giant capillaries, haemorrhages and density loss) and carotid ultrasound (CU)., Results: 402 subjects were included (76 % women, mean age 51 ± 16 years), 67 % had CVRF, 50 % RP and 38 % RD. Tortuosities were present in 100 % of CVRF participants. A statistically significant association was found between the presence of CVRF and all the NVC alterations: ramified capillaries (OR = 95.6), enlarged capillaries (OR = 59.2), giant capillaries (OR = 8.32), haemorrhages (OR = 17.6) and density loss (OR = 14.4). In particular, an association was found between giant capillaries with AH (p = 0,008) and OBE (p 〈0,001), and haemorrhages and density loss with ALC and OBE (p < 0,001). On the other hand, 40 subjects presented CU plaques (9.9 %), associated with enlarged capillaries (OR = 8.08), haemorrhages (OR = 4.04) and ramified capillaries (OR = 3.01). The pathological intima-media thickness was also associated with haemorrhages (OR = 3.14)., Conclusions: There is a clear association between CVRF and ultrasound atherosclerotic findings in carotid with NVC alterations. These findings are of special interest for a correct NVC interpretation and to avoid false positives in the diagnosis of primary and secondary RP., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interests regarding the publication of the paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the association between ethnicity and self-reported refractive errors (REs) among Peruvian children aged 7-11 years., Materials and Methods: We conducted a cross-sectional study incorporating a secondary data analysis of 2017-2021 data from the Peruvian Demographic and Health Survey (DHS). REs and ethnicity were obtained from focal child's mother's report. Four outcomes were assessed: hyperopia, myopia, astigmatism and any RE. We included potential confounders, such as age, sex, wealth index, area of residence, region of origin, frequency of watching TV and watching screens at less than 30 cm distance. Generalised linear models with the Poisson family and log link function were used to calculate crude prevalence ratio and adjusted prevalence ratio (aPR) with 95% confidence intervals (95% CI)., Results: Data from a total of 52,753 children were included. The prevalence of RE in children aged 7-11 years was 10.90% (95% CI 10.49-11.33), of which 5.19% were hyperopia, 3.35% myopia and 2.36% astigmatism. Those of the Aymara ethnicity were less likely to suffer from any RE and astigmatism (aPR = 0.68, 95% CI 0.46-0.99, p = 0.046; aPR = 0.70, 95% CI 0.53-0.92, p = 0.012, respectively), Members of Amazon groups were more likely to have hyperopia (aPR = 1.95, 95% CI 1.14-3.36, p = 0.015) and Quechuas were more likely to have myopia (aPR =1.29, 95% CI 1.02-1.62, p = 0.028), where all were compared to Mestizos., Conclusion: About 1 in 10 Peruvian children suffer from a RE. The most frequent RE in this study was hyperopia. Ethnic differences were seen in the frequency of RE., Competing Interests: Conflicts of interest None of the authors have any proprietary interests or conflicts of interest related to this submission., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Purpose: The oxygen depletion hypothesis has been proposed as a rationale to explain the observed phenomenon of FLASH-radiotherapy (FLASH-RT) sparing normal tissues while simultaneously maintaining tumor control. In this study we examined the distribution of DNA Damage Response (DDR) markers in irradiated 3D multicellular spheroids to explore the relationship between FLASH-RT protection and radiolytic-oxygen-consumption (ROC) in tissues., Methods: Studies were performed using a Varian Truebeam linear accelerator delivering 10 MeV electrons with an average dose rate above 50 Gy/s. Irradiations were carried out on 3D spheroids maintained under a range of O 2 and temperature conditions to control O 2 consumption and create gradients representative of in vivo tissues., Results: Staining for pDNA-PK (Ser2056) produced a linear radiation dose response whereas γH2AX (Ser139) showed saturation with increasing dose. Using the pDNA-PK staining, radiation response was then characterised for FLASH compared to standard-dose-rates as a function of depth into the spheroids. At 4 °C, chosen to minimize the development of metabolic oxygen gradients within the tissues, FLASH protection could be observed at all distances under oxygen conditions of 0.3-1 % O 2 . Whereas at 37 °C a FLASH-protective effect was limited to the outer cell layers of tissues, an effect only observed at 3 % O 2 . Modelling of changes in the pDNA-PK-based oxygen enhancement ratio (OER) yielded a tissue ROC g 0 -value estimate of 0.73 ± 0.25 µM/Gy with a k m of 5.4 µM at FLASH dose rates., Conclusions: DNA damage response markers are sensitive to the effects of transient oxygen depletion during FLASH radiotherapy. Findings support the rationale that well-oxygenated tissues would benefit more from FLASH-dose-rate protection relative to poorly-oxygenated tissues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Continuous Direct Compaction (CDC) has emerged as a promising route towards producing solid dosage forms while reducing material, development time and energy consumption. Understanding the response of powder processing unit operations, especially blenders, is crucial. There is a substantial body of work around how lubrication via batch blender operation affects tablet critical quality attributes such as hardness and tensile strength. But, aside from being batch operations, the design of these blenders is such that they operate with low-shear, low-intensity mixing at Froude number values significantly below 0.4 (Froude number Fr being the dimensionless ratio of inertial to gravitational forces). The present work explores the performance of a mini-blender which has a fundamentally different mode of operation (static vessel with rotating blades around a mixing shaft as opposed to rotating vessel with no mixing shaft). This difference allows a substantially wider operating range in terms of speed and shear (and Fr values). The present work evaluates how its performance compares to other blenders studied in the literature. Tablet compaction data from blends produced at various intensities and regimes of mixing in the mini-blender follow a common trajectory. Model equations from literature are suitably modified by inclusion of the Froude number Fr, but only for situations where the Froude number was sufficiently high (1 < Fr). The results suggest that although a similar lubrication extent plateau is eventually reached it is the intensity of mixing (i.e. captured using the Froude number as a surrogate) which is important for the lubrication dynamics in the mini-blender, next to the number of revolutions. The degree of fill or headspace, on the other hand, is only crucial to the performance of common batch blenders. Testing using alternative formulations shows the same common trend across mixing intensities, suggesting the validity of the approach to capture lubrication dynamics for this system., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bernhard Meir reports a relationship with Gericke AG that includes: employment. Sara Fathollahi reports a relationship with DFE Pharma GmbH & Co. KG that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Historically, toxicity concerns have existed in patients with large prostate glands treated with radiation therapy, particularly brachytherapy. There are questions whether this risk extends to stereotactic body radiation therapy (SBRT). In this retrospective review, we examine clinical outcomes of patients with prostate glands ≥100 cc treated curatively with SBRT., Methods and Materials: We retrospectively analyzed a large institutional database to identify patients with histologically confirmed localized prostate cancer in glands ≥100 cc, who were treated with definitive-robotic SBRT. Prostate volume (PV) was determined by treatment planning magnetic resonance imaging. Toxicity was measured using Common Terminology Criteria for Adverse Events, version 5.0. Many patients received the Expanded Prostate Cancer Index Composite Quality of Life questionnaires. Minimum follow-up (FU) was 2 years., Results: Seventy-one patients were identified with PV ≥100 cc. Most had grade group (GG) 1 or 2 (41% and 37%, respectively) disease. All patients received a total dose of 3500 to 3625 cGy in 5 fractions. A minority (27%) received androgen deprivation therapy (ADT), which was used for gland size downsizing in only 10% of cases. Nearly half (45%) were taking GU medications for urinary dysfunction before RT. Median toxicity FU was 4.0 years. Two-year rates of grade 1+ genitourinary (GU), grade 1+ gastrointestinal (GI), and grade 2+ GU toxicity were 43.5%, 15.9%, and 30.4%, respectively. Total grade 3 GU toxicities were very limited (2.8%). There were no grade 3 GI toxicities. On logistic regression analysis, pretreatment use of GU medications was significantly associated with increased rate of grade 2+ GU toxicity (odds ratio, 3.19; P = .024). Furthermore, PV (analyzed as a continuous variable) did not have an effect on toxicity, quality of life, or oncologic outcomes., Conclusions: With early FU, ultra large prostate glands do not portend increased risk of high-grade toxicity after SBRT but likely carry an elevated risk of low-grade GU toxicity., Competing Interests: Disclosures Dr Lischalk is a paid speaker for Accuray and Dr Haas has received a consulting honorarium from Accuray. The remaining authors have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor., Methods: A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement., Results: From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234)., Conclusions: With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited., (© 2024. The Author(s).)

Background: The growing threat from pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) poses a major public health concern in Latin America and the Caribbean (LAC). Therefore, this study aimed to summarize the available evidence on the prevalence of pre-XDR-TB and XDR-TB among patients with multidrug-resistant tuberculosis in LAC., Methods: A systematic review was conducted in the following databases on June 3, 2023: PubMed, Scopus, Ovid Medline, Web of Science, Scielo and LILACS. We estimated pooled proportions using a random effects model (Dersimonian and Laird). The 95% confidence intervals (95% CI) were calculated using the binomial exact method (Clopper-Pearson Method). Subgroup (by time period and country) and sensitivity analyses were performed., Results: Twenty-nine studies were eligible for qualitative synthesis and 27 for meta-analysis (n = 15,565). The pooled prevalence of XDR-TB in the study participants was 5% (95% CI: 3%-6%), while that of pre-XDR-TB was 10% (95% CI 7%-14%). Cuba (6%, 95% CI 0%-17%) and Peru (6%, 95% CI 5%-7%) had the highest pooled prevalence of XDR-TB. Regarding pre-XDR-TB, Brazil (16%, 95% CI 11%-22%) and Peru (13%, 95% CI: 9%-16%) showed the highest prevalence., Conclusions: The pooled prevalence of pre-XDR-TB and XDR-TB in LAC was 10% and 5%, respectively. Governments should strengthen drug-resistance surveillance and TB programs., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Data suggest cannabis users have similar or lower levels of blood lipids compared to nonusers. However, the extent to which cannabis users experience postprandial lipemia is not known. Eleven cannabis users and 11 nonusers completed either rest or 1 h of exercise at their ventilatory threshold the evening before a meal tolerance test (MTT). Substrate oxidation, blood pressure, and capillary blood were obtained before and every 30-60 min post-meal for 3 h. Linear mixed models were utilized to examine differences in variables between groups, conditions, across time, and their interactions. Exercise led to increased fat oxidation post-MTT (p < 0.05), with cannabis users exhibiting higher AUC compared to the control trial (p < 0.05). Exercise also caused significantly lower levels of triglycerides (p < 0.05). Metabolic flexibility was improved in cannabis users in the exercise trial only (p < 0.05). No effect of group, trial, or interactions were detected for other variables of interest (all p > 0.05). This study indicated that prior exercise improves lipid metabolism in cannabis users and nonusers after a high-fat meal test. Cannabis users appear sensitive to the effects of exercise. Future studies should incorporate additional meals and variables related to cardiovascular health and metabolism., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Modern literature has demonstrated improvements in long-term biochemical outcomes with the use of prophylactic pelvic nodal irradiation followed by a brachytherapy boost in the management of high-risk prostate cancer. However, this comes at the cost of increased treatment-related toxicity. In this study, we explore the outcomes of the largest cohort to date, which uses a stereotactic body radiation therapy (SBRT) boost following pelvic nodal radiation for exclusively high-risk prostate cancer., Methods and Materials: A large institutional database was interrogated to identify all patients with high-risk clinical node-negative prostate cancer treated with conventionally fractionated radiotherapy to the pelvis followed by a robotic SBRT boost to the prostate and seminal vesicles. The boost was uniformly delivered over three fractions. Toxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Oncologic outcomes were assessed using the Kaplan-Meier method. Cox proportional hazard models were created to evaluate associations between pretreatment characteristics and clinical outcomes., Results: A total of 440 patients with a median age of 71 years were treated, the majority of whom were diagnosed with a grade group 4 or 5 disease. Pelvic nodal irradiation was delivered at a total dose of 4,500 cGy in 25 fractions, followed by a three-fraction SBRT boost. With an early median follow-up of 2.5 years, the crude incidence of grade 2+ genitourinary (GU) and gastrointestinal (GI) toxicity was 13% and 11%, respectively. Multivariate analysis revealed grade 2+ GU toxicity was associated with older age and a higher American Joint Committee on Cancer (AJCC) stage. Multivariate analysis revealed overall survival was associated with patient age and posttreatment prostate-specific antigen (PSA) nadir., Conclusion: Utilization of an SBRT boost following pelvic nodal irradiation in the treatment of high-risk prostate cancer is oncologically effective with early follow-up and yields minimal high-grade toxicity. We demonstrate a 5-year freedom from biochemical recurrence (FFBCR) of over 83% with correspondingly limited grade 3+ GU and GI toxicity measured at 3.6% and 1.6%, respectively. Long-term follow-up is required to evaluate oncologic outcomes and late toxicity., Competing Interests: Author JL is a paid speaker for Accuray. JH is an Accuray consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lischalk, Akerman, Repka, Sanchez, Mendez, Santos, Carpenter, Wise, Corcoran, Lepor, Katz and Haas.)

The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a 'copy and paste' mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p) 1 . ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer 2,3 , autoimmunity 4,5 and ageing 6,7 , making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p 'core' (residues 238-1061, including the RT domain) by X-ray crystallography and cryo-electron microscopy in several conformational states. Our analyses identified two previously undescribed folded domains, extensive contacts to RNA templates and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed-ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry show that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signalling through cGAS/STING and resulting in interferon production 6-8 . In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which probably explains cytosolic priming. Other biochemical activities including processivity, DNA-directed polymerization, non-templated base addition and template switching together allow us to propose a revised L1 insertion model. Finally, our evolutionary analysis demonstrates structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on the evolutionary history of L1 and enable rational drug development targeting L1., (© 2023. The Author(s).)

Background: Human immunodeficiency virus (HIV) infection and sexually transmitted infections (STIs) are major global public health issues. Migrants represent a vulnerable group that faces multiple barriers to access to healthcare services, including HIV/STI testing. This study aimed to assess the factors associated with access to HIV/STI testing in male and female Venezuelan migrants in Peru., Methods: This was a cross-sectional study involving secondary data analysis of the 2022 Venezuelan Population Residing in Peru Survey. The study was conducted in the eight most populated cities inhabited by Venezuelan migrants and refugees. For each city, the sampling design was probabilistic, stratified, and independent. The outcome variable was whether participants had access to HIV or other STI testing during their stay in Peru. Statistical analysis was stratified by sex owing to potential effect modification. Crude and adjusted prevalence ratios were calculated using generalized linear models Poisson family with log link function. Confidence intervals were calculated to 95%., Results: A total of 3,723 male and 3,984 female migrants were included. Access to HIV/STI testing among male and female migrants was 19.85% and 25.16%, respectively. Among male migrants, being LGBTI, health insured, and married or cohabiting were associated with increased access to HIV/STI testing. Among females, those aged 18-44 years, those who were married or cohabiting and were health insured, and those residing for more than 1 year in Peru were significantly more likely to have access to HIV/STI testing. Moreover, physical/mental disability and unemployed status were associated with a lower probability of HIV/STI testing in females., Conclusions: Only two in ten Venezuelan migrants and refugees in Peru were screened for HIV/STI, with fewer males than females. Sex-specific sociodemographic, health-related, and migration-related variables were independently associated with access to HIV/STI testing., (© 2024. The Author(s).)

Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ∼100 copies are retrotransposition-competent. Retrotransposition is normally limited via epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, LINE-1 overexpression and retrotransposition are hallmarks of cancers. Here, we review mechanisms of LINE-1 regulation and how LINE-1 may promote genetic heterogeneity in tumors. Finally, we discuss therapeutic strategies to exploit LINE-1 biology in cancers., (© 2023 Mendez-Dorantes and Burns; Published by Cold Spring Harbor Laboratory Press.)

Purpose: The aim of this study concerns the evaluation of peripapillary vessel indices in childhood glaucoma (CG) and healthy subjects., Material and Methods: In this prospective, unicenter, observational cross-sectional study, patients with CG and age and sex-matched healthy subjects were included. We compared retinal nerve fiber layer (RNFL) measurements in optical coherence tomography (OCT), peripapillary vessel density (PVD), and the flux index (FI) of the superficial vascular plexus from OCT angiography (OCT-A) between CG patients and control groups., Results: We included 39 patients (68 eyes) with CG and 50 (95 eyes) healthy subjects. The peripapillary RNFL thickness, vessel density, and flux index were significantly lower in the CG group than in the control group. The mean PVD of CG patients was 0.52 ± 0.043%, compared with 0.55 ± 0.014%, p < 0.0001 in healthy subjects. The mean FI was 0.32 ± 0.054 versus 0.37 ± 0.028, p < 0.0001, in CG patients and healthy subjects, respectively. PVD and FI in the superior, inferior, and temporal sectors were significantly lower in CG. The peripapillary RNFL thickness showed a higher area under the ROC curve (AUROC) for discriminating healthy and CG eyes and was significantly different than the PVD (0.797, 95%CI 0.726-0.869; p < 0.0001 vs. 0.664, 95%CI 0.574-0.752; p 0.00037), p 0.012., Conclusions: PVD and FI show lower values in CG and correlate with RNFL thickness measurement but have lower diagnostic ability than RNFL thickness measurement. Our results reveal possible differences in the pathogenesis of microvascular compromise in childhood glaucoma patients.

Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aβ 42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aβ 42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aβ pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cisternas, Gherardelli, Gutierrez, Salazar, Mendez-Orellana, Wong and Inestrosa.)

Background: Optic nerve head (ONH) interpretation is a glaucoma screening method which may be influenced by criteria variability. Laguna ONhE software is a low-cost and non-invasive method of ONH analysis., Methods: We analysed the results of the Laguna ONhE application, interpreting 552 ONH images from the ACRIMA database, publicly available on the Internet, and compared them with the opinion of five experts. Diagnostic agreement was investigated using Cohen's kappa (κ) with 95% confidence., Results: The kappa concordance index obtained with Laguna ONhE and the majority of the experts' criterion (0.77) was significantly higher compared to that obtained with ACRIMA and the majority of the experts' criterion (0.61). In 44.7% of the cases there was absolute agreement among the 5 experts and the Laguna ONhE program. Removing borderline cases from the analysis yielded increased diagnostic agreement (0.81). The area under the receiver operating characteristic (AUROC) of the Laguna ONhE program (0.953, p < 0.001) was not significantly different than AUROC of the majority of the experts' criterion (0.925, p < 0.001), p = 0.052. Individually obtained expert's AUROCs were significantly lower (0.636 to 0.913; p < 0.01)., Conclusions: Laguna ONhE's agreement with the experts is high, particularly where the diagnosis may be more obvious by the appearance of the ONH.

Background: Social determinants of health are a well-described influencer of pregnancy-related morbidity and mortality. It is unclear how societal changes secondary to the COVID-19 pandemic altered the social determinants of health among pregnant patients., Objective: This study aimed to investigate differences in the social determinants of health among patients who experienced pregnancy before and during the COVID-19 pandemic., Study Design: This was a secondary analysis of an ongoing prospective cohort study examining the social determinants of health in postpartum patients at a single inner-city academic medical center. The planned secondary analysis was to compare the social determinants of health between patients that experienced societal changes before the pandemic and patients that experienced societal changes during the pandemic. Patients were included in the pandemic group if they delivered on or after March 30, 2020; moreover, patients in the pandemic group were compared with those who delivered before March 30, 2020 (referent group). Medical records were used to collect sociodemographic, pregnancy, and infant outcome data. The study participants were interviewed to collect detailed information regarding their perceived social, emotional, and physical environment as indicators of social determinants of health. Generalized linear modeling estimated the influence of social determinants of health  on births during the COVID-19 pandemic., Results: Overall, 577 patients were enrolled in the study, of which 452 (78%) delivered before the COVID-19 pandemic and 125 (22%) delivered during the pandemic. Patients who delivered during the pandemic were more likely to report limited social or emotional support (relative risk, 1.62; 95% confidence interval, 1.02-2.59) and higher race-based discrimination (relative risk, 1.59; 95% confidence interval, 1.00-2.53). Mothers in the prepandemic group were more likely to have used federally funded programs, such as Medicaid, food stamps, and the Special Supplemental Nutrition Program for Women, Infants, and Children, during their pregnancy. Furthermore, the referent group reported more limited access to transportation. In addition, mothers in the prepandemic group were more likely to initiate prenatal care at a later gestational age and have fewer total prenatal care visits., Conclusion: The COVID-19 pandemic created unprecedented changes in pregnancy care, and these were reflected in social determinants of health. It is imperative that we focus on the social determinants of health that were mitigated during this time and their effects on maternal and infant health., (© 2023 The Authors.)

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high mortality rate due to a lack of therapeutic targets. Many TNBC cells are reliant on extracellular arginine for survival and express high levels of binding immunoglobin protein (BiP), a marker of metastasis and endoplasmic reticulum (ER) stress response., Methods: In this study, the effect of arginine shortage on BiP expression in the TNBC cell line MDA-MB-231 was evaluated. Two stable cell lines were generated in MDA-MB-231 cells: the first expressed wild-type BiP, and the second expressed a mutated BiP free of the two arginine pause-site codons, CCU and CGU, termed G-BiP., Results: The results showed that arginine shortage induced a non-canonical ER stress response by inhibiting BiP translation via ribosome pausing. Overexpression of G-BiP in MDA-MB-231 cells promoted cell resistance to arginine shortage compared to cells overexpressing wild-type BiP. Additionally, limiting arginine led to decreased levels of the spliced XBP1 in the G-BiP overexpressing cells, potentially contributing to their improved survival compared to the parental WT BiP overexpressing cells., Conclusion: In conclusion, these findings suggest that the downregulation of BiP disrupts proteostasis during arginine shortage-induced non-canonical ER stress and plays a key role in cell growth inhibition, indicating BiP as a target of codon-specific ribosome pausing upon arginine shortage., (© 2023. The Author(s).)

Background: The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection., Methods: Patients received trotabresib 30 mg/day on days 1-4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity., Results: Twenty patients received preoperative trotabresib and underwent resection with no delays or cancelations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Six-month progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30., Conclusions: Trotabresib penetrates the blood-brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Objective: To assess the reproducibility of peripapillary, optic nerve head (PP-ONH) and macular vessel density (VD) by Spectral Domain optical coherence tomography angiography (SD OCT-A) in glaucoma patients and healthy subjects., Methods: Cross-sectional study assessing 63 eyes of 63 subjects, including 33 glaucoma patients and 30 healthy subjects. Glaucoma was classified in mild, moderate, or advanced. Two consecutive scans were acquired by Spectralis Module OCT-A (Heidelberg, Germany), and provided images of the superficial vascular complex (SVC), nerve fiber layer vascular plexus (NFLVP), superficial vascular plexus (SVP); deep vascular complex (DVC), intermediate capillary plexus (ICP) and deep capillary plexus (DCP). VD (%) was calculated by AngioTool. Intraclass correlation coefficients (ICCs) and coefficients of variation (CV) were calculated., Results: Among PP-ONH VD, better ICC presented advanced (ICC 0.86-0.96) and moderate glaucoma (ICC 0.83-0.97) compared with mild glaucoma (0.64-0.86). For the macular VD reproducibility, ICC results for superficial retinal layers were better for mild glaucoma (0.94-0.96) followed by moderated (0.88-0.93) and advanced glaucoma (0.85-0.91), and for deeper retinal layers ICC was better for moderate glaucoma (0.95-0.96) followed by advanced (0.80-0.86) and mild glaucoma (0.74-0.91). CVs ranged from 2.2% to 10.94%. Among healthy subjects, ICCs for the PP-ONH VD measurements (0.91-0.99) and for the macular VD measurements (0.93-0.97) were excellent in all layers, with CVs from 1.65% to 10.33%., Conclusions: SD OCT-A used to quantify macular and PP-ONH VD showed excellent and good reproducibility in most layers of the retina, both in healthy subjects and in glaucoma patients regardless of the severity of the disease., (Copyright © 2023 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To assess the correlation between COVID-19 vaccination coverage and the Human Development Index (HDI) at the provincial level in Peru., Study Design: Ecological study., Methods: We conducted a cross-sectional ecological study based on secondary data analysis. Coverages of the first, second , and third doses of the vaccine against COVID-19 and the HDI were evaluated. The magnitude of the correlations was assessed using Spearman's rank correlation coefficients with their corresponding bootstrapped 95% confidence intervals (95% CI). Scatter plots were also constructed., Results: A total of 196 provinces were included. There was a moderate correlation between the first dose of the COVID-19 vaccine and the HDI ( r  = 0.3807 [95% CI 0.2585-0.5030], p < 0.0001). The same direction was found for the second ( r  = 0.4064 [95% CI 0.2853-0.5276], p < 0.0001) and third dose ( r  = 0.4435 [95% CI 0.3201-0.5669], p < 0.0001)., Conclusions: A positive correlation was found between COVID-19 vaccination coverage and the HDI, suggesting the presence of inequalities in access to vaccines. Individualised strategies are needed in lower HDI regions to tackle inequalities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Ensuring broad COVID-19 vaccination coverage among migrants is a global public health concern. Thus, our study aimed to assess the factors associated with not receiving the primary series and booster dose of the COVID-19 vaccine among Venezuelan migrants in Peru., Methods: This was a cross-sectional study based on secondary data analysis of the 2022 Venezuelan Population Residing in Peru Survey. Our population included Venezuelan migrants and refugees over 18 years old living in Peru with complete information for the variables of interest. Two outcome variables were assessed: not receiving the primary series and not receiving the booster dose of the COVID-19 vaccine. Crude and adjusted prevalences were calculated with 95% confidence intervals., Results: A total of 7,727 Venezuelan adults were included in our study, of whom 6,511 completed the primary series. The overall COVID-19 vaccination coverage of the primary series was 84.17%, whilst the coverage of the booster dose was 28.06%. Being younger, uninsured, illegally-staying, and having a low educational level were associated with both outcomes., Conclusion: Several sociodemographic and migration-related variables were associated with both outcomes. Governmental policies prioritizing vaccination among Venezuelan migrants are needed to ensure broad coverage in this vulnerable group., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To quantify the inequalities of anemia in Peruvian children aged 6-59 months and uncover its contributing factors., Materials and Methods: We conducted a cross-sectional study based on the secondary data analysis of the 2021 Peruvian Demographic and Health Survey (DHS). Our sample included Peruvian children aged 6-59 months with complete data for the variables of interest. Anemia was defined as having a hemoglobin level of less than 11 g/dL, adjusted by altitude. Erreygers Concentration Index (ECI) and concentration curves were computed to estimate the socio-economic inequality in anemia among Peruvian children. Moreover, ECI was decomposed to figure out the contributing factors to the inequality of anemia and the residual variation., Results: Nationwide, the prevalence of anemia in Peruvian children was 29.47%. We found a pro-poor inequality regarding anemia at the national level (ECI = -0.1848). The determinants included in the model explained 81.85% of the overall socio-economic inequality in anemia. The largest contribution to inequality was from household- and community-related factors. Having a higher mother's education level (26.26%) and being from the highlands (24.91%) were the major significant contributors to the overall health inequality., Conclusion: Almost one-third of Peruvian children have anemia. A pro-poor inequality of anemia in Peruvian children was found. Public policies ought to address the major contributing factors of anemia inequality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Al-kassab-Córdova, Mendez-Guerra, Robles-Valcarcel, Iberico-Bellomo, Alva, Herrera-Añazco and Benites-Zapata.)

Introduction: Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear., Methods: This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure., Results: A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure., Discussion: An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy., Competing Interests: Author PD was employed by Merck & Co. JWL and JAH are paid speakers for Accuray. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​, (Copyright © 2023 Leu, Akerman, Mendez, Lischalk, Carpenter, Ebling, Haas, Witten, Barbaro, Duic, Tessler and Repka.)

Progenitor cells capable of self-renewal and differentiation in the adult human pancreas are an under-explored resource for regenerative medicine. Using micro-manipulation and three-dimensional colony assays we identify cells within the adult human exocrine pancreas that resemble progenitor cells. Exocrine tissues were dissociated into single cells and plated into a colony assay containing methylcellulose and 5% Matrigel. A subpopulation of ductal cells formed colonies containing differentiated ductal, acinar, and endocrine lineage cells, and expanded up to 300-fold with a ROCK inhibitor. When transplanted into diabetic mice, colonies pre-treated with a NOTCH inhibitor gave rise to insulin-expressing cells. Both colonies and primary human ducts contained cells that simultaneously express progenitor transcription factors SOX9, NKX6.1, and PDX1. In addition, in silico analysis identified progenitor-like cells within ductal clusters in a single-cell RNA sequencing dataset. Therefore, progenitor-like cells capable of self-renewal and tri-lineage differentiation either pre-exist in the adult human exocrine pancreas, or readily adapt in culture., Competing Interests: Conflict of interests H.T.K. maintains a patent no. 9,783,784 titled “Methods for establishing and improving the survival of a population of pancreatic progenitor or stem cells.” The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/aims: Vascular factors are involved in the development of glaucoma, including diseases such as hypercholesterolemia (HC), systemic arterial hypertension (SAH), and diabetes mellitus (DM). The aim of this study was to determine the effect of glaucoma disease on peripapillary vessel density (sPVD) and macular vessel density (sMVD) on the superficial vascular plexus, controlling differences on comorbidities such as SAH, DM and HC between glaucoma patients and normal subjects., Methods: In this prospective, unicenter, observational cross-sectional study, sPVD and sMVD were measured in 155 glaucoma patients and 162 normal subjects. Differences between normal subjects and glaucoma patients' groups were analyzed. A linear regression model with 95% confidence and 80% statistical power was performed., Results: Parameters with greater effect on sPVD were glaucoma diagnosis, gender, pseudophakia and DM. Glaucoma patients had a sPVD 1.2% lower than healthy subjects (Beta slope 1.228; 95%CI 0.798-1.659, p < 0.0001). Women presented 1.19% more sPVD than men (Beta slope 1.190; 95%CI 0.750-1.631, p < 0.0001), and phakic patients presented 1.7% more sPVD than men (Beta slope 1.795; 95%CI 1.311-2.280, p < 0.0001). Furthermore, DM patients had 0.9% lower sPVD than non-diabetic patients (Beta slope 0.925; 95%CI 0.293-1.558, p = 0.004). SAH and HC did not affect most of the sPVD parameters. Patients with SAH and HC showed 1.5% lower sMVD in the outer circle than subjects without those comorbidities (Beta slope 1.513; 95%CI 0.216-2.858, p = 0.021 and 1.549; 95%CI 0.240-2.858, p = 0.022 respectively., Conclusions: Glaucoma diagnosis, previous cataract surgery, age and gender seem to have greater influence than the presence of SAH, DM and HC on sPVD and sMVD, particularly sPVD.

Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.