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Long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p is not only expressed but also released by ovarian cancer and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed that released ORF1p is confidently detectable in conditioned media, ascites, and patients' plasma, implicating ORF1p as a potential biomarker. Interestingly, ORF1p expression is detectable in fallopian tube (FT) epithelial precursors of HGSOC but not in benign FT, suggesting that ORF1p expression in an early event in HGSOC development. Finally, treatment of FT cells with DNA methyltransferase inhibitors led to robust expression and release of ORF1p, validating the regulatory role of DNA methylation in LINE-1 repression in non-tumorigenic tissue., (© 2023. The Author(s).)

Objective: To identify the associated factors and assess the inequalities of full vaccination coverage (FVC) among Peruvian infants aged 12-23 months during the COVID-19 pandemic in a nationally representative sample., Methods: We carried out a population-based cross-sectional study based on a secondary data analysis using the 2021 Peruvian Demographic Health Survey (DHS) in infants aged 12 to 23 months. The sampling design was probabilistic, multistage, stratified, and independent at both departmental and area of residence levels. FVC was defined according to the WHO definition. We performed generalized linear models (GLM) Poisson family log link function to estimate crude (aPR) and adjusted prevalence ratios (aPR). Also, for inequality assessment, we calculated the concentration curve (CC), concentration index (CI), and Erreygers normalized concentration index (ECI)., Results: We included 4,189 infants in our analysis. Nationwide, the prevalence of FVC was 66.19% (95% CI: 64.33-68). Being younger, having a mother with no education or primary education, belonging to a large family, having no access to mass media, having had six or fewer ANC visits, and having a mother whose age was under 20 at first delivery were inversely associated with FVC. Meanwhile, living in the Highlands or on the rest of the coast, and living in rural areas were directly associated with FVC. We found a pro-rich inequality in FVC based on wealth-ranked households (CI: 0.0066; ECI: 0.0175)., Conclusion: FVC has dropped among Peruvian infants aged between 12 and 23 months. There were several factors associated with FVC. It was more concentrated among the better-off infants, although in low magnitude., 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined as persistent difficulty in maturing the socialization process. Health professionals have used traditional methods in the therapies performed on patients with the aim of improving the expression of emotions by patients. However, they have not been sufficient to detect the different emotions expressed in the face of people according to different sensations. Therefore, different artificial intelligence techniques have been applied to improve the results obtained in these therapies. In this article, we propose the construction of an intelligent mirror to recognize five basic emotions: angry, scared, sad, happy and neutral. This mirror uses convolutional neural networks to analyze the images that are captured by a camera and compare it with the one that the patient should perform, thus supporting the therapies performed by health professionals in children with ASD. The proposal presents the platform and computer architecture, as well as the evaluation by specialists under the technology acceptance model., (© The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2021, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: Invasive meningococcal disease (IMD) is a major health concern which can be prevented through vaccination. Conjugate vaccines against serogroups A, C, W, and Y and two protein-based vaccines against serogroup B are currently available in the European Union., Areas Covered: We present epidemiologic data for Italy, Portugal, Greece, and Spain using publicly available reports from national reference laboratories and national or regional immunization programs (1999-2019), aiming to confirm risk groups, and describe time trends in overall incidence and serogroup distribution, as well as impact of immunization. Analysis of circulating MenB isolates in terms of the surface factor H binding protein (fHbp) using PubMLST is discussed as fHbp represents an important MenB vaccine antigen. Predictions of potential reactivity of the two available MenB vaccines (MenB-fHbp and 4CMenB) with circulating MenB isolates are also provided as assessed using the recently developed MenDeVAR tool., Expert Opinion: Understanding dynamics of IMD and continued genomic surveillance are essential for evaluating vaccine effectiveness, but also prompting proactive immunization programs to prevent future outbreaks. Importantly, the successful design of further effective meningococcal vaccines to fight IMD relies on considering the unpredictable epidemiology of the disease and combining lessons learnt from capsule polysaccharide vaccines and protein-based vaccines.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4 + T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4 + T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4 + T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4 + T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

Purpose: Advancements in breast radiation therapy offer innumerable benefits to patients and the health care system. Despite promising outcomes, clinicians remain hesitant about long-term side effects and disease control with accelerated partial breast radiation therapy (APBI). Herein, we review the long-term outcomes of patients with early-stage breast cancer treated with adjuvant stereotactic partial breast irradiation (SAPBI)., Methods and Materials: This retrospective study examined outcomes of patients who received diagnoses of early-stage breast cancer treated with adjuvant robotic SAPBI. All patients were eligible for standard ABPI and underwent lumpectomy, followed by fiducial placement in preparation for SAPBI. Using fiducial and respiratory tracking to maintain a precise dose distribution throughout the course of treatment, patients received 30 Gy in 5 fractions on consecutive days. Follow-up occurred at routine intervals to evaluate disease control, toxicity, and cosmesis. Toxicity and cosmesis were characterized using the Common Terminology Criteria for Adverse Events version 5.0 and Harvard Cosmesis Scale, respectively., Results: Patients (N = 50) were a median age of 68.5 years at the time of treatment. The median tumor size was 7.2 mm, 60% had an invasive cell type, and 90% were estrogen receptor positive, progesterone receptor positive, or both. Patients (n = 49) were followed for a median of 4.68 years for disease control and 1.25 years for cosmesis and toxicity. One patient experienced local recurrence, 1 patient experienced grade 3+ late toxicity, and 44 patients demonstrated excellent cosmesis., Conclusions: To our knowledge, this is the largest retrospective analysis with the longest follow-up time for disease control among patients with early breast cancer treated with robotic SAPBI. With follow-up time for cosmesis and toxicity comparable to that of previous studies, results of the present cohort advance our understanding of the excellent disease control, excellent cosmesis, and limited toxicity that can be achieved by treating select patients with early-stage breast cancer with robotic SAPBI., (© 2022 The Author(s).)

Objectives: The objective is to examine racial and ethnic heterogeneity in older adults' functional limitations and physical health. Methods: Data were from 2011 to 2015 Health Outcomes Survey of Medicare Advantage beneficiaries 65 and older ( N = 828,946). Outcomes were Physical Component Summary (PCS) scores and need for assistance with activities of daily living (ADLs). Six non-Hispanic racial groups and five Hispanic subgroups were analyzed. Regression models adjusted for sociodemographic and health characteristics. Results: White and Asian respondents had the lowest unadjusted ADL difficulty rates and highest PCS scores. In adjusted analyses, Cuban respondents had the highest PCS scores and lowest rates of any ADL difficulty; White respondents had the lowest rates of specific ADL difficulties. Native Hawaiian or other Pacific Islander and multiple Hispanic respondents had the highest ADL difficulty rates. Discussion: Both the healthiest and highest need subgroups of Medicare Advantage beneficiaries were Hispanic. Understanding racial and ethnic subgroup differences may help target interventions to prevent or aid with functional limitations.

Volume staging involves dividing the target volume into smaller parts and treating each part separately. In this study, the feasibility of volume-staged stereotactic radiosurgery (VS-SRS) on a linear accelerator using volumetric modulated arc therapy (VMAT) and a frameless patient positioning system is investigated. Ten patients, previously treated with hypofractionated stereotactic radiotherapy with arteriovenous malformation (AVM) sized from 1.6 to 4.0 cm in diameter, were selected. VS-SRS plans were created with the VMAT technique on the Varian Eclipse treatment planning system (TPS) using the TrueBeam STx linear accelerator. For each patient, an AVM-VMAT set was planned with the AVM as the target and a PTV-VMAT set using the (PTV = AVM+1 mm) as the target. All targets were divided into two sub-volumes. The TPS data from the AVM-VMAT plans was compared to Gamma Knife (GK) VS-SRS plan data available in the literature. The AVM-VMAT and PTV-VMAT plans were compared to investigate the effect of a 1 mm PTV margin on normal brain (NB) dose. End-to-end testing was performed using a GaFchromic EBT3 film and point-dose measurements. Dosimetric effects of multiple setups were investigated through film-to-film comparisons. Median target dose coverage, NB V 12Gy , and conformity index for the AVM-VMAT plans were 97.5%, 17 cm 3 , and 0.8, respectively. PTV-VMAT plans attained comparable target dose coverage, but the average NB V 12Gy increased by 48.9% when compared to the AVM-VMAT plans. Agreement of point-dose measurements with TPS calculations was -0.6% when averaged over all patients. Gamma analysis passing rates were above 90% for all film-to-film comparisons (2%/1 mm criteria), and for the film to TPS comparison (5%/1 mm). This work suggests that VMAT is capable of producing VS-SRS plans with similar dose falloff characteristics as GK plans. NB dose depends on PTV margin size, and two-stage treatment setups do not appear to contribute additional uncertainty to treatment delivery., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas., Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint., Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response., Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Memory for aversive events is central to survival but can become maladaptive in psychiatric disorders. Memory enhancement for emotional events is thought to depend on amygdala modulation of hippocampal activity. However, the neural dynamics of amygdala-hippocampal communication during emotional memory encoding remain unknown. Using simultaneous intracranial recordings from both structures in human patients, here we show that successful emotional memory encoding depends on the amygdala theta phase to which hippocampal gamma activity and neuronal firing couple. The phase difference between subsequently remembered vs. not-remembered emotional stimuli translates to a time period that enables lagged coherence between amygdala and downstream hippocampal gamma. These results reveal a mechanism whereby amygdala theta phase coordinates transient amygdala -hippocampal gamma coherence to facilitate aversive memory encoding. Pacing of lagged gamma coherence via amygdala theta phase may represent a general mechanism through which the amygdala relays emotional content to distant brain regions to modulate other aspects of cognition, such as attention and decision-making., (© 2022. The Author(s).)

Objectives: Understanding the pathway by which neighbourhood factors influence glycaemic control may be crucial to addressing health disparities in diabetes. This study aimed to examine if the pathway between neighbourhood factors and glycaemic control is mediated by stress., Design: Structured equation modelling (SEM) was used to investigate direct and indirect effects in the relationship between neighbourhood factors, stress and glycaemic control, with standardised estimates to allow comparison of paths., Participants: Data was obtained from 615 adults with type 2 diabetes in the Southeastern United States., Primary and Secondary Outcome Measures: The primary outcome variable was glycaemic control determined by glycated haemoglobin (HbA1c) within the prior 6 months. Neighbourhood factors included neighbourhood violence, aesthetic quality of the neighbourhood, access to healthy food, and social cohesion. Stress was measured using the perceived stress scale., Results: In the final model (χ 2 (158)=406.97, p<0.001, root mean square error of approximation=0.05, p-close 0.38, Comparative Fit Index=0.97, Tucker-Lewis index=0.96, the coefficient of determination=1.0), violence (r=0.79, p=0.006), neighbourhood aesthetics (r=0.74, p=0.02) and social cohesion (r=0.57, p=0.04) were significantly associated with higher perceived stress. Stress (r=0.06, p=0.004) was directly associated with higher glycaemic control. Significant indirect effects existed between violence and higher HbA1c (r=0.05, p=0.04). After controlling for other neighbourhood factors, there was no significant relationship between access to healthy food and either stress or glycaemic control., Conclusions: While a number of neighbourhood factors were directly associated with stress, only neighbourhood violence had a significant indirect effect on glycaemic control via stress within the tested pathway. Future studies should examine individual-level stress management interventions and should consider community-level interventions targeting neighbourhood violence as strategies for addressing disparities in diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent years have seen the advent of Quality-by-Design (QbD) as a philosophy to ensure the quality, safety, and efficiency of pharmaceutical production. The key pharmaceutical processing methodology of Direct Compression to produce tablets is also the focus of some research. The traditional Design-of-Experiments and purely experimental approach to achieve such quality and process development goals can have significant time and resource requirements. The present work evaluates potential for using combined modelling and experimental approach, which may reduce this burden by predicting the properties of multicomponent tablets from pure component compression and compaction model parameters. Additionally, it evaluates the use of extrapolation from binary tablet data to determine theoretical pure component model parameters for materials that cannot be compacted in the pure form. It was found that extrapolation using binary tablet data - where one known component can be compacted in pure form and the other is a challenging material which cannot be - is possible. Various mixing rules have been evaluated to assess which are suitable for multicomponent tablet property prediction, and in the present work linear averaging using pre-compression volume fractions has been found to be the most suitable for compression model parameters, while for compaction it has been found that averaging using a power law equation form produced the best agreement with experimental data. Different approaches for estimating component volume fractions have also been evaluated, and using estimations based on theoretical relative rates of compression of the pure components has been found to perform slightly better than using constant volume fractions (that assume a fully compressed mixture). The approach presented in this work (extrapolation of, where necessary, binary tablet data combined with mixing rules using volume fractions) provides a framework and path for predictions for multicomponent tablets without the need for any additional fitting based on the multicomponent formulation composition. It allows the knowledge space of the tablet to be rapidly evaluated, and key regions of interest to be identified for follow-up, targeted experiments that that could lead to an establishment of a design and control space and forgo a laborious initial Design-of-Experiments., 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., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: The start of the COVID-19 pandemic led the Los Angeles safety net health system to dramatically reduce in-person visits and transition abruptly to telehealth/telemedicine services to deliver clinical care (remote telephone and video visits). However, safety net patients and the settings that serve them face a "digital divide" that could impact effective implementation of such digital care. The study objective was to examine attitudes and perspectives of leadership and frontline staff regarding telehealth integration in the Los Angeles safety net, with a focus on telemedicine video visits., Methods: This qualitative study took place in the Los Angeles County Department of Health Services (LAC DHS), the second-largest safety net health system in the US. This system disproportionately serves the uninsured, Medicaid, racial/ethnic minority, low-income, and Limited English Proficient (LEP) patient populations of Los Angeles County. Staff and leadership personnel from each of the five major LAC DHS hospital center clinics, and community-based clinics from the LAC DHS Ambulatory Care Network (ACN) were individually interviewed (video or phone calls), and discussions were recorded. Interview guides were based on the Consolidated Framework for Implementation Research (CFIR), and included questions about the video visit technology platform and its usability, staff resources, clinic needs, and facilitators and barriers to general telehealth implementation and use. Interviews were analyzed for summary of major themes., Results: Twenty semi-structured interviews were conducted in August to October 2020. Participants included LAC DHS physicians, nurses, medical assistants, and physical therapists with clinical and/or administrative roles. Narrative themes surrounding telehealth implementation, with video visits as the case study, were identified and then categorized at the patient, clinic (including provider), and health system levels., Conclusions: Patient, clinic, and health system level factors must be considered when disseminating telehealth services across the safety net. Participant discussions illustrated how multilevel facilitators and barriers influenced the feasibility of video visits and other telehealth encounters. Future research should explore proposed solutions from frontline stakeholders as testable interventions towards advancing equity in telehealth implementation: from patient training and support, to standardized workflows that leverage the expertise of multidisciplinary teams., 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., (© 2022 Casillas, Valdovinos, Wang, Abhat, Mendez, Gutierrez, Portz, Brown and Lyles.)

We assessed the circulation of severe acute respiratory syndrome coronavirus-2 variants amongst vaccinated military personnel in Bogotá, Colombia to evaluate the mutations of certain variants and their potential for breakthrough infection in vaccinated subjects. We observed that in vaccinated individuals the most frequent infecting lineage was Mu (B.1.621 and B.1.621.1). The above is possibly associated with specific mutations that confer it with vaccine-induced immune escape ability. Our findings highlight the importance of how genomic tracking coupled with epidemiological surveillance can assist in the study of novel emerging variants (e.g., Omicron) and their impact on vaccination efforts worldwide., (© 2022 Wiley Periodicals LLC.)

Objectives: Most acute stroke research is conducted at academic and larger hospitals, which may differ from many non-academic (ie, community) and smaller hospitals with respect to resources and consultant availability. We describe current emergency department (ED) and hospital-level stroke-related capabilities among a sample of community EDs participating in the Emergency Quality Network (E-QUAL) stroke collaborative., Methods: Among E-QUAL-participating EDs, we conducted a survey to collect data on ED and hospital stroke-related structural and process capabilities associated with quality of stroke care delivery and patient outcomes. EDs submitted data using a web-based submission portal. We present descriptive statistics of self-reported capabilities., Results: Of 154 participating EDs in 30 states, 97 (63%) completed the survey. Many were rural (33%); most (82%) were not certified stroke centers. Although most reported having stroke protocols (67%), many did not include hemorrhagic stroke or transient ischemic attack (45% and 57%, respectively). Capability to perform emergent head computed tomography and to administer thrombolysis were not universal (absent in 4% and 5%, respectively). Access to neurologic consultants varied; 18% reported no 24/7 availability onsite or remotely. Of those with access, 48% reported access through telemedicine only. Admission capabilities also varied with patient transfer commonly performed (79%)., Conclusion: Stroke-related capabilities vary substantially between community EDs and are different from capabilities typically found in larger stroke centers. These data may be valuable for identifying areas for future investment. Additionally, the design of stroke quality improvement interventions and metrics to evaluate emergency stroke care delivery should account for these key structural differences., Competing Interests: Marquita Decker‐Palmer reports being an employee of Genentech and holding shares/stock in the company. William Meurer reports consulting fees from ACEP for methodology statistics review for Annals of EM, consulting fees (modest) from Berry Consultants, LLC, and grant funding relevant to stroke from the Agench for Healthcare Research and Quality. Kori S. Zachrison, Latha Ganti, Dhruv Sharma, Pawan Goyal, Opeolu Adeoye, Joshua N. Goldstein, Edward C. Jauch, Bruce M. Lo, Tracy E. Madsen, John A. Oostema, Cindy Mendez‐Hernandez, and Arjun K. Venkatesh have no conflicts to report., (© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

CRISPR/Cas9-based genome editing has revolutionized experimental molecular biology and entered the clinical world for targeted gene therapy. Identifying DNA modifications occurring at CRISPR/Cas9 target sites is critical to determine efficiency and safety of editing tools. Here we show that insertions of LINE-1 (L1) retrotransposons can occur frequently at CRISPR/Cas9 editing sites. Together with PolyA-seq and an improved amplicon sequencing, we characterize more than 2500 de novo L1 insertions at multiple CRISPR/Cas9 editing sites in HEK293T, HeLa and U2OS cells. These L1 retrotransposition events exploit CRISPR/Cas9-induced DSB formation and require L1 RT activity. Importantly, de novo L1 insertions are rare during genome editing by prime editors (PE), cytidine or adenine base editors (CBE or ABE), consistent with their reduced DSB formation. These data demonstrate that insertions of retrotransposons might be a potential outcome of CRISPR/Cas9 genome editing and provide further evidence on the safety of different CRISPR-based editing tools., (© 2022. The Author(s).)

Background: Nonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to validate noninvasive tests for the diagnosis of NAFLD in PWH., Methods: This is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter [CAP]), and noninvasive markers of steatosis (triglyceride and glucose index [TyG], hepatic steatosis index [HSI], fatty liver index [FLI]) and fibrosis ([FIB]-4, aminotransferase-to-platelet ratio index [APRI], NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers., Results: Of 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75-1); CAP, 0.94 (0.88-1); FLI, 0.81 (0.58-1); HSI, 0.74 (0.62-0.87); and TyG, 0.75 (0.49-1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82-1), 0.96 (0.90-1), 0.97 (0.93-1), and 0.85 (0.68-1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97-1, P  < .001) and 0.92 (0.77-1, P  < .001)., Conclusions: Ultrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We clinically characterized PCR detected breakthrough infections among partially/fully vaccinated cases with majority given an inactivated vaccine, CoronaVac. From 1 March to 15 July 2021, we detected 182 SARS-CoV-2 infections among vaccinated cases with 129 classified as breakthrough infections. Majority were male, 30-39 y.o., and were asymptomatic or mildly symptomatic with few severe cases. Alpha, Beta and Delta VOCs were detected from sequenced breakthrough infections. Healthcare workers had significantly lower Ct values(higher viral loads) versus non-HCWs. Our results underscore the importance of regular PCR screening for HCWs due to the risk of SARS-CoV-2 transmission from asymptomatic breakthrough infections and provide evidence supporting administration of a booster dose especially to HCWs., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The use of treatment planning prostate MRI for Stereotactic Body Radiation Therapy (SBRT) is largely a standard, yet not all patients can receive MRI for a variety of clinical reasons. Thus, we aim to investigate the safety of patients who received CT alone based SBRT planning for the definitive treatment of localized prostate cancer., Methods: Our study analyzed 3410 patients with localized prostate cancer who were treated with SBRT at a single academic institution between 2006 and 2020. Acute and late toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Expanded Prostate Cancer Index Composite (EPIC) questionnaires evaluated QOL and PSA nadir was evaluated to detect biochemical failures., Results: A total of 162 patients (4.75%) received CT alone for treatment planning. The CT alone group was older relative to the MRI group (69.9 vs 67.2, p < 0.001) and had higher risk and grade disease (p < 0.001). Additionally, the CT group exhibited a trend in larger CTVs (82.56 cc vs 76.90 cc; p = 0.055), lower total radiation doses (p = 0.048), and more frequent pelvic nodal radiation versus the MRI group (p < 0.001). There were only two reported cases of Grade 3 + toxicity within the CT alone group. Quality of life data within the CT alone group revealed declines in urinary and bowel scores at one month with return to baseline at subsequent follow up. Early biochemical failure data at median time of 2.3 years revealed five failures by Phoenix definition., Conclusions: While clinical differences existed between the MRI and CT alone group, we observed tolerable toxicity profiles in the CT alone cohort, which was further supported by EPIC questionnaire data. The overall clinical outcomes appear comparable in patients unable to receive MRI for their SBRT treatment plan with early clinical follow up., (© 2022. The Author(s).)

Introduction: A picture version of the Free and Cued Selective Reminding Test (FCSRT) would assist in the assessment of memory function in patients with low levels of schooling. A shortened version would improve the test's applicability., Objectives: To analyse the diagnostic usefulness of a shortened picture version of the FCSRT for distinguishing patients with amnestic mild cognitive impairment (aMCI) from controls, without excluding participants with a low level of schooling., Methods: Phase I study of a diagnostic evaluation (convenience sampling; pre-test prevalence 50%). A blinded researcher independently administered the FCSRT to 30 patients with aMCI and 30 controls matched for age, sex, level of schooling and literacy, using images and omitting the usual 30-minutes delayed recall item. Three variables were recorded: free recall, total recall, and cue efficiency. Diagnostic accuracy was calculated using receiver operating characteristic curves and the area under the curve. The Youden index was used to identify optimal cut-off points., Results: Of all participants, 41.7% had not completed primary education. There were no differences between groups as regards sociodemographic variables. Area under the curve was excellent for free recall (0.99), total recall (0.95), and cue efficiency (0.93). The optimal cut-off points were 21/22, 43/44, and < 0.77, respectively., Conclusions: This preliminary analysis shows that a shortened picture version of the FCSRT may be useful and applicable for the diagnosis of aMCI without excluding individuals with a low level of schooling., (Copyright © 2019 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Anemia is a global public health issue that affects mainly children aged less than 5 years. In Peru, despite the reduction in the prevalence of anemia between 2010 and 2018, anemia remains a major concern, especially in high-risk zones such as rural areas. Several sociodemographic factors have been associated with anemia in children; however, components contributing to the urban-rural gap have not been previously assessed. The purpose of this study was to evaluate the determinants of the difference in anemia prevalence between urban and rural areas, and its spatial distribution in Peruvian children aged 6-59 months., Methods: A secondary data analysis was conducted using the 2019 Peruvian Demographic Health Survey. The study population included 18 846 children aged 6-59 months. A multivariate decomposition analysis for non-linear response model was performed to identify the factors contributing to the gap in the prevalence of anemia across urban and rural areas. Global Moran&acute;s I autocorrelation, Ordinary Kriging interpolation and Bernoulli-based purely spatial scan statistics were employed to assess the spatial pattern of anemia., Results: Nationwide, the prevalence of anemia in Peru was 29.47% (95%CI 28.63-30.33). In rural areas, it was 38.25%, and in urban areas 26.39%. The decomposition analysis revealed that 88.61% of the difference in the prevalence of anemia between urban and rural areas was attributed to the difference in the respondents' characteristics. Wealth index, mother&acute;s education, mother&acute;s employment status, number of living children and mother&acute;s age were key determinants contributing to the rural-urban gap. Spatial heterogeneity of anemia prevalence in childhood was observed at both inter- and intradepartmental level. The SaTScan spatial analysis identified six significant cluster areas with high prevalence of anemia in childhood., Conclusion: A considerable gap of anemia prevalence between urban and rural areas was found. Targeted interventions are necessary to reduce geographic disparities.

Purpose: We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system., Methods and Materials: Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival., Results: From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence., Conclusions: This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline., (Published by Elsevier Inc.)

Retrotransposons are genomic DNA sequences that copy themselves to new genomic locations via RNA intermediates; LINE-1 is the only active and autonomous retrotransposon in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues but is derepressed in many cancers, where LINE-1 retrotransposition is correlated with p53 mutation and copy number alteration (CNA). In cell lines, inducing LINE-1 expression can cause double-strand breaks (DSBs) and replication stress. Reanalyzing multiomic data from breast, ovarian, endometrial, and colon cancers, we confirmed correlations between LINE-1 expression, p53 mutation status, and CNA. We observed a consistent correlation between LINE-1 expression and the abundance of DNA replication complex components, indicating that LINE-1 may also induce replication stress in human tumors. In endometrial cancer, high-quality phosphoproteomic data allowed us to identify the DSB-induced ATM-MRN-SMC S phase checkpoint pathway as the primary DNA damage response (DDR) pathway associated with LINE-1 expression. Induction of LINE-1 expression in an in vitro model led to increased phosphorylation of MRN complex member RAD50, suggesting that LINE-1 directly activates this pathway., Competing Interests: Competing interest statement: D.F. is a founder and president of The Informatics Factory and serves or served on the scientific advisory board (SAB) or consults for Spectragen Informatics, Protein Metrics, and Preverna. J.D.B. is a founder and director of CDI Labs, Inc.; a founder of and consultant to Neochromosome, Inc.; a founder SAB member of and consultant to ReOpen Diagnostics, LLC; and serves or served on the SAB of the following: Sangamo, Inc., Modern Meadow, Inc., Rome Therapeutics, Inc., Sample6, Inc., Tessera Therapeutics, Inc., and the Wyss Institute. K.H.B. contributed a review with one of the reviewers of this manuscript within the last three years., (Copyright © 2022 the Author(s). Published by PNAS.)

Background: The burden of cardiovascular disease (CVD) is increasing in the aging population. However, little is known about CVD risk factors and outcomes for Asian American, Native Hawaiian, and Other Pacific Islander (NH/PI) older adults by disaggregated subgroups., Methods: Data were from the Centers for Medicare and Medicaid Services 2011-2015 Health Outcomes Survey, which started collecting expanded racial/ethnic data in 2011. Guided by Andersen and Newman's theoretical framework, multivariable logistic regression analyses were conducted to examine the prevalence and determinants of CVD risk factors (obesity, diabetes, smoking status, hypertension) and CVD conditions (coronary artery disease [CAD], congestive heart failure [CHF], myocardial infarction [MI], other heart conditions, stroke) for 10 Asian American and NH/PI subgroups and White adults., Results: Among the 639 862 respondents, including 26 853 Asian American and 4 926 NH/PI adults, 13% reported CAD, 7% reported CHF, 10% reported MI, 22% reported other heart conditions, and 7% reported stroke. CVD risk factors varied by Asian American and NH/PI subgroup. The prevalence of overweight, obesity, diabetes, and hypertension was higher among most Asian American and NH/PI subgroups than White adults. After adjustment, Native Hawaiians had significantly greater odds of reporting stroke than White adults., Conclusions: More attention should focus on NH/PIs as a priority population based on the disproportionate burden of CVD risk factors compared with their White and Asian American counterparts. Future research should disaggregate racial/ethnic data to provide accurate depictions of CVD and investigate the development of CVD risk factors in Asian Americans and NH/PIs over the life course., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electronic health (eHealth) literacy may affect telehealth uptake, yet few studies have evaluated eHealth literacy in underserved populations., Objective: The objective of this study was to describe technology access and use patterns as well as eHealth literacy levels among English-speaking and LEP patients in a Los Angeles safety net health system., Methods: Patients, aged ≥18 years with a diagnosis of diabetes mellitus and/or hypertension, and their caregivers were recruited from three primary care safety-net clinics in Los Angeles County (California) between June - July 2017. Participants' electronic health literacy was assessed by the eHealth Literacy Scale (eHEALS); participants were also asked about technology access and use. We examined these measures in English-speaking and limited English proficient (LEP) Spanish-speaking patients., Results: A total of 71 participants (62 patients and 9 caregivers) completed the questionnaire. The mean age of the respondents was 56 years old. More than half of participants used a phone that could connect to the Internet (67%). The mean score for 10 eHEALS items was in the moderate range (26/50 points). There was no difference in mean eHEALS between language groups. However, 47% of Spanish-speaking participants "agreed/strongly agreed" that they knew how to use the Internet to answer their health questions, compared to 68% of English-speaking participants (P<.05)., Conclusions: In this sample of patients from a diverse safety net population, perceived skills and confidence in engaging with electronic health systems were low, particularly among LEP Spanish-speakers, despite moderate levels of electronic health literacy. More studies are needed among diverse patient populations to better assess eHealth literacy and patients' digital readiness, and to examine how these patient metrics directly impact telehealth utilization., Competing Interests: Competing Interests: None declared., (Copyright © 2022, Ethnicity & Disease, Inc.)

Background: Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms., Objective: We aimed to study whether AD-related sex differences influence glucose metabolism., Methods: We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development., Results: Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males., Conclusion: Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD.

Objectives: Crossed cerebro-cerebellar BOLD activations have recently come to light as additional diagnostic features for patients with brain tumors. The covert verb generation (VG) task is a widely used language paradigm to determine these language-related crossed activations. Here we demonstrate these crossed activations in two additional language paradigms, the semantic and phonological association tasks. We propose the merit of these tasks to language lateralization determination in the clinic as they are easy to monitor and suitable for patients with aphasia., Methods: Patients with brain tumors localized at different cortical sites (n = 71) performed three language paradigms, namely the VG task as well as the semantic (SA) and phonological (PA) association tasks with button-press responses. Respective language activations in disparate cortical regions and the cerebellum were assigned laterality. Agreements in laterality between the two new tasks and the verb generation task were tested using Cohen's kappa., Results: Both tasks significantly agreed in cortical and cerebellar lateralization with the verb generation task in patients. Additionally, a McNemar test confirmed the presence of crossed activations in the cortex and the cerebellum in the entire subject population., Conclusion: We demonstrated that the semantic and phonological association tasks resulted in crossed cerebro-cerebellar language lateralization activations as those observed due to the covert verb generation task. This may suggest the possibility of these tasks being used conjointly with the traditional verb generation task, especially for subjects that may be unable to perform the latter., Key Points: • The semantic and phonological association tasks can be useful as additional presurgical fMRI language lateralization paradigms for brain tumor patients along with the standard verb generation task. • All three tasks also confirm the presence of crossed cerebro-cerebellar language activations in the current subject population., (© 2021. European Society of Radiology.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Purpose: Whole gland cryoablation is a guideline-approved definitive treatment for localized prostate cancer, and is being explored for partial gland ablation. However, there is limited data regarding management of cryoablation failures. Stereotactic body radiation therapy (SBRT) is a well-established method of primary treatment for prostate cancer. Here we review salvage SBRT after cryoablation failures., Methods and Materials: A large database of patients treated with definitive SBRT was interrogated to identify those who underwent primary cryoablation. All patients were determined to have progressive disease based on a rising prostate specific antigen and/or postcryoablation biopsy. All patients were treated with SBRT over 5 treatment fractions using a robotic radiosurgical platform. Baseline cryoablation characteristics and pre- and posttreatment Expanded Prostate Cancer Index Composite questionnaires were analyzed. Acute and late toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Cancer outcomes after salvage SBRT were stratified by disease and treatment characteristics., Results: A total of 51 patients were identified who underwent cryoablation followed by salvage SBRT. The majority (47%) were found to have intermediate-risk disease at the time of SBRT salvage and most commonly were treated with 3500 cGy in 5 fractions to the prostate and seminal vesicles. Only 1 grade 3+ toxicity was identified. Patient-reported quality of life metrics after SBRT salvage followed prior patterns observed in the de novo SBRT setting. With a median follow-up of 40 months, 76% of the cohort demonstrated disease control. Median time to prostate cancer recurrence was 57.5 months, and recurrence was predominantly seen in patients with underlying high-risk disease., Conclusions: This is the largest cohort of patients treated with any radiation therapy salvage after cryoablation and the first institution to report SBRT as a modality of salvage. Salvage SBRT after cryoablation results in low rates of high-grade toxicity, acceptable changes in patient-reported quality of life, and durable rates of long-term oncologic control., (© 2021 The Authors.)

Trypanosomatid infections are an important public health threat affecting many low-income countries across the tropics, particularly in the Americas. Trypanosomatids can infect many vertebrate, invertebrate, and plant species and play an important role as human pathogens. Among these clinically relevant pathogens are species from the genera Leishmania and Trypanosoma . Mixed trypanosomatid infections remain a largely unexplored phenomenon. Herein, we describe the application of an amplicon-based next-generation sequencing (NGS) assay to detect and identify trypanosomatid species in mammalian reservoirs, human patients, and sand fly vectors throughout regions of Leishmania endemicity. Sixty-five samples from different departments of Colombia, including two samples from Venezuela, were analyzed: 49 samples from cutaneous leishmaniasis (CL) patients, 8 from sand flies, 2 from domestic reservoirs (Canis familiaris), and 6 from wild reservoirs (Phyllostomus hastatus). DNA from each sample served to identify the presence of trypanosomatids through conventional PCR using heat shock protein 70 (HSP70) gene as the target. PCR products underwent sequencing by Sanger sequencing and NGS, and trypanosomatid species were identified by using BLASTn against a reference database built from trypanosomatid-derived HSP70 sequences. The alpha and beta diversity indexes of amplicon sequence variants were calculated for each group. The results revealed the presence of mixed infections with more than two Leishmania species in 34% of CL samples analyzed. Trypanosoma cruzi was identified in samples from wild reservoirs, as well as in sand fly vectors. Coinfection events with three different Leishmania species were identified in domestic reservoirs. These findings depose the traditional paradigm of leishmaniasis as being a single-species-driven infection and redraw the choreography of host-pathogen interaction in the context of multiparasitism. Further research is needed to decipher how coinfections may influence disease progression. This knowledge is key to developing an integrated approach for diagnosis and treatment. IMPORTANCE Traditionally, there has been a frequent, yet incorrect assumption that phlebotomine vectors, animal reservoirs, and human hosts are susceptible to Leishmania infection by a single parasite species. However, current evidence supports that these new vector-parasite-reservoir associations lend vectors and reservoirs greater permissiveness to certain Leishmania species, thus promoting the appearance of coinfection events, particularly in disease-endemic regions. The present study describes the application of an amplicon-based next-generation sequencing (NGS) assay to detect and identify trypanosomatid species in mammalian reservoirs, human patients, and sand fly vectors from regions of endemicity for leishmaniasis. This changes our understanding of the clinical course of leishmaniasis in areas of endemicity.

To assess the effectiveness and safety of the Preserflo Microshunt (PMS) implantation combined with cataract surgery in open-angle glaucoma (OAG) patients. Retrospective, open-label study conducted on insufficiently controlled OAG patients, who underwent a PMS implant procedure with mitomycin-C 0.2%, either alone or in combination with cataract surgery, and were followed for at least 12 months. Success was defined as an intraocular pressure (IOP) ≤ 18 mmHg and a reduction of at least 20% without (complete) or with (qualified) hypotensive medication. Fifty-eight eyes were included in the study, 35 eyes underwent PMS alone and 23 underwent PMS + Phaco. In the overall study sample, mean IOP was significantly lowered from 21.5 ± 3.3 mmHg at baseline to 14.6 ± 3.5 mmHg at month 12 (p < 0.0001). The IOP was significantly reduced in both groups; p < 0.0001 each, respectively. Ocular hypotensive medication was significantly reduced (p < 0.0001) in both groups. No significant differences were observed in IOP lowering or medication reduction between groups. At month 12, 62.1% eyes were considered as complete success and 82.8% eyes as qualified success. The most common adverse events were device close-to-endothelium, conjunctival fibrosis, and wound leakage. PMS, either alone or in combination with phacoemulsification, may be considered as a valuable option for treating OAG patients., (© 2021. The Author(s).)

Background: Historically, IBD has been thought to increase the underlying risk of radiation related toxicity in the treatment of prostate cancer. In the modern era, contemporary radiation planning and delivery may mitigate radiation-related toxicity in this theoretically high-risk cohort. This is the first manuscript to report clinical outcomes for men diagnosed with prostate cancer and underlying IBD curatively treated with stereotactic body radiation therapy (SBRT)., Methods: A large institutional database of patients (n = 4245) treated with SBRT for adenocarcinoma of the prostate was interrogated to identify patients who were diagnosed with underlying IBD prior to treatment. All patients were treated with SBRT over five treatment fractions using a robotic radiosurgical platform and fiducial tracking. Baseline IBD characteristics including IBD subtype, pre-SBRT IBD medications, and EPIC bowel questionnaires were reviewed for the IBD cohort. Acute and late toxicity was evaluated using the CTCAE version 5.0., Results: A total of 31 patients were identified who had underlying IBD prior to SBRT for the curative treatment of prostate cancer. The majority (n = 18) were diagnosed with ulcerative colitis and were being treated with local steroid suppositories for IBD. No biochemical relapses were observed in the IBD cohort with early follow up. High-grade acute and late toxicities were rare (n = 1, grade 3 proctitis) with a median time to any GI toxicity of 22 months. Hemorrhoidal flare was the most common low-grade toxicity observed (n = 3)., Conclusion: To date, this is one of the largest groups of patients with IBD treated safely and effectively with radiation for prostate cancer and the only review of patients treated with SBRT. Caution is warranted when delivering therapeutic radiation to patients with IBD, however modern radiation techniques appear to have mitigated the risk of GI side effects., (© 2021. The Author(s).)

Background/aims: The aim of this study was to assess the optic nerve head (ONH) and macular vessel density with optical coherence tomography angiography (OCT-A) and the ONH haemoglobin (ONH Hb) amount with Laguna ONhE program in open-angle glaucoma (OAG) patients., Methods: In this prospective observational cross-sectional study, 67 OAG patients and 41 healthy age-sex frequency matched subjects were examined with OCT-A and retinal photos. The circumpapillary (wcpVD), optic nerve head (iVD) and macular (wmVD) capillary vessel density of OCT-A and ONH colorimetric assessment to determine the ONH Hb amount using the Laguna ONhE program were evaluated., Results: Significant differences between normal subjects and glaucoma patients in the wcpVD (22.18±3.42 vs 16.03±2.89%; p<0.001), iVD (18.31±5.56 vs 12.52±4.67%; p<0.001), wmVD (15.60±2.34 vs 13.34±2.32%; p<0.001) and amount of ONH Hb (71.10±1.67 vs 68.86±2.46%; p<0.001) and in the papillary cup (68.14±5.25 vs 64.77±5.08%; p=0.001) were found. The Laguna ONhE glaucoma discriminant function (GDF) index had a negative value in the OAG patients and normal values in healthy subjects (-18.76±13.31 vs 7.98±14.09; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUROC) for discriminating between healthy and glaucomatous eyes was highest for wcpVD (0.93; 95% CI 0.86 to 0.97, p<0.0001), followed by GDF (0.92; 95% CI 0.86 to 0.97, p<0.0001), iVD (0.79; 95% CI 0.70 to 0.86; p<0.0001) and ONH Hb (0.78; 95% CI 0.69 to 0.85, p<0.0001). Pair wise comparisons showed that the AUROC of wcpVD (0.93) was not significantly different than GDF (0.92) (p=0.855)., Conclusion: Laguna ONhE program and OCT-A have similar diagnostic validity in open-angle glaucoma patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The continuing evolution of SARS-CoV-2 and the emergence of novel variants have raised concerns about possible reinfection events and potential changes in the coronavirus disease 2019 (COVID-19) transmission dynamics. Utilizing Oxford Nanopore technologies, we sequenced paired samples of three patients with positive RT-PCR results in a 1-2-month window period, and subsequent phylogenetics and genetic polymorphism analysis of these genomes was performed. Herein, we report, for the first time, genomic evidence of one case of reinfection in Colombia, exhibiting different SARS-CoV-2 lineage classifications between samples (B.1 and B.1.1.269). Furthermore, we report two cases of possible viral persistence, highlighting the importance of deepening our understanding on the evolutionary intra-host traits of this virus throughout different timeframes of disease progression. These results emphasize the relevance of genomic surveillance as a tool for understanding SARS-CoV-2 infection dynamics, and how this may translate effectively to future control and mitigations efforts, such as the national vaccination program.

An equation that uses heart rate index (HRI) defined as HR/HRrest to predict oxygen uptake (VO 2 ) in METs (e.g., METs = 6 × HRI - 5) has been developed retrospectively from aggregate data of 60 published studies. However, the prediction error of this model as used by an individual has not been established. Therefore, the purpose of this study was to examine the predictive validity of the HRI equation by comparing submaximal and maximal VO 2 predicted by the equation (VO 2 -Pred) with that measured by indirect calorimetry (VO 2 -Meas). Sixty healthy adults (age 20.5 ± 2.4 yr., body mass 69.4 ± 13.4 kg, height 1.7 ± 0.1 m) underwent a VO 2 max test and an experimental trial consisting of a 15-min resting measurement and three successive 10-min treadmill exercise bouts performed at 40%, 60% and 80% of VO 2 max. VO 2 and HR were recorded during both the submaximal and maximal exercises and used to obtain VO 2 -Pred and VO 2 -Meas for each intensity and for VO 2 max. Validation was carried out by paired t-test, regression analysis, and Bland-Altman plots. A modest but significant ( p < 0.05) correlation was observed between VO 2 -Meas and VO 2 -Pred at 40% ( r = 0.58), 60% ( r = 0.53), and 80% of VO 2 max ( r = 0.56) and at VO 2 max ( r = 0.50). No differences between VO 2 -Pred and VO 2 -Meas were found at 40% (5.53 ± 1.21 vs. 5.28 ± 0.98 METs, respectively) of VO 2 max, but VO 2 -Pred was higher ( p < 0.05) than VO 2 -Meas at 60% (8.42 ± 1.77 vs. 7.96 ± 1.39 METs, respectively) and 80% (10.79 ± 2.13 vs. 10.29 ± 1.81 METs, respectively) of VO 2 max. In contrast, VO 2 -Pred was lower ( p < 0.05) than VO 2 -Meas at VO 2 max (12.32 ± 2.30 vs. 13.38 ± 2.24 METs, respectively). Standard errors of the estimate were 0.81, 1.20, 1.54, and 1.97 METs at 40%, 60%, 80% of VO 2 max and at VO 2 max, respectively. These results suggest that further investigation aimed to establish the accuracy of using HRI to predict VO 2 is warranted.

Purpose : To evaluate the optic nerve head (ONH), macular vessel density, and retinal nerve fiber layer (RNFL) thickness differences between the genders. Material and methods : In this prospective case-control cross-sectional study 111 healthy subjects and 130 primary open-angle glaucoma (OAG) patients were examined with optical coherence tomography angiography (OCT-A (RS-3000 Advance (Nidek, Gamagori, Japan))). The vessel density in the peripapillary and macular area as well as the RNFL thickness was evaluated. Results : Men appeared to have less RNFL thickness compared with women in early glaucomatous group, being significant at the whole circumpapillary retinal nerve fiber layer (cpRNFL) thickness and inferior and nasal quadrants : (cpRNFL) (71.01 ± 9.32 vs 77.64 ± 9.95 μm; P = .001), superior quadrant (89.10 ± 16.63 vs 92.97 ± 17.53 μm; P = .284) , inferior quadrant (83.03 ± 19.17 vs 95.07 ± 21.70 μm; P = .006 ), temporal quadrant (57.11 ± 10.36 vs 61.78 ± 11.37 μm; P = .043 ), nasal quadrant (54.81 ± 11.42 vs 60.73 ± 11.62 μm; P = .016 ). Circumpapillary (wcpVD) and macular (wmVD) vessel density values were lower in men than women in the early stage OAG group, being wmVD significantly lower : wcpVD (15.53 ± 2.45% vs 16.81 ± 3.17%, P = .032 ) and wmVD values (12.51 ± 2.21 vs 13.63 ± 2.28%, P = .019 ), but not in the moderate OAG group (wcpVD 14.46 ± 2.20% vs 16.61 ± 3.10%, P = .056 and wmVD 12.61 ± 2.40% vs 12.74 ± 2.54%, P = .870). There were no significant differences between men and women for RNFL thickness and the vessel density parameters in normal group. Conclusion : Both, the thickness of the nerve fiber layer and peripapillary and macular vessel density are lower in men than in women with glaucoma, more markedly in early stage glaucomatous patients.

Background: Adhesion formation is a major problem when a mesh is exposed to intraabodminal viscera, with potential severe complications (bowel occlusion, fistulas or abscesses). New methods for preventing adhesions from a polypropylene mesh placed intra-abdominally or to solve difficult situations, such as when the peritoneum cannot be closed during a TAPP repair for an inguinal hernia, are still being seeked. This study mimics in an animal model a situation that can be found in clinical practice during laparoscopic inguinal hernioplasty. A polypropylene mesh could be exposed to the intra-abdominal cavity even when the peritoneum is closed due to different circumstances, with no options to guarantee the prosthetic material of being exposed to the intrabdominal viscera. Different options have been suggested to solve these situations, being proposed in this study to cover the visceral surface of the mesh with an absorbable sponge containing thrombin, fibrinogen, and clotting factors (Tachosil ® , Nycomed, Takeda, Osaka, Japan), to assess its use as a barrier to prevent postoperative adhesion formation., Material and Methods: Thirty Wistar white rats (300-450 mg) were included in this study as experimental animals, being randomized into three groups (A, B, and C). We performed a bilateral prosthetic repair with conventional polypropylene mesh (2 × 2 cm, 82 kD). Prosthesis fixation was performed as follows. Group A: absorbable suture; group B: metal staples; group C: metal tackers. A piece of insulating absorbable sponge (Tachosil ® 5 × 5 cm) was placed to cover the visceral surface of mesh placed at the right side of each animal. After 10 days, we performed a gross examination (by laparoscopy and laparotomy), measuring the quantity and the quality of the adhesions. Samples were taken for histopathological analysis., Results: Tachosil ® -treated prostheses showed a statistically significant decrease in the quality of the adhesion found (p < 0.05). In addition, a smaller quantity of adhesions was identified in barrier-treated animals, although this lacked statistical significance. The histologic analysis showed no significant differences: more edema with the untreated mesh and increased angiogenesis and a lower degree of necrosis in mesh covered with Tachosil ® ., Conclusions: The use of Tachosil ® as a barrier material led to the absence of strong adhesions as it prevented direct contact between the mesh and the internal organs, preventing major problems associated with strong adhesions.

Objectives: To determine the association between sociodemographic and reproductive factors with unwanted additional fertility (UAF) in Peru., Materials and Methods: We carried out an observational, cross-sectional analytical study based on the 2018 Demographic and Family Health Survey (DHS) in Peru. The UAF variable was defined as the numerical difference between the general fertility rate and the total fertility rate. This variable was divided into 2 categories, UAF was considered when the numerical difference was positive. The Poisson regression was used, both crude and adjusted., Results: We analyzed data from 6,944 women with an average age of 44.3 years (range, 40 to 49). The prevalence of UAF was found to be 72.5% (95% CI: 70.4%-74.4%). In the adjusted model, patients in the top wealth quintile (aPR 0.80; 95% CI: 0.69-0.93) were found to have a lower probability of having unwanted pregnancies when compared to those in the middle quintile. On the other hand, patients from rural areas (aPR 1.07; 95% CI: 1.01-1.14) had a higher probability of having unwanted pregnancies when compared to those from urban áreas., Conclusions: The prevalence of UAF in Peruvian women between 40 and 49 years old who participated in the 2018 DHS is high. Patients from rural areas have a higher probability of having unwanted pregnancies, and those in the top wealth quintile have a lower probability.

Background: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma., Methods: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing., Findings: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation., Interpretation: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting., Funding: Celgene Corporation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Interstitial lung disease (ILD) results in high morbidity and health-care utilization. Diagnostic delays remain common and often occur in nonpulmonology settings. Screening for ILD in these settings has the potential to reduce diagnostic delays and improve patient outcomes., Research Question: This study sought to determine whether a pulmonary function test (PFT)-derived diagnostic prediction tool (ILD-Screen) could accurately identify incident ILD cases in patients undergoing PFT in nonpulmonology settings., Study Design and Methods: Clinical and physiologic PFT variables predictive of ILD were identified by using iterative multivariable logistic regression models. ILD status was determined by using a multi-reader approach. An ILD-Screen score was generated by using final regression model coefficients, with a score ≥ 8 considered positive. ILD-Screen test performance was validated in an independent external cohort and applied prospectively to PFTs over 1 year to identify incident ILD cases at our institution., Results: Variables comprising the ILD-Screen were age, height, total lung capacity, FEV 1 , diffusion capacity, and PFT indication. The ILD-Screen showed consistent test performance across cohorts, with a sensitivity of 0.79 and a specificity of 0.83 when applied prospectively. A positive ILD-Screen strongly predicted ILD (OR, 18.6; 95% CI, 9.4-36.9) and outperformed common ILD clinical features, including cough, dyspnea, lung crackles, and restrictive lung physiology. Prospective ILD-Screen application resulted in a higher proportion of patients undergoing chest CT imaging compared with a historical control cohort (74% vs 56%, respectively; P = .003), with a significantly shorter median time to chest CT imaging (5.6 vs 21.1 months; P < .001)., Interpretation: The ILD-Screen showed good test performance in predicting ILD across diverse geographic settings and when applied prospectively. Systematic ILD-Screen application has the potential to reduce diagnostic delays and facilitate earlier intervention in patients with ILD., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

Background: The current study evaluated the metalloproteinases MMP-2 and MMP-9 expression in epithelial cells and the surrounding stroma in ovarian tumors and the association of MMPs with the histological subtypes, the clinical stage and the presence of steroid hormone receptors. Tumor samples were obtained from 88 patients undergoing surgical cytoreduction of primary ovarian tumors in Instituto Nacional de Cancerología, from México City. The formalin fixed and paraffin embedded samples were processed in order to demonstrate the presence of androgen receptor,estrogen receptor alpha, progesterone receptor, MMP-2,MMP-9 and collagen IV by immunohistochemistry and/or immunofluorescence., Results: MMP-2 and MMP-9 were differentially expressed in the epithelium and the stroma of ovarian tumors associated to histological subtype, clinical stage and sexual steroid hormone receptor expression. Based on Cox proportional hazard regression model we demonstrated that MMP-2 located in the epithelium and the stroma are independent prognostic biomarkers for overall survival in epithelial ovarian tumors. Kaplan Meir analysis of the combination of AR (+) with MMP-2 (+) in epithelium and AR (+) with MMP-2 (-) in stroma displayed a significant reduction of survival., Conclusions: The presence of MMP-2 in the stroma of the tumor was a protective factor while the presence of MMP-2 in the epithelium indicated an adverse prognosis. The presence of AR associated with MMP-2 in the tumor cells was a risk factor for overall survival in epithelial ovarian cancer.

Chromosomal double strand breaks (DSBs) can initiate several signaling events, such as ubiquitination, however the precise influence of such signaling on DSB repair outcomes remains poorly understood. With an RNA interference screen, we found that the E3 ubiquitin ligase RNF8 suppresses a deletion rearrangement mediated by canonical non-homologous end joining (C-NHEJ). We also found that RNF8 suppresses EJ without insertion/deletion mutations, which is a hallmark of C-NHEJ. Conversely, RNF8 promotes alternative EJ (ALT-EJ) events involving microhomology that is embedded from the edge of the DSB. These ALT-EJ events likely require limited end resection, whereas RNF8 is not required for single-strand annealing repair involving extensive end resection. Thus, RNF8 appears to specifically facilitate repair events requiring limited end resection, which we find is dependent on the DSB end protection factor KU. However, we also find that RNF8 is important for homology-directed repair (HDR) independently of KU, which appears linked to promoting PALB2 function. Finally, the influence of RNF8 on EJ is distinct from 53BP1 and the ALT-EJ factor, POLQ. We suggest that RNF8 mediates both ALT-EJ and HDR, but via distinct mechanisms, since only the former is dependent on KU., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A strategy to obtain biocatalysts formed by three enzyme layers has been designed using lipases A and B from Candida antarctica (CALA and CALB), the lipases from Rhizomucor miehei (RML) and Thermomyces lanuginosus (TLL), and the artificial chimeric phospholipase Lecitase Ultra (LEU). The enzymes were initially immobilized via interfacial activation on octyl-agarose beads, treated with polyethylenimine (PEI) and a new enzyme layer was immobilized on the octyl-enzyme-PEI composite by ion exchange, producing octyl-enzyme-PEI-enzyme biocatalysts. Except when using LEU, when the two-layer biocatalysts, a large percentage of the PEI-immobilized enzyme was released when a new batch of PEI was added. This was prevented by glutaraldehyde crosslinking. The enzyme modifications produced more active preparations in some cases while in other cases, the effect of the modifications was negative for enzyme activity. These effects of the enzymes modifications were also different when the enzyme was immobilized by interfacial activation or by ion exchange. In all cases, the 3-layer biocatalysts were more active than the single- or bi-layer biocatalysts with some of the assayed substrates. However, as the substrate diffusion problems increased when new enzyme layers were added, even a decrease in enzyme activity with some substrates was found after increasing the number of enzyme layers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per-allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56-0.86; P = 0.0008] and to a lesser extent in BRCA1 carriers (per-allele HR = 0.78, 95% CI 0.64-0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double-strand breaks (DSBs) by single-strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52 -/- mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52 S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wild-type; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008) and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52-dependent DSB repair are linked to reduced tumor risk in BRCA2-mutation carriers., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Epithelial ovarian cancer (EOC) is a heterogeneous disease that can be categorized into four major histological subtypes. Its etiology remains poorly understood due mainly to this heterogeneity. Follicle-stimulating hormone (FSH) has been implicated as a risk factor in EOC and has been suggested that may influence the development of specific subtypes. In addition, FSH regulates different aspects of ovarian cancer tumorigenesis. FSH downstream target genes in EOC have not been fully identified. Progranulin (PGRN) overexpression is associated with cell proliferation, invasion, chemoresistance, and shortened overall survival in ovarian cancer. Recently, we demonstrated that PGRN expression is regulated through the PI3K signaling pathway in clear cell ovarian carcinoma (CCOC) cells. In contrast, we also demonstrated that PGRN synthesis in serous ovarian cancer (SOC) cells is regulated via PKC but not by the PI3K signaling pathway. Several studies have demonstrated that FSH induces PKC and PI3K activation. Thus, this study was to investigate the effect of FSH on PGRN production in the CCOC cell line TOV-21G as compared to the SOC cell lines SKOV3 and OVCAR3. Cultured TOV-21G, SKOV3, and OVCAR3 cells were incubated with different concentrations of FSH for 48 h. PGRN mRNA and protein expression were assessed by RT-PCR and Western blotting, while PGRN secretion was measured by ELISA. PGRN mRNA and protein expression, as well as PGRN secretion, significantly increased after FSH stimulation in TOV-21G but not in SKOV3 and OVCAR3 cells. These data indicate that FSH induces PGRN expression and secretion only in CCOC cells. Establishing specific features for CCOC could reveal potential diagnostic and therapeutic targets.

Background: Pediatric kidney transplantation (PKTx) is the preferred therapy for children with end-stage renal disease (ESRD) worldwide. Regrettably, in Perú, access to PKTx is extremely difficult due to recipient/donor socio-economic status, health care structure and especially, scarcity of organs. Our center (the only pediatric institute in the country) has recently started a PKTx program with good midterm results. The aim of this study was to present our outcomes., Methods: Retrospective analysis of prospectively collected data between December 2017 and August 2019. Fourteen PKTx (< 18 years old) were achieved. As per our protocol: pre-implantation/protocol biopsies, antibody assessment (T/B cell flow cytometric plus HLA testing applying polymerase chain reaction-based technology), triple immunosuppression (tacrolimus, mycophenolate mofetil, steroids) and induction therapy was performed in every case., Results: The recipient's mean age at the time of PKTx was 14.14 ± 2.62, 8/14 (57.14%) were male, 50% developed ESRD due to undetermined etiology, 11/14 (78.57%) received a deceased donor allograft, and 9/14 (64.28%) required induction with thymoglobulin. Postoperative complications included: delayed graft function (1/14, 7.14%), 1 (7.14%) developed gross hematuria associated with allograft disfunction post-protocol allograft biopsy that was managed conservatively and 1 recipient (7.14%) developed grade II oligoastrocytoma, at 10 months post PKTx., Conclusions: PKTx is the best therapeutic option for children with ESRD. Our group demonstrated that even in countries with limited resources like Perú, good midterm results can be achieved. Emphasis should be given to improve access to transplantation especially in the setting of pediatric recipients., (Copyright © 2020 Elsevier Inc. All rights reserved.)