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Background To track improvement in diplopia symptoms with strabismus-specific health-related quality of life (HRQOL) questionnaire across a treatment consisting of prism correction followed by vision therapy/orthoptics when prism treatment alone has not succeeded. Methods Forty-eight participants with diplopia and a mean age of 62.45 were asked to complete an Adult Strabismus-20 (AS-20) questionnaire and a Diplopia Questionnaire (DQ) before and after prism correction. Inclusion criteria were diplopia reported on the DQ as “sometimes”, “often” or “always” at reading or straight-ahead distance. The prism correction was classified as successful if the participant reported “never” or “rarely” on the DQ for reading and straight-ahead distance; and unsuccessful if the perceived diplopia worsened or remained the same. For all participants, mean initial AS-20 scores were compared with mean post-prism correction scores, taking into account AS-20 subscales (reading and general functions, and self-perception and interaction). Participants in the failed prism treatment subgroup subsequently underwent a programme of vision therapy wearing their prism correction, the results of which were again determined by participants’ responses on the AS-20 questionnaire, completed before and after the vision therapy. Results Five of the 48 participants dropped out of the study. Prism correction was classified as successful in 22 of 43 participants (51%), and unsuccessful in 21 (49%). Those participants for whom the prism correction was classified as a success showed a statistically significant improvement (p = 0.01) in both reading and general functions. In the failed treatment subgroup, no significant change in AS-20 score was recorded for any of the domains (p = 0.1). After treatment with vision therapy/orthoptics, however, 13 of the 20 participants in the unsuccessful prism correction subgroup (one of them dropped out the study) achieved binocular vision and statistically significant improvement in reading and general functions (p = 0.01). Conclusions Although effective prism correction of diplopia is correlated with enhanced HRQOL, prism correction alone is frequently not sufficient to achieve this objective. In these cases, vision therapy/orthoptics treatment as a coadjutant to prism correction is shown to improve HRQOL.

Abstract Background Uveal melanoma metastasizes to the liver. We aimed to explore the metabolic activity of liver metastases (LM) as a biomarker for survival. Methods We analyzed newly diagnosed patients with metastatic UM (MUM) with LM detected by liver‐directed imaging and had undergone a PET/CT at diagnosis. Findings 51 patients were identified between 2004 and 2019. Median age was 62 years, 41% male and 22% ECOG ≥1. LDH, ALP, and GGT were elevated in 49%, 37%, and 57% of patients. Median LM SUVmax was 8.5 (3–42.2). Same size lesions presented a wide range of metabolic activity. Median OS was 17.3 m (95% CI:10.6–23.9). Patients with SUVmax ≥8.5 had an OS of 9.4 m (95% CI:6.4–12.3), whereas patients with SUVmax

Abstract. Objective. The aim of the study is to evaluate clinical features and outcomes after different therapeutic strategies for ductal prostate adenocarcinoma (DPC), a rare but aggressive subtype of invasive prostate cancer (PCa) accounting for, in the pure and mixed form, 1% or less and 5% or less, respectively, of all the newly diagnosed PCa. Materials and methods. Patients with a proven diagnosis of DPC undergoing surgery, radiotherapy, and androgen deprivation therapy, alone or in combination, were considered for this multicenter, retrospective study. The study assessed overall survival (OS), disease-free survival (DFS), and age-related disease-specific survival. Results. Eighty-one patients met the study inclusion criteria. Pure DPC was found in 29 patients (36%) and mixed ductal-acinar-PCa in 52 patients (64%). After a median follow-up of 63 months (range, 3–206 months), 3- and 5-year OS rates were 84% and 67%, respectively, and 3- and 5-year DFS rates were 54% and 34%, respectively. There were no significant differences in OS or DFS between the pure and mixed DPC groups. Pure DPC was associated with a higher rate of metastatic disease at onset. Patients 74 years or younger had better disease-specific survival (p=0.0019). A subgroup analysis favored radiotherapy as the primary treatment for nonmetastatic, organ-confined DPC (3- and 5-year DFS of 80% and 50%, respectively, compared with 5-year DFS of 35% for surgical patients; p = 0.023). Conclusions. Our study found DPC to be rarer, more aggressive, more likely to metastasize, and have a worse prognosis than the common acinar variant, especially in its pure form. Multicenter series are encouraged to obtain large data sets, or propensity score matching analyses with patients with conventional PCa are desirable to understand the best therapeutic approach and improve outcomes.

Alzheimer’s disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aβ deposits in retinal layers. Since brain Aβ transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aβ deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aβ, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.

Abstract Background An environment of gestational diabetes mellitus (GDM) can modify the phenotype of stem cell populations differentially according to their placental localization, which can be useful to study the consequences for the fetus. We sought to explore the effect of intrauterine GDM exposure on the angiogenic properties of human amniotic membrane stem cells (hAMSCs). Methods We comprehensively characterized the angiogenic phenotype of hAMSCs isolated from 14 patients with GDM and 14 controls with normal glucose tolerance (NGT). Maternal and fetal parameters were also recorded. Hyperglycemia, hyperinsulinemia and palmitic acid were used to in vitro mimic a GDM-like pathology. Pharmacological and genetic inhibition of protein function was used to investigate the molecular pathways underlying the angiogenic properties of hAMSCs isolated from women with GDM. Results Capillary tube formation assays revealed that GDM-hAMSCs produced a significantly higher number of nodes (P = 0.004), junctions (P = 0.002) and meshes (P

Tisagenlecleucel is associated with remarkable outcomes in treating patients up to the age of 25 years with refractory B-cell acute lymphoblastic leukemia (ALL). Yet, due to unique and potentially life-threatening complications, access remains limited to higher-resource and certified centers. Reports of inequity and related disparities in care are emerging. In this multicenter study of ALL patients admitted for anti-leukemia therapy, who required pediatric intensive care (ICU) support (n = 205), patients receiving tisagenlecleucel (n = 39) were compared to those receiving conventional chemotherapy (n = 166). The median time to ICU transfer was 6 (0–43) versus 1 (0–116) days, respectively (p < 0.0001). There was no difference in the use of vasopressor, ionotropic, sedating, and/or paralytic agents between groups, but use of dexamethasone was higher among tisagenlecleucel patients. Patients receiving tisagenlecleucel were more likely to have cardiorespiratory toxicity (p = 0.0002), but there were no differences in diagnostic interventions between both groups and/or differences in ICU length of stay and/or overall hospital survival. Toxicities associated with tisagenlecleucel are generally reversible, and our findings suggest that resource utilization once admitted to the ICU may be similar among patients with ALL receiving tisagenlecleucel versus conventional chemotherapy. As centers consider improved access to care and the feasibility of tisagenlecleucel certification, our study may inform strategic planning.

Abstract Background Non-convulsive status epilepticus (NCSE) is present in 10–30% of ICU patients with altered mental status (AMS) and is associated to poor outcomes. To our knowledge, there is no data describing the prevalence and outcomes of critically ill cancer patients with AMS associated to non-convulsive seizures (NCS) or NCSE. We aim to describe the outcomes and risk factors of critically ill cancer patients with encephalopathy associated with non-convulsive seizures (NCS). Methods This is a 3-year prospective observational study in a mixed oncological ICU at MD Anderson Cancer Center. Data of ICU patients with moderate to severe encephalopathy (Glasgow Coma Score < 13) that underwent EEG monitoring to rule out NCS were collected. Multivariate logistic regression was performed to identify risk factors and outcomes. Results Of the 317 patients with encephalopathy who underwent EEG monitoring, 14.5% had NCS. Known risk factors such as sepsis, CNS infection, antibiotics, and cardiac arrest were not associated with increased risk of NCS. Patients with NCS were more likely to have received recent chemotherapy (41.3% vs 21.4%; p = 0.0036), have a CNS disease (39% vs 24.4%; p = 0.035), and abnormal brain imaging (60.9% vs 44.6%; p = 0.041). Patients with lower SOFA scores, normal renal function, and absence of shock were likely to have NCS as the cause of their encephalopathy (p < 0.03). After multivariate analysis, only abnormal brain imaging and absence of renal failure were associated with NCS. Mortality was significantly lower in patients with non-convulsive seizures when compared to those without seizures (45.7% vs 64%; p = 0.022); however, there was no significant association of seizures and mortality on a multivariable logistic regression analysis. Conclusions NCS in critically ill cancer patients is associated with abnormalities on brain imaging and lower prevalence of organ failure. Diagnosis and treatment of NCS should be a priority in encephalopathic cancer patients, as they can have lower mortality than non-seizing patients. Opposite to other populations, NCS should not be considered a poor prognostic factor in critically ill encephalopathic cancer patients as they reflect a reversible cause for altered mentation.

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large B-cell lymphoma treated with SOC axi-cel or tisa-cel. Among the 165 patients evaluated, 27 (16%) developed at least one 30-day (30-d) major adverse CV event (MACE). Cumulatively, these patients experienced 21 arrhythmias, four exacerbations of heart failure/cardiomyopathy, four cerebrovascular accidents, three myocardial infarctions, and one patient died due to myocardial infaction. Factors significantly associated with an increased risk of 30-d MACE included age ≥60 years, an earlier start of cytokine release syndrome (CRS), CRS ≥ grade 3, long duration of CRS, and use of tocilizumab. After a median follow-up time of 16.2 months (range, 14.3-19.1), the occurrence of 30-d MACE was not significantly associated with progression-free survival or with overall survival. Our results suggest that the occurrence of 30-d MACE is more frequent among patients who are elderly, with early, severe, and prolonged CRS. However, with limited follow-up, larger prospective studies are needed, and multidisciplinary management of these patients is recommended.

It is clear that the corrosion resistance of carbon steels decreases as cold working amount increases, but for austenitic stainless steels, the relation between cold-working and corrosion performance is not clear. The electrochemical behavior of AISI 304 stainless steel with 3 different cold working amounts is characterized by Mott–Schottky analysis, OCP records, EIS and cyclic polarization curves. An innovative cell with gel electrolyte is used for an easy study of the deformed surfaces without modifying them. After the polarization tests, the influence of the deformation on the amount of pits and on their morphological characteristics is also analyzed. The microstructural changes caused by cold rolling are studied, and the residual stresses are determined by XRD using the sin2 ψ method. It is proved that AISI 304 stainless steel decreases its pitting resistance in a medium with chlorides when it is subjected to moderate cold rolling, but heavy thickness reduction causes a subsequent recovery of corrosion resistance. The results obtained suggest that this trend is related to changes in the magnitude and type of the stresses (tensile or compressive) on the surface of the material. Keywords: Austenitic stainless steel, Cold working, Pitting, Corrosion, Stress, Martensite

Introduction Medical students frequently report lack of confidence and skill in managing ill pediatric patients. We aimed to implement targeted learning interventions to address these knowledge gaps, specifically focusing on pediatric sepsis. Our objective was to create a curriculum to advance knowledge and confidence in identifying and managing pediatric sepsis. Methods We designed this curriculum to augment medical student pediatric ICU (PICU) and neonatal ICU (NICU) rotations. We first emailed students a pretest and upon completion, we emailed students a series of brief educational videos. Students then participated in a simulation experience designed to assess their ability to diagnose and manage severe sepsis. We provided immediate debriefing after each session. Upon completion of the simulation experience, we emailed students a posttest (identical to the pretest). The pre-/posttest included multiple-choice questions to assess the students’ ability to recognize and manage pediatric sepsis and septic shock, as well as Likert-scale questions assessing confidence levels in diagnosis and management of pediatric sepsis. We performed paired Student t tests comparing knowledge-based question scores and Likert-scale results. Results Of students, 40 enrolled in and 30 completed the curriculum between 2015 and 2020. When comparing pre- and posttest results, we found a significant improvement in knowledge scores (33% mean increase, 95% CI [22%-45%], p < .001) and confidence levels (mean increase in Likert scale score of 1.5, 95% CI [1.2-1.7], p < .001). Discussion Results suggested that the curriculum advanced students’ knowledge scores and improved self-reported confidence in managing theoretical pediatric patients with sepsis.

Pediatric, adolescent and young adult (AYA) patients receiving novel cancer immunotherapies may develop associated toxicities with overlapping signs and symptoms that are not always easily distinguished from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/clinical sequelae. We describe 2 diagnostically challenging cases of SARS-CoV-2 and Multi-Inflammatory Syndrome-Adult (MIS-A), in patients with a history of acute lymphoblastic leukemia following cellular therapy administration and review evolving characterization of both the natural course of SARS-CoV-2 infection and toxicities experienced in younger cancer immunotherapy patients. Vigilant monitoring for unique presentations and epidemiologic surveillance to promptly detect changes in incidence of either condition may be warranted.

No abstract available.

Numerous studies have shown evidence supporting the benefits of universal newborn screening for primary immunodeficiencies (PID) and for Spinal Muscular Atrophy (SMA). We have developed a four-plex, real-time PCR assay to screen for Severe Combined Immune Deficiencies (SCID), X-linked agammaglobulinemia (XLA), and SMA in DNA extracted from a single 3.2 mm punch of a dried blood spot (DBS). A simple, high-throughput, semi-automated DNA extraction method was developed for a Janus liquid handler that can process 384 DBS punches in four 96-well plates in just over one hour with sample tracking capability. The PCR assay identifies the absence of exon 7 in the SMN1 gene, while simultaneously evaluating the copy number of T-cell receptor excision circles (TREC) and Kappa-deleting recombination excision circles (KREC) molecules. Additionally, the amplification of a reference gene, RPP30, was included in the assay as a quality/quantity indicator of DNA isolated from the DBS. The assay performance was demonstrated on over 3000 DNA samples isolated from punches of putative normal newborn DBS. The reliability and analytical accuracy were further evaluated using DBS controls, and contrived and confirmed positive samples. The results from this study demonstrate the potential of future molecular DBS assays, and highlight how a multiplex assay could benefit newborn screening programs.

We describe a case of a systemic-to-pulmonary venous shunt secondary to superior vena cava obstruction in a patient with newly diagnosed non-Hodgkin lymphoma. This rare condition manifested with symptoms of dyspnea and hypoxemia that were out of proportion to the pleural effusion diagnosed on chest imaging. Standard treatment of such rare collateral plexuses is observation. However, it is important for clinicians to be cognizant that in rare cases such plexuses can lead to right-to-left shunt complications such as embolism.

An in-house, low-cost method was developed to determine the genotypic resistance of immunodeficiency virus type 1 (HIV-1) isolates. All 179 Venezuelan isolates analysed belonged to subtype B. Primary drug resistance mutations were found in 11% of 63 treatment-naïve patients. The prevalence of resistance in isolates from 116 HIV-positive patients under antiretroviral treatment was 47% to protease inhibitors, 65% to nucleoside inhibitors and 38% to non-nucleoside inhibitors, respectively. Around 50% of patients in the study harboured viruses with highly reduced susceptibility to the three classical types of drugs after only five years from their initial diagnoses.

Expanding tuberculosis (TB)-diagnostic services, including access to rapid tests, is a World Health Organization (WHO) strategy to accelerate progress toward ending TB. Faster and more sensitive molecular tests capable of diagnosing TB and drug-resistant TB have the technical capacity to address limitations associated with smears and cultures by increasing accuracy and shortening turnaround times as compared with those of these conventional laboratory methods. Nucleic acid amplification assays used to detect and analyze Mycobacterium tuberculosis (MTB)-complex nucleic acids can be used directly on specimens from patients suspected of having TB. Recently, several commercial molecular tests were developed to detect MTB and determine the drug resistance (DR) based on detection of specific genetic mutations conferring resistance. The first to be endorsed by the WHO was molecular line-probe assay technology. This test uses polymerase chain reaction (PCR) and reverse-hybridization methods to rapidly identify MTB and DR-related mutations simultaneously. More recently, the WHO endorsed Xpert MTB/RIF, Cepheid Inc, CA, USA, a fully automated assay used for TB diagnosis that relies upon PCR techniques for detection of TB and rifampicin resistance-related mutations. Other promising molecular TB assays for simplifying PCR-based testing protocols and increasing their accuracy are under development and evaluation. Although we lack a practical gold standard for the diagnosis of childhood TB, its bacteriological confirmation is always recommended to be sought whenever possible prior to a diagnostic decision being made. Conventional diagnostic laboratory TB tests are less efficient for children as compared with adults, because sufficient sputum samples are more difficult to collect from infants and young children, and their disease is often paucibacillary, resulting in smear-negative disease. These inherent challenges associated with childhood TB are due to immunological- and pathophysiological-response differences relative to those observed in adults. Several recent meta-analyses showed low sensitivity estimates of PCR-based TB assays for paucibacillary forms of TB (extrapulmonary TB and smear-negative pulmonary disease), which represent the vast majority of childhood TB cases. Despite the lack of evidence regarding use of the rapid molecular assays to identify TB and detect DR in children, and due to the clinical nature of childhood TB, TB-expert groups recommend including rapid methods for TB identification and DR detection in diagnostic algorithms for children suspected of both smear-positive and -negative pulmonary or extrapulmonary TB, both with or without human immunodeficiency virus (HIV)-coinfection, when combined with standard methods (including clinical, microbiological, and radiological assessment) for diagnosing active TB and conventional DR. Since 2011, the WHO has specifically recommended use of the Xpert MTB/RIF test as an initial diagnostic tool for children with suspected HIV-associated TB or multidrug-resistant TB based on successful treatment data related to adults. Implementation of the rapid molecular assays for rapid detection of TB and DR should occur in laboratories with proven capability to run molecular tests and where quality control systems are implemented. Molecular approaches should be more largely tested in children, given their status as the group in whom the diagnostic dilemma is most pronounced. These tests should also be included in specific childhood TB diagnostic algorithms adapted to the local/national context in combination with other strategies for improving diagnostics, including more effective specimen collection.

Cells generate energy by coupling a proton gradient across a phospholipid bilayer membrane with the activity of a cross-membrane ATP synthase enzyme. [...]

Here for the first time, we detail self-contained (wireless and self-powered) biodevices with wireless signal transmission. Specifically, we demonstrate the operation of self-sustained carbohydrate and oxygen sensitive biodevices, consisting of a wireless electronic unit, radio transmitter and separate sensing bioelectrodes, supplied with electrical energy from a combined multi-enzyme fuel cell generating sufficient current at required voltage to power the electronics. A carbohydrate/oxygen enzymatic fuel cell was assembled by comparing the performance of a range of different bioelectrodes followed by selection of the most suitable, stable combination. Carbohydrates (viz. lactose for the demonstration) and oxygen were also chosen as bioanalytes, being important biomarkers, to demonstrate the operation of the self-contained biosensing device, employing enzyme-modified bioelectrodes to enable the actual sensing. A wireless electronic unit, consisting of a micropotentiostat, an energy harvesting module (voltage amplifier together with a capacitor), and a radio microchip, were designed to enable the biofuel cell to be used as a power supply for managing the sensing devices and for wireless data transmission. The electronic system used required current and voltages greater than 44 µA and 0.57 V, respectively to operate; which the biofuel cell was capable of providing, when placed in a carbohydrate and oxygen containing buffer. In addition, a USB based receiver and computer software were employed for proof-of concept tests of the developed biodevices. Operation of bench-top prototypes was demonstrated in buffers containing different concentrations of the analytes, showcasing that the variation in response of both carbohydrate and oxygen biosensors could be monitored wirelessly in real-time as analyte concentrations in buffers were changed, using only an enzymatic fuel cell as a power supply.

Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24-26, 27-29, and 30-33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24-26, 27-29, and 30-33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis. Please see later in the article for the Editors' Summary.