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Allison F O’Neill,1 Raul C Ribeiro,2 Emilia M Pinto,3 Michael R Clay,4 Gerard P Zambetti,3 Brent A Orr,3 Christopher B Weldon,5 Carlos Rodriguez-Galindo2,6 1Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA; 2Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA; 3Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA; 4Department of Pathology, Children’s Hospital Colorado, Denver, CO, USA; 5Department of Surgery, Boston Children’s Hospital, Boston, MA, USA; 6Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USACorrespondence: Allison F O’Neill, Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue – DA3111, Boston, MA, 02215, USA, Email Allison_oneill@dfci.harvard.eduAbstract: Adrenocortical tumors (ACTs) are infrequent neoplasms in children and adolescents and are typically associated with clinical symptoms reflective of androgen overproduction. Pediatric ACTs typically occur in the context of a germline TP53 mutation, can be cured when diagnosed at an early stage, but are difficult to treat when advanced or associated with concurrent TP53 and ATRX alterations. Recent work has demonstrated DNA methylation patterns suggestive of prognostic significance. While current treatment standards rely heavily upon surgical resection, chemotherapy, and hormonal modulation, small cohort studies suggest promise for multi-tyrosine kinases targeting anti-angiogenic pathways or immunomodulatory therapies. Future work will focus on novel risk stratification algorithms and combination therapies intended to mitigate toxicity for patients with perceived low-risk disease while intensifying therapy or accelerating discoveries aimed at improving survival for patients with difficult-to-treat disease.Keywords: adrenocortical, pediatric, management, discovery, carcinoma, tumors

John D Rodriguez,1,2 Samantha Kerti,3 Adam Hamm,3 George W Ousler,1 Ethan Bensinger,1,2 Sadie Burnham,1,2 Mark B Abelson1,2,4,5 1Ora, Inc, Andover, MA, USA; 2Andover Eye Institute, Andover, MA, USA; 3Statistics and Data Corporation, Tempe, AZ, USA; 4Ophthalmology, Harvard Medical School, Cambridge, MA, USA; 5Mass Eye and Ear, Boston, MA, USACorrespondence: John D Rodriguez, Email jrodriguez@oraclinical.comPurpose: The absence of a standardized diagnostic method for clinical signs of Dry Eye Disease (DED) complicates clinical trials for future treatments. This paper evaluated Lissamine Green (LG) conjunctival staining as a valid, stable and modifiable endpoint for both clinical practice and clinical trials.Methods: Screening and pre-randomization data from two identically designed clinical trials for DED resulted in a pooled dataset of 494 subjects. Inclusion was based on reported symptoms, lissamine green (LG) conjunctival staining, Fluorescein (Fl) corneal and conjunctival staining, and Schirmer’s Test (ST). Outcome measures were assessed based on the modifiability of LG staining to exposure to a Controlled Adverse Environment (CAE®), correlation of LG to Fl staining, relative variation of LG staining scores and Schirmer test scores, and the correlation of LG staining with symptom scores.Results: The modifiability of LG conjunctival staining to environmental exposure was demonstrated, with nasal LG and FL staining displaying the most similar percent change. Nasal LG conjunctival staining scores for subjects with ST scores of less than 8mm were significantly higher than for subjects with ST greater than 8mm. LG staining scores were more consistent (25% change from baseline threshold) than ST scores. Finally, statistically significant correlations were found between LG staining and a number of symptom scores.Conclusion: This evaluation demonstrates the superiority of the utilization of a clinical endpoint focused on ocular surface damage. The reproducibility and modifiability of LG conjunctival staining to controlled adverse environment, coupled with its significant correlation with symptoms, positions it as an exemplary clinical sign endpoint for clinical management and in clinical trials. Our findings advocate for the adoption of LG conjunctival staining as a primary endpoint in both clinical research and drug development, offering a more effective means of identifying and addressing ocular surface damage in the realm of DED.Keywords: dry eye, conjunctiva, stain, lissamine green clinical trials, controlled adverse environment, disease models, drug screening, dry eye disease, efficacy endpoints

Daniel J Moore,1 Natasha I Leibel,2 William Polonsky,3 Henry Rodriguez4 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; 2Department of Pediatrics, Columbia University, New York, NY, USA; 3Behavioral Diabetes Institute, San Diego, CA, USA; 4USF Diabetes and Endocrinology Center, Morsani College of Medicine, University of South Florida, Tampa, FL, USACorrespondence: Henry Rodriguez, USF Diabetes and Endocrinology Center, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs. Blvd. MDC 62, Tampa, FL, 3612, USA, Tel +1 813-821-8011, Fax +1 813-974-3313, Email hrodrig1@usf.eduAbstract: Type 1 diabetes (T1D) is a complex, chronic autoimmune disease that affects over 1.6 million people in the United States. It is now understood that T1D may be undetected for many years while the disease progresses quietly without producing symptoms. T1D can be identified through diabetes-related autoantibody screening and staged accordingly, enabling healthcare providers to identify high-risk individuals in the early stages of the disease and either provide a stage-specific intervention or offer clinical trial opportunities to preserve beta cell function and anticipate the onset of clinical T1D. Evidence-based clinical practice guidelines currently do not exist for routine diabetes-related autoantibody screening of individuals at risk of developing T1D or of the general population. The purpose of this article is to help clinicians acquire an understanding of the rationale and protocols recommended for identifying patients at risk of developing T1D and monitoring such patients for autoimmune markers and progression of disease from Stage 1 to Stage 3 (clinical disease).Plain Language Summary: Type 1 diabetes (T1D) is a life-long condition where the body’s immune system (which normally fights infection) mistakenly attacks cells in the pancreas that make insulin. Insulin allows one to use energy from food and controls blood sugar levels. Without early recognition and treatment, high blood sugar can cause serious symptoms and life-threatening complications, such as diabetic ketoacidosis (DKA). DKA happens when there is very low insulin, and if not spotted early, it can cause coma and death. T1D can occur at any age. The chance of getting T1D is higher if another family member has it. T1D progresses silently for months or years before symptoms appear such as increased thirst, frequent urination, and unintentional weight loss. Healthcare providers can now screen and identify people who are at early stages of T1D (without symptoms) with blood tests called autoantibodies. Early detection through screening allows people to 1) learn about the disease before symptoms start and insulin is needed, 2) potentially receive treatments that delay T1D progression, and 3) participate in research trials. By detecting T1D at early stages, people can connect with the right care team and develop the skills needed to manage later stage T1D. Early detection has been shown to prevent hospitalization and life-threatening conditions. Screening for T1D will help people maximize their opportunities to delay T1D onset while preparing for diabetes care. Keywords: Type 1 Diabetes, autoantibodies, screening, immunotherapy

Brandon D Ayres,1 Marc R Bloomenstein,2 Jennifer Loh,3 Thomas Chester,4 Bobby Saenz,5,6 Julio Echegoyen,7 Shane R Kannarr,8 Tomasita C Rodriguez,9 Jaime E Dickerson Jr9,10 1Private Practice, Philadelphia, PA, USA; 2Schwartz Laser Eye Center, Scottsdale, AZ, USA; 3Loh Ophthalmology Associates, Miami, FL, USA; 4Cleveland Eye Clinic, Brecksville, OH, USA; 5Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX, USA; 6LASIK San Antonio, Kerrville, TX, USA; 7Gordon Schanzlin New Vision Institute, La Jolla, CA, USA; 8Kannarr Eye Care, Pittsburg, KS, USA; 9Sight Sciences, Menlo Park, CA, USA; 10North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USACorrespondence: Jaime E Dickerson Jr, Email jdickerson@sightsciences.comPurpose: To evaluate dry eye disease (DED) signs and symptoms six months after a single treatment with Localized Heat Therapy (LHT) (TearCare, Sight Sciences) for patients previously treated for six months with cyclosporine (0.05%) ophthalmic emulsion (CsA) BID (Restasis, Allergan).Setting: Nineteen ophthalmic and optometric practices in 11 US states.Design: Multicenter, cross-over, six month extension to the SAHARA randomized, controlled trial (RCT). Included patients were those randomized to CsA in Phase 1 of the SAHARA RCT.Methods: This was the second phase of the SAHARA RCT in which, following the 6-month endpoint, all patients that had been randomized to CsA discontinued CsA and were treated with LHT and subsequently followed for an additional six months. Outcome measures at 12 months for CsA patients crossed over to LHT included TBUT, OSDI and MGSS.Results: One hundred and sixty-one patients (322 eyes) were analyzed. Mean (SD) baseline TBUT prior to CsA was 4.4 (1.2) seconds, 5.6 (2.6) at 6 months which improved to 6.6 (3.2) and 6.1 (2.8) seconds (both P < 0.001) at 9 and 12 months (3, 6 months post LHT). Mean (SD) OSDI was 50.0 (14.9) at baseline and 34.2 (21.5) after CsA. With LHT at 6 months, this improved to 30.0 (20.6) and 31.0 (19.5) at 9 and 12 months (P = 0.162 vs month 6, P < 0.0001 vs baseline). MGSS was 7.1 (3.2) at baseline, 13.3 (8.2) at the end of CsA treatment which improved to 17.4 (8.8) and 16.1 (9.0) at 9 and 12 months; both P < 0.001.Conclusion: SAHARA showed 6-month superiority of LHT to CsA in clinical signs and non-inferiority in symptom scores. This extension shows that patients treated with CsA for 6 months can achieve meaningful additional improvement in signs and symptoms lasting for as long as 6 months following a single LHT treatment without the need for topical prescription therapy.Keywords: dry eye disease, meibomian gland dysfunction, restasis, tearcare, cyclosporine

Inequalities are essential in pure and applied mathematics. In particular, Opial’s inequality and its generalizations have been playing an important role in the study of the existence and uniqueness of initial and boundary value problems. In this work, some new Opial-type inequalities are given and applied to generalized Riemann-Liouville-type integral operators.

Sean Richard Davidson,1 Muhammed Y Idris,2,3 Christopher S Awad,2 Marshaleen Henriques King,1 Gloria E Westney,1 Mario Ponce,1 Anny D Rodriguez,2 Kim L Lipsey,4 Eric L Flenaugh,1 Marilyn G Foreman1,3 1Pulmonary and Critical Care Medicine Division, Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA; 2Clinical Research Center, Morehouse School of Medicine, Atlanta, GA, USA; 3Center of Excellence for the Validation of Digital Health Technologies and Clinical Algorithms, Morehouse School of Medicine, Atlanta, GA, USA; 4Bernard Becker Medical Library, Washington University in St. Louis, St. Louis, MO, USACorrespondence: Marilyn G Foreman, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30310, USA, Tel +1 404 616 4658, Fax +1 404 756 1328, Email mforeman@msm.eduAim: Increasing evidence suggests that the inclusion of self-identified race in clinical decision algorithms may perpetuate longstanding inequities. Until recently, most pulmonary function tests utilized separate reference equations that are race/ethnicity based.Purpose: We assess the magnitude and scope of the available literature on the negative impact of race-based pulmonary function prediction equations on relevant outcomes in African Americans with COPD.Methods: We performed a scoping review utilizing an English language search on PubMed/Medline, Embase, Scopus, and Web of Science in September 2022 and updated it in December 2023. We searched for publications regarding the effect of race-specific vs race-neutral, race-free, or race-reversed lung function testing algorithms on the diagnosis of COPD and COPD-related physiologic and functional measures. Joanna Briggs Institute (JBI) guidelines were utilized for this scoping review. Eligibility criteria: The search was restricted to adults with COPD. We excluded publications on other lung disorders, non-English language publications, or studies that did not include African Americans. The search identified publications. Ultimately, six peer-reviewed publications and four conference abstracts were selected for this review.Results: Removal of race from lung function prediction equations often had opposite effects in African Americans and Whites, specifically regarding the severity of lung function impairment. Symptoms and objective findings were better aligned when race-specific reference values were not used. Race-neutral prediction algorithms uniformly resulted in reclassifying severity in the African Americans studied.Conclusion: The limited literature does not support the use of race-based lung function prediction equations. However, this assertion does not provide guidance for every specific clinical situation. For African Americans with COPD, the use of race-based prediction equations appears to fall short in enhancing diagnostic accuracy, classifying severity of impairment, or predicting subsequent clinical events. We do not have information comparing race-neutral vs race-based algorithms on prediction of progression of COPD. We conclude that the elimination of race-based reference values potentially reduces underestimation of disease severity in African Americans with COPD.Keywords: lung function tests, lung function prediction equations, African Americans

Introduction: Medical residents commonly experience depressive and anxiety symptoms at higher rates compared to the general population. These symptoms have been associated with various sociodemographic risk factors as well as academic and healthcare demands. Objective: To determine the frequency of depressive or anxiety symptoms and associated factors among medical-surgical specialty students. Methods: A cross-sectional study was conducted in 2021, involving residents in medical-surgical specialties at a university in Medellín. Participants provided informed consent to participate. Three instruments were used: a sociodemographic and clinical survey, the Beck Anxiety Inventory, and the Beck Depression Inventory-II. Chi-square or Fisher’s exact tests were used to explore associations, and prevalence ratios (PR) with 95% confidence intervals were estimated. Multivariate analysis using binomial regression was also performed. Results: The study included 80 residents, of whom 57.5% were female. The median age was 28 (27-30 years). 17.5% had a personal history of mental illness, and 33.8% had a family history of mental illness. 72.5% consumed alcohol. 40% had depressive symptoms, and 11.3% had both anxiety and depressive symptoms. Factors associated with depressive symptoms were mistreatment, long working hours, and sleep disturbances. In the multivariate analysis, only sleep disturbance remained significantly associated (PR 8.7; 95% CI 1.2-63.2; p = 0.03). The variable associated with anxiety symptoms was mistreatment (PR 4.2; 95% CI 1.2-15.7; p = 0.02). Conclusion: A higher prevalence of depressive symptoms, contrary to expectations, was found compared to anxiety symptoms. The variables associated with depressive or anxiety symptoms were consistent with previous reports.

Tyree D Williams,1– 3 Talia Adler,2,4 Lindsey Smokoff,2,4 Anmoldeep Kaur,2,5 Benjamin Rodriguez,2,3,6 Kavita Jyoti Prakash,6 Edib Redzematovic,2 Turner S Baker,2,3,7 Benjamin I Rapoport,2,3 Edward S Yoon,8 Douglas P Beall,9 Jonathan S Dordick,1 Reade A De Leacy3 1Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA; 2Sinai BioDesign, Mount Sinai Medical System, New York, NY, USA; 3Department of Neurosurgery, Mount Sinai Medical System, New York, NY, USA; 4Columbia University School of General Studies, New York, NY, USA; 5Department of Neuroscience, Smith College, Northampton, MA, USA; 6Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7Department of Population Health Science & Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8Hospital for Special Surgery, New York, NY, USA; 9Spine Fracture Institute, Oklahoma City, OK, USACorrespondence: Benjamin Rodriguez, Department of Neurosurgery, Mount Sinai Medical System, One Gustave L. Levy Place, Box 1136, New York, NY, USA, Tel +1 615 524-0211, Email tyree.williams@mssm.eduAbstract: Vertebral compression fractures (VCFs) are common in osteoporotic patients, with a frequency projected to increase alongside a growing geriatric population. VCFs often result in debilitating back pain and decreased mobility. Cement augmentation, a minimally invasive surgical technique, is widely used to stabilize fractures and restore vertebral height. Acrylic-based cements and calcium phosphate cements are currently the two primary fill materials utilized for these procedures. Despite their effectiveness, acrylic bone cements and calcium phosphate cements have been associated with various intraoperative and postoperative incidents impacting VCF treatment. Over the past decade, discoveries in the field of biomedical engineering and material science have shown advancements toward addressing these limitations. This narrative review aims to assess the potential pitfalls and barriers of the various types of bone cements.Keywords: osteoporosis, vertebral compression fractures, bone cement, vertebroplasty, kyphoplasty, vertebral augmentation

The impending scarcity of the radio frequency (RF) spectrum has led to a boom in the development of complementary technologies such as visible light communication (VLC). Hybrid systems that complement both technologies have demonstrated numerous advantages in terms of data rate, bandwidth, and security. However, the successful operation of a hybrid VLC/RF network is highly dependent on the network selection process. In this paper, three network selection algorithms are proposed for hybrid VLC/RF systems in an indoor Internet of things (IoT)-home scenario. The proposed algorithms consider the signal-to-noise ratio (SNR), the available capacity of each network, the number of devices connected to each network, and the users’ location within the scenario. Each algorithm analyzes the data load requirements of each mobile terminal and IoT device according to these metrics. Based on this evaluation, the network that offers the best benefit in terms of signal quality, capacity, and throughput is selected. The numerical results show that the VLC network presents higher SNR values, especially for users near its access points. In addition, a higher bandwidth, a higher connection capacity, and an improvement in the quality of service are perceived from these positions. The three proposed selection algorithms presented good overall performance of the hybrid system, with the Analytical Algorithm offering the best performance for connected users, superior to the Sequential Algorithm by an average of 15.9%. The network selection algorithms efficiently allocated the maximum number of users for the VLC network, improving overall system performance and reducing the RF network data load.

We report room temperature heterodyne detection of a quantum cascade laser beaten with a local oscillator on a unipolar quantum photodetector in two different atmospheric windows, at 4.8 µm and 9 µm. A noise equivalent power of few pW is measured by employing an active stabilization technique in which the local oscillator and the signal are locked in phase. The measured heterodyne noise equivalent power is six orders of magnitude lower than that obtained with direct detection.

Recent advances in photonic optimization have enabled calculation of performance bounds for a wide range of electromagnetic objectives, albeit restricted to single-material systems. Motivated by growing theoretical interest and fabrication advances, we present a framework to bound the performance of photonic heterostructures and apply it to investigate maximum absorption characteristics of multilayer films and compact, free-form multi-material scatterers. Limits predict trends seen in topology-optimized geometries – often coming within factors of two of specific designs – and may be utilized in conjunction with inverse designs to predict when heterostructures are expected to outperform their optimal single-material counterparts.

The molecular contamination of an animal facility was investigated during and after an infection with highly pathogenic African swine fever virus (ASFV) among domestic pigs. The investigation evaluated the risk of indirect transmission of the disease and indicated points that may facilitate cleaning and disinfection processes.

Brandon D Ayres,1 Marc R Bloomenstein,2 Jennifer Loh,3 Thomas Chester,4 Bobby Saenz,5,6 Julio Echegoyen,7 Shane R Kannarr,8 Victor L Perez,9 Tomasita C Rodriguez,10 Jaime E Dickerson Jr10,11 1Private Practice, Philadelphia, PA, USA; 2Schwartz Laser Eye Center, Scottsdale, AZ, USA; 3Loh Ophthalmology Associates, Miami, FL, USA; 4Cleveland Eye Clinic, Brecksville, OH, USA; 5Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX, USA; 6LASIK San Antonio, Kerrville, TX, USA; 7Gordon Schanzlin New Vision Institute, La Jolla, CA, USA; 8Kannarr Eye Care, Pittsburg, KS, USA; 9Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA; 10Sight Sciences, Menlo Park, CA, USA; 11North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USACorrespondence: Jaime E Dickerson Jr, Email jdickerson@sightsciences.comPurpose: We compare outcomes in eyes with dry eye disease (DED) treated with TearCare (TC) or topical cyclosporine 0.05% (RESTASIS; CsA).Setting: Nineteen ophthalmic and optometric practices in 11 US states.Design: Multicenter, randomized, assessor-masked, controlled IRB-approved trial. Eligible subjects: ≥ 22 years of age, dry eye symptoms within 3– 6 months, Tear Break-up Time (TBUT) ≥ 1 to ≤ 7 s, Meibomian Gland Secretion Score (MGSS) ≤ 12, Ocular Surface Disease Index (OSDI) of 23– 79. Randomized (1:1) to TC or CsA. TC subjects treated at baseline and month 5; CsA was twice daily for 6 months.Methods: Follow-up visits were scheduled for Day 1, Week 1, Months 1, 3, and 6 with primary inference at Month 6. Primary outcomes: TBUT and OSDI; secondary outcomes: MGSS, conjunctival and corneal staining, eye dryness score (EDS), symptoms assessment in dry eye (SANDE) score, and Schirmer tear score (STS). Safety assessments included adverse events, best corrected visual acuity, intraocular pressure, and slit-lamp findings.Results: Overall, 345 subjects, 172 TC and 173 CsA. TBUT improved at all time points in both groups (p< 0.0001), with statistically greater improvement for TC versus CsA (p=0.0006). OSDI improved significantly at all time points in both groups (p< 0.0001) with no significant differences between treatments. MGSS and other measures of meibomian gland function improved significantly more with TC eyes versus CsA; other secondary outcomes showed significant improvements in both groups with no difference between groups. Treatment-related adverse events were uncommon (10 total, 8 in the CsA group consistent with prior CsA studies); most (9/10) mild.Conclusion: TC provides statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland secretion, and non-inferior improvement in OSDI, corneal and conjunctival staining, SANDE, EDS, and STS versus CsA. TC should be a preferred treatment for DED associated with MGD.Keywords: dry eye disease, meibomian gland dysfunction, restasis, TearCare, cyclosporine

En el marco del cambio climático, la producción en suelos salinos surge como un desafío global de gran importancia, especialmente en regiones áridas de Argentina. Este estudio se enfoca en la alfalfa (Medicago sativa), una forrajera relevante en Argentina, y tiene como objetivo evaluar el comportamiento en distintas etapas del desarrollo ante condiciones salinas en dos cultivares, Monarca (M) y Kumen (Ku). El cultivar Ku aceleró el proceso de germinación y retrasó el efecto negativo de la salinidad sobre el crecimiento durante el período vegetativo con respecto a M. Estas diferencias podrían considerarse como indicadores potenciales de la tolerancia a la salinidad en el cultivar Ku. Asimismo, la evaluación de la sobrevivencia demostró diferencias significativas en condiciones salinas, siendo Ku menos afectado que M (-15%). Se propone que las respuestas en Ku estarían asociadas a su capacidad distintiva para enfrentar el estrés salino, subrayando la complejidad de los mecanismos de adaptación en la alfalfa. Estos hallazgos ofrecen perspectivas de análisis en términos de espacio (distintos órganos) y tiempo (diferentes etapas de desarrollo de la alfalfa) para aportar a la comprensión de la disparidad en las respuestas de cultivares en salinidad, cruciales para la sostentabilidad agrícola-ganadera en suelos salinos de regiones áridas y semiáridas en Argentina.