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Abstract Percutaneous renal biopsy is commonly used for kidney cancer diagnosis. However, the biopsy procedure remains challenging in sampling accuracy. Here we introduce a forward-viewing optical coherence tomography probe for differentiating tumor and normal tissues, aiming at precise biopsy guidance. Totally, ten human kidney samples, nine of which had malignant renal carcinoma and one had benign oncocytoma, were used for system evaluation. Based on their distinct imaging features, carcinoma could be efficiently distinguished from normal renal tissues. Additionally, oncocytoma could be differentiated from carcinoma. We developed convolutional neural networks for tissue recognition. Compared to the conventional attenuation coefficient method, convolutional neural network models provided more accurate carcinoma predictions. These models reached a tissue recognition accuracy of 99.1% on a hold-out set of four kidney samples. Furthermore, they could efficiently distinguish oncocytoma from carcinoma. In conclusion, our convolutional neural network-aided endoscopic imaging platform could enhance carcinoma diagnosis during percutaneous renal biopsy procedures.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

Purpose: Trabeculectomy surgery is a commonly performed procedure for treatment of glaucoma. While the goal is to lower intraocular pressure, over-filtration may cause hypotony with ocular structural changes and vision loss. Observations: A 53-year-old woman with primary open-angle glaucoma was referred to our service for further evaluation. The patient previously underwent trabeculectomy 9 years prior and was found to have a cataract and hypotony maculopathy in the right eye. Treatment options included cataract surgery alone, bleb revision alone, or combined cataract extraction and bleb revision. Biometry revealed corneal astigmatism in the right eye, and significant disparity in axial length between the two eyes. Since the axial length and corneal astigmatic changes were presumed to be at least partially reversible, measurements from the non-operative left eye influenced the lens selection for the hypotonous right eye. The patient underwent combined phacoemulsification and bleb revision. While IOP increased and hypotony was partly reversed, there was hyperopic and astigmatic refractive surprise after surgery.The patient subsequently underwent intraocular lens exchange using biometric values of the previously hypotonous eye and met the target post-operative refractive goal. Conclusions and importance: This case demonstrates changes to the axial length and ocular structure following longstanding hypotony maculopathy may be permanent, even after restoration of normotensive intraocular pressure.

Agricultural development is essential for world trade and the global economy. This research investigates the relationship between Foreign Direct Investment (FDI) and fossil fuel energy consumption with agricultural productivity (AP). The study used the panel data of BRICS nations from 1991-2019. For data analysis, panel regression analysis along with descriptive statistics was used. The study’s findings are that FDI and FFEC significantly influence the AP of BRICS nations. The FFEC has a positive influence on the AP, while FDI has a negative influence on the AP of BRICS nations. Further, the results revealed that trade openness and gross capital formation have a weak but significant influence on agricultural productivity.

Bacteria that cause infectious diseases adopt biofilms as one of their most prevalent lifestyles. Biofilms enable bacteria to tolerate environmental stress and evade antibacterial agents. This bacterial defense mechanism has rendered the use of antibiotics ineffective for the treatment of infectious diseases. However, many highly drug-resistant microbes have rapidly emerged owing to such treatments. Different signaling mechanisms regulate bacterial biofilm formation, including cyclic dinucleotide (c-di-GMP), small non-coding RNAs, and quorum sensing (QS). A cell density-dependent phenomenon, QS is associated with c-di-GMP (a global messenger), which regulates gene expression related to adhesion, extracellular matrix production, the transition from the planktonic to biofilm stage, stability, pathogenicity, virulence, and acquisition of nutrients. The article aims to provide information on inhibiting biofilm formation and disintegrating mature/preformed biofilms. This treatment enables antimicrobials to target the free-living/exposed bacterial cells at lower concentrations than those needed to treat bacteria within the biofilm. Therefore, a complementary action of antibiofilm and antimicrobial agents can be a robust strategic approach to dealing with infectious diseases. Taken together, these molecules have broad implications for human health.

Dengue is caused by a mosquito-transmitted flavivirus. The disease is now endemic to many tropical and subtropical regions, manifesting as approximately 96 million symptomatic cases of dengue each year. Clinical trials have shown TAK-003 (Qdenga®), a live attenuated dengue tetravalent vaccine, to be well-tolerated, immunogenic, and efficacious in adults with no prior exposure to dengue virus infection living in non-endemic regions, as well as in adults and children living in dengue-endemic areas. This open-label, single-arm phase 3 trial (NCT03771963) was conducted in two dengue non-endemic areas of the USA, and it evaluated the immunogenicity and safety of naturally-aged TAK-003 administered to adult participants. Overall, the immunogenicity data from this trial are consistent with those reported from other TAK-003 phase 2 and 3 trials, and the safety data are consistent with the broader integrated safety data analysis. The data show that naturally-aged TAK-003 had a well-tolerated reactogenicity and adverse events profile when administered in the second half of its clinical 24-month shelf-life and that it still elicited an immune response that persisted up to 6 months after the second dose against all four dengue serotypes, with no important safety risks identified during the trial.

Tyramide-conjugated DNA barcodes can be used to perform CODEX imaging without modifying primary antibodies and could complement existing CODEX workflows for multiplexed imaging.

Safely opening university campuses has been a major challenge during the COVID-19 pandemic. Here, the authors describe a program of public health measures employed at a university in the United States which, combined with other non-pharmaceutical interventions, allowed the university to stay open in fall 2020 with limited evidence of transmission.

Abstract We examined whether subjectively and objectively measured sleep health composites have a relationship with heart disease. 6,820 adults (M age = 53.4 years) from the Midlife in the United States study provided self-reported sleep characteristics and heart disease history. A smaller sample (n = 663) provided actigraphy sleep data. We tested two sleep health composites, based on self-report only and both self-report and actigraphy, across multiple sleep dimensions. We used a weighted sum approach, where higher scores indicated more sleep health problems. Modified Poisson regressions adjusted for sociodemographics and known risk factors. Having more sleep health problems was associated with a higher risk of heart disease using the self-report sleep health composite (aRR = 54%, P

Present study was conducted to observe effect of supplementing rumen protected methionine and choline on leukogram profile, oxidative stress, inflammatory and immunomodulatory responses during transition period in Surti buffaloes. Twenty-seven pregnant Surti buffaloes were selected and divided into three groups of nine animals each with following diet regime: Group I (Control)-basal diet, Group II (RPM)-basal diet+rumen protected methionine and Group III (RPM+RPC)-basal diet+rumen protected methionine+rumen protected choline. Supplementation of RPM @ 10 g/buffalo/day and RPC @ 50 g/buffalo/day was done from -15 d prepartum to 30 d postpartum. Blood samples were collected at start of experiment, 1st, 3rd and 6th week postpartum. At 1st and 3rd week postpartum, significantly higher level of GSH, SOD as well as TAS and lower level of LPO were observed in Group II and III as compared to control. Group III had highest SOD as well as TAS and lowest LPO levels. TNF-α and haptaglobin during postpartum period were significantly lower in Group II and III. Group III had lowest levels of TNF-α at 1st and 3rd week and haptoglobin at 1st, 3rd and 6th week postpartum. In vitro neutrophil phagocytic activity and lymphocyte proliferation were significantly higher in Group III followed by Group II and control during entire postpartum period. It was concluded that supplementation of rumen protected methionine and choline during transition phase of Surti buffaloes reduces oxidative stress as well as inflammatory tendencies and increases antioxidant status as well as immune response. Beneficial effects of supplementing both are more than supplementing rumen protected methionine alone.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Abstract Background Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation

Abstract Fluid overload is a common complication in patients with cirrhosis. B-type natriuretic peptide (BNP) is a marker of increased blood volume, commonly used in heart failure, that has been shown to be elevated in patients with liver disease. This study examined if BNP levels can be used to determine prognosis and predict worsening of ascites in patients with cirrhosis without concomitant heart disease. A retrospective study was performed at a large urban hospital in Chicago, Illinois and included 430 patients with cirrhosis who had BNP levels ordered during their hospital stay. Patients with clinical heart failure, arrhythmias or pulmonary hypertension were excluded. The primary outcome was 90-day mortality and the secondary outcome was a requirement for therapeutic paracentesis in the 90 days following BNP results. 53 patients (12%) had BNP levels ≥ 300 pg/mL. They had significantly increased serum levels of creatinine, bilirubin, and International Normalized Ratio (INR) when compared to those with BNP

Purpose: To develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography. Design: Cross-sectional study. Participants: Forty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK. Methods: Scheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT. Main Outcome Measures: Predictive power (R2) and mean difference between predicted and observed change in CCT. Results: The gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R2 = 0.80; 95% confidence interval [CI], 0.71–0.89) and the mean difference between predicted and observed change was, by definition, 0 μm. When the same 5 parameters were fit to the validation group, the model performed very highly (R2 = 0.89; 95% CI, 0.84–0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R2 = 0.78; 95% CI, 0.68–0.88), and the mean difference was 4 μm (predicted minus observed). Conclusions: Scheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

Purpose: Describe a case of intraocular plasmacytoma in a patient with multiple myeloma successfully treated with photon irradiation. Observations: A 61-year-old man with a history of relapsing/refractory multiple myeloma and left frontal bone plasmacytoma treated with monthly belantamab mafodotin salvage chemotherapy developed bilateral treatment-related corneal keratopathy. An iris mass was incidentally noted in the right eye during a follow-up examination. The mass was amelanotic with diffuse intrinsic vasculature involving the pupillary margin from 1:30 to 10:30. Fundus examination showed an irregularly shaped amelanotic superotemporal scleral lesion in the right eye and two smaller amelanotic scleral lesions in the left eye. Given known systemic multiple myeloma and history of left frontal bone plasmacytoma, a presumed diagnosis of iris and scleral plasmacytoma was made. Due to rapid progression of the iris plasmacytoma despite systemic chemotherapy, the patient was treated with 20 Gy photon irradiation to the anterior and posterior segments of both eyes. One month after photon irradiation, there was complete regression of the iris plasmacytoma, and the scleral lesions in both eyes also appeared to be regressing despite systemic progression of multiple myeloma. Conclusions and importance: Intraocular plasmacytoma is rare and can occur in isolation but typically occurs as a manifestation of systemic multiple myeloma. Intraocular plasmacytoma can be successfully treated with photon irradiation in patients with multiple myeloma who progress on systemic chemotherapy.

Abstract: Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

BackgroundIdentifying Obstructive Sleep Apnea (OSA) phenotypes among middle-aged and older Hispanics/Latinos can facilitate personalized care, better inform treatment decisions, and could lead to improved clinical outcomes.MethodsWe focused on middle-aged and older adults (ages ≥45-74 years at baseline) with an apnea-hypopnea index (AHI) ≥5 from the HCHS/SOL (2008-2011) (unweighted n = 3,545). We used latent class analyses (LCA) to identify empirical and clinically meaningful OSA phenotypes. Sleep variables included AHI, percent sleep time SpO2ResultsAverage AHI, ESS, WHIIRS, and sleep duration were 18.1±19.5, 6.3±6.1, 7.4±6.6, and 7.8±1.7 hours, respectively, and 2.9% had zero percent time SpO2 ConclusionsOSA subtypes in diverse U.S. Hispanic/Latino adults have different cardiovascular complications. More targeted research, that takes these variations into account, could help ameliorate Hispanic/Latino sleep and cardiovascular health disparities.

Purpose: To report a case of recurrent iris post-transplant lymphoproliferative disorder (PTLD) treated with ultra-low-dose (boom-boom) radiotherapy (RT). Observations: A 12-year-old Caucasian male with a history of bilateral, recurrent iris PTLD of the extranodal marginal zone lymphoma (MALT) type presented with persistent bilateral anterior chamber cellular infiltration, which was incompletely controlled on topical corticosteroids, and with elevated intraocular pressure (IOP) in the right eye secondary to steroid response. The patient was diagnosed with PTLD recurrence and was successfully treated with ultra-low-dose RT to both eyes in 2 fractions of 2 Gy. At 15 month follow-up the patient maintained complete disease control with normal IOP off all topical ophthalmic medications. Conclusions and Importance: Ultra-low-dose RT for ocular PTLD of the MALT subtype represents a novel therapeutic approach that may provide a durable treatment response and could be considered as either primary or adjuvant therapy for this rare condition.

Primary cultures of human corneal endothelial cells (HCECs) are an important model system for studying the pathophysiology of corneal endothelium. The purpose of this study was to identify and validate an optimal primary culture model of normal and Fuchs endothelial corneal dystrophy (FECD) endothelial cells by comparing cell morphology and marker expression under different media conditions to in vivo donor tissues. Primary and immortalized HCECs, isolated from normal and FECD donors, were cultured in proliferation media (Joyce, M4, Bartakova) alone or sequentially with maturation media (F99, Stabilization 1, M5). CD56, CD73 and CD166 expressions were quantified in confluent and matured cell lines by flow cytometry. HCECs that were allowed to proliferate in Joyce's medium followed by maturation in low-mitogen containing media yielded cells with similar morphology to corneal endothelial tissues. Elevated expression of CD56 and CD166 and low expression of CD73 correlated with regular, hexagonal-like HCEC morphology. CD56:CD73 > 2.5 was most consistent with normal HCEC morphology and mimicked corneal endothelial tissue. Immortalization of normal HCECs by hTERT transduction showed morphology and CD56:CD73 ratios similar to parental cell lines. HCECs established from FECD donors showed reduced CD56:CD73 ratios compared to normal HCECs which coincided with reduced uniformity and regularity of cell monolayers. Overall, a dual media system with Joyce's medium for proliferation and a low-mitogen media for maturation, provided normal cultures with regular, hexagonal-like cell morphologies consistent with corneal endothelial cells in vivo. CD56:CD73 expression ratio >2.5 was predictive of in vivo-like cellular morphology.

BackgroundData on the prevalence and correlates of restless legs syndrome (RLS) in people with HIV are limited. This study sought to determine the prevalence of RLS, associated clinical correlates, and characterize sleep-related differences in men with and without HIV.MethodsSleep-related data were collected in men who have sex with men participating in the Multicenter AIDS Cohort Study (MACS). Demographic, health behaviors, HIV status, comorbidities, and serological data were obtained from the MACS visit coinciding with sleep assessments. Participants completed questionnaires, home polysomnography, and wrist actigraphy. RLS status was determined with the Cambridge-Hopkins RLS questionnaire. RLS prevalence was compared in men with and without HIV. Multinomial logistic regression was used to examine correlates of RLS among all participants and men with HIV alone. Sleep-related differences were examined in men with and without HIV by RLS status.ResultsThe sample consisted of 942 men (56% HIV+; mean age 57 years; 69% white). The prevalence of definite RLS was comparable in men with and without HIV (9.1% vs 8.7%). In multinomial regression, HIV status was not associated with RLS prevalence. However, white race, anemia, depression, and antidepressant use were each independently associated with RLS. HIV disease duration was also associated with RLS. Men with HIV and RLS reported poorer sleep quality, greater sleepiness, and had worse objective sleep efficiency/fragmentation than men without HIV/RLS.ConclusionsThe prevalence of RLS in men with and without HIV was similar. Screening for RLS may be considered among people with HIV with insomnia and with long-standing disease.

Expansion of CTG trinucleotide repeats (TNR) in the transcription factor 4 (TCF4) gene is highly associated with Fuchs Endothelial Corneal Dystrophy (FECD). Due to limitations in the availability of DNA from diseased corneal endothelium, sizing of CTG repeats in FECD patients has typically been determined using DNA samples isolated from peripheral blood leukocytes. However, it is non-feasible to extract enough DNA from surgically isolated FECD corneal endothelial tissue to determine repeat length based on current technology. To circumvent this issue, total RNA was isolated from FECD corneal endothelium and sequenced using long-read sequencing. Southern blotting of DNA samples isolated from primary cultures of corneal endothelium from these same affected individuals was also assessed. Both long read sequencing and Southern blot analysis showed significantly longer CTG TNR expansion (>1000 repeats) in the corneal endothelium from FECD patients than those characterized in leukocytes from the same individuals (

Background: Short-term medical missions prevail as the most common form of international medical volunteerism, but they are ill-suited for medical education and training local providers in resource-limited settings. Objective: The purpose of this study is to evaluate the effectiveness of a longitudinal educational program in training clinicians how to perform point-of-care ultrasound (POCUS) in resource-limited clinics. Design: A retrospective study of a four-month POCUS training program was conducted with clinicians from a rural hospital in Haiti. The model included one-on-one, in-person POCUS teaching sessions by volunteer instructors from the United States and Europe. The Haitian trainees were assessed at the start of the program and at its conclusion by a direct objective structured clinical examination (OSCE), administered by the visiting instructors, with similar pre- and post- program ultrasound competency assessments. Results: Post-intervention, a significant improvement in POCUS competency was observed across six different fundamental areas of ultrasound (p < 0.0001). According to our objective structured clinical examination (OSCE), the mean assessment score increased from 0.47 to 1.68 out of a maximum score of 2 points, and each trainee showed significant overall improvement in POCUS competency independent of the initial competency pre-training (p < 0.005). There was a statistically significant improvement in POCUS application for five of the six medically relevant assessment categories tested. Conclusion: Our results provide a proof-of-concept for the longitudinal education-centered healthcare delivery framework in a resource-limited setting. Our longitudinal model provides local healthcare providers the skills to detect and diagnose significant pathologies, thereby reducing avoidable morbidity and mortality at little or no addition cost or risk to the patient. Furthermore, training local physicians obviates the need for frequent volunteering trips, saving costs in healthcare training and delivery.

Background: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. Methods: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses. Findings: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT). Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

Objective: Sleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-). Methods: Using data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared. Results: In the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P

The poor immune response elicited by trivalent influenza vaccines (TIVs) in children can be enhanced by the addition of adjuvants. This observer-blind, randomized Phase III trial assessed the immunogenicity and safety of the MF59-adjuvanted trivalent influenza vaccine FLUAD® (aTIV) and a non-adjuvanted TIV, in healthy children (aged 6 to 2, showing that the immunogenicity of aTIV was superior to that of TIV for all 3 strains. Solicited adverse events (AEs) were experienced more frequently with aTIV than TIV by younger children (aged 6 to

Introduction: Upper Tract Urothelial Carcinoma (UTUC) is a rare disease with few prognostic determinants. We sought to evaluate the impact of tumor size and location on patient survival following nephroureterectomy for UTUC. Materials and Methods: Data on 8284 patients treated with radical nephroureterectomy for UTUC in the United States between 1998 and 2011 were analyzed from the National Cancer Data Base. Univariable survivorship curves were generated based on pT stage, pN stage, grade, tumor size, and tumor site (renal pelvis vs. ureter). A Cox proportional hazards model was used to evaluate the effect of age, comorbidity, T stage, lymph node involvement, tumor site, and tumor size on survival. Results: The median follow-up time was 46 months. A majority of the patients were male (55.4%) with a tumor size of ≥3.5 cm (52.0%) and pT stage

Introduction: We aimed to evaluate the relative prognostic impact of the most common variant histologies on disease-specific survival (DSS) in patients undergoing radical cystectomy. Materials and Methods: The Surveillance, Epidemiology, and End Result database was used to identify patients who underwent radical cystectomy for bladder cancer from 1990 to 2007. Patients with urothelial cell carcinoma (UCC), squamous cell carcinoma (SCC), adenocarcinoma (AC), sarcoma, small cell carcinoma, signet ring carcinoma, and spindle cell carcinoma were included in the study. Multivariable analysis was performed using Cox proportional hazards model to assess independent predictors of disease-specific survival (DSS). Mortality rates were estimated using Kaplan–Meier analyses. Results: A total of 14,130 patients met inclusion criteria with the following histologies: UCC (90.1%), SCC (4.6%), AC, (2.3%), sarcoma (0.8%), small cell carcinoma (0.8%), signet ring carcinoma (0.5%), and spindle cell carcinoma (0.9%). Three-year DSS was most favorable in patients with UCC (63.7%; 95% confidence interval [62.9%–64.8%]) and AC (65.3% [59.3%–70.6%]), whereas 3-year DSS was the least favorable for small cell carcinoma (41.6% [31.3%–51.6%]) and sarcoma (45.4% [35.1%–55.1%]). In the multivariable analysis, independent predictors of DSS were age, marital status, grade, T-stage, N-stage, and variant histology. With respect to UCC, there was an increased risk of disease-specific death associated with all variants except AC. Sarcoma and spindle cell carcinoma were associated with the highest risk of death. Conclusions: With the exception of AC, the most common variant bladder cancer histologies are all independently associated with worse DSS relative to UCC in patients undergoing radical cystectomy.

Hispanics/Latinos face specific sociocultural stressors associated with their marginalized status in the United States. While stress is known to cause poor sleep, the differential effects of the specific stressors faced by Hispanics/Latinos have not been evaluated. Using cross-sectional data from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study, we conducted weighted generalized linear models to evaluate the associations of acculturation stress, ethnic discrimination, and chronic moderate/severe stress with self-reported sleep outcomes (insomnia symptoms, daytime sleepiness, sleep duration) in individual and aggregate models adjusted for site, socio-demographics, behavioral, and medical conditions. Participants included 5313 Hispanic/Latino adults; 43.5% ≥ age 45, 54.8% female, and 22.0% US-born. Chronic moderate/severe stress, ethnic discrimination, and acculturation stress were each positively associated with sleep. In the adjusted aggregate model, only chronic moderate/severe stress was associated with insomnia symptoms (exp(b) = 1.07 for each additional stressor, 95% CI = 1.05, 1.09). Both acculturation stress (exp(b) = 1.05 for each additional SD, 95% CI = 1.02, 1.10) and ethnic discrimination (exp(b) = 1.05 for each additional SD, 95% CI = 1.01, 1.08) were associated with daytime sleepiness. Each SD increase in ethnic discrimination related to a 16% and 13% increased prevalence of short (< 7 h) (RRR = 1.16, 95% CI = 1.02, 1.31) and long sleep duration (> 9 h) (RRR = 1.13, 95% CI = 1.00, 1.27), respectively. These associations were consistent across sex. Acculturation stress and ethnic discrimination are associated with poor sleep in Hispanics/Latinos. Future research should explore whether behavioral sleep interventions minimize the impact of sociocultural stressors on sleep.

Abstract: Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.

Abstract Background Hyalinizing trabecular tumors (HTT) are rare follicular cell-derived tumors of the thyroid gland that are infrequently reported in otolaryngology literature. We present here an interesting case of HTT which provides the basis for review of this entity’s clinical characteristics, criteria useful in making the diagnosis, and any currently available therapeutic modalities. Case presentation A 70-year-old Caucasian female underwent a CT scan of her chest and was incidentally found to have a nodule within the right thyroid lobe. Gross examination of the excised thyroid lobe revealed a circumscribed and encapsulated lesion (tan / gritty in texture), confined to the gland. Histologic sections of the lesion revealed a circumscribed neoplasm with a trabecular and organoid architecture associated with abundant dystrophic calcification. Neoplastic cells showed a spindled morphology with clumped chromatin and ample eosinophilic cytoplasm. Conclusions Histologically, HTT is a follicular cell-derived tumor composed of neoplastic cells arranged in a trabecular pattern with hyalinization and calcification of extracellular material. Distinguishing features of HTT include minimal cytologic atypia with a low nuclear: cytoplasmic ratio, cellular aggregates around hyalinized material, and nuclei with clumped chromatin and occasional grooves and/or pseudoinclusions. Though debated in the literature, the general consensus is that this tumor is a benign entity. It is our hope that additional clinical research will elicit awareness of these rare tumors.

Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.

Objective: To assess the safety and immunogenicity of the MF59-adjuvanted seasonal trivalent inactivated influenza vaccine (aIIV3; Fluad) in children aged 6 months through 5 years who are at risk of influenza complications. Methods: A retrospective analysis was performed to examine unsolicited adverse events (AEs) in an integrated dataset from six randomized clinical studies that compared aIIV3 with non-adjuvanted inactivated influenza vaccines (IIV3). The integrated safety set comprised 10 784 children, of whom 373 (3%) were at risk of influenza complications. Results: The at-risk safety population comprised 373 children aged 6 months through 5 years: 179 received aIIV3 and 194 received non-adjuvanted IIV3 (128 subjects received a licensed IIV3). The most important risk factors were respiratory system illnesses (62–70%) and infectious and parasitic diseases (33–39%). During the treatment period, unsolicited AEs occurred in 54% of at-risk children and 55% of healthy children who received aIIV3; of those receiving licensed IIV3, 59% of at-risk and 62% of healthy subjects reported an unsolicited AE. The most common AEs were infections, including upper respiratory tract infection. Serious AEs (SAEs) were reported in

Objective: To demonstrate the potential of an MF59-adjuvanted inactivated trivalent seasonal influenza vaccine (aIIV3; Fluad™) to improve the immune response in young children, we review the immunogenicity, efficacy, and safety/tolerability of aIIV3 from a comprehensive clinical development program in a pediatric population with a specific need for improved influenza vaccines. Methods: Data were analyzed from a series of 1 phase Ib, 3 phase II, and 2 phase III studies involving 11,942 children aged 6 months through 5 years. Results: The clinical data showed that aIIV3 had statistically significantly greater immunogenicity and efficacy in the prevention of influenza compared to conventional inactivated trivalent seasonal influenza vaccines (IIV3s). The safety profile of aIIV3 was generally similar to that of nonadjuvanted IIV3, apart from an increased frequency of solicited adverse events (AEs) following vaccination. The majority of solicited AEs were mild or moderate in severity and resolved within 1 to 3 days. Conclusions: aIIV3 was well tolerated, with immunogenicity and efficacy exceeding that of conventional IIV3 in children 6 months through 5 years of age. The MF59-adjuvanted vaccine has the potential to fulfill an unmet clinical need in the prevention of seasonal influenza in this age group. Keywords: Children, Influenza, Vaccine, Adjuvant, MF59

Background. Sleep disorders and fatigue are highly prevalent in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) patients but there is limited evidence on the effect of kidney transplant (KTx) on these. Methods. In a prospective cohort study of patients with advanced CKD (estimated glomerular filtration rate