IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model.

ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

The American Society for Microbiology collaboration with the CDC Laboratory Medicine Best Practices initiative for evidence-based laboratory medicine.

SUMMARYClinical medicine has embraced the use of evidence for patient treatment decisions; however, the evaluation strategy for evidence in laboratory medicine practices has lagged. It was not until the end of the 20th century that the Institute of Medicine (IOM), now the National Academy of Medicine, and the Centers for Disease Control and Prevention, Division of Laboratory Systems (CDC DLS), focused on laboratory tests and how testing processes can be designed to benefit patient care. In collaboration with CDC DLS, the American Society for Microbiology (ASM) used an evidence review method developed by the CDC DLS to develop a program for creating laboratory testing guidelines and practices. The CDC DLS method is called the Laboratory Medicine Best Practices (LMBP) initiative and uses the A-6 cycle method. Adaptations made by ASM are called Evidence-based Laboratory Medicine Practice Guidelines (EBLMPG). This review details how the ASM Systematic Review (SR) Processes were developed and executed collaboratively with CDC's DLS. The review also describes the ASM transition from LMBP to the organization's current EBLMPG, maintaining a commitment to working with agencies in the U.S. Department of Health and Human Services and other partners to ensure that EBLMPG evidence is readily understood and consistently used.

sPDGFRß and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aß)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor ß (sPDGFRß) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aß40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRß and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

NPP-669, a Novel Broad-Spectrum Antiviral Therapeutic with Excellent Cellular Uptake, Antiviral Potency, Oral Bioavailability, Preclinical Efficacy, and a Promising Safety Margin.

DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize ß-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.

Using smartphone-GPS data to quantify human activity in green spaces.

Cities are growing in density and coverage globally, increasing the value of green spaces for human health and well-being. Understanding the interactions between people and green spaces is also critical for biological conservation and sustainable development. However, quantifying green space use is particularly challenging. We used an activity index of anonymized GPS data from smart devices provided by Mapbox (www.mapbox.com) to characterize human activity in green spaces in the Greater Toronto Area, Canada. The goals of our study were to describe i) a methodological example of how anonymized GPS data could be used for human-nature research and ii) associations between park features and human activity. We describe some of the challenges and solutions with using this activity index, especially in the context of green spaces and biodiversity monitoring. We found the activity index was strongly correlated with visitation records (i.e., park reservations) and that these data are useful to identify high or low-usage areas within green spaces. Parks with a more extensive trail network typically experienced higher visitation rates and a substantial proportion of activity remained on trails. We identified certain land covers that were more frequently associated with human presence, such as rock formations, and find a relationship between human activity and tree composition. Our study demonstrates that anonymized GPS data from smart devices are a powerful tool for spatially quantifying human activity in green spaces. These could help to minimize trade-offs in the management of green spaces for human use and biological conservation will continue to be a significant challenge over the coming decades because of accelerating urbanization coupled with population growth. Importantly, we include a series of recommendations when using activity indexes for managing green spaces that can assist with biomonitoring and supporting sustainable human use.

Dietary Intake Correlated to Waist-To-Hip Ratio in Patients on Maintenance Hemodialysis.

OBJECTIVE: Individuals with end-stage kidney disease (ESKD) receiving maintenance hemodialysis (MHD) are at risk for protein-energy wasting (PEW). Inadequate dietary intake and altered anthropometrics are two criteria of the PEW diagnosis. This study explored whether individuals with ESKD on MHD meet the National Kidney Foundation Kidney Disease Outcome Quality Initiative (NKF-KDOQI) 2020 guidelines for nutritional adequacy on a dialysis treatment day (DD) and explored the relationship between dietary energy [DEI] and protein [DPI] intake and anthropometrics. METHODS: This was a secondary analysis of clinical and demographic data for 142 adults from the Rutgers Nutrition and Kidney Disease database. The study assessed the relationships between DEI, DPI, and anthropometrics, including body mass index (BMI), BMI category, waist circumference, and waist-to-hip ratio (WHR) using Pearson's or Spearman's correlation and one-way ANOVA. RESULTS: The sample had a median age of 55.7 years; 58% were male, 83.8% were Black/African American, with a median dialysis vintage of 42.0 months (e.g., 3.5 years). Seventy-five percent of the data sample were overweight or obese. The WHR was 1.0 ± 0.8 cm for males and 0.9 ± 0.1 for females. DEI and DPI on a DD did not meet the NKF-KDOQI 2020 guidelines. Median DEI was 17.6 ± 8.4 kcal/kg and DPI was 0.7 ± 0.4 g/kg. In the total sample, significant positive correlations were found between DEI (r = 0.74, P = 0.03) and DPI (r = 0.18, P = 0.037) and WHR. In females, a significant positive correlation was identified between DPI and WHR (r = 0.26, P = 0.046). CONCLUSIONS: These findings suggest that the nutritional intake of individuals with ESKD receiving MHD is inadequate to meet NKF-KDOQI 2020 guidelines on a DD. WHR may be a useful tool to assess alterations in anthropometrics related to DEI or DPI in this population, but more research is warranted.

Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death.

Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective cytosolic protein turnover that targets specific proteins to lysosomes for degradation. Enhancing protein degradation mechanisms has been shown to be beneficial in multiple models of cardiac disease, including myocardial infarction (MI) and ischemia-reperfusion (I/R) injury. However, the causal role of CMA in cardiomyocyte injury and death is largely unknown. Hypoxia is an important contributor to both MI and I/R damage, which are major, precedent causes of heart failure. Upregulating CMA was hypothesized to protect against hypoxia-induced cardiomyocyte death. Lysosome-associated membrane protein 2a (Lamp2a) overexpression and knockdown were used to causally study CMA's role in hypoxically stressed cardiomyocytes. LAMP2a protein levels were used as both a primary indicator and driver of CMA function. Hypoxic stress was stimulated by CoCl2 treatment, which increased LAMP2a protein levels (+1.4-fold) and induced cardiomyocyte apoptosis (+3.2-4.0-fold). Lamp2a siRNA knockdown (-3.2-fold) of control cardiomyocytes increased apoptosis (+1.8-fold) suggesting that loss of CMA is detrimental for cardiomyocyte survival. However, there was neither an additive nor a synergistic effect on cell death when Lamp2a-silenced cells were treated with CoCl2. Conversely, Lamp2a overexpression (+3.0-fold) successfully reduced hypoxia-induced apoptosis by ∼50%. LAMP2a was also significantly increased (+1.7-fold) in ischemic heart failure patient samples, similar to hypoxically stressed cardiomyocytes. The failing ischemic hearts may have had insufficient CMA activation. To our knowledge, this study for the first time establishes a protective role for CMA (via Lamp2a overexpression) against hypoxia-induced cardiomyocyte loss and reveals the intriguing possibility that CMA activation may offer a cardioprotective treatment for ischemic heart disease.

Incorporating parameter variability into Monod models of nutrient-limited growth of non-diazotrophic and diazotrophic cyanobacteria.

Models are widely used tools in aquatic science to understand the mechanism of phytoplankton growth and anticipate the occurrence of harmful algal blooms. However, model parameterization remains challenging and issues that may introduce prediction uncertainty exist. Many models use the Monod equation to predict cyanobacteria growth rate based on ambient nutrient concentrations. The half-saturation concentrations in the Monod equation varies greatly among different studies and depends on environmental conditions. In this study, we estimated the growth rate due to nutrient limitations for two cyanobacteria species (Microcystis aeruginosa and Dolichospermum flos-aquae) using a modified Monod model which allows the half-saturation concentration to vary according to initial nitrogen (N) conditions. The model is calibrated against observations from laboratory experiment where cyanobacteria growth and ambient nutrient concentrations were measured simultaneously, which is rarely done in the literature. Our results show this modified model produce better predictions on growth rate and biomass, indicating many commonly used mechanistic models may need improvement regarding phytoplankton growth representation. Furthermore, our study quantifies the flexibility in cyanobacteria growth parameter across a wide range of environmental N in eutrophic lakes thus provides important information for large-scale modelling applications.

Untargeted metabolomic analysis of thoracic blood from badgers indicate changes linked to infection with bovine tuberculosis (Mycobacterium bovis): a pilot study.

INTRODUCTION: Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB) in cattle, represents a major disease burden to UK cattle farming, with considerable costs associated with its control. The European badger (Meles meles) is a known wildlife reservoir for bTB and better knowledge of the epidemiology of bTB through testing wildlife is required for disease control. Current tests available for the diagnosis of bTB in badgers are limited by cost, processing time or sensitivities. MATERIALS AND METHODS: We assessed the ability of flow infusion electrospray-high-resolution mass spectrometry (FIE-HRMS) to determine potential differences between infected and non-infected badgers based on thoracic blood samples obtained from badgers found dead in Wales. Thoracic blood samples were autoclaved for handling in a containment level 2 (CL2) hazard laboratory. RESULTS: Here we show the major differences associated with with M. bovis infection were changes to folate, pyrimidine, histidine, glycerophospholipid and phosphonate metabolism. CONCLUSIONS: Our studies have indicated differences in the metabolomic signature of badgers found dead in relation to their infection status, suggesting metabolomics could hold potential for developing novel diagnostics for bTB in badgers. As well as highlighting a potential way to handle samples containing a highly pathogenic agent at CL2 for metabolomics studies.

Minimally invasive aortic valve repair using geometric ring annuloplasty.

OBJECTIVES: As aortic valve repair (AVr) for aortic insufficiency (AI) expands, minimally invasive (Mi) approaches are increasingly being applied. Cardiac surgical techniques can be more difficult through small incisions, and this report analyzes medium-term outcomes for MiAVr facilitated by geometric ring annuloplasty. METHODS: Since 2013, 58 patients were selected for AVr through upper sternotomy third-interspace incisions. The average age was 58.9 ± 15.4 (mean ± SD) years, 71% were male, and preoperative AI grade was 3.6 ± 0.8. Sixty-two percent (36/58) had a proximal aortic replacement for ascending aortic aneurysms (n = 26) and/or remodeling grafts for aortic root aneurysms (n = 10). Annuloplasty rings were placed subannularly (69% trileaflet; 31% bicuspid), and leaflet procedures were performed in 70%. The average ring diameter was 21.6 ± 1.4 mm, and the average aortic clamp time was 113 ± 35 min. RESULTS: After repair, AI grade fell to an average of 0.5 ± 0.6 (p < .0001), with a mean valve gradient of 12.5 ± 7.1 mmHg. No operative mortalities or major complications occurred. Three patients required reoperations for bleeding, and two had pacemakers. At an average follow-up of 38 months (maximal 88 months), three late deaths and no valve-related complications were observed. Four patients required reoperative aortic valve replacement over follow-up, and Kaplan-Meier survival and freedom from reoperation both exceeded 80% at 88 months. At the last follow-up, the average AI grade was 0.7 ± 0.7, and the mean valve gradient was 12.7 ± 6.3 mmHg. CONCLUSIONS: Geometric ring annuloplasty was safe and seemed to facilitate performing AVr ± proximal aortic replacement through Mi incisions. Hemodynamic improvements were significant, medium-term clinical outcomes were acceptable, and results could improve further with experience.

Design of new imidazole derivatives with anti-HCMV activity: QSAR modeling, synthesis and biological testing.

The problem of designing new antiviral drugs against Human Cytomegalovirus (HCMV) was addressed using the Online Chemical Modeling Environment (OCHEM). Data on compound antiviral activity to human organisms were collected from the literature and uploaded in the OCHEM database. The predictive ability of the regression models was tested through cross-validation, giving coefficient of determination q2 = 0.71-0.76. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with reasonable accuracy within the applicability domain (q2 = 0.70-0.74). The models were applied to screen a virtual chemical library of imidazole derivatives, which was designed to have antiviral activity. The six most promising compounds were identified, synthesized and their antiviral activities against HCMV were evaluated in vitro. However, only two of them showed some activity against the HCMV AD169 strain.

Filociclovir Is a Potent In Vitro and In Vivo Inhibitor of Human Adenoviruses.

Human adenovirus (HAdV) infection is common in the general population and can cause a range of clinical manifestations, among which pneumonia and keratoconjunctivitis are the most common. Although HAdV infections are mostly self-limiting, infections in immunocompromised individuals can be severe. No antiviral drug has been approved for treating adenoviruses. Filociclovir (FCV) is a nucleoside analogue which has successfully completed phase I human clinical safety studies and is now being developed for treatment of human cytomegalovirus (HCMV)-related disease in immunocompromised patients. In this report, we show that FCV is a potent broad-spectrum inhibitor of HAdV types 4 to 8, with 50% effective concentrations (EC50s) ranging between 1.24 and 3.6 µM and a 50% cytotoxic concentration (CC50) of 100 to 150 µM in human foreskin fibroblasts (HFFs). We also show that the prophylactic oral administration of FCV (10 mg/kg of body weight) 1 day prior to virus challenge and then daily for 14 days to immunosuppressed Syrian hamsters infected intravenously with HAdV6 was sufficient to prevent morbidity and mortality. FCV also mitigated tissue damage and inhibited virus replication in the liver. The 10-mg/kg dose had similar effects even when the treatment was started on day 4 after virus challenge. Furthermore, FCV administered at the same dose after intranasal challenge with HAdV6 partially mitigated body weight loss but significantly reduced pathology and virus replication in the lung. These findings suggest that FCV could potentially be developed as a pan-adenoviral inhibitor.

Posttransplant chimeric antigen receptor therapy.

Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

The effect of chronic dosing and p53 status on the genotoxicity of pro-oxidant chemicals in vitro.

In this study, we have studied the cytotoxicity and genotoxic potency of 3 pro-oxidants; H2O2, menadione and KBrO3 in different dosing scenarios, namely acute (1-day dosing) and chronic (5-days). For this purpose, relative population doubling (RPD%) and mononucleated micronucleus (MN) test were used. TK6 cells and NH32 were employed in in vitro experiments. In the study, the total acute dose was divided into 5 days for each prooxidant chemicals by dose fractionation (1/5th per day) method. Acute dosing was compared to chronic dosing. The oxidative stress caused by the exposure of cells with pro-oxidant chemicals to the cells was determined by an optimized 2',7'-dichlorofluorescein diacetate (DCFHDA) test method. The antioxidant levels of the cell lines were altered with buthionine sulfoxide (BSO) and N-acetyl cysteine (NAC), and the effect of antioxidant capacity on the MN formation in the cells was observed with this method. In the case of H2O2 and menadione, fractional dosing has been observed to result in lower toxicity and lower genotoxicity. But in the case of KBrO3, unlike the other 2 pro-oxidants, higher MN induction was observed with fractionated doses. DCFHDA test clearly demonstrated ROS induction with H2O2 and menadione but not with KBrO3. Unexpectedly, DCFHDA test demonstrated that KBrO3 did not cause an increase ROS levels in both acute and chronic dosing, suggesting an alternative ROS induction mechanism. It was also observed that, treatment with BSO and NAC, caused increasing and decreasing of MN fold change respectively, allowing further ROS specific mechanisms to be explored. Hence, dose fractionation expectedly caused less MN, cytotoxicity and ROS formation with H2O2 and menadione exposure, but not with KBrO3. This implies a unique mechanism of action for KBrO3 induced genotoxicity. Chronic dosing in vitro may be a valuable approach allowing better understanding of how chemicals damage DNA and pose human hazards.

Test-Retest Reliability and Validity of the Nutrition-Specific Quality of Life Questionnaire.

OBJECTIVE: The purpose of this study is to test the Nutrition-Specific Quality of Life (NSQOL) questionnaire for test-retest reliability and validity in a sample of patients on maintenance hemodialysis (MHD). DESIGN AND METHODS: Test-retest reliability of the NSQOL questionnaire via two patient interviews and comparison of the NSQOL questionnaire to a comprehensive nutrition assessment performed by a registered dietitian nutritionist for validity testing. This study was conducted in one outpatient MHD center in Chicago, IL. Adults, aged 18 years or older, treated with MHD for at least six months prior to start of the study. A Spearman's correlation coefficient was used to determine test-retest reliability and a Cronbach's alpha was used to determine the internal consistency of the 2 NSQOL questionnaires. Validity testing was done by comparing the NSQOL questionnaire to the most recent comprehensive nutrition assessment. RESULTS: The sample consisted of 17 men (63%) and 10 women (37%), with a mean age of 60 ± 13, who were mostly African American (63%) and Caucasian (26%). There was a significant correlation (P = .001) between the initial NSQOL interview and repeat NSQOL interview in all questions except for question 14 (P = .100). The NSQOL questionnaire was found to have excellent internal consistency with an α = 0.900. No significant relationship was found among total NSQOL score and age, dialysis vintage, albumin, or normalized protein catabolic rate; however, older participants had lower total NSQOL questionnaire scores. Although not statistically significant, there was variability between NSQOL questionnaire score and nutritional status. CONCLUSIONS: The NSQOL questionnaire was found to be reliable and had high internal consistency in this sample of patients receiving MHD. The NSQOL questionnaire may be beneficial for monitoring nutrition quality of life changes in-between nutrition assessment intervals.

Blood Viral Load in Symptomatic Congenital Cytomegalovirus Infection.

BACKGROUND: Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear. METHODS: Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy. RESULTS: Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1-5.65 vs 3.32 log, range 1-5.36; P = .001), thrombocytopenia (3.68 log, range 1-5.65 vs 3.43 log, range 1-5.36; P = .03), and transaminitis at presentation (3.73 log, range 1-5.60 vs 3.39 log, range 1-5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing. CONCLUSIONS: In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes.

Combined Topical Anti-inflammatory and Oral Acetazolamide in the Treatment of Central Serous Chorioretinopathy.

SIGNIFICANCE: Central serous chorioretinopathy (CSCR) is still a therapeutic challenge with no criterion standard treatment. However, anatomic changes at the level of the retinal pigment epithelium could prove of predictive value in the course of the disease for selective treatment in cases of increased risk of chronicity. PURPOSE: This pilot study analyzes the efficacy for treating acute CSCR with combined systemic acetazolamide 250 mg twice a day and nepafenac 0.1% eye drops three times a day in comparison with an untreated control group. It also evaluates the presence a pigment epithelial detachment (PED) as a risk factor for chronic CSCR. METHODS: Nineteen consecutive patients (group 1) with new or new onset of recurrent CSCR were treated with oral acetazolamide and nepafenac eye drops for at least 2 months. A control group of 14 patients (group 2) with new or new onset of recurrent CSCR were untreated while under regular observation for 4 months. Primary end points were central macular thickness and best-corrected visual acuity after 4 months. Secondary end points were complete regression of subretinal fluid at 3 months and association of PED at baseline with recurrent or chronic CSCR imaged by optical coherence tomography. RESULTS: Group 1 showed significantly faster resolution of subretinal fluid with a mean central macular thickness at 4 months of 271 ± 85 µm compared with 322 ± 79 µm for group 2 (P < .05), but with no functional benefit with a best-corrected visual acuity at 4 months of 0.8 ± 0.2 for group 1 compared with 0.9 ± 0.1 for the control group (P < .05). Patients with a small flat PED were at a higher risk of developing chronic CSCR compared with patients with a dome-shaped or no PED (P < .05). CONCLUSIONS: Central serous chorioretinopathy remains a therapeutic challenge. This pilot study shows faster resolution of subretinal fluid with treatment but without functional benefit compared with observation. The presence of small, flat PED was associated with development of chronic CSCR.

New 2-Oxoimidazolidine Derivatives: Design, Synthesis and Evaluation of Anti-BK Virus Activities in Vitro.

A series of novel 2-oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated in vitro. Bioassays showed that the synthesized compounds 1-{[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfamoyl}piperidine-4-carboxylic acid (5) and N-Cyclobutyl-N'-[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50 =5.4 and 5.5 µm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50 ) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant-BKPyV agents.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

A convolutional neural network to filter artifacts in spectroscopic MRI.

PURPOSE: Proton MRSI is a noninvasive modality capable of generating volumetric maps of in vivo tissue metabolism without the need for ionizing radiation or injected contrast agent. Magnetic resonance spectroscopic imaging has been shown to be a viable imaging modality for studying several neuropathologies. However, a key hurdle in the routine clinical adoption of MRSI is the presence of spectral artifacts that can arise from a number of sources, possibly leading to false information. METHODS: A deep learning model was developed that was capable of identifying and filtering out poor quality spectra. The core of the model used a tiled convolutional neural network that analyzed frequency-domain spectra to detect artifacts. RESULTS: When compared with a panel of MRS experts, our convolutional neural network achieved high sensitivity and specificity with an area under the curve of 0.95. A visualization scheme was implemented to better understand how the convolutional neural network made its judgement on single-voxel or multivoxel MRSI, and the convolutional neural network was embedded into a pipeline capable of producing whole-brain spectroscopic MRI volumes in real time. CONCLUSION: The fully automated method for assessment of spectral quality provides a valuable tool to support clinical MRSI or spectroscopic MRI studies for use in fields such as adaptive radiation therapy planning.