Differential expression analysis identifies candidate synaptogenic molecules for wiring direction-selective circuits in the retina.

An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There are multiple subtypes of DS retinal ganglion cells (DSGCs) that prefer motion along one of 4 preferred directions. This computation is mediated by selective wiring of a single inhibitory interneuron, the starburst amacrine cell (SAC), with each DSGC subtype preferentially receiving input from a subset of SAC processes. We hypothesize that the molecular basis of this wiring is mediated in part by unique expression profiles of DSGC subtypes. To test this, we first performed paired recordings from isolated mouse retina of both sexes to determine that postnatal day 10 (P10) represents the age at which asymmetric synapses form. Second, we performed RNA-sequencing and differential expression analysis on isolated P10 ON-OFF DSGCs tuned for either nasal or ventral motion and identified candidates which may promote direction-specific wiring. We then used a conditional knockout strategy to test the role of one candidate, the secreted synaptic organizer cerebellin-4 (Cbln4), in the development of DS tuning. Using two-photon calcium imaging, we observed a small deficit in directional tuning among ventral-preferring DSGCs lacking Cbln4, though whole-cell voltage clamp recordings did not identify a significant change in inhibitory inputs. This suggests that Cbln4 does not function primarily via a cell-autonomous mechanism to instruct wiring of DS circuits. Nevertheless, our transcriptomic analysis identified unique candidate factors for gaining insights into the molecular mechanisms that instruct wiring specificity in the DS circuit.Significance Statement By performing mRNA transcriptome analysis on three populations of direction-selective ganglion cells - two preferring horizontal motion and one preferring vertical motion - we identified differentially expressed candidate molecules potentially involved in cell subtype-specific synaptogenesis within this circuit. We tested the role of one differentially expressed candidate, Cbln4, enriched in ventral-preferring DSGCs. Using a targeted knockout approach, the deletion of Cbln4 led to a small reduction in direction-selective tuning while maintaining dendritic morphology and normal strength and asymmetry of inhibitory synaptic transmission. Overall, we have shown that this approach can be used to identify interesting candidate molecules, and future functional studies are required to reveal the mechanisms by which these candidates influence synaptic wiring within specific circuits.

RobOCTNet: Robotics and Deep Learning for Referable Posterior Segment Pathology Detection in an Emergency Department Population.

Purpose: To evaluate the diagnostic performance of a robotically aligned optical coherence tomography (RAOCT) system coupled with a deep learning model in detecting referable posterior segment pathology in OCT images of emergency department patients. Methods: A deep learning model, RobOCTNet, was trained and internally tested to classify OCT images as referable versus non-referable for ophthalmology consultation. For external testing, emergency department patients with signs or symptoms warranting evaluation of the posterior segment were imaged with RAOCT. RobOCTNet was used to classify the images. Model performance was evaluated against a reference standard based on clinical diagnosis and retina specialist OCT review. Results: We included 90,250 OCT images for training and 1489 images for internal testing. RobOCTNet achieved an area under the curve (AUC) of 1.00 (95% confidence interval [CI], 0.99-1.00) for detection of referable posterior segment pathology in the internal test set. For external testing, RAOCT was used to image 72 eyes of 38 emergency department patients. In this set, RobOCTNet had an AUC of 0.91 (95% CI, 0.82-0.97), a sensitivity of 95% (95% CI, 87%-100%), and a specificity of 76% (95% CI, 62%-91%). The model's performance was comparable to two human experts' performance. Conclusions: A robotically aligned OCT coupled with a deep learning model demonstrated high diagnostic performance in detecting referable posterior segment pathology in a cohort of emergency department patients. Translational Relevance: Robotically aligned OCT coupled with a deep learning model may have the potential to improve emergency department patient triage for ophthalmology referral.

Factors affecting turnaround time of SARS-CoV-2 sequencing for inpatient infection prevention and control decision making: analysis of data from the COG-UK HOCI study.

BACKGROUND: Barriers to rapid return of sequencing results can affect the utility of sequence data for infection prevention and control decisions. AIM: To undertake a mixed-methods analysis to identify challenges that sites faced in achieving a rapid turnaround time (TAT) in the COVID-19 Genomics UK Hospital-Onset COVID-19 Infection (COG-UK HOCI) study. METHODS: For the quantitative analysis, timepoints relating to different stages of the sequencing process were extracted from both the COG-UK HOCI study dataset and surveys of study sites. Qualitative data relating to the barriers and facilitators to achieving rapid TATs were included from thematic analysis. FINDINGS: The overall TAT, from sample collection to receipt of sequence report by infection control teams, varied between sites (median 5.1 days, range 3.0-29.0 days). Most variation was seen between reporting of a positive COVID-19 polymerase chain reaction (PCR) result to sequence report generation (median 4.0 days, range 2.3-27.0 days). On deeper analysis, most of this variability was accounted for by differences in the delay between the COVID-19 PCR result and arrival of the sample at the sequencing laboratory (median 20.8 h, range 16.0-88.7 h). Qualitative analyses suggest that closer proximity of sequencing laboratories to diagnostic laboratories, increased staff flexibility and regular transport times facilitated a shorter TAT. CONCLUSION: Integration of pathogen sequencing into diagnostic laboratories may help to improve sequencing TAT to allow sequence data to be of tangible value to infection control practice. Adding a quality control step upstream to increase capacity further down the workflow may also optimize TAT if lower quality samples are removed at an earlier stage.

Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies.

Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1-3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.

Intravenous tissue plasminogen activator for acute ischemic stroke in patients with renal dysfunction.

OBJECTIVE: This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. DESIGN: We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and <60 ml/min/1.73 m2 or on dialysis and by the propensity score from August 2006 to May 2015. The odds ratio of poor functional outcome (modified Rankin Scale ≥2) was calculated for patients with tPA treatment (N = 705), compared to those without tPA treatment (N = 2820), by eGFR levels, at 1, 3 and 6 months after ischemic stroke. We also evaluated the risks of intracerebral hemorrhage, upper gastrointestinal bleeding, mortality, between the two groups by eGFR levels. RESULTS: Among patients with eGFR levels of <60 ml/min/1.73 m2, tPA therapy reduced the odds ratio of poor functional outcome to 0.60 (95% confidence interval = 0.42-0.87) at 6 months after ischemic stroke. The tPA therapy was not associated with increased overall risk of upper gastrointestinal bleeding, but with increased risk of intracerebral hemorrhage. The low eGFR was not a significant risk factor of intracerebral hemorrhage among ischemic stroke patients receiving tPA treatment. CONCLUSIONS: tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.

Update on Retinal Drug Toxicities.

PURPOSE OF REVIEW: This review aims to provide an update on the clinical presentations and diagnostic findings of drug-induced retinal toxicities. RECENT FINDINGS: Several newly FDA-approved medications have been associated with acute retinal toxicities, including brolucizumab, MEK inhibitors, ulixertinib, and FGFR inhibitors. Additionally, as previously believed-to-be well-tolerated medications, such as pentosan sulfate sodium, anti-retroviral therapies, and certain intraoperative ocular medications, are used more frequently or for longer periods of time, associated toxic retinopathies and inflammatory reactions have been reported. Finally, advances in ocular imaging have revealed novel findings in hydroxychloroquine and tamoxifen maculopathies. SUMMARY: Discovery of new medications, increased frequency of use, and longer-term use have led to increased reports of retinal toxicities. Advances in retinal imaging have allowed for earlier detection of subclinical changes associated with these medications, which may help prevent progression of disease. However, more research is needed to determine the point at which vision loss becomes irreversible. Risks and benefits must be assessed prior to discontinuation of the offending, but potentially lifesaving, therapy.

Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.

LESSONS LEARNED: Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. BACKGROUND: The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance. METHODS: In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. RESULTS: Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. CONCLUSION: The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.

An Evaluation of the Microvasculature of Macular Nodules in Coats Disease Using Optical Coherence Tomography Angiography: A Report of 3 Cases.

Purpose: This work aimed to examine the microvasculature of macular fibrosis in Coats disease. Methods: Three boys (aged 3, 4, and 6 years) with Coats disease (stages 2B to 3A2) and macular fibrotic nodules were imaged using optical coherence tomography angiography (OCTA) on the Spectralis spectral-domain OCT tabletop and investigational portable Spectralis Flex module (version 6.9, Heidelberg Engineering). Results: In 2 eyes, a neovascular complex was observed in the avascular slab on OCTA. This neovascular complex had vessels connected to diving vessels from the superficial vascular complex that traveled through the deep vascular complex to the avascular complex. In the third eye, no neovascular complex was observed on OCTA at presentation, but on subsequent examinations fluorescein leakage was observed and cross-sectional OCTA further confirmed the presence of angiographic flow in the nodule. Conclusions: OCTA demonstrates the presence of type 3 neovascularization in fibrotic nodules in Coats disease.

Parathyroidectomy slows renal function decline in patients with primary hyperparathyroidism.

PURPOSE: Primary hyperparathyroidism has deleterious effects on health and causes nephrolithiasis and osteoporosis. However, it remains unclear whether parathyroidectomy benefits kidney function among patients with primary hyperparathyroidism. METHODS: In this retrospective study, patients with primary hyperparathyroidism receiving parathyroidectomy in a tertiary medical center between 2003 and 2017 were followed up until December 31 2017, death, or requiring renal replacement therapy. Impact of parathyroidectomy on kidney function was examined using longitudinal estimated glomerular filtration rate (eGFR) change scales: single, average, absolute difference, percent change, annual decline rate, and slope. We applied linear mixed-effect model to determine the effect of parathyroidectomy on kidney function. RESULTS: During study period, 167 patients with primary hyperparathyroidism were identified from 498 parathyroidectomized patients, and finally, 27 patients fulfilled our stringent criteria. Median follow-up duration was 1.50 years (interquartile range 1.05-1.81) before surgery and 2.47 years (1.37-6.43) after surgery. Although parathyroidectomy did not affect amount of proteinuria and distribution of eGFR, parathyroidectomy significantly slowed decline rate of eGFR compared with that before surgery (- 1.67 versus - 2.73 mL/min/1.73 m2/year, p < 0.001). More importantly, parathyroidectomy made more beneficial effects on kidney function in patients with age < 65 years and those without chronic kidney disease or hypertension. CONCLUSIONS: Our study showed that parathyroidectomy slows renal function decline irrespective of age or comorbidities, which offers novel insight into the revision of guidelines for surgical indications in primary hyperparathyroidism. Given small sample size, further large-scale controlled studies are warranted to confirm our findings.

Clinicopathologic correlation of aniridia: Optical coherence tomography angiography and histopathologic observations.

PURPOSE: To describe optical coherence tomography angiography (OCTA) findings in a patient with aniridia and correlate with representative histopathology. OBSERVATIONS: OCTA images of the macula of a pediatric aniridic patient, who has nystagmus and impaired vision bilaterally, demonstrate a complete absence of the foveal avascular zone (FAZ) in both the superficial and deep vascular complexes (SVC and DVC). In addition, larger superficial blood vessels were found to be abnormally diving from the SVC into the DVC. Similarly, immunofluorescence with confocal microscopy imaging of a retinal histopathology specimen from a 2 month old aniridic patient demonstrated larger vessels diving in the same manner. CONCLUSIONS AND IMPORTANCE: This study highlights the clinical, imaging and histopathologic findings of aniridia. Supine OCTA imaging, performed during examination under anesthesia, allowed for visualization of retinal microvasculature in eyes with nystagmus. The histopathology images helped validate OCTA findings that, with further investigation, may lead to new information about the development of abnormal retinal microvasculature.

Increased incidence and recurrence rates of acute diverticulitis in patients with irritable bowel syndrome.

AIM: Acute diverticulitis (AD) is commonly diagnosed in outpatient and emergency departments and is associated with severe complications such as perforation and fistula. Symptoms of irritable bowel syndrome (IBS), such as abdominal pain, constipation and diarrhoea, are also common with AD. This study aimed to evaluate the strength of a possible association between IBS and AD. METHOD: This retrospective study analysed records from Taiwan's National Health Insurance Research Database and involved a total of 25 810 patients, including 12 905 IBS patients diagnosed between 2000 and 2012. The IBS and non-IBS cohorts were matched by propensity score for age, gender, comorbidities and medication, then compared for confounding variables by the chi-square test or Student's t-test. The association between AD and IBS was determined using Cox proportional hazards models. Kaplan-Meier curves assessed the cumulative incidence of AD in IBS patients. RESULTS: The overall incidence of AD was 3.95-fold higher in the IBS cohort than in the non-IBS cohort (63.34 vs 16.02 per 100 000 person-years, respectively) and IBS was an independent risk factor for subsequent diagnosis of AD in multivariate Cox proportional hazards regression model adjusted hazards ratio (aHR = 3.84, 95% CI = 2.29-6.44, P < 0.001) and Kaplan-Meier (log-rank test, P < 0.001) analysis. IBS was also associated with a high recurrence rate of AD (aHR = 8.30, 95% CI = 1.07-64.30, P = 0.04). CONCLUSION: The epidemiological evidence in this study demonstrates that patients with IBS are associated with a higher incidence of AD and also its recurrence.

Implementation of a Hepatic Artery Infusion Program: Initial Patient Selection and Perioperative Outcomes of Concurrent Hepatic Artery Infusion and Systemic Chemotherapy for Colorectal Liver Metastases.

BACKGROUND: Hepatic artery infusion (HAI) combined with systemic chemotherapy is a treatment strategy for patients with unresectable liver-only or liver-dominant colorectal liver metastases (CRLM). Although HAI has previously been performed in only a few centers, this study aimed to describe patient selection and initial perioperative outcomes during implementation of a new HAI program. METHODS: The study enrolled patients with CRLM selected for HAI after multi-disciplinary review November 2018-January 2020. Demographics, prior treatment, and perioperative outcomes were assessed. Objective hepatic response was calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. RESULTS: During a 14-month period, 21 patients with CRLM underwent HAI pump placement. Of these 21 patients, 20 (95%) had unresectable disease. Most of the patients had synchronous disease (n = 18, 86%) and had received prior chemotherapy (n = 20, 95%) with extended treatment cycles (median 16; interquartile range, 8-22; range, 0-66). The median number of CRLMs was 7 (range, 2-40). Operations often were performed with combined hepatectomy (n = 4, 19%) and/or colectomy/proctectomy (n = 11, 52%). The study had no 90-day mortality. The overall surgical morbidity was 19%. The HAI-specific complications included pump pocket seroma (n = 2), hematoma (n = 1), surgical-site infection (n = 1), and extrahepatic perfusion (n = 1). HAI was initiated in 20 patients (95%). The hepatic response rates at 3 months included partial response (n = 4, 24%), stable disease (n = 9, 53%), and progression of disease (n = 4, 24%), yielding a 3-month hepatic disease control rate (DCR) of 76%. CONCLUSION: Implementation of a new HAI program is feasible, and HAI can be delivered safely to selected patients with CRLM. The initial response and DCR are promising, even for patients heavily pretreated with chemotherapy.

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.

The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug-induced immune response. Previous reports have found that CXCL10, also known as interferon-γ-induced protein (IP)-10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP-10 in DRESS and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown. OBJECTIVES: This comparative prospective cohort study aimed to ascertain the roles of the IP-10/CXCR3 axis in DRESS and SJS/TEN. METHODS: Plasma IP-10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP-10, human herpesvirus (HHV)-6 reactivation and the development of long-term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs). RESULTS: Significantly higher plasma IP-10 levels were observed in patients with DRESS with long-term sequelae (effect size 0·81) and also in those with HHV-6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP-10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV-6 reactivation. The percentages of CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were also higher in the PBMCs of HHV-6-reactivated patients with DRESS than in those of patients with SJS/TEN. CONCLUSIONS: Higher plasma IP-10 levels are associated with the development of long-term sequelae in DRESS. Higher IP-10/CXCR3 expression in skin and more abundant CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were observed in patients with DRESS with HHV-6 reactivation. The IP-10/CXCR3 axis is associated with HHV-6 reactivation and development of long-term sequelae in DRESS. What is already known about this topic? Elevated levels of interferon-γ-induced protein-10 (IP-10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Patients with DRESS tend to develop long-term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP-10 has been associated with these autoimmune diseases in previous studies. What does this study add? The patients with DRESS with HHV-6 reactivation exhibited higher levels of IP-10 in the plasma and skin than the patients with DRESS without HHV-6 reactivation and the patients with SJS/TEN. Patients with DRESS with higher plasma IP-10 levels tended to develop sequelae during long-term follow-up. What is the translational message? IP-10 is a useful biomarker to predict the development of long-term sequelae in patients with DRESS. Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804-805.

Comparable efficacy and safety of brodalumab in obese and nonobese patients with psoriasis: analysis of two randomized controlled trials.

BACKGROUND: Obesity is associated with psoriasis and negatively affects response to therapy. OBJECTIVES: To evaluate the efficacy and safety of brodalumab in nonobese vs. obese patients with psoriasis. METHODS: This is a post hoc analysis of the prospective, phase III, multicentre, randomized, placebo- and active-comparator-controlled AMAGINE-2 and AMAGINE-3 trials, in which patients were randomized to treatment with brodalumab 210 mg every 2 weeks, ustekinumab or placebo for a 12-week induction phase. At week 12, patients who received brodalumab 210 mg every 2 weeks continued brodalumab, those treated with ustekinumab continued ustekinumab, and those who received placebo switched to brodalumab 210 mg every 2 weeks. Patients were categorized by body mass index (BMI) category (< 30 or ≥ 30 kg m-2 ) and efficacy was evaluated using the physician-rated Psoriasis Area and Severity Index and static Physician's Global Assessment instruments. RESULTS: In total, 281 of 687 patients (40·9%) were obese. Skin clearance was comparable across BMI subgroups in brodalumab-treated patients. Psoriasis Area and Severity Index 100% improvement rates in nonobese and obese patients at week 12 were 54·1% and 49·5%, respectively, and at week 52 they were 72·6% and 64·8%, respectively. Week 12 ustekinumab responses were lower than brodalumab responses and were 6-17% lower in obese than in nonobese patients. No appreciable differences in overall safety were observed between nonobese and obese patients. CONCLUSIONS: The efficacy and safety of brodalumab did not differ between patients with moderate-to-severe psoriasis who had a BMI < 30 kg m-2 or a BMI ≥ 30 kg m-2 .

Factors influencing the survival of implant-supported ceramic-ceramic prostheses: A randomized, controlled clinical trial.

OBJECTIVE: The goals of this research are: (1) to determine the clinical survival of ceramic-ceramic 3-unit implant supported fixed dental prostheses (FDPs) compared with control metal-ceramic and; (2) to analyze the effects of design parameters such as connector height, radius of curvature of gingival embrasure, and occlusal veneer thickness. MATERIALS AND METHODS: This randomized, controlled clinical trial enrolled 96 participants with 129 3-unit implant-supported FDPs. Participants were randomized to receive different design combinations to include FDP material, thickness of occlusal veneer ceramic, radius of curvature of gingival embrasure and connector height. Participants were recalled for 6 months, 1year and yearly thereafter for the next 5 years. FDPs were examined for evidence of fracture and radiographs were made to assess viability of implants. Fractographic analyses and Kaplan Meier survival analysis was used to analyze the data. RESULTS: 27 FDPs, representing 21%, exhibited chipping fractures of the veneer during the 5-year observation period. There was no statistically significant effect of type of material, veneer thickness, radius of curvature of gingival embrasure and connector height on occurrence of fracture. Fractographic and occlusal analyses reveal that fractures originated from the occlusal surface and that occlusion was the most important factor in determining survival. Stresses calculated at failure demonstrated lower values compared with in vitro data. CONCLUSION: Implant-supported ceramic-ceramic prosthesis is a viable alternative to metal-ceramic. Survival analysis for both materials were comparable and design parameters employed in this study did not affect survival as long as zirconia was used as the core material.

Levofloxacin-resistant Stenotrophomonas maltophilia: risk factors and antibiotic susceptibility patterns in hospitalized patients.

BACKGROUND: Levofloxacin has been considered as an alternative treatment for Stenotrophomonas maltophilia infection. However, levofloxacin-resistant S. maltophilia (LRSM) are emerging worldwide. AIM: To investigate LRSM risk factors in hospitalized patients and to determine antibiotic susceptibility patterns of LRSM isolates. METHODS: In a retrospective matched case-control-control study, LRSM patients (the case group) were compared with two control groups: levofloxacin-susceptible S. maltophilia (LSSM) patients (control group A) and non-S. maltophilia-infected patients (control group B). Conditional logistic regression was used to analyse risk factors for LRSM occurrence. Tigecycline, ceftazidime, colistin, and trimethoprim/sulfamethoxazole (TMP/SMX) susceptibilities in collected LRSM clinical isolates were determined. FINDINGS: A total of 105 LRSM, 105 LSSM, and 105 non-S. maltophilia-infected patients were analysed. The first multivariate analysis (cases vs group A) revealed that previous fluoroquinolones use was significantly associated with LRSM occurrence, and the second multivariate analysis (cases vs group B) revealed that previous fluoroquinolone use, previous intensive care unit stay, and the number of previous exposures to different classes of antibiotics were significantly associated with LRSM occurrence. Of all the LRSM isolates tested for antibiotic susceptibility, ceftazidime, TMP/SMX, tigecycline, and colistin resistance rates were 42.0, 99.0, 78.0, and 40.0%, respectively. CONCLUSION: LRSM antibiotic susceptibility patterns revealed multiple-drug resistance, which further limits treatment options for clinicians. To reduce LRSM occurrence, proper use of antibiotics, especially fluoroquinolones, is mandatory.

Appearance of pediatric choroidal neovascular membranes on optical coherence tomography angiography.

PURPOSE: Compared with fluorescein angiography (FA), the gold standard for diagnosing choroidal neovascularization (CNV) activity, optical coherence tomography angiography (OCTA) is non-invasive without risks associated with fluorescein dye use, and may be especially advantageous in the diagnosis and monitoring of children with CNV. METHODS: Eight eyes from eight patients aged 12 months to 18 years were imaged with the investigational Spectralis OCTA (version 6.9, Heidelberg Engineering, Heidelberg, Germany) and the RTVue XR Avanti (Optovue Inc., Fremont, CA, USA). Two patients were imaged during examination under anesthesia while six patients were imaged in the clinic. Demographic information, ocular characteristics, treatment history, and imaging studies (color photos, fluorescein angiography, OCT) were collected and reviewed. RESULTS: Three eyes had active CNV while five had quiescent CNV at the time of imaging. CNV was idiopathic or secondary to trauma, retinal vascular dysgenesis versus retinopathy of prematurity, pigmentary retinopathy, Best vitelliform macular dystrophy, panuveitis, morning glory disc anomaly, and optic disc drusen. OCTA of two active CNV demonstrated presence of a main trunk with multiple fine capillaries, vessel loops, and anastomoses. OCTA was repeated after treatment for two CNV and demonstrated a decrease in size with loss of fine capillaries, vessel loops, and anastomoses. For the third active CNV, OCTA verified flow in the CNV complex despite the uncertainty of FA hyperfluorescence in the setting of grossly abnormal retinal vasculature. The five quiescent CNV all lacked fine capillaries, vessel loops, and anastomoses on OCTA. CONCLUSION: OCTA demonstrates morphological differences between active and quiescent pediatric CNV.