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Background The impact of packed Red Blood Cell (pRBC) transfusion on oncological outcomes after liver transplantation (LT) for Hepatocellular Carcinoma (HCC) remains controversial. We evaluated the impact of pRBC transfusion on HCC recurrence and overall survival (OS) after LT for HCC. Methods Patients with HCC transplanted between 2000 and 2018 were included and stratified by receipt of pRBC transfusion. Outcomes were HCC recurrence and OS. Propensity score matching was performed to account for confounders. Results Of the 795 patients, 234 (29.4%) did not receive pRBC transfusion. After matching the 1-, 3-, and 5-year cumulative incidence of recurrence was 6.6%, 12.5% and 14.8% for no-pRBC transfusion, and 8.6%, 18.8% and 21.3% (p = 0.61) for pRBC transfusion. The OS at 1-, 3-, 5-year was 93.0%, 84.6% and 75.8% vs 92.0%, 79.7% and 73.5% (p = 0.83) for no-pRBC transfusion and pRBC transfusion, respectively. There were no differences in recurrence (HR 1.13, 95%CI 0.71–1.78, p = 0.61) or OS (HR 1.04, 95%CI 0.71–1.54, p = 0.83). Conclusion Perioperative administration of pRBC in liver transplant recipients for HCC resulted in a nonsignificant increase of HCC recurrence and death after accounting for confounder. Surgeons should continue to exercise cation and optimize patients iron stores medically preoperatively.

Desymmetrisation of robenidine (1: N ',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 mu g mL(-1). Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 mu g mL(-1). Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16-64 mu g mL(-1) active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 mu g mL(-1). A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16-64 mu g mL(-1). In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 mu g mL(-1) to inactive (MIC>128 mu g mL(-1)) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 mu g mL(-1) against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 mu g mL(-1) with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains. Refereed/Peer-reviewed

Dolutegravir (DTG) is now a component of preferred first-line antiretroviral therapy (ART) worldwide. ADVANCE and NAMSAL were two landmark clinical trials conducted exclusively in sub-Saharan Africa, which studied the effectiveness of DTG-based first-line regimens for ART-naive individuals. In this review, we examine the data from these studies to consider the contributions of adherence and HIV drug resistance to treatment failure on DTG-based ART, as compared with efavirenz (EFV)-based ART, which has a lower genetic barrier to resistance. We also discuss the implications of virologic failure on DTG and consolidate currently available data to conclude with recommendations for virologic monitoring on DTG-based ART.

BACKGROUND AND PURPOSE This study evaluates the incidence, prevalence and survival trends of motor neurone disease (MND) in Northern Ireland from 2015 to 2019. METHODS A capture-recapture analysis was performed using five independent data sources. Incidence and prevalence rates were standardized to the European Standard Population. Survival outcomes were analysed using Kaplan-Meier curves and Cox regression analysis. RESULTS Amongst 254 total cases of MND, capture-recapture analysis estimated three missing cases (case ascertainment 98.8%). Age standardized incidence of captured cases was 3.12 per 100,000 (2.73, 3.50) and standardized prevalence ranged from 9.45 to 6.49 per 100,000 from 2015 to 2019. Standardized incidence and prevalence rates in 2006 were 1.4 and 3.3 per 100,000 respectively. Of identified cases, 133 (52.4%) were male; 94.5% had amyotrophic lateral sclerosis; median age of onset was 67 years; median time to diagnosis was 12 months (95% confidence interval 11.2, 12.8); survival from diagnosis was 12 months (95% confidence interval 10.6, 15.4); 25 (9.8%) reported a family history of MND or frontotemporal dementia; and a known MND-associated genetic mutation was identified in 7.9% of total cases, of which the most common was C9orf72 (5.7% of all patients). Factors associated with improved survival were younger age at onset, longer time to diagnosis, attendance at regional MND clinic, and initial neurology presentation as outpatient (all p

Purpose The purpose of this study was to report a case of infective necrotizing scleritis following XEN Gel Stent with mitomycin-C. Methods Case report. This is a case report of a 68-year-old woman. Results XEN Gel Stent glaucoma surgery enhanced with mitomycin-C 0.04% and combined with cataract surgery was performed at a regional center to manage the patient's primary open-angle glaucoma. Past medical history was significant for rheumatoid arthritis requiring treatment with methotrexate and adalimumab. Periocular pain and swelling developed 14 months after the initial operation, followed by a rapid deterioration of visual acuity to 20/60, intraocular pressure of 4 mm Hg, and worsening pain 5 months later. On initial presentation to Sydney Eye Hospital, 180 degrees of scleral necrosis was evident with a moderate anterior segment inflammatory reaction and a large temporal choroidal effusion due to hypotony. Empirical hourly topical ofloxacin and cephalothin 5% drops, with oral moxifloxacin, were initiated. Conjunctival swab grew Staphylococcus aureus and Staphylococcus lugdunensis. Significant clinical improvement occurred, but the XEN Gel Stent became exposed after 9 days of treatment with worsening hypotony. Urgent surgical revision was performed to remove the XEN Gel Stent and apply a tutoplast plug with overlying amniotic membrane graft. Intraocular pressure gradually improved over 6 weeks to 15 mm Hg with reversal of hypotonous changes, and visual acuity stabilized at 20/40. Conclusions To our knowledge, this is the first reported case of necrotizing scleritis following XEN Gel Stent insertion. It is a reminder that infection should always be the primary differential diagnosis in patients with surgical-induced necrotizing scleritis.

Supplemental Digital Content is Available in the Text. The largest case series to date describing uveitis occurring secondary to systemic treatments for malignant melanoma. Twenty-two cases are described. Uveitis occurred after treatment with checkpoint, BRAF, and mitogen-activated protein kinase inhibitors., Background/Purpose: To report the largest case series to date of uveitis occurring in association with immunomodulatory therapy for malignant melanoma. Methods: A retrospective multicenter case review. Twenty-two patients with uveitis occurring in association with either immunotherapy or targeted immune therapy for malignant melanoma were identified. Results: Of 22 patients, 11 had anterior uveitis in isolation. The remainder showed a variety of clinical features including panuveitis, ocular hypotony, papillitis, cystoid macular edema, and melanoma-associated retinopathy. Most patients responded well to treatment. Conclusion: We report the largest case series to date of patients with uveitis secondary to drug treatment for malignant melanoma. These cases are likely to increase in number in the future as newer immunomodulatory therapies for cancers are developed and the indications for these drugs increase. A dilemma arises when patients respond well to these drugs but develop vision-threatening side effects.

Background Despite recent incentives through Medicare (Australia’s universal health insurance scheme) to increase retinal screening rates in primary care, comprehensive diabetic retinopathy (DR) screening has not been reached in Australia. The current study aimed to identify key factors affecting the delivery of diabetic retinopathy (DR) screening in Australian general practices. Methods A descriptive qualitative study involving in-depth interviews was carried out from November 2019 to March 2020. Using purposive snowballing sampling, 15 general practitioners (GPs) were recruited from urban and rural general practices in New South Wales and Western Australia. A semi-structured interview guide was used to collect data from participants. All interviews were conducted over the phone by one facilitator, and each interview lasted up to 45 min. The Socio-Ecological Model was used to inform the content of the interview topic guides and subsequent data analysis. Recorded data were transcribed verbatim, and thematic analysis was conducted to identify and classify recurrent themes. Results Of 15 GPs interviewed, 13 were male doctors, and the mean age was 54.7 ± 15.5 years. Seven participants were practising in urban areas, while eight were practising in regional or remote areas. All participants had access to a direct ophthalmoscope, but none owned retinal cameras. None of the participants reported performing DR screening. Only three participants were aware of the Medicare Benefits Schedule (MBS) items 12,325 and 12,326 that allow GPs to bill for retinal screening. Seven themes, a combination of facilitators and barriers, emerged from interviews with the GPs. Despite the strong belief in their role in managing chronic diseases, barriers such as costs of retinal cameras, time constraints, lack of skills to make DR diagnosis, and unawareness of Medicare incentives for non-mydriatic retinal photography made it difficult to conduct DR screening in general practice. However, several enabling strategies to deliver DR screening within primary care include increasing GPs’ access to continuing professional development, subsidising the cost of retinal cameras, and the need for a champion ace to take the responsibility of retinal photography. Conclusion This study identified essential areas at the system level that require addressing to promote the broader implementation of DR screening, in particular, a nationwide awareness campaign to maximise the use of MBS items, improve GPs’ competency, and subsidise costs of the retinal cameras for small and rural general practices.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Cataract surgery is a safe, effective and common elective procedure in Australia but access is inequitable. True waiting times for cataract care are undisclosed or inconsistently reported by governments. Estimates of true waiting times range from 4 to 30 months and have been extended during the coronavirus disease 2019 (COVID-19) pandemic. Comparative analysis revealed that reducing waiting periods from 12 to 3 months would result in estimated public health system cost savings of $6.6 million by preventing 50 679 falls. Investment in public cataract services to address current unmet needs would prevent avoidable vision impairment and associated negative consequences.

OBJECTIVES To characterize the epidemiology of children and adolescents admitted for deliberate self-harm to PICUs in the United States by examining patient demographics, diagnoses, modes of self-harm, and outcomes. DESIGN Descriptive analysis of a large, multicenter, quality-controlled database. SETTING The 137 PICUs participating in the Virtual Pediatric Systems database during the study period. PATIENTS Children between 6 and 18 years old admitted to a participating PICU from January 1, 2009, to December 31, 2017, with a diagnosis involving deliberate self-harm or a suicide attempt. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 9,197 admissions for self-harm, females accounted for 6,740 (73.3%), whereas males incurred 174 of the 284 deaths (61.3%). Admissions for self-harm doubled over the study period (0.56% in 2009 vs 1.13% in 2017), with an increase observed across every age group. After PICU care, most patients were transferred to a general care floor (51.1%) or to a psychiatric rehabilitation facility (31.8%). Intentional drug ingestion (84%) was the most common mode of self-harm but was associated with less than 1% of the fatalities. Asphyxia/hanging or firearms were a factor in 411 (4.5%) and 106 (1.2%) of the admissions but were associated with 117 (28.5%) and 55 (51.9%) of the deaths, respectively. CONCLUSIONS PICU admissions due to self-harm increased for all age groups during the study period. Females accounted for most of these admissions, whereas males accrued most of the in-hospital deaths. Intentional drug ingestion was the most common mode of self-harm and was rarely fatal, whereas asphyxia and firearms were the mechanisms associated with the highest mortality.

Background Clinical practice guidelines aim to support clinicians in providing clinical care and should be supported by evidence. There is currently no information on whether clinical practice guidelines in laparoscopic surgery are supported by evidence. Methods We performed a systematic review and identified clinical practice guidelines of laparoscopic surgery published in PubMed and Embase between March 2016 and February 2019. We performed an independent assessment of the strength of recommendation based on the evidence provided by the guideline authors. We used the ‘Appraisal of Guidelines for Research & Evaluation II’ (AGREE-II) Tool’s ‘rigour of development’, ‘clarity of presentation’, and ‘editorial independence’ domains to assess the quality of the guidelines. We performed a mixed-effects generalised linear regression modelling. Results We retrieved 63 guidelines containing 1905 guideline statements. The median proportion of ‘difference in rating’ of strength of recommendation between the guideline authors and independent assessment was 33.3% (quartiles: 18.3%, 55.8%). The ‘rigour of development’ domain score (odds ratio 0.06; 95% confidence intervals 0.01–0.48 per unit increase in rigour score; P value = 0.0071) and whether the strength of recommendation was ‘strong’ by independent evaluation (odds ratio 0.09 (95% confidence intervals 0.06–0.13; P value Conclusion A considerable proportion of guideline statements in clinical practice guidelines in laparoscopic surgery are not supported by evidence. Guideline authors systematically overrated the strength of the recommendation (i.e., even when the evidence points to weak recommendation, guideline authors made strong recommendations).

Purpose To determine classification criteria for Fuchs uveitis syndrome. Design Machine learning of cases with Fuchs uveitis syndrome and 8 other anterior uveitides. Methods Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand eighty-three cases of anterior uveitides, including 146 cases of Fuchs uveitis syndrome, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for Fuchs uveitis syndrome included unilateral anterior uveitis with or without vitritis and either: 1) heterochromia or 2) unilateral diffuse iris atrophy and stellate keratic precipitates. The overall accuracy for anterior uveitides was 97.5% in the training set (95% confidence interval [CI] 96.3, 98.4) and 96.7% in the validation set (95% CI 92.4, 98.6). The misclassification rates for FUS were 4.7% in the training set and 5.5% in the validation set, respectively. Conclusions The criteria for Fuchs uveitis syndrome had a low misclassification rate and appeared to perform well enough for use in clinical and translational research.

Objectives To assess fairness and bias of a previously validated machine learning opioid misuse classifier. Materials & Methods Two experiments were conducted with the classifier’s original (n = 1000) and external validation (n = 53 974) datasets from 2 health systems. Bias was assessed via testing for differences in type II error rates across racial/ethnic subgroups (Black, Hispanic/Latinx, White, Other) using bootstrapped 95% confidence intervals. A local surrogate model was estimated to interpret the classifier’s predictions by race and averaged globally from the datasets. Subgroup analyses and post-hoc recalibrations were conducted to attempt to mitigate biased metrics. Results We identified bias in the false negative rate (FNR = 0.32) of the Black subgroup compared to the FNR (0.17) of the White subgroup. Top features included “heroin” and “substance abuse” across subgroups. Post-hoc recalibrations eliminated bias in FNR with minimal changes in other subgroup error metrics. The Black FNR subgroup had higher risk scores for readmission and mortality than the White FNR subgroup, and a higher mortality risk score than the Black true positive subgroup (P Discussion The Black FNR subgroup had the greatest severity of disease and risk for poor outcomes. Similar features were present between subgroups for predicting opioid misuse, but inequities were present. Post-hoc mitigation techniques mitigated bias in type II error rate without creating substantial type I error rates. From model design through deployment, bias and data disadvantages should be systematically addressed. Conclusion Standardized, transparent bias assessments are needed to improve trustworthiness in clinical machine learning models.

Purpose To determine classification criteria for Vogt-Koyanagi-Harada (VKH) disease Design Machine learning of cases with VKH disease and 5 other panuveitides. Methods Cases of panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand twelve cases of panuveitides, including 156 cases of early-stage VKH and 103 cases of late-stage VKH, were evaluated. Overall accuracy for panuveitides was 96.3% in the training set and 94.0% in the validation set (95% confidence interval 89.0, 96.8). Key criteria for early-stage VKH included: 1) exudative retinal detachment with characteristic appearance on fluorescein angiogram or optical coherence tomography or 2) panuveitis with ≥2 of 5 neurologic symptoms/signs. Key criteria for late-stage VKH included history of early-stage VKH and either: 1) sunset glow fundus or 2) uveitis and ≥1 of 3 cutaneous signs. The misclassification rates in the learning and validation sets for early-stage VKH were 8.0% and 7.7%, respectively, and for late-stage VKH 1.0% and 12%, respectively. Conclusions The criteria for VKH had a reasonably low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for juvenile idiopathic arthritis (JIA)-associated chronic anterior uveitis (CAU). Design Machine learning of cases with JIA CAU and 8 other anterior uveitides. Methods Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand eighty-three cases of anterior uveitides, including 202 cases of JIA CAU, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for JIA CAU included 1) chronic anterior uveitis (or if newly diagnosed insidious onset) and 2) JIA, except for the systemic, rheumatoid factor-positive polyarthritis, and enthesitis related arthritis variants. The misclassification rates for JIA CAU were 2.4% in the training set and 0% in the validation set, respectively. Conclusions The criteria for JIA CAU had a low misclassification rate and appeared to perform well enough for use in clinical and translational research.

Hong The Nguyen,1,2 Ngoc Dong Pham,3 Tung Quoc Mai,2 Hang Thi Thuy Do,3 Duong Thi Nga Nguyen,3 Peter McCluskey,4 Trong Van Pham2 1Department of Ophthalmology, 108 Military Central Hospital, Hanoi, Vietnam; 2Department of Ophthalmology, Hanoi Medical University, Hanoi, Vietnam; 3Department of Cornea, Vietnam National Eye Hospital, Hanoi, Vietnam; 4Department of Ophthalmology, University of Sydney, Sydney, NSW, AustraliaCorrespondence: Tung Quoc MaiDepartment of Ophthalmology, Hanoi Medical University, 1 Ton That Tung Street, Hanoi, 100000, VietnamTel +84 915644181Email maiquoctung@hmu.edu.vnPurpose: To evaluate the result of tectonic deep anterior lamellar keratoplasty (DALK) for keratitis with perforation and descemetocele.Patients and Methods: A prospective clinical study of 36 patients (36 eyes) treated with tectonic DALK for corneal perforation or descemetocele from microbial keratitis managed at the Vietnam National Eye Hospital over a two-year period. The surgical technique was manual lamellar dissection. The grafts were harvested from the anterior corneal cap of pre-cut donor tissues used for DSAEK or donor corneas with a low endothelial cell count.Results: A mean age was 55.36 ± 13.98 years (ranged from 25 to 75 years). Female gender represented 52%. causative agents were herpes simplex virus (58.3%), bacteria (22.2%), fungi (13.9%) and microsporidia (5.6%). There were 24 eyes with descemetocele (66.7%) and 12 with perforation (33.3%). There were 33 successful cases (91.7%) and 3 failed cases (8.3%). Best corrected visual acuity (BCVA) improved in 28 eyes (84.8%). The range of post-operative BCVA was from hand motions to 20/70. Eleven eyes (33.3%) attained vision 20/200 and higher. Clear graft was obtained in 15 eyes (45.5%), while mild or severe graft opacity was observed in 14 eyes (42.4%), and 4 eyes (12.1%), respectively. Surgical complications included descemet rupture (20.8%), pseudo anterior chamber (41.6%), persistent corneal epithelial defects (8.3%), reinfection (11.1%), glaucoma or ocular hypertension (5.6%) and cataract (8.3%).Conclusion: The study demonstrates that DALK is an effective procedure to treat corneal descemetocele, especially when an urgent penetrating keratoplasty (PKP) cannot be performed.Keywords: deep anterior lamellar keratoplasty, DALK, descemetocele, corneal perforation, corneal transplantation

Purpose To determine classification criteria for varicella zoster virus (VZV) anterior uveitis DESIGN: Machine learning of cases with VZV anterior uveitis and 8 other anterior uveitides. Methods Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand eighty-three cases of anterior uveitides, including 123 cases of VZV anterior uveitis, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for VZV anterior uveitis included unilateral anterior uveitis with either 1) positive aqueous humor polymerase chain reaction assay for VZV; 2) sectoral iris atrophy in a patient ≥60 years of age; or 3) concurrent or recent dermatomal herpes zoster. The misclassification rates for VZV anterior uveitis were 0.9% in the training set and 0% in the validation set, respectively. Conclusions The criteria for VZV anterior uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for multifocal choroiditis with panuveitis (MFCPU) DESIGN: : Machine learning of cases with MFCPU and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the posterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 138 cases of MFCPU, were evaluated by machine learning. Key criteria for MFCPU included: 1) multifocal choroiditis with the predominant lesions size >125 µm in diameter; 2) lesions outside the posterior pole (with or without posterior involvement); and either 3) punched-out atrophic chorioretinal scars or 4) more than minimal mild anterior chamber and/or vitreous inflammation. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for MFCPU were 15% in the training set and 0% in the validation set. Conclusions The criteria for MFCPU had a reasonably low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for Behcet disease uveitis. Design Machine learning of cases with Behcet disease and 5 other panuveitides. Methods Cases of panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation set. Results One thousand twelve of cases panuveitides, including 194 cases of Behcet disease with uveitis, were evaluated by machine learning. The overall accuracy for panuveitides was 96.3% in the training set and 94.0% in the validation set (95% confidence interval 89.0, 96.8). Key criteria for Behcet disease uveitis were a diagnosis of Behcet disease using the International Study Group for Behcet Disease criteria and a compatible uveitis, including: 1) anterior uveitis; 2) anterior chamber and vitreous inflammation; 3) posterior uveitis with retinal vasculitis and/or focal infiltrates; or 4) panuveitis with retinal vasculitis and/or focal infiltrates. The misclassification rates for Behcet disease uveitis were 0.6 % in the training set and 0% in the validation set, respectively. Conclusions The criteria for Behcet disease uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for sarcoidosis-associated uveitis DESIGN: Machine learning of cases with sarcoid uveitis and 15 other uveitides. Methods Cases of anterior, intermediate, and panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training sets to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation sets. Results One thousand eighty-three anterior uveitides, 589 intermediate uveitides, and 1012 panuveitides, including 278 cases of sarcoidosis-associated uveitis, were evaluated by machine learning. Key criteria for sarcoidosis-associated uveitis included a compatible uveitic syndrome of any anatomic class and evidence of sarcoidosis, either 1) a tissue biopsy demonstrating non-caseating granulomata or 2) bilateral hilar adenopathy on chest imaging. The overall accuracy of the diagnosis of sarcoidosis-associated uveitis in the validation set was 99.7% (95% confidence interval 98.8, 99.9).The misclassification rates for sarcoidosis-associated uveitis in the training sets were: anterior uveitis 3.2%, intermediate uveitis 2.6%, and panuveitis 1.2%; in the validation sets the misclassification rates were: anterior uveitis 0%, intermediate uveitis 0%, and panuveitis 0%, respectively. Conclusions The criteria for sarcoidosis-associated uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for birdshot chorioretinitis. Design Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with: 1) the characteristic appearance a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots ("birdshot" spots); 2) absent to mild anterior chamber inflammation; and 3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either: 1) classic "birdshot spots" or 2) characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set. Conclusions The criteria for birdshot chorioretinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Albumin solution is a colloid used for resuscitation in cardiac surgical patients, but it is unclear if it offers advantages over crystalloids. We examined current clinical practice across 11 cardiac surgical centres and the association of albumin with outcomes in a cohort of bleeding cardiac surgical patients. This was a post hoc analysis of data from the Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery (FIBRES) trial. Multivariable regression models adjusted for demographic and surgical characteristics were used to examine predictors of early albumin administration (within the initial 24 perioperative hours), late albumin administration (from 24 hr to seven days after cardiopulmonary bypass), and the association of albumin use with 28-day acute kidney injury, mortality, and length of hospital and intensive care unit (ICU) stay. Of the 735 patients included, 525 (71%) received albumin, ranging from 4.8% to 97.4% of patients across institutions, with 475 (64.6%) receiving albumin early (5% or 25% solution). In the adjusted models, female sex and preoperative hospital admission were associated with early use, while heart failure, female sex, bleeding severity, older age, and prior albumin use were predictors of later administration. Early albumin use was not associated with differences in acute kidney injury (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI], 0.96 to 3.27; P = 0.07), mortality (aOR 1.66; 95% CI, 0.99 to 2.78; P = 0.05), or length of ICU stay (P = 0.11) or hospital stay (P = 0.67). Albumin use is common but highly variable within and across sites. Albumin use was not associated with improved outcomes. High quality randomized controlled trials should clarify its role in cardiac surgical patients.

Purpose Mer tyrosine kinase-retinitis pigmentosa (MERTK-RP) causes a primary defect in the retinal pigment epithelium, which subsequently affects rod and cone photoreceptors. The study aims to identify the most appropriate MERTK-RP biomarkers to measure disease progression for deciding the optimum therapeutic trial intervention time. Materials and methods Patients' data from baseline (BL) and last follow-up (LFU) were reviewed. Best corrected visual acuity (BCVA), spectral domain-optical coherence tomography (SD-OCT), ultra-widefield fundus autofluorescence (UWF-FAF) patterns, kinetic perimetry (KP), and electroretinography (ERG) parameters were analyzed. Results Five patients were included with the mean age of 17.7 ± 14.4 years old (6.7-42.3) at BL and mean BCVA follow-up of 8.4 ± 5.1 years. Mean BCVA at BL and LFU were 0.84 ± 0.86 LogMAR and 1.14 ± 0.86 LogMAR, respectively. The BCVA decline rate was 0.05 ± 0.03 LogMAR units/year. Ellipzoid zones (EZ) were measurable in eight eyes with mean BL length of 1293.75 ± 421.07 µm and reduction of 140.95 ± 69.28 µm/year and mean BL CMT of 174.2 ± 37.52 µm with the rate of 11.2 ± 12.77 µm declining/year. Full-field ERG (ffERG) and pattern ERG (pERG) were barely recordable. UWF-FAF showed central macular hyper-autofluorescence (hyperAF). KP (III4e and V4e) was normal in two eyes, restricted nasally in four eyes, superior wedge defect in two eyes and undetectable in two eyes. The four restricted nasally KPs became worse, while the others stayed almost unchanged. Conclusions This cohort showed early visual loss, moderately rapid EZ reduction and macular hyperAF. EZ, CMT, and BCVA were consistently reduced. Relative rapid decline in these biomarkers reflecting visual function suggests an early and narrow timespan for intervention.

In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 μM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.

Background Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 (COVID‐19). We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. Methods We performed a single‐center prospective study of 14 adult COVID‐19(+) intensive care unit patients who were age‐ and sex‐matched to 14 COVID‐19(−) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher's linear discriminant function. Linear repeated‐measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts. Results Elevated D‐dimer was the strongest contributor in distinguishing COVID‐19 status; however, D‐dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor‐1 (PAI‐1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k‐means clustering on these biomarkers alone identified two clusters of COVID‐19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI‐1 levels, and lower plasminogen levels. Conclusions Longitudinal trajectories of clot lysis time, sTM, PAI‐1, and plasminogen may have predictive ability for mortality in COVID‐19.

A 66-years-old Vietnamese healthy female patient presented with prolonged severe right ocular pain and complete vision loss in that eye. Anterior segment assessment including gonioscopy identified angle-closure configuration. A suspected ciliary body melanoma was seen through the pupil. Posterior segment examination revealed a large tumor mass and 360° retinal detachment (kissing configuration). An ultrasound examination was consistent with a uveal tumor. The painful, blind right eye with a tumor mass was enucleated. Histopathology confirmed a type A uveal spindle cell melanoma associated with total serous retinal detachment without evidence of tumor necrosis, epithelioid cells, scleral, or optic nerve infiltration. There was no evidence of metastasis after 1-year of follow-up. It is critically important to differentiate primary and secondary angle closure, especially in cases with life-threatening ocular malignancy as uveal melanoma.

Background Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy. Methods Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO. Conclusion Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.

Veterinary nurses work closely with their patients to deliver a high quality of care. This care is implemented using nursing care plans (NCPs). This article aims to evaluate the use of a nursing care plan and its value in practice as well as enhancing nurses' understanding of them. Within this article the author will be discussing the actual and potential problems and implementing the nursing interventions in a nursing care plan pre, post surgery and at discharge in a thyroidectomy case. Veterinary nurses play an important role in making sure the NCP is successful and patients receive the best quality of care. This article evaluates the benefits and disadvantages of NCPs to determine whether they are useful for nursing care of surgical cases.

Objective To systematically review health care professionals’ practices and attitudes toward addressing sexuality with people who are living with chronic disease and disability. Data Sources Scopus, PubMed, PsycINFO, Cumulative Index to Nursing and Allied Health, Allied and Complementary Medicine Database, and MEDLINE were searched to August 2020 for English language publications. Reference lists of relevant publications were also searched. Study Selection Eligible studies reported on knowledge, attitudes, and behaviors of health care professionals about addressing sexuality in the context of chronic disease and disability. The search yielded 2492 records; 187 full texts were assessed for eligibility and 114 documents were included (103 unique studies). Study quality was rated using the Mixed Methods Appraisal Tool. Data Extraction Characteristics of included studies were recorded independently by 2 authors. Differences were resolved through discussion or by a third author. Data Synthesis A sequential, exploratory mixed studies approach was used for synthesis. Pooled analysis showed that 14.2% (95% CI, 10.6-18.9 [I2=94.8%, P Conclusion Despite recognizing the value of sexuality to health and well-being, most health professionals regardless of clinical context fail to routinely include assessment of sexuality in their practice. Professionals have limited knowledge and confidence when addressing sexuality and experience significant discomfort when raising this topic with people living with chronic disease and disability. Multicomponent implementation programs are needed to improve health professionals’ knowledge, competence, and comfort when addressing sexuality for people living with chronic disease and disability.