Modelling of AgrA inhibitors to combat anti-microbial resistance in Staphylococcus aureus.

Staphylococcus aureus is a Gram-positive bacterium found on human skin that causes skin and soft tissue infections, as well as pneumonia, osteomyelitis, and endocarditis. The prevalence of antibiotic resistant strains has made the treatments less effective. An efficient alternate method for battling these contagious diseases is anti-virulence strategy. The AgrA protein, a key activator of Accessory Gene Regulator system in S. aureus, is vital to the virulence of the organism and, consequently, its pathogenesis. Using a Machine Learning algorithm, the Support Vector Machine (SVM), and a ligand-based pharmacophore modelling method, prediction models of AgrA inhibitors were developed. The metrics of the SVM model were inadequate, hence it was not used for virtual screening. For ligand-based pharmacophore modelling, 14 of 29 compounds were removed from the active set due to a lack of shared pharmacophore properties, and 504 compounds were designated as decoys. A 3D pharmacophore model was created using LigandScout 4.4.5, with a fit score of 57.48, including a positive ionizable group, one hydrogen bond donor, and three hydrogen bond acceptors. The model after further validation was used to virtually screen an external database which resulted in six hits. These compounds were docked with the AgrA domain crystal structure to determine the inhibitor activity. Further, each docked complex was subjected to a 100 ns molecular dynamics simulation. CID238 and CID20510252 demonstrated potent inhibitory binding interactions and hence can be used to develop AgrA inhibitors in future after proper validation.Communicated by Ramaswamy H. Sarma.

Comparison of Weight-Gain-Based Prediction Models for Retinopathy of Prematurity in an Australian Population.

Purpose: Four weight-gain-based algorithms are compared for the prediction of type 1 ROP in an Australian cohort: the weight, insulin-like growth factor, neonatal retinopathy of prematurity (WINROP) algorithm, the Children's Hospital of Philadelphia Retinopathy of Prematurity (CHOPROP), the Colorado Retinopathy of Prematurity (CO-ROP) algorithm, and the postnatal growth, retinopathy of prematurity (G-ROP) algorithm. Methods: A four-year retrospective cohort analysis of infants screened for ROP in a tertiary neonatal intensive care unit in Brisbane, Australia. The main outcome measures were sensitivities, specificities, and positive and negative predictive values. Results: 531 infants were included (mean gestational age 28 + 3). 24 infants (4.5%) developed type 1 ROP. The sensitivities, specificities, and negative predictive values, respectively, for type 1 ROP (95% confidence intervals) were for WINROP 83.3% (61.1-93.3%), 52.3% (47.8-56.7%), and 98.4% (96.1-99.4%); for CHOPROP 100% (86.2-100%), 46.0% (41.7-50,3%), and 100% (98.4-100%); for CO-ROP 100% (86.2-100%), 32.0% (28.0%-36.1%), and 100% (98.3-100%); and for G-ROP 100% (86.2-100%), 28.2% (24.5-32.3%), and 100% (97.4-100%). Of the five infants with persistent nontype 1 ROP that underwent treatment, only CO-ROP was able to successfully identify all. Conclusions: CHOPROP, CO-ROP, and G-ROP performed well in this Australian population. CHOPROP, CO-ROP, and G-ROP would reduce the number of infants requiring examinations by 43.9%, 30.5%, and 26.9%, respectively, compared to current ROP screening guidelines. Weight-gain-based algorithms would be a useful adjunct to the current ROP screening.

Multicenter Validation of Deep Learning Algorithm ROP.AI for the Automated Diagnosis of Plus Disease in ROP.

Purpose: Retinopathy of prematurity (ROP) is a sight-threatening vasoproliferative retinal disease affecting premature infants. The detection of plus disease, a severe form of ROP requiring treatment, remains challenging owing to subjectivity, frequency, and time intensity of retinal examinations. Recent artificial intelligence (AI) algorithms developed to detect plus disease aims to alleviate these challenges; however, they have not been tested against a diverse neonatal population. Our study aims to validate ROP.AI, an AI algorithm developed from a single cohort, against a multicenter Australian cohort to determine its performance in detecting plus disease. Methods: Retinal images captured during routine ROP screening from May 2021 to February 2022 across five major tertiary centers throughout Australia were collected and uploaded to ROP.AI. AI diagnostic output was compared with one of five ROP experts. Sensitivity, specificity, negative predictive value, and area under the receiver operator curve were determined. Results: We collected 8052 images. The area under the receiver operator curve for the diagnosis of plus disease was 0.75. ROP.AI achieved 84% sensitivity, 43% specificity, and 96% negative predictive value for the detection of plus disease after operating point optimization. Conclusions: ROP.AI was able to detect plus disease in an external, multicenter cohort despite being trained from a single center. Algorithm performance was demonstrated without preprocessing or augmentation, simulating real-world clinical applicability. Further training may improve generalizability for clinical implementation. Translational Relevance: These results demonstrate ROP.AI's potential as a screening tool for the detection of plus disease in future clinical practice and provides a solution to overcome current diagnostic challenges.

Increased risk of retinopathy of prematurity since increased O2 saturation targets: A multi-centre study.

BACKGROUND/AIMS: Retinopathy of prematurity (ROP) is a leading cause of visual impairment in premature neonates. The BOOST II, SUPPORT and COT trials recommended increasing O2 saturation targets for pre-term neonates to reduce mortality; however, this is a risk factor for ROP. We aimed to determine whether these targets increased prevalence of ROP among pre-term neonates and higher risk groups. METHODS: Retrospective cohort study conducted using data from the Australian and New Zealand Neonatal Network. 17 298 neonate cohort born 2012-2018 at <32 weeks' GA and/or <1500 g BW was analysed. Adjusted odds ratios (aORs) were calculated for post-2015 risk of: any ROP; ROP ≥ Stage 2; and treated ROP. Sub-analysis stratified at <28 GA, < 26 weeks' GA, <1500 g BW and <1000 g BW was performed. RESULTS: Risk of any ROP increased in the post-2015 group (aOR = 1.23, 95% confidence interval (CI) = 1.14-1.32), <28 weeks' GA (aOR = 1.31, 95% CI = 1.17-1.46), <26 weeks (aOR = 1.57, 95% CI = 1.28-1.91), <1500 g (aOR = 1.24, 95% CI = 1.14-1.34) and <1000 g (aOR = 1.34, 95% CI = 1.20-1.50). ROP ≥ Stage 2 increased at <28 weeks (aOR = 1.30, 95% CI = 1.16-1.46), <26 weeks (aOR = 1.57, 95% CI = 1.28-1.91), <1500 g (aOR = 1.18, 95% CI = 1.08-1.30), and <1000 g (aOR = 1.26, 95% CI = 1.13-1.42). CONCLUSION: O2 therapy guidelines since 2015 have resulted in decreased mortality but increased risk of ROP. Individualised NICU adjustments of ROP screening/follow-up methods are necessary to address the clinical burden.

Comparison of biometric and refractive changes in intermittent exotropia with and without overminus lens therapy.

BACKGROUND: Overminus lens is an effective non-surgical treatment of intermittent exotropia (IXT). Whether this treatment causes development of myopia is recently debated. This study evaluated ocular biometric changes in IXT children treated with and without overminus lens. METHODS: Children with IXT were randomly assigned to control and overminus groups. Cycloplegic refraction, axial length and other parameters (keratometry, anterior chamber depth and lens thickness) were evaluated for up to 30 months and compared between the groups. Axial length to corneal curvature (AL/CR) ratio was examined as an indicator of myopia progression. Changes prior to and after overminus were also assessed in a subgroup. RESULTS: Mean age of the total 84 subjects (58% women) was 7.2 years (range 4-15 years). Baseline refractive and biometric parameters of 39 control and 45 overminus subjects were not significantly different. Mean±SD change in refraction was -0.34±0.45D in controls and -0.41±0.66D in overminus group (p=0.527). AL increased by 0.29±0.20 millimetre (mm) in controls and 0.28±0.23 mm in overminus group (p=0.766). In the subgroup, the changes before and after overminus therapy was not significantly different (p>0.05). AL/CR ratio was maintained from baseline to follow-up visit (p=0.298) in both groups. CONCLUSION: No significant differences in biometry or refraction were found between the two groups and before and after the therapy. We conclude that the overminus therapy in children, not accounting for other myopia risk factors, does not affect normal refractive growths.

Validity and repeatability of contour-based visotec distance stereoacuity test.

CLINICAL RELEVANCE: The clinical assessment of distance stereoacuity is important in some ocular conditions. Given the different neurophysiological mechanism for crossed and uncrossed stereoacuities, evaluation of both may provide additional insight into binocular vision disorders. BACKGROUND: Clinical devices measuring distance crossed and uncrossed stereopsis are not readily available. Visotec Distance Stereo Test (VDST) is a contour-based device designed to measure both forms of distance stereoacuity. This study assesses the validity and test-retest reliability of the device in comparison to the random dot-based Randot Distance Stereo Test (RDST). METHOD: VDST and RDST were administered to a total of 107 children, that included 51 'normal' and 56 'abnormal' (37 intermittent exotropia and 19 amblyopia) between the ages of 5 and 15 years. Two examiners retested stereoacuities in a sub-set of 62 randomly selected subjects. Stereoacuity was transformed to log scale. 95% limits of agreement were calculated for test-retest reliability. The Bland-Altman plot was used to demonstrate the agreement between the tests and the examiners. RESULTS: The mean ± SD crossed distance stereoacuities using VDST in normal, intermittent exotropia and amblyopic children were 93.1 ± 43.8, 161.9 ± 89.8 and 236.3 ± 122.4 arcseconds, respectively. For uncrossed stereoacuity, these were 104.7 ± 54.0, 187.6 ± 89.6 and 265.5 ± 144.0 arcseconds, respectively. Crossed stereoacuity was significantly better than uncrossed stereoacuity. 95% limits of test-retest agreement for crossed and uncrossed stereoacuities using the VDST were 0.27 and 0.30, respectively. An exact test-retest match using VDST was 84% in normals and 77% in abnormals for crossed and 83% in normal and 74% in abnormal for uncrossed stereoacuities. CONCLUSION: VDST is a reliable, valid and easy-to-administer distance crossed and uncrossed stereoacuity measuring device. Further studies are required to establish the clinical importance of assessing these two forms stereoacuities in relation to various binocular vision disorders.

Assessment of distance-near control disparity in basic and divergence excess paediatric intermittent exotropia.

CLINICAL RELEVANCE: In intermittent exotropia (IXT), deviation is better controlled at near fixation. Understanding of the mechanism responsible for this common observation may improve clinical management of IXT. BACKGROUND: The physiological basis for the distance-near difference in control of deviation in IXT is vastly undetermined. A new parameter, 'control score disparity (CSD)', defined as the difference between distance and near control scores, is introduced. Association of CSD with positive fusional amplitude (PFA), accommodative convergence to accommodation (AC/A) ratio and distance angle of deviation was investigated to further understand the mechanisms. METHOD: Patients aged between four and fifteen years with basic and divergence excess IXT were included. Subjects with previous strabismus surgery, amblyopia and inability to perform clinical tests were excluded. A standardized office-based scoring system was used to assess IXT controls. Subjects were sub-divided into group 1 (CSD <2) and group 2 (CSD ≥2). Pearson's univariate and regression analysis were used to determine relationships between CSD and other independent variables. RESULTS: Mean age of the total 141 subjects (57.6% female) was 6.8 ± 2.5 years. Basic IXT was more common (60%) and 60% had CSD ≥2. The mean±SD distance angle of deviation, AC/A ratio, PFA and CSD were 22.1 ± 6.6 prism dioptres, 5.0 ± 1.0, 28.6 ± 6.3 prism dioptre and 2.0 ± 0.5, respectively. CSD was significantly correlated to PFA (r = 0.64, p < 0.001) and AC/A ratio (r = 0.27, p < 0.001) in overall samples and Group 2 subjects (r = 0.41, p = 0.001). CONCLUSIONS: PFA is a major factor associated with the distance/near difference of IXT control. Individuals with a higher PFA demonstrated greater CSD. While AC/A ratio was associated in better control at near in divergence excess IXT, magnitude of angle appears irrelevant.

Accommodative Lag Persistence in Treated Anisometropic, Strabismic, and Mixed Amblyopia.

Background: Amblyopic eyes typically exhibit greater lag of accommodation. Whether this improves after amblyopia treatment is inconclusive. The aim of this study is to report post-treatment accommodative response in amblyopia and to investigate if the lag is associated with visual acuity, treatment duration, and amblyopia type. Methods: Monocular and binocular accommodative responses were measured using Nott's method of dynamic retinoscopy in amblyopia of anisometropic, strabismic, and combined anisometropic-strabismic types and age-matched controls with normal vision. The results were compared using the nonparametric Wilcoxon signed ranks test. Linear regression analysis was used to examine association of the lag to refractive error, duration of therapy, and visual acuity. Results: Mean ± SD age of 46 amblyopic and 20 control subjects were 6.9 ± 1.8 and 6.9 ± 2.2 years, respectively. At the time of the study, 30 amblyopic subjects were receiving patching therapy and ceased in the remainder. In amblyopic eyes, mean ± SD monocular and binocular lags were 1.2 ± 0.6D and 1.0 ± 0.5D (p < 0.001), respectively, compared to 0.6 ± 0.3D and 0.5 ± 0.2D (p < 0.005), respectively, in nonamblyopic eyes and 0.4 ± 0.2D and 0.3 ± 0.2D (p=0.093), respectively, in the controls. By types, the monocular lag was significantly higher than the binocular lag (p=0.001) in mixed amblyopia (p=0.004); they were similar in anisometropic (p=0.283) and strabismic (p=0.743) amblyopia. Monocular lag was significantly correlated to BCVA (r = 0.46; p=0.001) and refraction (r = 0.42; p=0.001) but not to patching duration (r = 0.1; p=0.280). Conclusion: Inadequate accommodative response, a higher lag, persists in amblyopic eyes even after the treatment. Impaired accommodative response is partly determined by posttherapy visual acuity. Further studies investigating the effect of accommodative lag on visual recovery and whether optical correction of the deficiency may improve visual outcome of the treatment are recommended.

Idiopathic intracranial hypertension in a child with Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is known to be associated with hydrocephalus, but not with idiopathic intracranial hypertension (IIH). Case presentation: We describe such a case and propose the pathogenesis. We also discuss the challenges of diagnosis, treatment, and monitoring outcomes in this population that is already at high risk of vision loss from retinal dystrophy. CONCLUSION: IIH can result from a combination of risk factors in conjunction with the underlying dysfunctional cilia in BBS patients. Monitoring disease progression is difficult, and as such IIH may be underdiagnosed or missed. Management must be adjusted to account for BBS patients' impaired metabolic and renal physiology. It is important that clinicians be aware of these challenges in this vulnerable population, and regular monitoring should be done to avoid preventable vision loss.

A case of non-traumatic Purpureocillium lilacinum (Paecilomyces lilacinus) endophthalmitis in a child.

PURPOSE: The aim of this report is to cover a novel presentation and subsequent management of Purpureocillium (Paecilomyces) oculomycosis in a child, and to review the available literature on Purpureocillium endophthalmitis. OBSERVATIONS: This report is of a four year old boy from Australia. There have been 13 previous reports of Purpureocillium endophthalmitis, comprising 30 adult cases. CONCLUSIONS: AND IMPORTANCE. Purpureocillium is an emerging ocular infection, associated with use of this fungus as a biological control agent. This case highlights the importance of early consideration of intraocular fluid sampling in a case of vitritis non-responsive to steroid treatment. statementThe first reported case of atraumatic Purpureocillium lilacinum endophthalmitis, occurring in a child. All published Purpureocillium endophthalmitis cases are reviewed.

Optimised minus lens overcorrection for paediatric intermittent exotropia: A randomised clinical trial.

BACKGROUND: Aim of this study was to evaluate the efficacy of a novel algorithm to customise overminus lens therapy in intermittent exotropia (IXT) based on clinical factors associated with control of the deviation. METHODS: Clinical parameters in IXT vary among individuals. Based on individual's physiological factors, an algorithm was developed. Children aged between 4 and 15 years with IXT were randomised into OML and observation groups. Participants in the observation group were corrected for any significant refractive error. IXT control score, angle of deviation, refraction, axial length and stereopsis were examined at baseline and follow up ranging between 6 and 15 months and compared. Compliance and tolerance to OML was determined by a symptom survey. RESULTS: The OML power ranged between -1.00D and - 6.25D. Of the total 141 participants (mean age 6.8 ± 2.5 year), 77 were in the OML and 66 were in observation group. IXT control score improved (mean difference - 2.5 ± 1.1; p < 0.001) and angle of deviation reduced (6.9 ± 7.2pd; p < 0.001) significantly in the OML group only. Compliance rate to OML wear was 80%; 90% never or rarely experienced asthenopia symptoms. Slightly greater myopic shift (-0.36 ± 0.53D vs. -0.18 ± 0.55D) and change in axial length (0.17 vs. 0.14 mm) were observed in the OML group, but these differences were not statistically significant. CONCLUSIONS: A customised OML, calculated using this novel algorithm was effective in improving distance control, angle of deviation and stereopsis. Glasses wear was highly tolerable.

Community based vision screening in preschool children; performance of the Spot Vision Screener and optotype testing.

BACKGROUND: Children's vision screening children commonly uses optotype-based visual acuity or instrument-based methods measuring amblyogenic risk factors (ARFs). OBJECTIVE: To compare the performance of the Spot Vision Screener (SVS) (PediaVision, Welch Allyn, NY) and a nurse-administered visual acuity screen (NVAS) in identifying ARFs and decreased visual acuity. METHODS: A prospective, cross-sectional population-based study of preschool children in South-East Queensland, Australia. Eligible participants had both forms of screening by trained community nurses. All children with an abnormal result by either method as well as a cohort of randomly selected children who passed both assessments were assessed at a tertiary paediatric ophthalmology clinic. RESULTS: Over a 10 month period, 2237 children (mean age; 64.4 ± 4.0 months) were screened from 38 schools. 6.4% of children failed SVS and 8.3% failed NVAS (with 3.8% overlap, failing both). The positive predictive value (PPV) in identifying either ARFs and/or reduced VA for the SVS and NVAS was 70.4% (95% Confidence Interval (CI): 61.6%-78.2%) and 60.5% (95% CI: 52.6%-67.9%) respectively. Highest PPV to detect either ARFs and/or reduced VA was achieved by a 'hybrid' method by combining failed NVAS and failed SVS: 91.0% (95% CI: 82.4 to 96.3) but this would risk children with sight impairment being missed in the community. CONCLUSION: To our knowledge, this is the first population-based study providing detailed comparative measures of diagnostic accuracy for NVAS and SVS in preschool children. One in ten preschool children failed one or both screens. A number of children who required ophthalmic intervention were missed if only one screening method was utilized.

The presence and progression of choroidal neurofibromas in a predominantly pediatric population with neurofibromatosis type-1.

Background: Obtaining a definitive neurofibromatosis type-1 (NF1) diagnosis may take years. The natural history of choroidal neurofibromas in NF1 is unknown. This study evaluates a predominantly pediatric patient cohort for ocular features in NF1, including presence and progression of choroidal abnormalities, to determine their natural history, relationship to other NF1 features, and additive value in NF1 diagnosis.Methods: Retrospective analysis of 106 patients referred for Ophthalmic monitoring or diagnosis of NF1 between January 2012 and December 2018. Clinical records and Near-Infrared Reflectance (NIR) Optical Coherence Tomography imaging were analyzed for prevalence and progression of choroidal neurofibromas on NIR, and relation to other NF1 diagnostic criteria.Results: 54.7% of patients referred had a confirmed NF1 diagnosis, and 45.4% were NF1 suspects. First ophthalmic review resulted in an additional 6.6% patients meeting the diagnostic criteria, and 14.2% later developed sufficient features (total n = 80). Choroidal neurofibromas were present in 75.7% of patients that had NIR imaging and met diagnostic criteria, and detected in the absence of, or prior to Lisch nodules in 13.5%. Progression in the size and number of choroidal neurofibromas occurred in 26 eyes (32.5%) of 14 patients (35.0%), all under 16 years old. Patients without choroidal neurofibromas at first examination never developed them over the study period.Conclusion: Choroidal neurofibromas, detected by NIR imaging, are common in NF1, present early with frequent progression, and represent an additional tool to aid NF1 diagnosis in young children.

Rapid Assessment of Avoidable Blindness and Willingness to Pay for Cataract Surgery in Tribal Region of Surat District of Gujarat State, India.

AIM: To estimate prevalence and causes of avoidable blindness among people ≥50 years and to assess willingness to pay (WTP) for cataract surgery in tribal region of south Gujarat, India. METHODS: A cross-sectional population based survey was conducted with 44 randomly selected clusters each having 50 people aged ≥50 years selected by probability proportional to size of sampling. Adults identified with cataract causing visual loss (<6/18) in any eye were interviewed to assess their WTP for surgery. RESULTS: Total of 2137 examined out of 2200 people enumerated (response rate 97.1%). The prevalence of blindness (Presenting Visual Acuity (PVA)<3/60 in better eye) was 2.23% (95% CI: 2.95%-1.51%). Cataract was main cause of blindness (67.3%) followed by corneal scarring (8.2%). Major barrier to cataract surgery cited by bilaterally blind people was lack of escort to the surgical facility (34.3%). Cataract surgical coverage (CSC) was 84.9% (eyes) and 92% (persons). Of the 492 people interviewed to assess WTP for their surgery, only 36.4% people were willing to pay. CONCLUSION: The tribal population has a high poverty profile in India. Within this group, cataract remains the main treatable cause of blindness despite a high CSC. Assessment of barriers suggested that a well-coordinated outreach programme with free transport facilities to the surgical facility is required along with strategies to improve accessibility and prioritising cataract blind in the community. One-third of people were willing to pay for their surgeries implying that cross subsidization or tier system could be feasible for eye care programme sustainability.

A density functional theory/time-dependent density functional theory study of the structure-related photochemical properties of hydroxylated polybrominated diphenyl ethers and methoxylated polybrominated diphenyl ethers and metal ion effects.

As the derivatives and structural analogs of polybrominated diphenyl ethers (PBDEs), hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and methoxylated polybrominated diphenyl ethers (MeO-PBDEs) have attracted increasing concern. However, knowledge of the photochemical behaviors of OH-PBDEs and MeO-PBDEs in water is limited. Here, we used density functional theory and time-dependent density functional theory to examine the structure-related photochemical properties of OH-PBDEs and MeO-PBDEs in water and the effects of metal ions as environmental factors. Eight 6-OH-PBDEs with 1-8 bromine substituents and eight 6-MeO-PBDEs with 1-8 bromine substituents were selected for this study. The optimized geometries of the selected congeners and their complexes with metals in the lowest excited triplet state (T1) showed that one C-Br bond moderately or significantly elongated. The elongated C-Br bond in the T1 state was shown in the ortho-position for the 6-OH-PBDE congeners and the ortho-position or the meta-position for the 6-MeO-PBDE congeners. For the selected congeners, there were significant positive linear correlations between the number of bromine atoms (NBr) and the calculated average atomic charge of bromine and maximum electronic absorbance wavelength (λmax), and a negative linear correlation between the NBr and average bond dissociation energy of C-O bonds (BDEC-O). The photoreactivities of the 6-OH-PBDEs and 6-MeO-PBDEs increased with an increase in the bromination degree with or without metal ions. The calculated average atomic charge of bromine and BDEC-O of the complexes with Mg2+/Zn2+ was higher and lower than those of the corresponding monomers, respectively, indicating that the presence of Mg2+/Zn2+ increased the photoreactivity (debromination and dissociation of C-O bond) of the selected 6-OH-PBDEs and 6-MeO-PBDEs. The effects of the coordination of Mg2+/Zn2+ may be overestimated due to their missing explicit solvation shell. These results provide vital insight into the photochemical properties of OH-PBDEs and MeO-PBDEs in water.

TD-DFT insights into the sensing potential of the luminescent covalent organic framework for indoor pollutant formaldehyde.

This paper investigates the sensitivity of the luminescent thieno[2,3-b]thiophene-based covalent organic framework (TT-COF) towards the formaldehyde using the density functional theory and time-dependent method. The hydrogen bonding dynamics is explored by comparison of geometries, electronic transition energies, binding energies, UV-vis, and infrared spectra. Frontier molecular orbitals examination, natural population analysis, and plotted electron density difference map describe the quenching process explicitly via electron density distribution. The MOMAP program illuminates the quenching owing to TT-COF-HCHO complex radiative rate constant. Furthermore, the S1-T1 energy gap describes the facilitation of the luminescence quenching through the intersystem crossing. Above all results elaborate the TT-COF's potential to detect the formaldehyde.