Deep learning and inverse discovery of polymer self-consistent field theory inspired by physics-informed neural networks.

We devise a deep learning solver inspired by physics-informed neural networks (PINNs) to tackle the polymer self-consistent field theory (SCFT) equations for one-dimensional AB-diblock copolymers. The PINNs framework comprises two parallel feedforward neural networks that separately represent the segmental partition functions and self-consistent chemical potential fields. The two networks are coupled through a loss function incorporating the governing equation, initial and boundary conditions, and the incompressibility constraint. To avoid the metastable homogeneous solution, the network parameters are initialized based on known self-consistent fields obtained from the numerical pseudospectral method. For copolymers of length N at a given volume fraction of A block (f) and the reduced Flory-Huggins interaction parameter (χN), the minimization of the loss function leads to the converged network parameters that successfully capture the stable lamellar phase. The periodicity of the lamellar structure is correctly reproduced for the explored sets of [f,χN], irrespective of the presumed computational domain size for initialization. Moreover, the proposed PINNs are applicable to the inverse discovery of the interaction parameter and the embedded chemical potential fields for an observed structure. This capability of solving the inverse SCFT problem demonstrates the potential of using PINNs to accelerate the exploration of new polymeric materials.

Effective interventions to improve the quality of critically high point-of-care glucose meter results.

OBJECTIVES: Point-of-care testing (POCT) is testing performed outside the traditional laboratory, often at the patient bedside. In hospital settings, blood glucose is the most common POCT. Staff performing POCT are not usually laboratory trained; they are clinical staff with a primary focus on treating patients. Clinical staff find POCT quality assurance (QA) practices burdensome and are often non-compliant. In hospitals within EORLA (Eastern Ontario Regional Laboratories Association), all critically high POCT glucose results must be repeated prior to acting, according to policy. Compliance with this policy is audited regularly. DESIGN: and methods: All POCT glucose tests performed in participating sites between January and June 2018 and June and December 2019 were audited for compliance with the critical repeat policy. The discordant repeat rate was also determined for each audit period. Between January and May 2019, there were interventions aimed at improving compliance with the repeat policy. RESULTS: Compliance with the critical repeat policy increased from 30 to 57% in 2019 compared to 2018, following nursing education and implementation of notifications on the glucose meters themselves. The rate of discordant repeat results (>20% different from initial) also improved at most sites in 2019 compared to 2018. Nurses cited insufficient cleaning of patient hands prior to initial testing as the primary reason for discordant repeats. CONCLUSIONS: Operator compliance with POCT QA policies is an ongoing challenge requiring continual audit, feedback and education. A strong POCT multi-disciplinary committee with supports from senior and clinical leadership in an organization are key to improving compliance.

Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy.

The internal motions of integral membrane proteins have largely eluded comprehensive experimental characterization. Here the fast side-chain dynamics of the α-helical sensory rhodopsin II and the ß-barrel outer membrane protein W have been investigated in lipid bilayers and detergent micelles by solution NMR relaxation techniques. Despite their differing topologies, both proteins have a similar distribution of methyl-bearing side-chain motion that is largely independent of membrane mimetic. The methyl-bearing side chains of both proteins are, on average, more dynamic in the ps-ns timescale than any soluble protein characterized to date. Accordingly, both proteins retain an extraordinary residual conformational entropy in the folded state, which provides a counterbalance to the absence of the hydrophobic effect. Furthermore, the high conformational entropy could greatly influence the thermodynamics underlying membrane-protein functions, including ligand binding, allostery, and signaling.

Polo-like kinase 1 as a therapeutic target for malignant peripheral nerve sheath tumors (MPNST) and schwannomas.

Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are two dominantly inherited disorders that cause tumors in Schwann cells. NF1 patients have a high risk for malignant peripheral nerve sheath tumors (MPNST), which are often inoperable and do not respond well to current chemotherapies or radiation. NF2 patients have a high risk for schwannomas. To identify potential therapeutic targets in these two tumors, we screened the NF1 MPNST cell line, ST88-14, and the NF2 schwannoma cell line, HEI-193, against ~2000 drugs of known mechanisms of action (including ~600 cancer relevant drugs), and also screened the cell lines against an siRNA library targeting most protein kinases. Both the drug screen and the siRNA screen identified Polo-like kinase 1 (PLK1) among the most potent hits in both cell lines. Since PLK1 acts on the cell cycle primarily at the G2/M transition, the same stage where aurora kinase (AURKA) acts, we explored PLK1 and its relationship to aurora kinase in MPNST. Quantitative profiling of PLK1 inhibitors against a panel of 10 neurofibromatosis cell lines found that they were potent inhibitors and, unlike AURKA inhibitors, were not more selective for NF1 over NF2 tumor cells. Furthermore, one PLK1 inhibitor, BI6727 stabilized tumor volume in MPNST xenografts. We conclude that PLK1 is a therapeutic target for MPNSTs and schwannomas, but inhibitors may have a narrow therapeutic index that limits their use as a single agent.

Improving yields of deuterated, methyl labeled protein by growing in H2O.

Solution NMR continues to make strides in addressing protein systems of significant size and complexity. A fundamental requirement to fully exploit the 15N-1H TROSY and 13C-1H3 methyl TROSY effects is highly deuterated protein. Unfortunately, traditional overexpression in Escherichia coli (E. coli) during growth on media prepared in D2O leads to many difficulties and limitations, such as cell toxicity, decreased yield, and the need to unfold or destabilize proteins for back exchange of amide protons. These issues are exacerbated for non-ideal systems such as membrane proteins. Expression of protein during growth in H2O, with the addition of 2H-labeled amino acids derived from algal extract, can potentially avoid these issues. We demonstrate a novel fermentation methodology for high-density bacterial growth in H2O M9 medium that allows for appropriate isotopic labeling and deuteration. Yields are significantly higher than those achieved in D2O M9 for a variety of protein targets while still achieving 75-80% deuteration. Because the procedure does not require bulk D2O or deuterated glucose, the cost per liter of growth medium is significantly decreased; taking into account improvements in yield, these savings can be quite dramatic. Triple-labeled protein is also efficiently produced including specific 13CH3 labeling of isoleucine, leucine, and valine using the traditional ILV precursors in combination with an ILV-depleted mix of 2H/15N amino acids. These results are demonstrated for the membrane protein sensory rhodopsin II and the soluble proteins human aldoketoreductase AKR1c3, human ubiquitin, and bacterial flavodoxin. Limitations of the approach in the context of very large molecular weight proteins are illustrated using the bacterial Lac repressor transcription factor.

Comprehensive pharmacological profiling of neurofibromatosis cell lines.

Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide. We profiled seven NF1-associated MPNST cell lines (ST88-14, ST88-3, 90-8, sNF02.2, T265, S462TY, SNF96.2), one sporadic MPNST cell line (STS26), one schwannoma from a NF2 patient (HEI193), one NF2-deficient malignant meningioma (KT21-MG-Luc5D), one mouse NF2 schwannoma (SC4) and one sporadic rat schwannoma (RT4-67 or RT4). NF1 cells were primarily distinguished from NF2 cells and the sporadic MPNST cell line by their sensitivity to MEK and ERK inhibitors, and to a smaller extent their sensitivity to BH3 mimetics and farnesyl transferase inhibitors. The platform was highly successful in predicting the effects of clinical trials for Neurofibromas.

Pediatric reference value distributions and covariate-stratified reference intervals for 29 endocrine and special chemistry biomarkers on the Beckman Coulter Immunoassay Systems: a CALIPER study of healthy community children.

BACKGROUND: The CALIPER program is a national research initiative aimed at closing the gaps in pediatric reference intervals. CALIPER previously reported reference intervals for endocrine and special chemistry markers on Abbott immunoassays. We now report new pediatric reference intervals for immunoassays on the Beckman Coulter Immunoassay Systems and assess platform-specific differences in reference values. METHODS: A total of 711 healthy children and adolescents from birth to <19 years of age were recruited from the community. Serum samples were collected for measurement of 29 biomarkers on the Beckman Coulter Immunoassay Systems. Statistically relevant age and/or gender-based partitions were determined, outliers removed, and reference intervals calculated in accordance with Clinical and Laboratory Standards Institute (CLSI) EP28-A3c guidelines. RESULTS: Complex profiles were observed for all 29 analytes, necessitating unique age and/or sex-specific partitions. Overall, changes in analyte concentrations observed over the course of development were similar to trends previously reported, and are consistent with biochemical and physiological changes that occur during childhood. Marked differences were observed for some assays including progesterone, luteinizing hormone and follicle-stimulating hormone where reference intervals were higher than those reported on Abbott immunoassays and parathyroid hormone where intervals were lower. CONCLUSIONS: This study highlights the importance of determining reference intervals specific for each analytical platform. The CALIPER Pediatric Reference Interval database will enable accurate diagnosis and laboratory assessment of children monitored by Beckman Coulter Immunoassay Systems in health care institutions worldwide. These reference intervals must however be validated by individual labs for the local pediatric population as recommended by CLSI.

Lattice dystrophy-like localized amyloidosis of the cornea secondary to trichiasis.

PURPOSE: To report a case of stellate and branching linear corneal stromal amyloid deposits secondary to trichiasis and the use of molecular genetic analysis to exclude lattice corneal dystrophy. METHODS: Case report and review of the literature. A 30-year-old man with a history of chronic ocular irritation was found to have distichiasis, epiblepharon, and unilateral corneal amyloidosis indistinguishable from lattice corneal dystrophy. Screening of the TGFBI gene was performed to rule out a previously reported mutation associated with lattice corneal dystrophy. RESULT: A corneal biopsy performed before presentation to the authors confirmed the presence of corneal amyloidosis. Screening of exons 4, 11, 12, and 14 in the TGFBI gene identified 2 previously reported polymorphisms, Leu472Leu and Phe540Phe, but no other coding region changes. CONCLUSION: Corneal stromal amyloidosis clinically resembling lattice corneal dystrophy may be associated with trichiasis. The exclusion of a TGFBI-associated corneal dystrophy in this case, leaving trichiasis as the most likely cause of the corneal amyloid deposition, demonstrates the utility of molecular genetic analysis in confirming or refuting a presumptive clinical diagnosis.

Macular hemorrhage after laser in situ keratomileusis (LASIK) with femtosecond laser flap creation.

PURPOSE: To report the first case of macular hemorrhage following laser in situ keratomileusis (LASIK) with femtosecond laser flap creation. DESIGN: Observational case report. METHODS: A 36-year-old woman underwent uncomplicated, bilateral, simultaneous LASIK procedures for correction of moderate myopia (-5.00 diopters OD and -6.00 diopters OS). LASIK flap creation was performed using the IntraLase femtosecond laser. RESULTS: On postoperative day 1, the patient's uncorrected and best-corrected visual acuities were 20/20 OD and 20/40 OS. A dilated fundoscopic examination revealed a one-third disk diameter macular hemorrhage OS. An intravenous fluorescein angoiogram ruled out the presence of predisposing macular pathology. Two months after LASIK, the macular hemorrhage had cleared, and 6 months later, the BCVA improved to 20/25 OS. CONCLUSIONS: Macular hemorrhage may occur after LASIK, even in the absence of previously identified risk factors, such as high myopia, pre-existing choroidal neovasculaization, lacquer cracks, and sudden changes in intraocular pressure associated with microkeratome-assisted flap creation.

Custom-contoured ablation pattern method for the treatment of decentered laser ablations.

PURPOSE: To evaluate the custom-contoured ablation pattern (C-CAP) method as a tool for providing customized laser ablations for decentered ablations based on corneal topography data. SETTING: Department of Ophthalmology, Stanford University, Stanford, California, USA. METHODS: In a prospective noncomparative interventional case series, 8 eyes from 7 post-laser in situ keratomileusis (LASIK) patients and 1 post-photorefractive keratectomy (PRK) patient with symptomatic laser decentration were treated with the C-CAP method. The Zeiss Humphrey topography system was used to identify and analyze decentered ablations. The computer software allowed the surgeon to preoperatively model the effect of various ablation schemes on the preoperative topography until a scheme that alleviated the decentration was identified. The planned ablation parameters, which included size, depth, and location of the ablation, were programmed into the Visx S4 excimer laser before treatment. RESULTS: The mean follow-up after C-CAP ablation was 4.2 months (range 1.8 to 6.3 months). At the last postoperative examination, no eye lost a line of best spectacle-corrected visual acuity (BSCVA). The uncorrected visual acuity (UCVA) improved by 3 lines in 1 eye (12.5%), by 2 lines in 1 eye (12.5%), and by 1 line in 3 eyes (37.5%); it remained unchanged in 2 eyes (25.0%) and decreased by 1 line in 1 eye (12.5%). The BSCVA improved by 3 lines in 1 eye (12.5%), by 2 lines in 2 eyes (25.0%), and by 1 line in 3 eyes (37.5%); it remained unchanged in 2 eyes (25.0%). In all eyes, including those without improvement in UCVA or BSCVA, a significant improvement in centration and subjective complaints was achieved. The pre-C-CAP and post-C-CAP root-mean-square (RMS) wavefront data were available in 5 of 8 eyes. The total and higher-order RMS aberrations decreased by 41.7% (P =.0027) and 45.5% (P =.039), respectively, after C-CAP treatment. CONCLUSIONS: Early U.S. results show the topography-driven C-CAP method is an effective tool to address untreatable postsurgical decentration. This method is presented as a technique to enhance the overall quality of vision, reduce patient-perceived visual aberrations, regularize the corneal surface, and maximize BSCVA.

Anterior basement membrane corneal dystrophy and pseudo-unilateral lattice corneal dystrophy in a patient with recurrent corneal erosions.

PURPOSE: To report the utility of genetic testing in the diagnosis and management of patients with suspected corneal dystrophies. DESIGN: Case report. METHODS: A 58-year-old man with a history of recurrent corneal erosions was diagnosed with bilateral anterior basement membrane dystrophy and unilateral lattice corneal dystrophy. All 17 exons of the TGFBI gene were screened for mutations previously associated with lattice corneal dystrophy as well as novel coding region changes. RESULTS: No mutations were found in the 17 exons of the TGFBI gene. A nucleotide change in exon 6 (651C>G) did not result in a change in the encoded amino acid (Leu217Leu). CONCLUSIONS: In cases of suspected TGFBI corneal dystrophies, genetic testing is a useful tool to confirm the clinical diagnosis. In this case of suspected unilateral lattice corneal dystrophy, screening of the TGFBI gene ruled out the diagnosis, raising the possibility that the corneal changes were related to the coexistent anterior basement membrane dystrophy.

Dense pigmentation of the posterior lens capsule associated with the pigment dispersion syndrome.

PURPOSE: To report an unusual case of pigment dispersion syndrome associated with unilateral dense pigmentation of the posterior lens capsule. METHODS: Case report. RESULTS: A 59-year-old male with bilateral pigment dispersion syndrome presented with progressive decrease in visual acuity in the left eye over the past 10 to 20 years. Clinical examination revealed the typical findings of pigment dispersion syndrome including the presence of bilateral Krunkenberg spindles, iris transillumination defects, and heavy trabecular meshwork pigmentation. Of note, there was remarkably dense pigmentation of the posterior lens capsule in the eye with decreased visual acuity. CONCLUSION: Pigmentation of the posterior lens capsule may be a rare finding associated with pigment dispersion syndrome. Such a finding suggests that there may be aqueous flow into the retrolental space in some patients with this condition. The optimal treatment of this unusual condition remains undetermined.

Two-year results of conductive keratoplasty for the correction of low to moderate hyperopia.

PURPOSE: To evaluate the 2-year postoperative safety, efficacy, predictability, and stability results of conductive keratoplasty (CK) to correct low to moderate hyperopia. SETTING: Department of Ophthalmology, Stanford University Medical Center, Stanford, California, USA. METHODS: In a prospective nonrandomized noncontrolled trial, 25 eyes of 14 patients with +0.75 to +3.00 diopters (D) of hyperopia and

The sensitivity and specificity of single-field nonmydriatic monochromatic digital fundus photography with remote image interpretation for diabetic retinopathy screening: a comparison with ophthalmoscopy and standardized mydriatic color photography.

PURPOSE: To evaluate single-field digital monochromatic nonmydriatic fundus photography as an adjunct in the screening of diabetic retinopathy. DESIGN: Prospective, comparative, observational case series. METHODS: Patients with type I and type II diabetes mellitus (n = 197) were sequentially evaluated by three different techniques: single-field digital monochromatic nonmydriatic photography; dilated ophthalmoscopy by an ophthalmologist; and seven Early Treatment Diabetic Retinopathy Study (ETDRS) standardized 35-mm color stereoscopic mydriatic images. The seven stereoscopic color photographs served as the reference standard and were compared with either ophthalmoscopy or a single digital photograph transmitted electronically to a reading site. Levels of agreement were determined by kappa analyses. The sensitivity and specificity of the three methods were compared based on a threshold for referral to further ophthalmologic evaluation (ETDRS level > or =35). RESULTS: There was highly significant agreement (kappa = 0.97, P =.0001) between the degree of retinopathy detected by a single nonmydriatic monochromatic digital photograph and that seen in seven standard 35-mm color stereoscopic mydriatic fields. The sensitivity of digital photography compared with color photography was 78%, with a specificity of 86%. Agreement was poor (kappa = 0.40, P =.0001) between mydriatic ophthalmoscopy and the seven-field standard 35-mm color photographs. Sensitivity of ophthalmoscopy compared with color photography was 34%, with a specificity of 100%. CONCLUSION: A single nonmydriatic monochromatic wide-field digital photograph of the disk and macula was more sensitive for diabetic retinopathy screening than mydriatic ophthalmoscopy, the currently accepted screening method. When adjudicated by standard seven-field color photographs, the higher sensitivity of digital photography primarily reflected the reduced sensitivity of ophthalmoscopy in detecting early retinopathy.

Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV infected patients: natural history and clinical predictors.

PURPOSE: To characterize the natural course and clinical predictors of cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients after initiation of highly active antiretroviral therapy (HAART). METHODS: Retrospective analysis of 53 HIV-positive patients (73 eyes with CMV retinitis) treated with and without HAART. All participants continued to take anti-CMV therapy. Survival analysis was used to characterize the natural course of CMV retinitis. Proportional hazards analysis was performed to assess the correlation of the nine potential clinical predictors (baseline CD4 count, post-HAART CD4 count, post-HAART rise in CD4 count, baseline weight, post-HAART rise in weight, post-HAART percentage rise in weight, log of baseline HIV viral load, log of minimum post-HAART HIV viral load, and post-HAART log unit reduction in HIV viral load) with the duration of CMV retinitis remission. RESULTS: Patients receiving HAART had a median CMV retinitis remission duration of 574 days (95% confidence interval, 336-NA) whereas those not receiving HAART had a median remission duration of 80.5 days (95% confidence interval, 28-NA; P < 0.001). Within the HAART-treated population, the minimal viral load reached after HAART was the only clinical predictor to demonstrate significance (P = 0.0075). Several other clinical predictors demonstrated borderline significance; however, this was most likely due to the high correlation of these variables with the minimum post-HAART viral load. A potential secondary clinical predictor identified was the post-HAART rise in CD4 count (P = 0.085). CONCLUSION: With the introduction of HAART, HIV-infected patients have much longer remission durations from recurrent CMV retinitis. The minimum HIV viral load level reached after the initiation of HAART treatment appears to be more important than other clinical variables in the prediction of favorable CMV retinitis remission status. Furthermore, a rise in CD4 T-lymphocyte count by itself appears to be a less significant clinical predictor but may be useful in combination with the HIV viral load data. Selective discontinuation of anti-CMV therapy may be considered in patients with a favorable set of clinical predictors.