Monte-Carlo simulation of a thick lens IOL power calculation.

BACKGROUND: The purpose of this Monte-Carlo study is to investigate the effect of using a thick lens model instead of a thin lens model for the intraocular lens (IOL) on the resulting refraction at the spectacle plane and on the ocular magnification based on a large clinical data set. METHODS: A pseudophakic model eye with a thin spectacle correction, a thick cornea (curvatures for both surfaces and central thickness) and a thick IOL (equivalent power PL derived from a thin lens IOL, Coddington factor CL (uniformly distributed from -1.0 to 1.0), either preset central thickness LT = 0.9 mm (A) or optic edge thickness ET = 0.2 mm, (B)) was set up. Calculations were performed on a clinical data set containing 21 108 biometric measurements of a cataractous population based on linear Gaussian optics to derive spectacle refraction and ocular magnification using the thin and thick lens IOL models. RESULTS: A prediction model (restricted to linear terms without interactions) was derived based on the relevant parameters identified with a stepwise linear regression approach to provide a simple method for estimating the change in spectacle refraction and ocular magnification where a thick lens IOL is used instead of a thin lens IOL. The change in spectacle refraction using a thick lens IOL with (A) or (B) instead of a thin lens IOL with identical power was within limits of around ±1.5 dpt when the thick lens IOL was placed with its haptic plane at the plane of the thin lens IOL. In contrast, the change in ocular magnification from considering the IOL as a thick lens instead of a thin lens was small and not clinically significant. CONCLUSION: This Monte-Carlo simulation shows the impact of using a thick lens model IOL with preset LT or ET on the resulting spherical equivalent refraction and ocular magnification. If IOL manufacturers would provide all relevant data on IOL design data and refractive index for all power steps, this would make it possible to perform direct calculations of refraction and ocular magnification.

Impact of uncertainties in biometric parameters on intraocular lens power formula predicted refraction using a Monte-Carlo simulation.

PURPOSE: The purpose of this study was to investigate the uncertainty in the formula predicted refractive outcome REFU after cataract surgery resulting from measurement uncertainties in modern optical biometers using literature data for within-subject standard deviation Sw. METHODS: This Monte-Carlo simulation study used a large dataset containing 16 667 preoperative IOLMaster 700 biometric measurements. Based on literature Sw values, REFU was derived for both the Haigis and Castrop formulae using error propagation strategies. Using the Hoya Vivinex lens (IOL) as an example, REFU was calculated both with (WLT) and without (WoLT) consideration of IOL power labelling tolerances. RESULTS: WoLT the median REFU was 0.10/0.12 dpt for the Haigis/Castrop formula, and WLT it was 0.13/0.15 dpt. WoLT REFU increased systematically for short eyes (or high power IOLs), and WLT this effect was even more pronounced because of increased labelling tolerances. WoLT the uncertainty in the measurement of the corneal front surface radius showed the largest contribution to REFU, especially in long eyes (and low power IOLs). WLT the IOL power uncertainty dominated in short eyes (or high power IOLs) and the uncertainty of the corneal front surface in long eyes (or low power IOLs). CONCLUSIONS: Compared with published data on the formula prediction error of refractive outcome after cataract surgery, the uncertainty of biometric measures seems to contribute with ⅓ to ½ to the entire standard deviation. REFU systematically increases with IOL power and decreases with axial length.

Monte-Carlo simulation for calculating phakic supplementary lenses based on a thick and thin lens model using anterior segment OCT data.

BACKGROUND: Phakic lenses (PIOLs, the most common and only disclosed type being the implantable collamer lens, ICL) are used in patients with large or excessive ametropia in cases where laser refractive surgery is contraindicated. The purpose of this study was to present a strategy based on anterior segment OCT data for calculating the refraction correction (REF) and the change in lateral magnification (ΔM) with ICL implantation. METHODS: Based on a dataset (N = 3659) containing Casia 2 measurements, we developed a vergence-based calculation scheme to derive the REF and gain or loss in ΔM on implantation of a PIOL having power PIOLP. The calculation concept is based on either a thick or thin lens model for the cornea and the PIOL. In a Monte-Carlo simulation considering, all PIOL steps listed in the US patent 5,913,898, nonlinear regression models for REF and ΔM were defined for each PIOL datapoint. RESULTS: The calculation shows that simplifying the PIOL to a thin lens could cause some inaccuracies in REF (up to ½ dpt) and ΔM for PIOLs with high positive power. The full range of listed ICL powers (- 17 to 17 dpt) could correct REF in a range from - 17 to 12 dpt with a change in ΔM from 17 to - 25%. The linear regression considering anterior segment biometric data and the PIOLP was not capable of properly characterizing REF and ΔM, whereas the nonlinear model with a quadratic term for the PIOLP showed a good performance for both REF and ΔM prediction. CONCLUSION: Where PIOL design data are available, the calculation concept should consider the PIOL as thick lens model. For daily use, a nonlinear regression model can properly predict REF and ΔM for the entire range of PIOL steps if a vergence calculation is unavailable.

Prediction of spectacle refraction uncertainties with discrete IOL power steps and manufacturing tolerances according to ISO using a Monte Carlo model.

PURPOSE: The purpose of this study was to develop a concept for predicting the effects of both discrete intraocular lens (IOL) power steps (PS) and power labelling tolerances (LT) on the uncertainty of the refractive outcome (REFU). DESIGN: Retrospective non-randomised cross-sectional Monte Carlo simulation study. METHODS: We evaluated a dataset containing 16 669 IOLMaster 700 preoperative biometric measurements. The PS and the delivery range of two modern IOLs (Bausch and Lomb enVista and Alcon SA60AT) were considered for this Monte Carlo simulation. The uncertainties from PS or LT were assumed to be normally distributed according to ±½ the IOL PS or the ISO 11979 LT. REFU was recorded and analysed for all simulations. RESULTS: With both lenses the REFU from discrete PS ranged from 0.11 to 0.12 dpt. Due to the larger PS for low/high power lenses with the enVista/SA60AT, REFU is more dominant in initially myopic/hyperopic eyes. REFU from LT ranged from 0.18 to 0.19 dpt for both lenses. Since LT increases stepwise with IOL power, REFU is more prevalent in initially hyperopic eyes requiring high IOL power values, and for lenses with a wide delivery range towards higher powers. CONCLUSIONS: Since surgeons and patients are typically aware of the effect of discrete PS on REFU, these might be tolerated in cataract surgery. However, REFU resulting from LT is inevitable while the true measured IOL power is not reported on the package, leading to background noise in postoperative achieved refraction.

Assessment of yeast physiology during industrial-scale brewing practices using the redox-sensitive dye resazurin.

Beer refermentation in bottles is an industrial process utilized by breweries where yeast and fermentable extract are added to green beer. The beer is refermented for a minimum of 2 weeks before distribution, with the physiological state of the yeast a critical factor for successful refermentation. Ideally, fresh yeast that is propagated from a dedicated propagation plant should be used for refermentation in bottles. Here, we explored the applicability of the fluorescent and redox-sensitive dye, resazurin, to assess cellular metabolism in yeast and its ability to differentiate between growth stages. We applied this assay, with other markers of yeast physiology, to evaluate yeast quality during a full-scale industrial propagation. Resazurin allowed the discrimination between the different growth phases in yeast and afforded a more in-depth understanding of yeast metabolism during propagation. This assay can be used to optimize the yeast propagation process and cropping time to improve beer quality.

Translation model for CW chord to angle Alpha derived from a Monte-Carlo simulation based on raytracing.

BACKGROUND: The Chang-Waring chord is provided by many ophthalmic instruments, but proper interpretation of this chord for use in centring refractive procedures at the cornea is not fully understood. The purpose of this study is to develop a strategy for translating the Chang-Waring chord (position of pupil centre relative to the Purkinje reflex PI) into angle Alpha using raytracing techniques. METHODS: The retrospective analysis was based on a large dataset of 8959 measurements of 8959 eyes from 1 clinical centre, using the Casia2 anterior segment tomographer. An optical model based on: corneal front and back surface radius Ra and Rp, asphericities Qa and Qp, corneal thickness CCT, anterior chamber depth ACD, and pupil centre position (X-Y position: PupX and PupY), was defined for each measurement. Using raytracing rays with an incident angle IX and IY the CW chord (CWX and CWY) was calculated. Using these data, a multivariable linear model was built up in terms of a Monte-Carlo simulation for a simple translation of incident ray angle to CW chord. RESULTS: Raytracing allows for calculation of the CW chord CWX/CWY from biometric measures and the incident ray angle IX/IY. In our dataset mean values of CWX = 0.32±0.30 mm and CWY = -0.10±0.26 mm were derived for a mean incident ray angle (angle Alpha) of IX = -5.02±1.77° and IY = 0.01±1.47°. The raytracing results could be modelled with a linear multivariable model, and the effect sizes for the prediction model for CWX are identified as Ra, Qa, Rp, CCT, ACD, PupX, PupY, IX, and for CWY they are Ra, Rp, PupY, and IY. CONCLUSION: Today the CW chord can be directly measured with any biometer, topographer or tomographer. If biometric measures of Ra, Qa, Rp, CCT, ACD, PupX, PupY are available in addition to the CW chord components CWX and CWY, a prediction of angle Alpha is possible using a simple matrix operation.

Translation model for anterior segment tomographic data to corneal spherical aberration derived from a Monte-Carlo simulation based on raytracing.

BACKGROUND: Intraocular lenses with a negative aspherical design for correction of corneal spherical aberration (SA) have gained popularity in recent decades. In most cases, a 'one size fits all' concept is followed, where all eyes receive lenses with the same SA correction. The purpose of this study is to develop a strategy based on raytracing using anterior segment tomography data to extract corneal SA and to provide simple multivariable linear models for prediction of corneal SA. METHODS: The analysis was based on a large dataset of 8737 measurements of 8737 eyes from 1 clinical centre, using the Casia2 anterior segment tomographer. An optical model based on: corneal front and back surface radius Ra and Rp, asphericities Qa and Qp, corneal thickness CCT, anterior chamber depth ACD, and pupil centre position (X-Y position: PupX and PupY ), was defined for each measurement. Corneal SA was derived using a 6-mm aperture perpendicular to the incident ray and centred on the chief ray, and linear prediction models were derived for SA using biometric data. Cross-validation was used for model performance evaluation. RESULTS: Using raytracing, the wavefront error within an aperture (6-mm diameter centred on the intersection of the chief ray with the cornea) was calculated and corneal SA was extracted. After identifying the relevant effect sizes (Ra, Qa, Rp Qp, ACD, PupX and PupY ) using stepwise linear regression, linear mixed-effects models (model 1: all effect sizes, model 2: Ra, Qa, Rp and Qp, model 3: Ra and Qa) were set up on the training data in terms of a Monte-Carlo simulation. On the test data (training data), model 1 with a mean absolute/root-mean-squared prediction error of 0.0095/0.0130 (0.0095/0.0127) performed similarly to model 2 with 0.0097/0.0131 (0.0096/0.0127), and both outperformed model3 with 0.0152/0.0197 (0.0148/0.0190). CONCLUSION: Based on the Casia2 anterior segment tomographer, corneal SA could be derived using shape data (curvature and asphericities) of both corneal surfaces (model 2). This information could easily be used for selection of the appropriate negative aspherical lens design in cataract surgery.

Calculation of Equivalent and Toric Power in AddOn Lenses Based on a Monte Carlo Simulation.

INTRODUCTION: Additional lenses implanted in the ciliary sulcus (AddOn) are one option for permanent correction of refractive error or generate pseudoaccommodation in the pseudophakic eye. The purpose of this paper was to model the power and magnification behaviour of toric AddOn and to show the effect sizes with a Monte Carlo simulation. METHODS: Anonymized data of a cataractous population uploaded for formula constant optimization were extracted from the IOLCon platform. After filtering out data with refractive spherical equivalent (RSEQ) between -0.75 and 0.25 dpt and refractive cylinder (RCYL) lower than 0.75, for each of the N = 6,588 records, a toric AddOn was calculated which transfers the refraction error from spectacle plane to AddOn plane using a matrix-based calculation strategy based on linear Gaussian optics. The equivalent (AddOnEQ) and toric (AddOnCYL) power of the AddOn and the overall lateral magnification change and meridional magnification were derived for the situations before and after AddOn implantation, and a linear modelling was fitted for all 4 parameters. RESULTS: RSEQ is the dominant effect size in the prediction of AddOnEQ and overall change in magnification (ΔM), whereas the lens position (LP), corneal thickness (CCT), and mean corneal radius (CPa) play a minor role. In a simplified model, AddOnEQ can be estimated by 0.0179 + 1.4104 RSEQ. RCYL and corneal radius difference (CPad) are the dominant effect sizes in the prediction of AddOnCYL and the change in meridional magnification (ΔMmer), whereas LP, CCT, CPa, and RSEQ play a minor role. In a simplified model, AddOnCYL can be predicted by -0.0005 + 0.0328 CPad + 1.4087 RCYL. Myopic eyes gain in overall magnification, whereas in hyperopic eyes, we observe a loss. Meridional distortion could be in general reduced to 35% on average with a toric AddOn. CONCLUSION: Our simulation shows that with a linear model, the equivalent and toric AddOn power, as well as overall change in magnification, meridional distortion before and after AddOn implantation, and the reduction in meridional distortion, can be easily predicted from the biometric data in pseudophakic eyes with moderate refractive error.

Back-calculation of keratometer index based on OCT data and raytracing - a Monte Carlo simulation.

PURPOSE: This study aims to develop a raytracing-based strategy for calculating corneal power from anterior segment optical coherence tomography data and extracting the individual keratometer index, which converts the corneal front surface radius to corneal power. METHODS: A large OCT dataset (10,218 eyes of 8,430 patients) from the Casia 2 (Tomey, Japan) was post-processed in MATLAB (MathWorks, USA). Radius of curvature, asphericity of the corneal front and back surface, central corneal thickness and pupil size (aperture) were used to trace a bundle of rays through the cornea and derive the best focus plane. Corneal power was calculated with respect to the corneal front vertex plane, and the keratometer index was back-calculated using corneal power and front surface radius. Keratometer index was analysed in a multivariate linear model. RESULTS: The averaged resulting keratometer index was 1.3317 ± 0.0017 with a median of 1.3317 and range from 1.3233 to 1.3390. In a univariate model, only the front surface asphericity affected the keratometer index. The multivariate model for modelling the keratometer index using all 6 input parameters performed very well (RMS error: 5.54e-4, R2 : 0.90, significance vs. constant model: <0.0001). CONCLUSIONS: In the classical calculation, the keratometer index used for converting corneal radius to dioptric power uses several model assumptions. As these assumptions are not generally satisfied, corneal power cannot be calculated from corneal front surface radius alone. Considering all 6 input variables, the linear prediction model performs well and can be used if all input parameters are measured with a tomographer.

[How does the Regional Psychiatry Budget (RPB) work in an area with initially low capacity of psychiatric hospital beds?]. / Wie wirkt das Regionale Psychiatriebudget (RPB) in einer Region mit initial niedriger Bettenmessziffer?

OBJECTIVE: To analyze the impact of a capitated multi-sector-financing model for psychiatric care (RPB) in the model region Rendsburg-Eckernförde on costs and effectiveness of care. METHODS: In a prospective controlled cohort study 244 patients with a diagnosis according to ICD-10: F10, F2 or F3 were interviewed in the model region (MR) and compared to 244 patients from a control region (CR) financed according to the fee-for-service principle. At baseline, 1.5 years and 3.5 years follow-up patients were interviewed using measures of psychopathology (CGI-S, HONOS, SCL-90 R/GSI, PANSS, BRMAS/BRMES), functioning (GAF, SOFAS), quality of life (EQ-5 D) and service use/costs (CSSRI). RESULTS: Subjective symptom severity (GSI) and functioning (GAF) developed more favourably in the MR than in the CR, the HONOS score developed slightly worse in the MR. The latter effect occurred mainly in ICD-10: F10 patients, while patients with F2/3 rather did benefit under RPB conditions. The development of total costs of care was not different between MR and CR. The potential to reduce costs of in-patient care was low due to the initially low capacity of inpatient beds. CONCLUSIONS: The RPB did not reduce the total costs of mental health care, but certain diagnosis groups may benefit from improved trans-sectoral treatment flexibility.

Integrated and translational nonclinical in vivo cardiovascular risk assessment: gaps and opportunities.

Cardiovascular (CV) safety concerns are a significant source of drug development attrition in the pharmaceutical industry today. Though current nonclinical testing paradigms have largely prevented catastrophic CV events in Phase I studies, many challenges relating to the inability of current nonclinical safety testing strategies to model patient outcomes persist. Contemporary approaches include a spectrum of evaluations of CV structure and function in a variety of laboratory animal species. These approaches might be improved with a more holistic integration of these evaluations in repeat-dose studies, addition of novel endpoints with greater sensitivity and translational application, and use of more relevant animal models. Particular opportunities present with advances in imaging capabilities applicable to rodent and non-rodent species, technical capabilities for measuring CV function in repeat-dose animal studies, detection and quantitation of microRNAs and wider use of alternative animal models. Strategic application of these novel opportunities considering putative CV risk associated with the molecular drug target as well as inherent risks present in the target patient population could tailor or 'personalize' nonclinical safety assessment as a more translational evaluation. This paper is a call to action for the clinical and nonclinical drug safety communities to assess these opportunities to determine their utility in filling potential gaps in our current cardiovascular safety testing paradigms.

Negative ion fragmentations of deprotonated peptides. The unusual case of isoAsp: a joint experimental and theoretical study. Comparison with positive ion cleavages.

The following peptides have been examined in this study: GLDFG(OH), caeridin 1.1 [GLLDGLLGLGGL(NH(2))], 11 Ala citropin 1.1 [GLFDVIKKVAAVIGGL(NH(2))], Crinia angiotensin [APGDRIYVHPF(OH)] and their isoAsp isomers. It is not possible to differentiate between Asp- and isoAsp-containing peptides (used in this study) using negative ion electrospray mass spectrometry. This is because the isoAsp residue cleaves to give the same fragment anions as those formed by delta and gamma backbone cleavage of Asp. The isoAsp fragmentations are as follows: RNHCH(CO(2)H)(-)CHCONHR' --> [RNH(-)(HO(2)CCH=CHCONHR')] --> RNH(-)+HO(2)CCH=CHCONHR' and RNHCH(CO(2)H)(-)CHCONHR' --> [RNH(-)(HO(2)CCH=CHCONHR'] --> (-)O(2)CCH=CHCONHR'+RNH(2). Calculations at the HF/6-31+G(d)//AM1 level of theory indicate that the first of these isoAsp cleavage processes is endothermic (by +115 kJ mol(-1)), while the second is exothermic (-85 kJ mol(-1)). The barrier to the highest transition state is 42 kJ mol(-1). No diagnostic cleavage cations were observed in the electrospray mass spectra of the MH(+) ion of the Asp- and isoAsp-containing peptides (used in this study) to allow differentiation between these two amino acid residues.

Characteristic negative ion fragmentations of deprotonated peptides containing post-translational modifications: mono-phosphorylated Ser, Thr and Tyr. A joint experimental and theoretical study.

Peptides and proteins may contain post-translationally modified phosphorylated amino acid residues, in particular phosphorylated serine (pSer), threonine (pThr) and tyrosine (pTyr). Following earlier work by Lehmann et al., the [M-H]- anions of peptides containing pSer and pThr functionality show loss of the elements of H3PO4. This process, illustrated for Ser (and using a model system), is CH3CONH-C(CH2OPO3H2)CONHCH(3) --> [CH3CONHC(==CH2)CONHCH3 (-OPO3H2)] (a) --> [CH3CONHC(==CH2)CONHCH3-H]- + H3PO4, a process endothermic by 83 kJ mol(-1) at the MP2/6-31++G(d,p)//HF/6-31++G(d,p) level of theory. In addition, intermediate (a) may decompose to yield CH3CONHC(==CH2)CONHCH3 + H2PO4 - in a process exothermic by 3 kJ mol(-1). The barrier to the transition state for these two processes is 49 kJ mol(-1). Characteristic cleavages of pSer and pThr are more energetically favourable than the negative ion backbone cleavages of peptides described previously. In contrast, loss of HPO3 from [M-H]- is characteristic of pTyr. The cleavage [NH2CH(CH2-C6H4-OPO3H-)CO2H] --> [NH2C(CH2-C6H4-O-)CO2H (HPO3)] (b) --> NH2CH(CH2-C6H4-O-)CO2H + HPO3 is endothermic by 318 kJ mol(-1) at the HF/6-31+G(d)//AM1 level of theory. In addition, intermediate (b) also yields NH2CH(CH2-C6H4-OH)CO2H + PO3 - (reaction endothermic by 137 kJ mol(-1)). The two negative ion cleavages of pTyr have a barrier to the transition state of 198 kJ mol(-1) (at the HF/6-31+G(d)//AM1 level of theory) comparable with those already reported for negative ion backbone cleavages.

Genotoxicity assessment of the antiepileptic drug AMP397, an Ames-positive aromatic nitro compound.

AMP397 is a novel antiepileptic agent and the first competitive AMPA antagonist with high receptor affinity, good in vivo potency, and oral activity. AMP397 has a structural alert (aromatic nitro group) and was mutagenic in Salmonella typhimurium strains TA97a, TA98 and TA100 without S9, but negative in the nitroreductase-deficient strains TA98NR and TA100NR. The amino derivative of AMP397 was negative in wild-type strains TA98 and TA100. AMP397 was negative in a mouse lymphoma tk assay, which included a 24h treatment without S9. A weak micronucleus induction in vitro was found at the highest concentrations tested in V79 cells with S9. AMP397 was negative in the following in vivo studies, which included the maximum tolerated doses of 320mg/kg in mice and 2000mg/kg in rats: MutaMouse assay in colon and liver (5x320mg/kg) at three sampling times (3, 7 and 31 days after the last administration); DNA binding study in the liver of mice and rats after a single treatment with [14C]-AMP397; comet assay (1x2000mg/kg) in jejunum and liver of rats, sampling times 3 and 24h after administration; micronucleus test (2x320mg/kg) in the bone marrow of mice, sampling 24h after the second administration. Based on these results, it was concluded that AMP397 has no genotoxic potential in vivo. In particular, no genotoxic metabolite is formed in mammalian cells, and, if formed by intestinal bacteria, is unable to exert any genotoxic activity in the adjacent intestinal tissue. These data were considered to provide sufficient safety to initiate clinical development of the compound.