Medico-legal evaluation of burn trauma injuries. Epidemiological features and predictors of mortality and other adverse outcomes.

INTRODUCTION: Burn trauma is a devastating, life-threatening public health issue responsible for significant morbidity and mortality. Developing countries suffer more from the medical, psychological, and economic consequences of burns. The current study aimed to investigate the medicolegal aspects of burn trauma by identifying the epidemiological factors and injury characteristics associated with increased risk of mortality, intentional infliction, and different types of complications. METHODS: A prospective cross-sectional study was conducted enrolling the burn trauma patients admitted to Burn Unit, Tanta University Hospital, Egypt over one year. RESULTS: The current study was conducted among 138 burn trauma patients with a case fatality rate of 13.8 %. Of them, 5.8 % were victims of intentional burns, 44.9 % were complicated, and the length of hospital stay ranged between one day and 52 days. Patients aged less than 10 years constituted about 33.3 %. The burn trauma was the highest in June, May and March. Intentionally exposed patients, patients with third-degree burns affecting the head, neck and trunk and those with burns involving a total body surface area (TBSA) of more than 33 % were at high mortality risk. Intentional burns were induced mainly by flame (100 %) and characterized by high severity (TBSA = 85 % and 87.5 % third-degree burns). Intentional burns involved mainly the trunk (p = 0.002) and external genitalia (p = 0.022). The involved TBSA and the highest burn degree were significant predictors of mortality with an excellent area under curves of 0.956 and 0.870, respectively and (p < 0.001). The TBSA of more than 17 % and the burn degrees above the second were significant predictors of in hospital complications (p < 0.001). Daytime intentional burns, burns involving the upper extremities and face, deep and widely distributed burns, and infected wounds were associated with a significant need for surgical treatments. The median length of hospital stay was ten days, primarily attributed to the in hospital complications (p = 0.02). CONCLUSION: A high degree of vigilance and accurate assessment of burn size, depth and distribution with meticulous interpretation of the mechanism of infliction are central not only for treatment interventions but from the medicolegal point of view.

Biophysical, histological, and bioaccumulation properties of Tilapia muscle affected by water pollution with heavy elements and microbes at the El-Rahawy drain in Egypt.

The leakage of sewage and agricultural drains has led to the contamination of freshwater branches with toxic heavy elements. This raises concerns about their toxic effects on aquatic ecosystems, especially on fish. Tilapia is regarded as an important protein source in Egypt and many other countries. The biophysical, nutritional, and histological aspects of water pollution in the El-Rahawy and Al-Qatta locations of the Nile on Nilotic tilapia muscle were evaluated by assessing the level of contamination of Nilotic tilapia fish. The current study showed that water of the Rosetta branch water was polluted with a very high level at El-Rahawy Drain discharge (RD) location, and with a high level at Al-Qatta (Q) location, while El-Rahawy (R) location was polluted with a lower level. The study traced the pollution effects on Tilapia (Nilotic) muscles in the previous locations. Bioaccumulation factor (BAF) showed a high value of all heavy metals in Tilapia muscle at the Q and R locations. Contrary to what was expected, discharge (RD) location contamination caused BAF increment of heavy metals in Tilapia muscles at upstream R location. All these results were compared with measured dielectric parameters of Tilapia muscle samples in the frequency range (0.02-1000) kHz. There was an increase in conductivity (σac), dielectric constant (ε'), dielectric loss (ε″), penetration depth (dp), and dissipated power (PD) values of Tilapia muscle, with increasing pollution level. The values of permittivity at low and high frequencies (ε's & ε'∞) for Tilapia muscle decreased by increasing pollution. Finally, the variation of these parameters, based on that proportionality relationship, can be considered as a physical indicator for fish contamination affected by their environment pollution, although these parameters need further studies in a controlled (qualitatively and quantitatively) polluted media.

Deformable registration with intensity correction for CESM monitoring response to Neoadjuvant Chemotherapy.

This paper proposes a robust longitudinal registration method for Contrast Enhanced Spectral Mammography in monitoring neoadjuvant chemotherapy. Because breast texture intensity changes with the treatment, a non-rigid registration procedure with local intensity compensations is developed. The approach allows registering the low energy images of the exams acquired before and after the chemotherapy. The measured motion is then applied to the corresponding recombined images. The difference of registered images, called residual, makes vanishing the breast texture that did not changed between the two exams. Consequently, this registered residual allows identifying local density and iodine changes, especially in the lesion area. The method is validated with a synthetic NAC case where ground truths are available. Then the procedure is applied to 51 patients with 208 CESM image pairs acquired before and after the chemotherapy treatment. The proposed registration converged in all 208 cases. The intensity-compensated registration approach is evaluated with different mathematical metrics and through the repositioning of clinical landmarks (RMSE: 5.9 mm) and outperforms state-of-the-art registration techniques.

Acaricide resistance and novel photosensitizing approach as alternative acaricides against the camel tick, Hyalomma dromedarii.

The control of the camel tick, Hyalomma dromedarii is very crucial. This study evaluated the novel toxicity of photosensitizers and Phoxim insecticide against H. dromedarii males using the adult immersion tests. Ticks were subjected to sunlight for 10 min post-treatment (PT). The optical characters of the applied materials were determined by UV-Vis spectroscopy (250-900 nm wavelengths). The intensity of spectra decreased as dye concentration decreased. The optical bandgap energies of the dyes at different concentrations were not changed as the concentration changed and decreased as the absorption peak of individual dyes red-shifted. The mortalities 72 h PT reached 42.2%, 44.4%, 51.1%, 71.1%, 46.7%, 48.9%, 44.4%, and 55.6% for chlorophyllin, echinochrome, field stain, methylene blue, phthalocyanine, rhodamine 6G, riboflavin, and safranin, respectively. Methylene blue recorded the highest median lethal concentration (LC50 = 127 ppm) followed by safranin, field stain, rhodamine 6G, phthalocyanine, echinochrome riboflavin, and chlorophyllin (LC50 = 209, 251, 271, 303, 324, 332, and 362 ppm, respectively, 72 h PT). Their median lethal time, LT50, values PT with 240 ppm were 45, 87, 96, 72, 129, 115, 131, and 137 h, respectively. The relative toxicities of the LC50 values 72 h PT showed that chlorophyllin, echinochrome, field stain, methylene blue, phthalocyanine, rhodamine 6G, riboflavin, and safranin were 3.2, 3.6, 4.6, 9.1, 3.8, 4.3, 3.5, and 5.6 times, respectively, more effective than Phoxim. Methylene blue, safranin, and field stain showed a broad absorbance area indicating a large photoactivity and better phototoxicity and could be used as alternative agents to synthetic acaricides.

Does Improvement towards a Normal Cervical Sagittal Configuration Aid in the Management of Lumbosacral Radiculopathy: A Randomized Controlled Trial.

A randomized controlled study with a six-month follow-up was conducted to investigate the effects of sagittal head posture correction on 3D spinal posture parameters, back and leg pain, disability, and S1 nerve root function in patients with chronic discogenic lumbosacral radiculopathy (CDLR). Participants included 80 (35 female) patients between 40 and 55 years experiencing CDLR with a definite hypolordotic cervical spine and forward head posture (FHP) and were randomly assigned a comparative treatment control group and a study group. Both groups received TENS therapy and hot packs, additionally, the study group received the Denneroll cervical traction orthotic. Interventions were applied at a frequency of 3 x per week for 10 weeks and groups were followed for an additional 6-months. Radiographic measures included cervical lordosis (CL) from C2-C7 and FHP; postural measurements included: lumbar lordosis, thoracic kyphosis, trunk inclination, lateral deviation, trunk imbalance, surface rotation, and pelvic inclination. Leg and back pain scores, Oswestry Disability Index (ODI), and H-reflex latency and amplitude were measured. Statistically significant differences between the groups at 10 weeks were found: for all postural measures, CL (p = 0.001), AHT (p = 0.002), H-reflex amplitude (p = 0.007) and latency (p = 0.001). No significant difference for back pain (p = 0.2), leg pain (p = 0.1) and ODI (p = 0.6) at 10 weeks were identified. Only the study group's improvements were maintained at the 6-month follow up while the control groups values regressed back to baseline. At the 6-month follow-up, it was identified in the study group that improved cervical lordosis and reduction of FHP were found to have a positive impact on 3D posture parameters, leg and back pain scores, ODI, and H-reflex latency and amplitude.

Reduction of Thoracic Hyper-Kyphosis Improves Short and Long Term Outcomes in Patients with Chronic Nonspecific Neck Pain: A Randomized Controlled Trial.

This study investigates thoracic hyper kyphosis (THK) rehabilitation using the Denneroll™ thoracic traction orthosis (DTTO). Eighty participants, with chronic non-specific neck pain (CNSNP) and THK were randomly assigned to the control or intervention group (IG). Both groups received the multimodal program; IG received the DTTO. Outcomes included formetric thoracic kyphotic angle ICT­ITL, neck pain and disability (NDI), head repositioning accuracy (HRA), smooth pursuit neck torsion test (SPNT) and overall stability index (OSI). Measures were assessed at baseline, after 30 treatment sessions over the course of 10 weeks, and 1-year after cessation of treatment. After 10 weeks, the IG improved more in neck pain intensity (p < 0.0001) and NDI (p < 0.001). No differences were found for SPNT (p = 0.48) and left-sided HRA (p = 0.3). IG improved greater for OSI (p = 0.047) and right sided HRA (p = 0.02). Only the IG improved in THK (p < 0.001). At 1-year follow-up, a regression back to baseline values for the control group was found for pain and disability such that all outcomes favored improvement in the IG receiving the DTTO; all outcomes (p < 0.001). The addition of the DTTO to a multimodal program positively affected CNSNP outcomes at both the short and 1-year follow-up.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

BACKGROUND: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules. OBJECTIVES: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. PATIENTS/METHODS: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.

The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this study was to propose a more informative, although less laborious, IVGTT design to be used for model-based assessment of SI and SG . The IVGTT design was optimized simultaneously for all design variables: glucose and insulin infusion doses, time of glucose dose and start of insulin infusion, insulin infusion duration, sampling times, and number of samples. Design efficiency was used to compare among different designs. The simultaneously optimized designs showed a profound higher efficiency than both standard rich (32 samples) and sparse (10 samples) designs. The optimized designs, after removing replicate sample times, were 1.9 and 7.1 times more efficient than the standard rich and sparse designs, respectively. After including practical aspects of the designs, for example, sufficient duration between samples and avoidance of prolonged hypoglycemia, we propose 2 practical designs with fewer sampling times and lower input of glucose and insulin than standard designs, constrained to prevent hypoglycemia. The optimized practical rich design is equally efficient in assessing SI and SG as the rich standard design, but with half the number of the samples, while the optimized practical sparse design has 1 less sample and requires 4.6 times fewer individuals for equal certainty when assessing SI and SG than the sparse standard design.

Measurement of maternal serum amyloid A as a novel marker of preterm birth.

OBJECTIVE: To study the association between maternal serum amyloid A (mSAA) levels and preterm birth (PTB). METHODS: This prospective observational nested case control study was conducted at Ain Shams University Maternity Hospital, Cairo, Egypt, between May 2017 and December 2017. The study recruited pregnant women at 26-34 weeks presented with threatened preterm labor (PTL). Women with PTB were included in cases group while control group included women who continued pregnancy and delivered at term. Serum samples were collected to measure mSAA levels. The main outcome of the study was the association between mSAA levels and PTB. Secondary outcomes included neonatal intensive care unit admissions and neonatal mortality. RESULTS: Fifty-eight women were included in the final analysis (29 in each group). Women with PTB had a statistically significant higher mSAA levels [5.1 (4.5-7.7) vs. 1.2 (0.0-2.5) mg/l, for cases and controls respectively, p < .001]. Higher mSAA levels were also observed among women whose babies were admitted to NICU, but there was no significant relation between mSAA level and neonatal death. A statistically significant negative correlation was found between mSAA and gestational age at delivery and neonatal birth weight. mSAA had an excellent value to predict PTB (AUC = 0.972 [95% CI, 0.891-0.998], p < .0001), fair value to predict admission to NICU and a poor value to predict neonatal death. CONCLUSIONS: mSAA level was found to be elevated among women with threatened PTL who end with PTB; mSAA is a potentially useful predictive marker of PTB that warrant further study. CLINICALTRIALS.GOV: NCT01639027.

Influence of Aquatain™, a monomolecular surface film on surface tension for controlling the filarial vector Culex pipiens (Diptera: Culicidae).

Surface tension is a phenomenon in the liquid media and plays an important part in the development and survival of aquatic animals. Influence of Aquatain™ monomolecular film on surface tension was determined against mosquito larvae and pupae at different temperatures (10, 15, 20, 25, 30 and 35 °C) and Aquatain™ doses (0.5, 1.0 and 2.0 ml/m2). In the laboratory, Aquatain™ showed larvicidal and pupicidal effects against the filarial vector Culex pipiens. Higher mortality was observed in late and more weighted instars/stages than young ones as well as in the pupal stage. The pupal mortality reached 76.2%, 86% and 93.3% after 12 h post-treatment at 0.5, 1.0 and 2.0 ml/m2, respectively, and it was completely eliminated (100%) within 24 h compared to 15.1%, 26.9% and 38.2% for 1st larval instar, respectively. Also, results showed at 0.5 ml/m2 with temperature range: 10, 15, 20, 25, 30 and 35 °C, the mortality reached 4.0, 6.7, 10.8, 17.3, 22.7, 29.3% and 32, 44, 54, 72, 84, 97.3% for 1st and 4th larval instar, respectively, where the surface tension (γ) was 65.6, 62.4, 58.0, 57.0, 54.2 and, 49.6 dyn/cm, while the Aquatain™ was more effective on mosquito larvae and pupae at high doses with the temperature range. On the other hand, without Aquatain™ dose, the mortality value ranged between 0.0 - 1.2%, and the surface tension (γ) was 74.5 dyne/cm, which is considered as an accidental death. Aquatain™ was effective against all aquatic phases of mosquitoes, especially against the last and weighted ones. Not only was the efficacy of Aquatain™ increased by increasing the dose, but it also increased with the increased temperature of the environment. This efficiency of Aquatain™ is due to its ability to reduce the surface tension of the water medium, preventing different stages of mosquitoes from reaching the surface for breathing thereby leading to suffocation and death. Therefore, we recommended Aquatain™ in programmes for mosquito control and other aquatic insects as a safe, cost-effective control agent.

One-Step Synthesis of Polypyrrole-Coated Gold Nanoparticles for Use as a Photothermally Active Nano-System.

OBJECTIVE: This paper introduces a simple one-step and ultra-fast method for synthesis of highly photothermally active polypyrrole-coated gold nanoparticles. The synthesis process is so simple that the reaction is very fast without the need for any additives or complicated steps. METHODOLOGY: Polypyrrole-coated gold nanoparticles (AuPpy NPs) were synthesized by reacting chloroauric acid (HAuCl4) with pyrrole (monomer) in aqueous medium at room temperature. These nanoparticles were characterized by UV-visible-NIR spectrometry, transmission electron microscopy (TEM), AC conductivity, zeta sizer and were evaluated for dark cytotoxicity and photocytotoxicity using human hepatocellular carcinoma (HepG2) cell line as a model for cancer cells. RESULTS: The synthesized AuPpy NPs showed a peak characteristic for gold nanoparticles (530-600 nm, molar ratio dependent) and a wide absorption band along the visible-NIR region with intensity about triple or even quadruple that of polypyrrole synthesized by the conventional FeCl3 method at the same concentration and under the same conditions. TEM imaging showed that the synthesized AuPpy NPs were composed of spherical or semi-spherical gold core(s) of about 4-10 nm coated with distinct layer(s) of polypyrrole seen either loosely or in clusters. Mean sizes of the synthesized nanoparticles range between ~25 and 220 nm (molar ratio dependent). Zeta potentials of the AuPpy NPs preparations indicate their good colloidal stability. AC conductivity values of AuPpy NPs highly surpass that of Ppy prepared by the conventional FeCl3 method. AuPpy NPs were non-toxic even at high concentrations (up to 1000 µM pyrrole monomer equivalent) under dark conditions. Unlikely, light activated the photothermal activity of AuPpy NPs in a dose-dependent manner. CONCLUSION: This method simply and successfully synthesized AuPpy NPs nanoparticles that represent a safe alternative photothermally active multifunctional tool instead of highly toxic and non-biodegradable gold nanorods.

The integrated glucose insulin minimal model: An improved version.

This paper describes the improved integrated minimal model for healthy subjects and patients with type 2 diabetes and the work leading up to this model. The original integrated minimal model characterizes simultaneously glucose and insulin following intravenous glucose tolerance test (IVGTT) in healthy subjects and provides apart from estimates of indices for insulin sensitivity (Si) and glucose effectiveness (SG), also full simulation capabilities. However, this model was developed using IVGTT data of total glucose and consequently, the model cannot separate hepatic glucose production from glucose disposal. By fitting the original integrated minimal model to IVGTT data of labelled and total glucose, we show that all parameter estimates of the glucose sub-model were significantly different between the fits, in particular, SG, which was ~3 fold higher with total, compared to labelled glucose. In addition, the time profiles of hepatic glucose production, obtained from the model, were unphysiological in most subjects. To correct these flaws, we developed the improved integrated minimal model based on the non-integrated, two-compartment minimal model. The improved integrated minimal model showed physiologically plausible dynamic time profiles of hepatic glucose production and all parameter estimates were compatible with those reported in original publication of the non-integrated minimal model. The integrated minimal model offers the benefits of the original integrated minimal model with simulation capabilities, in presence of endogenous insulin, combined with the benefits of the non-integrated minimal model, which accurately estimates the clinical indices of insulin sensitivity and glucose effectiveness. In addition, the improved integrated minimal model describes, apart from healthy subjects, also patients with type 2 diabetes.

Translation Between Two Models; Application with Integrated Glucose Homeostasis Models.

PURPOSE: For some biological systems, there exist several models with somewhat different features and perspectives. We propose an evaluation method for NLME models by analyzing real and simulated data from the model of main interest using a structurally different, but similar, NLME model. We showcase this method using the Integrated Glucose Insulin (IGI) model and the Integrated Minimal Model (IMM). Additionally, we try to map parameters carrying similar information between the two models. METHODS: A bootstrap of real data and simulated datasets from both the IMM and IGI models were analyzed with the two models. Important parameters of the IMM were mapped to IGI parameters using a large IMM simulated dataset analyzed under the IGI model. RESULTS: Comparison of the parameters estimated from real data and data simulated with the IMM and analyzed with the IGI model demonstrated differences between real and IMM-simulated data. Comparison of the parameters estimated from real data and data simulated with the IGI model and analyzed with the IMM also demonstrated differences but to a lower extent. The strongest parameter correlations were found for: insulin-dependent glucose clearance (IGI) ~ insulin sensitivity (IMM); insulin-independent glucose clearance (IGI) ~ glucose effectiveness (IMM); and insulin effect parameter (IGI) ~ insulin action (IMM). CONCLUSIONS: We demonstrated a new approach to investigate models' ability to simulate real-life-like data, and the information captured in each model in comparison to real data, and the IMM clinically used parameters were successfully mapped to their corresponding IGI parameters.

Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment.

Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucose-insulin (IGI) model, and the integrated minimal model (IMM). One dataset was simulated from each model then analyzed with the two models. CWRES outputted from each model fitting were modeled to capture systematic trends in CWRES as well as the magnitude of structural model misspecifications in terms of difference in objective function values (ΔOFVBias). The estimates of CWRES bias were used to calculate the corresponding bias in conditional predictions by the inversion of first-order conditional estimation method's covariance equation. Time, glucose, and insulin concentration predictions were the investigated independent variables. The new method identified correctly the bias in glucose sub-model of the integrated minimal model (IMM), when this bias occurred, and calculated the absolute and proportional magnitude of the resulting bias. CWRES bias versus the independent variables agreed well with the true trends of misspecification. This method is fast easily automated diagnostic tool for model development/evaluation process, and it is already implemented as part of the Perl-speaks-NONMEM software.

Variability Attribution for Automated Model Building.

We investigated the possible advantages of using linearization to evaluate models of residual unexplained variability (RUV) for automated model building in a similar fashion to the recently developed method "residual modeling." Residual modeling, although fast and easy to automate, cannot identify the impact of implementing the needed RUV model on the imprecision of the rest of model parameters. We used six RUV models to be tested with 12 real data examples. Each example was first linearized; then, we assessed the agreement in improvement of fit between the base model and its extended models for linearization and conventional analysis, in comparison to residual modeling performance. Afterward, we compared the estimates of parameters' variabilities and their uncertainties obtained by linearization to conventional analysis. Linearization accurately identified and quantified the nature and magnitude of RUV model misspecification similar to residual modeling. In addition, linearization identified the direction of change and quantified the magnitude of this change in variability parameters and their uncertainties. This method is implemented in the software package PsN for automated model building/evaluation with continuous data.

Model-Based Residual Post-Processing for Residual Model Identification.

The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data. The extended RUV models evaluated were autocorrelated errors, dynamic transform both sides, inter-individual variability on RUV, power error model, t-distributed errors, and time-varying error magnitude. The agreement in improvement in goodness-of-fit between implementing these extended RUV models on the original model and implementing these extended RUV models on CWRES was evaluated in real and simulated data examples. Real data exercise was applied to three other diagnostics: conditional weighted residuals with interaction (CWRESI), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE). CWRES modeling typically predicted (i) the nature of model misspecifications, (ii) the magnitude of the expected improvement in fit in terms of difference in objective function value (ΔOFV), and (iii) the parameter estimates associated with the model extension. Alternative metrics (CWRESI, IWRES, and NPDE) also provided valuable information, but with a lower predictive performance of ΔOFV compared to CWRES. This method is a fast and easily automated diagnostic tool for RUV model development/evaluation process; it is already implemented in the software package PsN.

Study Design Selection in Early Clinical Anti-Hyperglycemic Drug Development: A Simulation Study of Glucose Tolerance Tests.

In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug. Five drug effects in diabetes therapeutic areas were investigated using six study designs. Power to detect drug effect was assessed using the likelihood ratio test, whereas precision and accuracy of the quantification of drug effect was assessed using stochastic simulation and estimations. An overall summary was developed to aid designing the studies of antihyperglycemic drug development using model-based analysis. This guidance is to be used when the integrated glucose insulin model is used, involving the investigated drug mechanisms of action.

Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg-1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using Emax model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC50. The EC50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC50, Ke and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.

Does rehabilitation of cervical lordosis influence sagittal cervical spine flexion extension kinematics in cervical spondylotic radiculopathy subjects?

OBJECTIVE: To test the hypothesis that improvement of cervical lordosis in cervical spondylotic radiculopathy (CSR) will improve cervical spine flexion and extension end range of motion kinematics in a population suffering from CSR. METHODS: Thirty chronic lower CSR patients with cervical lordosis < 25° were included. IRB approval and informed consent were obtained. Patients were assigned randomly into two equal groups, study (SG) and control (CG). Both groups received stretching exercises and infrared; the SG received 3-point bending cervical extension traction. Treatments were applied 3 × per week for 10 weeks, care was terminated and subjects were evaluated at 3 intervals: baseline, 30 visits, and 3-month follow-up. Radiographic neutral lateral cervical absolute rotation angle (ARA C2-C7) and cervical segmental (C2-C7 segments) rotational and translational flexion-extension kinematics analysis were measured for all patients at the three intervals. The outcome were analyzed using repeated measures one-way ANOVA. Tukey's post-hoc multiple comparisons was implemented when necessary. Pearson correlation between ARA and segmental translational and rotational displacements was determined. RESULTS: Both groups demonstrated statistically significant increases in segmental motion at the 10-week follow up; but only the SG group showed a statistically significant increase in cervical lordosis (p < 0.0001). At 3-month follow up, only the SG improvements in segmental rotation and translation were maintained. CONCLUSION: Improved lordosis in the study group was associated with significant improvement in the translational and rotational motions of the lower cervical spine. This finding provides objective evidence that cervical flexion/extension is partially dependent on the posture and sagittal curve orientation. These findings are in agreement with several other reports in the literature; whereas ours is the first post treatment analysis identifying this relationship.