Urine Osmolality Is a Potential Marker of Longer-term Efficacy of Tolvaptan in ADPKD: A Post-hoc Analysis.

BACKGROUND: Total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) are measures of progression and treatment response in autosomal dominant polycystic kidney disease (ADPKD), but utility is limited by the long follow-up required for change assessment. In an analysis of data from the 3-year TEMPO 3:4 trial, we evaluated relationships among a short-term indicator of drug activity (change in urine osmolality [Uosm]) and longer-term outcomes to evaluate Uosm as a potential marker of efficacy. METHODS: Linear regression modeling and single-point analyses assessed relationships among change in Uosm to week 3, change in TKV to month 12, and change in eGFR to month 36 in subjects treated with tolvaptan (n=961) or placebo (n=483). Multivariate models evaluated the proportion of the tolvaptan treatment effect on eGFR attributable to change in Uosm. RESULTS: Change in TKV to month 12 and Uosm to week 3 each correlated with change in eGFR to month 36, regardless of treatment assignment. A greater decrease in Uosm from baseline to week 3 was indicative of a slower decrease in eGFR to month 36 (slope estimate of -0.01, P <0.00001). The effect of tolvaptan on Uosm accounted for 68.8% of the treatment effect on change in eGFR to month 36. Simulations of TEMPO 3:4 under the null hypothesis (i.e., replacement of all values for change in Uosm from baseline to week 3 with values from the placebo arm only) yielded a Type 1 error rate indicating an acceptable risk of falsely concluding treatment efficacy based on change in Uosm as a trial endpoint. CONCLUSIONS: Change in Uosm is a potential biomarker for long-term treatment outcome with tolvaptan and might expedite clinical trials and treatment decision-making for drugs with similar mechanisms of action.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T < 0.5 ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360 mg SC and 180 mg IM with a maintenance dose of 360 mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Theories of motivation: A comprehensive analysis of human behavior drivers.

This paper explores theories of motivation, including instinct theory, arousal theory, incentive theory, intrinsic theory, extrinsic theory, the ARCS model, self-determination theory, expectancy-value theory, and goal-orientation theory. Each theory is described in detail, along with its key concepts, assumptions, and implications for behavior. Intrinsic theory suggests that individuals are motivated by internal factors like enjoyment and satisfaction, while extrinsic theory suggests that external factors like rewards and social pressure drive behavior. Arousal theory says that to feel motivated, people try to keep an optimal level of activation or excitement. Incentive theory suggests that behavior is driven by the promise of rewards or the threat of punishment. The ARCS model, designed to motivate learners, incorporates elements of attention, relevance, confidence, and satisfaction. Self-determination theory proposes that individuals are motivated by their needs for autonomy, competence, and relatedness. The expectation-value theory suggests that behavior is influenced by individuals' beliefs about their ability to succeed and the value they place on the task. The goal-orientation theory suggests that individuals have different goals for engaging in a behavior. By understanding these different theories of motivation, educators, coaches, managers, and individuals may analyze what drives behavior and how to harness it to achieve their goals. In essence, a nuanced comprehension of these diverse motivation theories equips individuals across varied domains with a strategic toolkit to navigate the complex landscape of human behavior, fostering a more profound understanding of what propels actions and how to channel these insights toward the attainment of overarching goals.

Estimating risk of rapid disease progression in pediatric patients with autosomal dominant polycystic kidney disease: a randomized trial of tolvaptan.

BACKGROUND: Tolvaptan preserves kidney function in adults with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. A trial (NCT02964273) evaluated tolvaptan safety and pharmacodynamics in children (5-17 years). However, progression risk was not part of study eligibility criteria due to lack of validated criteria for risk assessment in children. As risk estimation is important to guide clinical management, baseline characteristics of the study participants were retrospectively evaluated to determine whether risk of rapid disease progression in pediatric ADPKD can be assessed and to identify parameters relevant for risk estimation. METHODS: Four academic pediatric nephrologists reviewed baseline data and rated participant risk from 1 (lowest) to 5 (highest) based on clinical judgement and the literature. Three primary reviewers independently scored all cases, with each case reviewed by two primary reviewers. For cases with discordant ratings (≥ 2-point difference), the fourth reviewer provided a secondary rating blinded to the primary evaluations. Study participants with discordant ratings and/or for whom data were lacking were later discussed to clarify parameters relevant to risk estimation. RESULTS: Of 90 evaluable subjects, primary reviews of 69 (77%) were concordant. The proportion considered at risk of rapid progression (final mean rating ≥ 3.5) by age group was: 15-17 years, 27/34 (79%); 12- < 15, 9/32 (28%); 4- < 12, 8/24 (33%). The panelists agreed on characteristics important for risk determination: age, kidney imaging, kidney function, blood pressure, urine protein, and genetics. CONCLUSIONS: High ratings concordance and agreement among reviewers on relevant clinical characteristics support the feasibility of pediatric risk assessment.

Breaking the Mold: Surgical Exploration for Spinal Impalement Injury Without Neurological Deficit.

Spinal cord injuries (SCI) are a significant burden on society, particularly affecting the working population. Traumatic SCI can result from violent confrontations, involving firearms, knives, or edged weapons. Although surgical techniques for these injuries are not well defined, surgical exploration, decompression, and removal of the foreign body are currently indicated for patients with spinal stab wound injuries with neurologic impairment. We present a case of a 32-year-old male patient who presented to the emergency department with a stab injury with a knife. Radiographs and CT scans revealed a broken knife blade with a midline trajectory in the lumbar spine, moving toward the vertebral body of L2 occupying less than 10% of the intramedullary canal. The patient underwent surgery, and the knife was successfully extracted without any complications. Post-operative MRI showed no signs of cerebrospinal fluid (CSF) leak, and the patient did not exhibit any sensorimotor deficit. The acute trauma life support (ATLS) procedure must be followed while treating a patient with penetrating spinal trauma with or without neurological impairment. After availing appropriate investigations, any attempt to remove a foreign object should be done. Although spinal stab wound injuries are uncommon in developed nations, they continue to be a source of traumatic cord damage in underdeveloped countries. Our case highlights the successful surgical management of a spinal stab wound injury with a good outcome.

Achieving Rapid Healing and Low Complication Rates in Patellar Fracture Fixation: The Benefits of Cerclage and Figure-of-Eight Configuration.

Background and objective Patellar fractures account for around 1% of all fractures. Conservative treatment is advised in patients without any incompatibility of articular surfaces or those with intact extensor mechanisms. More than a 2-mm articular gap due to fracture warrants surgical intervention. Tension band wiring (TBW) is a commonly used practice for fixation, However, there is still controversy about its effectiveness and complications arising due to the hardware. Modification of this technique by using K-wires has been considered a method of choice, but this technique is associated with complications due to K-wires. The Pyrford technique is a method for patellar fracture fixation by circumferential cerclage and anterior TBW. We employed the figure-of-eight configuration over the circumferential wire. This study aimed to analyze the outcomes of TBW of the patella without K-wires by assessing the rate of complication and functional outcomes. Materials and methods A total of 38 patients with OTA 34C type, simple and comminuted type of patella fractures aged between 22 and 70 years were treated with circumferential cerclage and figure-of-eight TBW. All patients underwent patellar fixation with cerclage and through direct purchase of SS wire via quadriceps and patellar tendon. Patients were followed up for one to three years. We analyzed differences in the range of motion, fracture reduction, fracture healing time, Bostman score for knee function, and complications. Results The mean age of the patients was 45 years. After TBW without K-wires, fracture healing and functional outcomes were satisfactory according to patient feedback and clinocoradiological examinations. Of note, 35 out of 38 patients (92%) had gained up to 90 degrees of active flexion at the end of one week. One patient (2.42%) developed a superficial infection. All fractures had achieved union at the end of 16 weeks. Malunion or nonunion was not noted in any of the cases. There was no case of implant removal. The average Bostman score at the 12-month follow-up was 28.5 ±1.5. The incidence of complications due to K-wire was nullified. Conclusion Based on our findings, the described method leads to better functional outcomes, decreasing hardware-related complications, and can be used in simple as well as comminuted fractures. The fracture healing and functional outcomes and rate of complications were satisfactory.

Morphological and microsatellite marker-based characterization and diversity analysis of novel vegetable soybean [Glycine max (L.) Merrill].

BACKGROUND: Vegetable soybean seeds are among the most popular and nutrient-dense beans in the world due to their delicious flavor, high yield, superior nutritional value, and low trypsin content. There is significant potential for this crop that Indian farmers do not fully appreciate because of the limited germplasm range. Therefore, the current study aims to identify the diverse lines of vegetable soybean and explore the diversity produced by hybridizing grain and vegetable-type soybean varieties. Indian researchers have not yet published work describing and analysing novel vegetable soybean for microsatellite markers and morphological traits. METHODS AND RESULTS: Sixty polymorphic SSR markers and 19 morphological traits were used to evaluate the genetic diversity of 21 newly developed vegetable soybean genotypes. A total of 238 alleles, ranging from 2 to 8, were found, with a mean of 3.97 alleles per locus. The polymorphism information content varied from 0.05 to 0.85, with an average of 0.60. A variation of 0.25-0.58 with a mean of 0.43 was observed for Jaccard's dissimilarity coefficient. CONCLUSION: The diverse genotypes identified can be helpful to understand the genetics of vegetable soybean traits and can be used in improvement programs; study also explains the utility of SSR markers for diversity analysis of vegetable soybean. Here, we identified the highly informative SSRs with PIC > 0.80 (satt199, satt165, satt167, satt191, satt183, satt202, and satt126), which apply to genetic structure analysis, mapping strategies, polymorphic marker surveys, and background selection in genomics-assisted breeding.

Prevalence of Radiographic Signs of Pincer Deformities in Asymptomatic Indian Individuals: A Retrospective Analysis.

Objective: Femoroacetabular impingement (FAI) is the result of abnormal contact between the proximal femur and the acetabulum rim. Pincer impingement is the result of a globally deep acetabulum, focal anterior overcoverage or less commonly posterior overcoverage. The presence of radiological signs of femoroacetabular impingement (FAI) is not necessarily associated with symptoms. The study aims to find the prevalence of such signs in asymptomatic adult individuals. Methods: Data of 714 patients (1428 hips) who have undergone PBH-AP (Pelvis Both hip- Anterior-Posterior view) radiograph for conditions unrelated to the disorders of the hip were taken for study. We evaluated the images for the presence of a cross-over sign (COS) and ischial spine sign (ISS) and measured Lateral Central-Edge (LCE) angle (Wiberg) and Tonnis angle (TA). Results: Mean age was 33.4 ± 9.8 years. Positive cross-over signs and ischial spine signs were seen in 26.6% and 13.9%, respectively; LCE angle > 40° in 25.5% and Tonnis angle ≤ 0° in 13.5% patients. 36.7% of patients showed atleast one radiological sign of acetabulum overcoverage. There was a significant difference in means of the values of LCE angle and Tonnis angle between males and females (2.9 and - 1.2, respectively). There was no significant difference in prevalence of COS and ISS among the two genders. Conclusion: This study shows that there is higher prevalence of radiographic signs (36.7%) of pincer deformity among asymptomatic adults. Therefore, new clinical studies are required to clarify the actual significance of these findings.

Management of Phytophthora parasitica causing gummosis in citrus using biogenic copper oxide nanoparticles.

AIM: The main aim of the present study was to develop nanotechnology-based solutions for the management of a fungus, Phytophthora parasitica causing gummosis in citrus. METHODS AND RESULTS: Biogenic copper nanoparticles (CuONPs) were synthesized using two different biocontrol agents, Pseudomonas fluorescens and Trichoderma viride and characterized using different analytical techniques. Furthermore, in vitro (at the concentrations of 10, 15, 30, 50, 70, 100 and 150 mg/L) and in vivo (at the concentration of 100 mg/L) activities of these nanoparticles were evaluated for their antifungal efficacy against P. parasitica. The results obtained confirmed the synthesis of irregular-shaped CuONPs having a size in the range 40-100 nm in case of P. fluorescens, whereas, spherical CuONPs in the size range 20-80 were recorded in case of T. viride. As far as the in vitro antifungal efficacies of both these CuONPs is concerned, the maximum percent growth inhibition was observed in case of CuONPs synthesized from T. viride compared to CuONPs from P. fluorescens. However, in case of in vivo antifungal efficacies, CuONPs synthesized from T. viride showed the activity significantly higher than the conventionally used Bordeaux mixture. CONCLUSIONS: It can be concluded that biosynthesized CuONPs can be effectively used as a potential fungicide against P. parasitica. SIGNIFICANCE AND IMPACT OF THE STUDY: The application of nanoparticles having antifungal activities can be used as alternative fungicides to the conventional chemical fungicides. It has the potential to revolutionize the existing management strategies available for plant pathogenic fungi.

Unexplored nutritive potential of tomato to combat global malnutrition.

Tomato, a widely consumed vegetable crop, offers a real potential to combat human nutritional deficiencies. Tomatoes are rich in micronutrients and other bioactive compounds (including vitamins, carotenoids, and minerals) that are known to be essential or beneficial for human health. This review highlights the current state of the art in the molecular understanding of the nutritional aspects, conventional and molecular breeding efforts, and biofortification studies undertaken to improve the nutritional content and quality of tomato. Transcriptomics and metabolomics studies, which offer a deeper understanding of the molecular regulation of the tomato's nutrients, are discussed. The potential uses of the wastes from the tomato processing industry (i.e., the peels and seed extracts) that are particularly rich in oils and proteins are also discussed. Recent advancements with CRISPR/Cas mediated gene-editing technology provide enormous opportunities to enhance the nutritional content of agricultural produces, including tomatoes. In this regard, genome editing efforts with respect to biofortification in the tomato plant are also discussed. The recent technological advancements and knowledge gaps described herein aim to help explore the unexplored nutritional potential of the tomato.

Transcriptomic signature reveals mechanism of flower bud distortion in witches'-broom disease of soybean (Glycine max).

BACKGROUND: Soybean (Glycine max L. Merril) crop is major source of edible oil and protein for human and animals besides its various industrial uses including biofuels. Phytoplasma induced floral bud distortion syndrome (FBD), also known as witches' broom syndrome (WBS) has been one of the major biotic stresses adversely affecting its productivity. Transcriptomic approach can be used for knowledge discovery of this disease manifestation by morpho-physiological key pathways. RESULTS: We report transcriptomic study using Illumina HiSeq NGS data of FBD in soybean, revealing 17,454 differentially expressed genes, 5561 transcription factors, 139 pathways and 176,029 genic region putative markers single sequence repeats, single nucleotide polymorphism and Insertion Deletion. Roles of PmbA, Zn-dependent protease, SAP family and auxin responsive system are described revealing mechanism of flower bud distortion having abnormalities in pollen, stigma development. Validation of 10 randomly selected genes was done by qPCR. Our findings describe the basic mechanism of FBD disease, right from sensing of phytoplasma infection by host plant triggering molecular signalling leading to mobilization of carbohydrate and protein, phyllody, abnormal pollen development, improved colonization of insect in host plants to spread the disease. Study reveals how phytoplasma hijacks metabolic machinery of soybean manifesting FBD. CONCLUSIONS: This is the first report of transcriptomic signature of FBD or WBS disease of soybean revealing morphological and metabolic changes which attracts insect for spread of disease. All the genic region putative markers may be used as genomic resource for variety improvement and new agro-chemical development for disease control to enhance soybean productivity.

Innovation at the Intersection of Clinical Trials and Real-World Data Science to Advance Patient Care.

While efficacy and safety data collected from randomized clinical trials are the evidentiary standard for determining market authorization, this alone may no longer be sufficient to address the needs of key stakeholders (regulators, providers, and payers) and guarantee long-term success of pharmaceutical products. There is a heightened interest from stakeholders on understanding the use of real-world evidence (RWE) to substantiate benefit-risk assessment and support the value of a new drug. This review provides an overview of real-world data (RWD) and related advances in the regulatory framework, and discusses their impact on clinical research and development. A framework for linking drug development decisions with the value proposition of the drug, utilizing pharmacokinetic-pharmacodynamic-pharmacoeconomic models, is introduced. The summary presented here is based on the presentations and discussion at the symposium entitled Innovation at the Intersection of Clinical Trials and Real-World Data to Advance Patient Care at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2017 Annual Meeting.

Harnessing the Potential of Emerging Digital Health and Biological Sampling Technologies for Clinical Drug Development: Promise to Reality.

Advances in emerging innovative technologies have led to optimistic outlooks on their transformative potential for healthcare and clinical trials.1 Given the increased attention, this white paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) presents perspectives on pharmaceutical and biotechnology industry trends for innovative digital health, adherence, and outpatient sampling technologies. As stimulus for cross-company scientific dialog points to consider for adoption, implementation, and recommendations to broaden uptake are proposed.

Evaluation of Model-Based Prediction of Pharmacokinetics in the Renal Impairment Population.

Dose recommendations for specific populations are not always provided and, when available, typically rely on empirical derivation from a small fraction of the general population. In this study, a prediction/confirmation framework was applied to 2 model-based methods, physiologically based pharmacokinetics (PBPK) and a static model, to evaluate their ability to predict clearance in mild, moderate, and severe renal impairment populations and to inform dosing recommendations in these populations. Simulated renal impairment/healthy subject AUC ratios (AUCRs) from PBPK and static models were compared with observed AUCRs from dedicated clinical studies in renal impairment subjects for 7 drugs eliminated primarily by renal clearance. Both PBPK and static model predictions were within 2-fold of observed AUCRs for most compounds across all renal impairment categories. Predictions were generally more accurate for the mild and moderate renal impairment populations, with the majority of AUCR predictions within 80% to 125% of observed values for both methods. However, the accuracy of predictions was lower for the severe renal impairment population using the PBPK method. Given the accuracy observed, both methods may be suitable for prospective predictions for early decision-making, but are likely not sufficient sole justification for dose recommendations. There is a need to assess a larger database of compounds to enhance the predictive power of currently available tools.

Utility of Model-Based Approaches for Informing Dosing Recommendations in Specific Populations: Report From the Public AAPS Workshop.

This report summarizes the discussions and recommendations of the workshop titled "Specific Population Drug Dosing Recommendations: Shifting from Clinical Studies to Predict and Confirm," which preceded the 2015 American Association of Pharmaceutical Scientists annual meeting. Participants from the pharmaceutical industry, regulatory agencies (FDA and EMA), and academia discussed the current state, challenges, opportunities, and future direction of utilizing model-based approaches to inform dosing recommendations in specific populations.

Cytological behaviour of floral organs and in silico characterization of differentially expressed transcript-derived fragments associated with 'floral bud distortion' in soybean.

An attempt was made to understand the 'floral bud distortion' (FBD), an unexplored disorder prevailing in soybean. Cytological behaviour of floral reproductive organs and in silico characterization of differentially expressed transcript-derived fragments (TDFs) in symptomatic and asymptomatic soybean plants were carried out. Pollens in asymptomatic plants do not have defects in number, size, shape and function. However, in symptomatic plant, pollens were found nonviable, abnormal in shape and with reduced germination ability. Here, we employed a computational approach, exploring invaluable resources. The tissue-specific transcript profile of symptomatic and asymptomatic sources was compared to determine differentially expressed TDFs associated with FBD to improve its basic understanding. A total of 60 decamer primers produced 197 scorable amplicons, ranged 162-1130 bp, of which 171 were monomorphic and 26 were differentially regulated. Reproducible TDFs were sequenced and characterized for their homology analysis, annotation, protein-protein interaction, subcellular localization and their physical mapping. Homology-based annotation of TDFs in soybean revealed presence of two characterized and seven uncharacterized hits. Annotation of characterized sequences showed presence of genes, namely auxin response factor 9 (ARF9) and forkhead-associated (FHA) domain, which are directly involved in plant development through various pathways, such as hormonal regulation, plant morphology, embryogenesis and DNA repair.

Osteochondromas at Unusual Sites- Case Series with Review of Literature.

INTRODUCTION: Osteochondromas are benign tumours of the skeletal system. Their commonplace of occurrence is around growing ends of long bones like lower end of femur and upper end of tibia, but literature describing their incidence around flat bones of body like pelvis, scapula and small bones of hand, foot is rare. CASE REPORT: We describe two cases of osteochondromas at unusual sites, one on the dorsal aspect of scapula and other at the base of first metatarsal. Patient with scapular osteochondroma had difficulty in sleeping in supine position while that with metatarsal osteochondroma had discomfort while walking. CONCLUSION: Depending on the site of occurrence, osteochondromas can give rise to different local symptoms. Possibility of osteochondroma should be kept in mind during differential diagnosis of bony swelling in flat bones as well as small bones.

Parameters influencing Agrobacterium-mediated transformation system in safflower genotypes AKS-207 and PKV Pink.

Shoot regeneration in safflower (Carthamus tinctorius 'AKS 207' and 'PKV Pink') genetically transformed using Agrobacterium was used for assessing various constraints to the efficiency of transformation including infection period, virulence induction medium, co-cultivation period, bacterial titre, selection regime, and the natural phenolic compound acetosyringone. Transformation frequency was promising with 8-10-day-old cotyledonary leaf explants. Therefore, explants of that age cultured on Agrobacterium minimal medium (AB) containing 100 µM acetosyringone were infected with Agrobacterium (cell titre 0.5 OD600nm) for 15 min followed by 48 h of co-cultivation on kanamycin-enriched medium (50 mg/L). Transformation of the shoots was confirmed using ß-glucuronidase (GUS) histochemical assay and polymerase chain reaction (PCR). With the transformation protocol thus optimized, the transformation frequency as determined using GUS assays was 54.0 % for AKS 207 and 47.6 % for PKV Pink. The corresponding figures using PCR were 27.0 and 33.3 %. The transformed shoots required 10-14 weeks of culture initiation but produced very few roots.

Reporting guidelines for population pharmacokinetic analyses.

The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including pharmacokinetics/pharmacodynamics and simulation reports.