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.

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.

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.

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.

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.

Reporting guidelines for population pharmacokinetic analyses.

The purpose of this work was to develop a consolidated set of guiding principles for 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 (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two 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 two 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 six questions that need to be addressed throughout the report. We recommend eight 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 towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics 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 PKPD and simulation reports.

Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies.

BACKGROUND & AIMS: Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development. METHODS: We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals. RESULTS: The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection. CONCLUSIONS: SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.

Response-guided telaprevir therapy in prior relapsers? The role of bridging data from treatment-naïve and experienced subjects.

The purpose of this report is to illustrate the US Food and Drug Administration's rationale for approving response-guided therapy (RGT) for telaprevir (TVR) in combination with pegylated interferon-α and ribavirin (P/R) for the treatment of adults with genotype 1 chronic hepatitis C who were prior relapsers. RGT was prospectively evaluated in two registration trials of treatment-naïve subjects. In these studies, RGT allowed subjects who achieved undetectable hepatitis C virus RNA from weeks 4 and 12, known as extended rapid virologic response (eRVR), to stop all treatments at 24 weeks. A patient without eRVR received an additional 36 weeks of P/R after 12 weeks of a TVR triple regimen (total of 48 weeks). However, RGT in prior P/R relapsers was not prospectively evaluated. Empirical cross-trial data indicated high sustained virologic response rates (>90%) in prior relapsers achieving eRVR, irrespective of P/R duration (24 or 48 weeks). Further analyses demonstrated that interferon responsiveness does not change in P/R-experienced subjects with a second round of P/R. The comparability in interferon responsiveness across treatment courses allowed us to bridge data between treatment-naïve and P/R-experienced subjects to support the approval of RGT in prior relapse subjects.

Implications of choosing a correlation structure on model selection and parameter estimation.

The purpose of this research was to evaluate implications of choosing a statistical or biological correlation structure on model selection and parameter estimation. were performed with and without biological (weight as a common covariate) or statistical (off diagonal element in omega matrix) correlation between clearance (CL) and volume of distribution (Vd). One-compartment model with IV bolus administration was used with 30% interindividual variability (%CV) on CL and Vd. The results were compared for model selection, parameter equivalence, bias, and imprecision. We found that estimation of fixed-effect parameters (CL, Vd) was robust and estimates of random-effect parameters were not influenced by inclusion or exclusion of statistical correlation irrespective of true correlation structure. However, CVCL and CVV were inflated (by 18 - 35%) when true biological correlation was ignored or accounted for by statistical correlation. It is important to note that in spite of the inflated estimates; these values represent the true variability in the simulated dataset, i.e., reflecting the random variance plus the variance associated with weight. Therefore, if statistical correlation was used in absence of true covariate information, the range of individual parameters in future simulations would be similar compared to a model that uses true biological correlation. A true correlation structure is unknown for real life examples; a statistical correlation is a suitable alternative.

Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?

OBJECTIVES: Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue. DESIGN/METHODS: DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV-RIF interaction were also explored. RESULTS: In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype. CONCLUSION: Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF.

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.

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.

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.

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.

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.

Interferon responsiveness does not change in treatment-experienced hepatitis C subjects: implications for drug development and clinical decisions.

BACKGROUND: The purpose of this research was to compare interferon (IFN) responsiveness in treatment-naive and pegylated interferon α-ribavirin (P/R)-experienced subjects and to understand the implications of comparability in IFN responsiveness across treatment courses on drug development and clinical decision making. METHODS: Data from 3750 subjects treated with P/R in 8 trials were reviewed. The change in hepatitis C virus (HCV) RNA at week 4 in response to P/R was compared according to end-of-study (EOS) status (responder, relapser, partial and null responder) for treatment-naive subjects and the previous P/R response status (known as prior relapsers, prior partial responders, and prior null responders at the baseline) for P/R-experienced subjects. RESULTS: In subjects receiving a first course of P/R treatment (treatment-naive subjects), HCV RNA change after 4 weeks of P/R was correlated with EOS status on a P/R regimen. Importantly, for the first time, we have quantitatively demonstrated that IFN responsiveness in P/R-experienced subjects administered a second course of P/R treatment was similar to the IFN responsiveness in the treatment-naive subjects with corresponding EOS status. CONCLUSIONS: We contend that P/R-experienced subjects are represented within treatment-naive subjects. There are 2 important implications of this finding: (1) from a drug development perspective, a successful direct antiviral plus P/R therapy (IFN-based triple therapy) trial in P/R-experienced subjects may serve as supportive evidence in treatment-naive subjects; and (2) from a clinical decision perspective, previous P/R exposure should not alter new treatment decisions involving IFN-based triple therapy, as the IFN responsiveness to a second course of IFN is comparable.

From in vitro EC50 to in vivo dose-response for antiretrovirals using an HIV disease model. Part I: a framework.

Plasma drug concentrations and human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) data from short-term monotherapy trials in antiretroviral (ARV) naïve/experienced HIV-infected patients for one drug (i.e., lead case, a representative drug for a given class) from four distinct classes of ARV drugs [non-nucleoside reverse transcriptase inhibitors (NNRTIs); nucleotide reverse transcriptase inhibitors (NtRTIs); co-receptor antagonists (CRAs); and integrase strand transfer inhibitors (INSTIs)] were obtained. For each drug (the lead case; for example, etravirine for NNRTIs), the pharmacokinetic (PK)-pharmacodynamic (PD) disease model was used to estimate the in vivo IC50 value based on the relationship between plasma drug concentrations and HIV-1 RNA decline. The disease model was a mechanistic viral dynamic model with the addition of a transduction delay for HIV-1 RNA decay. The model characterized the observed time-course of plasma drug concentrations and HIV-1 RNA in each lead case trial reasonably well. The estimated viral dynamic parameters were in good agreement with the literature values. The scaling factor (SF) was calculated as a ratio using the estimated in vivo IC50 value and protein binding corrected EC50 value for the lead case. For NNRTIs, the calculated SF was found to be 9.47 based on etravirine analysis. Using the same approach, the SF for CRAs (maraviroc), INSTIs (GSK1349572), and NtRTIs (tenofovir) were 4.35, 1.63, and 0.27. The SF is reflective of the uncertainty between in vitro measurement of drug potency and the specific model-based drug potency parameter (IC50). The use of SF and PK-PD disease models can be a valuable tool to predict dose-response of NMEs and support rational dose selection for monotherapy trials.

From in vitro EC50 to in vivo dose-response for antiretrovirals using an HIV disease model. Part II: application to drug development.

The purpose of this research was to qualify a previously derived quantitative model-based framework that proposed an in vitro-in vivo linkage to predict the dose-response relationship of an antiretroviral (ARV) new molecular entity (NME) in a monotherapy trial. Human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) data from monotherapy trials in ARV naïve/experienced HIV-infected subjects for eight drugs (i.e. application case, a representative drug for a given class used for external validation) across four distinct classes of ARV agents (co-receptor antagonists; non-nucleoside reverse transcriptase inhibitors; nucleotide reverse transcriptase inhibitors; and integrase strand transfer inhibitors) were obtained. Using the in vitro EC50 (protein binding corrected) and a class-specific scaling factor (SF), the in vivo IC50 was calculated for each drug. The integrated pharmacokinetic (PK)-pharmacodynamic (PD) disease model used the predicted in vivo IC50 to simulate the HIV-1 RNA-time profiles for dosing regimens that were studied in the monotherapy trials for each drug. The simulated HIV-1 RNA time profiles were then compared to the observed data. The simulated HIV-1 RNA-time profiles matched well with those observed in the monotherapy trials except for one drug in the INSTIs class. The derived SF represents a useful in vitro-in vivo linkage to predict the dose-response relationship for a NME using in vitro data. The mechanistic PK-PD disease model-based framework is useful to assist the dose selection for monotherapy trials and comparator modeling approaches.

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.