The impact of multimodal forms of transport on a cargo carrier's liability

International multimodal transport continues to grow exponentially, while the relevant international legal framework becomes increasingly fragmented and complex. The establishment of a widely acceptable uniform international legal framework for multimodal transport contracts has proven to be extremely difficult, in spite of the various attempts initiated by some international organizations. Owing to the increasing use of containers to consolidate cargo, multimodal transport practice has become inevitable in the field of international trade based on its numerous advantages over the traditional unimodal carriage practices. Therefore, the urgent need of an internationally legal instrument to govern liability issues arising from multimodal carriage transactions is highly requested by trading parties. This research, however, present the difficulties involve when trying to establish liability issues arising from multimodal carriage claims and the impact it has on contracting parties who are never certain on which regime their contracts are based, instead depends on already existing unimodal liability regimes to sort out their disputes. The strengths and weaknesses of the two most recent attempts at producing a uniform legal regime for multimodal transport namely: The United Nations Convention on International Multimodal Transport of Goods 1980 (The UN Convention of 1980) and The United Nations Convention on Contracts for the International Carriage of Goods Wholly or Partly by Sea (The Rotterdam Rules) are also examined in this research as none of these attempts appears to be a tenable solution. However, in the absence of a truly accepted international uniform legal regime for multimodal transport contracts, some nations, regional and sub-regional laws and regulations on multimodal transport contracts have been initiated. Despite the recognition of the Rotterdam Rules in certain jurisdictions, it will probably fail to achieve the aim of uniformity as intended because it’s merely a “maritime-plus” Convention. With the continuous development of containerization, there is an imperative need to have a multimodal transport convention which is broad enough in scope to govern the rights and liabilities of all parties in a multimodal carriage contracts, including inland carriers and their contractors or sub-carriers (referred to as performing parties) in the new Convention

Exploring challenges faced by level three National Certificate vocational students in understanding hyperbolic functions in mathematics

The results of mathematics level 3 have always been a problem at TVET colleges as this hampers the certification rate and the progress of the students to level 4. Students who did not do well in the current subject are not allowed to register that subject in the following level. Even though the students are allowed to progress to level 4 they won’t be certificated for both levels until they pass the remaining subject. The above challenges made the researcher to check during the marking and moderation of November / December examination the course of poor results for mathematics level 3. In the process of checking the researcher discovered that rectangular hyperbola is one of the topics that the students of mathematics level 3 are struggling with. This study therefore focuses on exploring the challenges faced by TVET Level 3 NCV students in understanding the hyperbolic function in mathematics. In addition to the literature review, an empirical investigation based on a qualitative approach and involving semi-structured interviews with the students of a TVET college in North West was conducted to collect data. The analysis of documents relevant to the study was also used as the other method. The study used participatory action research, where the researcher, collaborators and students work alongside each other to collect data and to improve practice and follow the spiral pattern of reflection, analysing the results and adapting the action. The research design and methodology was qualitative. This helped the researcher to understand the challenges students faced in the learning of rectangular hyperbola and also came up with ways to minimise those challenges. The data collection methods used was interviewing using semi-structured questions, pre-test and post-tests. During data collection different interventions (IN1 –IN3) was used depending on the understanding of the students. For ethical consideration, ethical clearance was obtained from UNISA. DHET, the principal of the college, collaborators, parents and students will also give written consent on forms which will be sent out explaining what we envisage. Since research was voluntary, an explanation was given that this was not compulsory and that participation was completely voluntary and that they could withdraw at any time. In this study, various methods to empower students were recommended. Recommendations are also made on what was found in this study, as are recommendations for further study.Mathematics EducationM. Ed. (Mathematics Education

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM) : Clinical and Population Pharmacokinetic Analyses

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers. Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications. Results: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab. Conclusion: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM. Trial Registration: ClinicalTrials.gov number, NCT01998971

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM) : Clinical and Population Pharmacokinetic Analyses

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers. Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications. Results: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab. Conclusion: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM. Trial Registration: ClinicalTrials.gov number, NCT01998971

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) µg/mL for DARA SC and 496 (SD, 231) µg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice