Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

The success of Australia’s ‘No Jab,No Pay’ policy at a local level; retrospective clinical audit of a single medical practice assessing incidence of catch-up vaccinations

Vaccination is a vital health care initiative to prevent individual and population infection. To increase vaccination rates the federal government implemented the ‘No Jab, No Pay’ policy, where eligibility for several government benefits required children to be fully vaccinated by removing ‘conscientious objections’ and expanding the age range of children whose families receive benefits. This study assesses the impact of this policy at a local area within a single medical practice community in NSW, Australia. A retrospective clinical audit was performed between 2012 and 2017 on a single general practice's vaccination records for children ≤19 years. Catch-up vaccinations were assessed based on age at vaccination. Incidence of catch-up vaccinations was assessed for each of four years before and two years after the implementation of the ‘No Jab, No Pay’ policy in January 2016, along with the age of children and vaccination(s) given. Catch-up vaccinations were assessed temporally either side of implementation of ‘No Jab, No Pay’. Comparing the average annual vaccination catch-up incidence rate of 6.2% pre-implementation (2012–2015), there was an increase to 9.2% in 2016 (p < .001) and 7.8% in 2017 (p = .027). Secondary outcome measurement of catch-up vaccination incidence rates before (2012–2015) and after (2016–2017) ‘No Jab, No Pay’ implementation showed statistically significant increases for children aged 8–11 years (3.2%–5.6%, p = .038), 12–15 years (7.5%–14.7%, p < .001) and 16–19 years (3.3%–10.2%, p < .001) along with a statistically significant reduction in children aged 1–3 years (11.4%–6.2%, p = .015). Also, catch-up rates for DTPa significantly increased after program implementation. This study demonstrates that the Australian federal government vaccination policy ‘No Jab, No Pay’ was coincident with an increase in catch-up vaccinations within a rural NSW community served by one medical practice, especially for older children.     

基于标准化患者法评价四川农村基层医生两种慢性病诊断准确性及其影响因素

目的 运用标准化患者法评估四川农村地区基层医生不稳定型心绞痛和2型糖尿病两种慢性病诊断准确性现状,探讨基层医生两种慢性病诊断准确性的主要影响因素,为提升基层医生两种慢性病诊断准确性提供科学依据。方法 采用多阶段随机整群抽样方法,抽取四川省自贡市5个区/县50个乡镇100个村为研究现场,以调查当日在岗的全科及内科医生作为研究对象。共进行两轮数据采集,第1轮采集样本乡镇卫生院和村卫生室医生的基本信息;第1轮调查完成1个月后,运用标准化患者法开展第2轮调查,收集农村基层医生对不稳定型心绞痛和2型糖尿病诊断结果信息。运用Logistic回归分析农村基层医生不稳定型心绞痛和2型糖尿病诊断准确性的影响因素。结果 共纳入172名农村基层医生,完成186次标准化患者访问,正确诊断率为48.39%。其中不稳定型心绞痛的正确诊断率为18.68%(17/91),2型糖尿病的正确诊断率为76.84%(73/95)。Logistic回归分析显示,具有执业医师资质的农村基层医生更有可能做出正确诊断(OR=4.857,95%CI=1.076~21.933,P=0.040)。农村基层医生在诊断过程中涉及的必要问诊和检查条目越多,做出正确诊断的概率越高(OR=1.627,95%CI=1.065~2.485,P=0.024)。与不稳定型心绞痛相比,农村基层医生对2型糖尿病做出正确诊断的可能性更高(OR=6.306,95%CI=3.611~11.013,P<0.001)。结论 四川农村基层医生不稳定型心绞痛和2型糖尿病诊断准确性整体较差,建议以基层医生慢性病诊断过程质量改善为突破口,提升基层医生执业水平,进而提高慢性病诊断准确性。     

Orientation and mobility outcome measures

Despite orientation and mobility (O&M) being a significant factor determining quality of life of people with low vision or blindness, there are no gold standard measures or agreement on how to measure O&M performance. In the first part of this systematic review, an inventory of O&M outcome measures used by recent studies to assess the performance of orientation and/or mobility of adults with vision impairment (low vision and blindness) is presented. A wide variety of O&M outcome measures have been implemented in different fields of study, such as epidemiologic research and interventional studies evaluating training, assistive technology, vision rehabilitation and vision restoration. The most frequent aspect of outcome measures is efficiency such as time, distance, speed and percentage of preferred walking speed, followed by obstacle contacts and avoidance, and dis/orientation and veering. Other less commonly used aspects are target identification, safety and social interaction and self-reported outcome measures. Some studies employ sophisticated equipment to capture and analyse O&M performance in a laboratory setting, while others carry out their assessment in real-world indoor or outdoor environments. In the second part of this review, the appropriateness of implementing the identified outcome measures to assess O&M performance in clinical and functional O&M practice is evaluated. Nearly a half of these outcome measures meet all four criteria of face validity (either clinical or functional), responsiveness, reliability and feasibility and have the potential to be implemented in clinical or functional O&M practice. The findings of this review confirm the complicated and dynamic nature of O&M. Multiple measures are required in any evaluation of O&M performance to facilitate holistic assessment of O&M abilities and limitations of each individual.