Role of CDK4/6 inhibitors in patients with hormone receptor (HR)-positive, human epidermal receptor-2 negative (HER-2) metastatic breast cancer study protocol for a systematic review, network meta-analysis and cost-effectiveness analysis.

INTRODUCTION: It is currently unclear which cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, combined with endocrine therapy, is the preferred treatment approach in patients with hormone receptor (HR)-positive, human epidermal receptor-2 (HER2) negative metastatic breast cancer. The aim of this study was to evaluate the existing evidence for the comparative efficacy, safety and cost-effectiveness of different CDK4/6 inhibitors for metastatic breast cancer in first-line and second-line settings. METHODS AND ANALYSIS: We will systematically conduct a literature search in Embase, PubMed and the Cochrane Library and additional searches by handsearching citations of previous systematic reviews. We will also screen major conference proceedings (American Society of Clinical Oncology, European Society of Medical Oncology and San Antonio Breast Cancer Symposium). Preliminary scoping searches were conducted in July 2021, but the search will be updated when new trials are available. The primary outcome was progression-free survival. The secondary outcomes were overall survival, objective response rates, grade 3-4 haematological and non-haematological toxicities, quality-adjusted life years and incremental cost-effectiveness ratios. The risk of bias will be assessed by Cochrane risk of bias tools, and the quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation. Subgroup analyses and sensitivity analyses will be performed to further confirm our findings. In addition, one-way sensitivity analysis and probabilistic sensitivity analyses will be conducted to determine uncertainty. ETHICS AND DISSEMINATION: This study does not require ethics approval as only secondary data will be collected. The results of our study will provide an overview of the current level of CDK4/6 inhibitors for patients with HR-positive, HER2-negative metastatic breast cancer, and undertake subgroup analyses to explore variables that might affect these effects. The results of this study will be presented at an international clinical conference and published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021266597.

Linezolid Pharmacokinetics/Pharmacodynamics-Based Optimal Dosing for Multidrug-Resistant Tuberculosis.

OBJECTIVES: Linezolid can significantly impact drug-resistant tuberculosis (DR-TB) patient outcomes. However, the long-term use of this drug for TB treatment has been limited by adverse reactions and uncertainty regarding optimal dosage regimens for balancing drug efficacy and safety across different populations. This study attempted to find the optimal dosing regimen of linezolid in different populations. METHODS: A total of 355 blood samples were collected from 126 DR-TB patients. Population pharmacokinetic analysis (using a one-compartment model) and dose simulations were conducted using NONMEM and R software. The ratio between the area under the free drug plasma concentration-time curve to the MIC (fAUC/MIC) of > 119 and trough concentration (Cmin) ≤ 2 mg/L served as efficacy and safety targets, respectively, toward the formulation of optimal dosage regimens based on a ≥ 90% cumulative fraction of response. RESULTS: Body weight and blood urea nitrogen levels were the most significant covariates of apparent volume, while creatinine clearance and haemoglobin level significantly influenced apparent clearance. The probability of target attainment for different dosage regimens was evaluated via Monte Carlo simulation. For subjects with MICs of 0.125, 0.25 and 0.5 mg/L, specific total daily doses of ≥ 300 mg, ≥ 450 mg and ≥ 900 mg were required to reach the target, respectively. Subjects with body weight ≤ 70 kg and MIC ≥ 1 mg/L received a total 1200 mg daily dose to reach the probability of target attainment target. Notably, single dosing was safer than multiple dosing at the same daily dose. The optimal dosage regimens for subjects with body weight < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d (once daily), respectively. CONCLUSION: Optimal dosage regimens for patients weighing < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d, respectively. A single dose was safer than multiple doses.

Cost-effectiveness analysis of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer.

Background: Radiotherapy is an effective curative treatment option for intermediate- to high-risk localized prostate cancer. According to the HYPO-RT-PC trial (ISRCTN45905321), there was no significant difference in 5 years of follow-up in terms of failure-free survival, overall survival, urinary toxicity, and bowel toxicity, while erectile function decreased between ultra-hypofractionated radiotherapy with conventionally fractionated radiotherapy, except that the incidence of urinary toxicity in ultra-hypofractionated radiotherapy was higher at 1 year of follow-up. We evaluated the cost-effectiveness of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer from the Chinese payer's perspective. Methods: We developed a Markov model with a 15-year time horizon to compare the cost and effectiveness of ultra-hypofractionated radiotherapy with those of conventionally fractionated radiotherapy for localized intermediate- to high-risk prostate cancer. The outcomes were measured in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and willingness-to-pay (WTP). Univariable and probability sensitivity analyses were performed to evaluate the robustness of the Markov model. Results: Based on the Markov model, conventionally fractionated radiotherapy yielded 2.32 QALYs compared with 2.14 QALYs in ultra-hypofractionated radiotherapy in China. The cost of ultra-hypofractionated radiotherapy was found to be decreased by about 14% folds ($4,251.04) in comparison with that of conventionally fractionated radiotherapy. The ICER of conventionally fractionated radiotherapy versus that of ultra-hypofractionated radiotherapy was $23,616.89 per QALY in China. The failure-free survival with grade 2 or worse urinary toxicity and the discount rate per annum were the most sensitive parameters utilized in ultra-hypofractionated radiotherapy. The cost-effectiveness acceptability curve showed that conventionally fractionated radiotherapy had 57.7% probability of being cost-effective under the Chinese WTP threshold. Conclusion: From the perspective of Chinese payers, ultra-hypofractionated radiotherapy was not a cost-effective strategy compared with conventionally fractionated radiotherapy for patients with localized intermediate- to high-risk prostate cancer. Nevertheless, reduction of the grade 2 or worse urinary toxicity of ultra-hypofractionated radiotherapy could alter the results.

Health risk assessment by consumption of vegetables irrigated with reclaimed waste water: A case study in Thika (Kenya).

Current study was conducted to assess remediation efficiency of heavy metals in Thika waste water treatment plant, human health risk posed by consumption of vegetables irrigated with its reclaimed waste water, and vegetables supplied at Makongeni market. Concentration of Cu, Zn, Cr, Ni and Pb was investigated in the sludge, waste water and vegetables, spinach (Spinacea oleracea), kales (Brassica oleracea var. acephala) and coriander (Coriandrum sativum). Thika waste water treatment plant was efficient in heavy metal remediation. Effluent heavy metal concentration was within recommended concentration for irrigation. Dietary intake of heavy metals and target hazard quotient were used to evaluate health risk posed to consumers. Heavy metals concentrations of vegetables sampled and analyzed were within world health organization permissible limit. Thika waste water treatment plant was found to be efficient; however, regular dredging is essential to reduce accumulated heavy metals in the sludge. Moreover, the study outcome revealed that besides reclaimed waste water that may be perceived to pose great health risk to consumers, the whole food production and distribution chain should be monitored to guarantee food safety.

Assessment of macrophyte, heavy metal, and nutrient concentrations in the water of the Nairobi River, Kenya.

Nairobi River tributaries are the main source of the Athi River. The Athi River basin is the fourth largest and important drainage system in Kenya covering 650 km and with a drainage area of 70,000 km2. Its water is used downstream by about four million people not only for irrigation but also for domestic purposes. However, its industrial, raw sewer, and agricultural pollution is alarming. In order to understand distribution and concentration of heavy metals and nutrients in the water of Nairobi River, 28 water samples were collected in the rainy season (October) of 2015 and dry season (June) of 2016. Cd, Cu, Cr, Zn, As, Pb, Fe, Ni, Mn, NO3-, and TP were analyzed. Only Cr, Pb, Fe, and Mn had concentrations exceeding the WHO permissible limit for drinking water. Out of the 28 sites examined in the study, one site had Pb exceeding the WHO recommended level. Similarly, three sites exceeded the same level for Cr. Only three sites were within the WHO permissible limits for drinking water for Mn while just four sites were within USEPA limit for Fe. Industrial effluent, domestic sewerage, agricultural activities, and solid waste were the main sources of pollution. Significant spatial variation of both heavy metals and nutrients concentration was observed and emanated from point source pollution. Eleven out of 31 macrophytes species that were identified along the river and its tributaries are effective heavy metal and nutrient bioaccumulators and may be used in phytoremediation.

Design, tolerance, and fabrication of an optical see-through head-mounted display with free-form surface elements.

Free-form surfaces (FFSs) provide more freedom to design an optical system with fewer elements and hence to reduce the size and weight of the overall system than rotationally symmetric optical surfaces. In this paper, an optical see-through (OST), head-mounted display (HMD) consisting of a free-form, wedge-shaped prism and a free-form lens is designed and fabricated through the injection molding method. The free-form prism for the projection system is designed with a field-of-view (FOV) of 36°; the free-form lens is cemented to the prism for the see-through system to achieve a FOV of 50°. The free-form prism and lens are expanded at the edge area during the design stage in order to reduce the effects of surface deformation in the working area in molding fabrication process and to improve ergonomic fit with the head of a user. The tolerance analyzes considering the mold design for the free-form optical systems are carried out using the Monte Carlo method. The FFS optical elements are successfully fabricated and the system performance is carefully examined. The results indicate that the performance of the OST-HMD is sufficient for both entertainment and scientific applications.

Chemical and genetic assessment of variability in commercial Radix Astragali (Astragalus spp.) by ion trap LC-MS and nuclear ribosomal DNA barcoding sequence analyses.

Radix Astragali (Huangqi) has been demonstrated to have a wide range of immunopotentiating effects and has been used as an adjuvant medicine during cancer therapy. Identity issues in the collection of Radix Astragali exist because many sympatric species of Astragalus occur in the northern regions of China. In order to assess the quality, purity, and uniformity of commercial Radix Astragali, 44 samples were purchased from herbal stores in Hong Kong and New York City. The main constituents, including four isoflavonoids and three saponins, were quantitatively determined by liquid chromatography mass spectrometry (LC-MS). There was significant sample-to-sample variability in the amounts of the saponins and isoflavonoids measured. Furthermore, DNA barcoding utilizing the variable nuclear ITS spacer regions of the 44 purchased Radix Astragali samples were sequenced, aligned and compared. Eight polymorphic point mutations were identified which separated the Radix Astragali samples into three groups. These results indicate that the chemical and genetic variability that exists among Radix Astragali medicinal products is still a consistency and quality issue for this herbal. Two-way ANOVA analysis showed significant effects on the contents of the seven tested compounds when both phylogenetic and geographic (i.e., point of purchase) factors were considered. Therefore, chemical profiles determined by LC-MS and DNA profiles in ITS spacer domains could serve as barcode markers for quality control of Radix Astragali.