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Size of tropical cyclone (TC) is often asymmetric in nature. Yet, there is a lack of systematic, clean, and intuitive definition/expression to specify the asymmetry of TC size. Here, we introduce a novel index, TC size asymmetry index (SAI), which specifies both the degree and pattern of the asymmetry synthetically. In particular, the symbolic form of SAI is vividly designated for identifying the latter. The SAI proposes 1 quasi-symmetric pattern and 28 asymmetric patterns in total. The 41-year (1979–2019) global climatology of SAI shows that the distribution of the degree of TC size asymmetry is trimodal. Elementarily, the degree and pattern of asymmetry are found to be TC intensity, TC movement, time, and space dependent. The introduction of SAI provides an insight into the subject and lays an important foundation for future applications and research. Furthermore, besides meteorology, it could inspire other fields to index the geometric asymmetries of other kinds. [ABSTRACT FROM AUTHOR]

Background: Patients with cancer may be at increased risk of osteoporosis and fracture; however, gaps exist in the existing literature and the association between cancer and fracture requires further examination. Methods: We conducted a population-based cohort study of Ontario patients with cancer (breast, prostate, lung, gastrointestinal, haematologic) diagnosed between January 2007 to December 2018 and 1:1 matched non-cancer controls. The primary outcome was incident fracture (end of follow-up December 2019). Multivariable Cox regression analysis was used to estimate the relative fracture risk with sensitivity analysis accounting for competing risk of death. Results: Among 172,963 cancer patients with non-cancer controls, 70.6% of patients with cancer were <65 years old, 58% were female, and 9375 and 8141 fracture events were observed in the cancer and non-cancer group, respectively (median follow-up 6.5 years). Compared to non-cancer controls, patients with cancer had higher risk of fracture (adjusted HR [aHR] 1.10, 95% CI 1.07–1.14, p < 0.0001), which was also observed for both solid (aHR 1.09, 95% CI 1.05–1.13, p < 0.0001) and haematologic cancers (aHR 1.20, 95% CI 1.10–1.31, p < 0.0001). Sensitivity analysis accounting for competing risk of death did not change these findings. Conclusions: Our study indicates that patients with cancer are at modest risk of fractures compared to non-cancer controls. [ABSTRACT FROM AUTHOR]

This review explores the current body of evidence pertaining to tracheostomy placement in COVID-19 seropositive patients and summarizes the research by tracheostomy indications, timing, and procedure. Literature review was performed in accordance with the 2020 PRISMA guidelines and includes 12 papers discussing protocols for adult patients seropositive for COVID-19. The studies demonstrated high mortality rates after tracheostomy, especially in geriatric patients, and suggested a multifactorial determination of whether to perform a tracheostomy. There was inconclusive data regarding wait time between testing seropositive, tracheostomy, and weaning off of ventilation. COVID-19 generally reaches highest infectivity between days 9 and 10; furthermore, high early mortality rates seen in COVID-19 may confound mortality implicated by tracheostomy placement. Due to the aerosol-generating nature of tracheostomy placement, management and maintenance, techniques, equipment, and personnel should be carefully considered and altered for COVID-19 patients. With surgical tracheostomy, literature suggested decreased usage of electrocautery; with percutaneous tracheostomy, single-use bronchoscope should be used. The nonemergent exchange of tracheostomy should be done only after the patient tested negative for COVID-19. Placement of tracheostomy should only be considered in COVID-19 patients who are no longer transmissible, with rigorous attention to safety precautions. Understanding procedures for airway maintenance in a respiratory disease like COVID-19 is imperative, especially due to current shortages in ventilators and PPE. However, because of a lack of available data and its likelihood of change as more data emerges, we lack complete guidelines for tracheostomy placement in COVID-19 seropositive patients, and those existing will likely evolve with the disease. [ABSTRACT FROM AUTHOR]

Major adverse cardiovascular and cerebrovascular events (MACCE) is an important cause of morbidity and mortality during perioperative period. In this study, we looked for national trends in perioperative MACCE and its components as well as cancer types associated with high rates of perioperative MACCE during major cancer surgeries. This study was a retrospective analysis of the National Inpatient Sample, 2005–2014. Hospitalizations for surgeries of prostate, bladder, esophagus, pancreas, lung, liver, colorectal, and breast among patients 40 years and greater were included in the analysis. MACCE was defined as a composite measure that included in-hospital all-cause mortality, acute myocardial infarction (AMI), and ischemic stroke. A total of 2,854,810 hospitalizations for major surgeries were included in this study. Of these, 67,316 (2.4%) had perioperative MACCE. Trends of perioperative MACCE showed that it decreased significantly for AMI, death and any MACCE, while stroke did not significantly change during the study period. Logistic regression analysis for perioperative MACCE by cancer types showed that surgeries for esophagus, pancreas, lung, liver, and colorectal cancers had significantly greater odds for perioperative MACCE. The surgeries identified to have greater risks for MACCE in this study could be risk stratified for better informed decision-making and management. [ABSTRACT FROM AUTHOR]

The size of tropical cyclone (TC), defined as the radius of gale‐force (34‐kt) 10‐m winds (R34) from a TC centre, is often asymmetric but received limited attention. Understanding the asymmetry of TC size is particularly essential to enhance the applicability, predictability, and preparedness for the parties in the coastal regions. In this study, the ERA5 reanalysis data are first validated by the QuikSCAT satellite data. Results demonstrate that the radius of ERA5 32‐kt 10‐m winds estimates best R34 in the QuikSCAT satellite data with a promising linear relationship (r =.75). A 41‐year (1979–2019) homogeneous ERA5 global climatology of TC size asymmetry is hence established based on this linear regression model. Both the temporal and spatial characteristics of the TC size asymmetry are investigated and discussed. This study lays the important groundwork for future sophisticated research on TC size. [ABSTRACT FROM AUTHOR]

Introduction: Traumatic brain injury (TBI) is one of the leading causes of fatal trauma, and patients often require prolonged ventilation and tracheostomy. There are currently no standardized guidelines regarding the optimal timing of tracheostomy placement for mechanically ventilated patients with severe TBI. This review aims to investigate the impact of tracheostomy timing on the clinical outcomes in patients with severe TBI.Methods: A literature search was conducted according to PRISMA 2020 guidelines. PubMed, Google Scholar, EMBASE, MedLine, Web of Science, Cochrane, and CINAHL were searched for studies evaluating the impact of early versus late tracheostomy on TBI patient outcomes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Newcastle-Ottawa Scale (NOS) were used for quality of evidence and risk of bias assessment, respectively.Results: A total of nine studies met eligibility criteria. All nine studies investigated tracheostomy timing in severe TBI patients and demonstrated that early tracheostomy is associated with decreased ICU length-of-stay (LOS) and increased ventilator free-days compared to late tracheostomy.Conclusion: Current evidence suggests that patients with severe TBI following traumatic injury may benefit from an early tracheostomy due to improved clinical outcomes, including decreased MV duration and ICU-LOS, compared to late tracheostomy. Further multi-institutional studies are needed to develop evidence-based guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Extrapolation of time-to-event data from clinical trials is commonly used in decision models for health technology assessment (HTA). The objective of this study was to assess performance of standard parametric survival analysis techniques for extrapolation of time-to-event data for a single event from clinical trials with limited data due to small samples or short follow-up.Methods: Simulated populations with 50,000 individuals were generated with an exponential hazard rate for the event of interest. A scenario consisted of 5000 repetitions with six sample size groups (30-500 patients) artificially censored after every 10% of events observed. Goodness-of-fit statistics (AIC, BIC) were used to determine the best-fitting among standard parametric distributions (exponential, Weibull, log-normal, log-logistic, generalized gamma, Gompertz). Median survival, one-year survival probability, time horizon (1% survival time, or 99th percentile of survival distribution) and restricted mean survival time (RMST) were compared to population values to assess coverage and error (e.g., mean absolute percentage error).Results: The true exponential distribution was correctly identified using goodness-of-fit according to BIC more frequently compared to AIC (average 92% vs 68%). Under-coverage and large errors were observed for all outcomes when distributions were specified by AIC and for time horizon and RMST with BIC. Error in point estimates were found to be strongly associated with sample size and completeness of follow-up. Small samples produced larger average error, even with complete follow-up, than large samples with short follow-up. Correctly specifying the event distribution reduced magnitude of error in larger samples but not in smaller samples.Conclusions: Limited clinical data from small samples, or short follow-up of large samples, produce large error in estimates relevant to HTA regardless of whether the correct distribution is specified. The associated uncertainty in estimated parameters may not capture the true population values. Decision models that base lifetime time horizon on the model's extrapolated output are not likely to reliably estimate mean survival or its uncertainty. For data with an exponential event distribution, BIC more reliably identified the true distribution than AIC. These findings have important implications for health decision modelling and HTA of novel therapies seeking approval with limited evidence. [ABSTRACT FROM AUTHOR]

Precision medicine in oncology poses unique challenges to the generation of clinical and economic evidence used for cost-effectiveness analyses that can inform health technology assessment. The conduct of randomized controlled trials for biomarker-specific therapies targeted towards small populations has limitations in regard to feasibility, timeliness, and cost. These limitations result in associated challenges for groups involved in the generation of economic evidence to inform treatment-related decision making, including the Committee of Economic Analysis (CEA) at the Canadian Cancer Trials Group (CCTG). We provide a high-level description and vision about the new paradigm of clinical trial design, generation of economic evidence, and novel approaches to economic evaluations necessary in the space of precision medicine in oncology in Canada. The CEA’s previous approach to precision medicine, including master protocol designs and single-arm studies, is reviewed. Methods and approaches currently under consideration by the CEA and national collaborators, such as the role of real-world and clinical trial evidence in enabling lifecycle assessment of therapies, are explored. Finally, future initiatives being planned in the space of precision medicine at CCTG, such as the incorporation of correlative studies to identify and test high-performing biomarkers in trials, are discussed. [ABSTRACT FROM AUTHOR]

It has been revealed that the vertical wind shear (VWS) can result in the rainfall asymmetry of tropical cyclone (TC), where the VWS is conventionally defined as the environmental horizontal winds between 200‐ and 850‐hPa levels within a certain area from the TC centre. The rainfall maximum is generally displaced downshear to downshear‐left side in the Northern Hemisphere or downshear to downshear‐right side in the Southern Hemisphere. Here, we revisit the rainfall asymmetries of TCs over the western North Pacific using the state‐of‐art Global Precipitation Measurement data. Observations pose that using the conventional VWS to interpret the TC rainfall asymmetry is inopportune. The conventional VWS can only largely grasp the rainfall asymmetry in the inner core of TC, but not in the outer core. We, therefore, explicitly propose a new VWS, namely the effective VWS, to fill this gap. The effective shear layer responsible for the rainfall asymmetry is a function of TC intensity and core region. In addition, we suggest that the angle difference between the effective shears for the inner‐core and outer‐core rainfall asymmetries can help to comprehend the spirality of the rainfall asymmetries that are, the fashions, or patterns of the rainbands. Meanwhile, the moisture flux convergence and storm motion show little effect on the rainfall asymmetry. This study advances the understanding of TC rainfall asymmetry and provides scientific support for disaster prediction, prevention, and mitigation. [ABSTRACT FROM AUTHOR]

Background: Evaluating the relevance of published health utilities to the context of a cost-utility analysis (CUA) remains an essential, yet often overlooked, task. Objective: The objective of this study was to provide guidance on this process through the development of the Health utility Application Tool (HAT). Methods: We conducted semi-structured telephone interviews with Canadian stakeholders from reimbursement bodies, academia, and the pharmaceutical industry to identify current practices and perspectives of the application of the health utility literature to CUAs. An online survey with international members of the general health economics and outcomes research community was also conducted to gather opinions on key concepts. Results: Based on the themes emerging from the interviews and online questionnaire, the HAT includes questions prompting investigators to consider the following constructs: similarity of the clinical condition in the health utility study and the CUA; similarity of health utility study participant demographics and the demographics of the CUA's target population; similarity of the health state descriptions in the health utility study and the CUA; and the method of assigning utility weights. Considerations of transparency prompted additional items, including: means by which the health utility study was identified; type of respondents; study design; and measure used to collect health utility estimates. Conclusion: The HAT is intended to guide the evaluation of the applicability of published health utilities for a CUA, thus promoting transparency and accountability in the selection of model inputs. [ABSTRACT FROM AUTHOR]

Why would dictators purge members of their ruling coalition? Some argue that doing so can minimize the risk to dictators' political survival, while others contend that dictators who mount purges are motivated by the desire to share resources with fewer allies. In this study, we analyze an original dataset, compiled from biographical data on the subordinates of the founding emperors of seven ancient Chinese imperial dynasties. Analyzing the data with competing risks models, we find that military experience is a strong predictor of political purges. Emperors were less likely to execute officers who had fought in more battles, but more likely to execute commanders, especially those who had established military credentials prior to the founding of an empire. In addition, the incidence of political purges heightened toward the end of an emperor's life, which implies that the founding emperors were concerned about the security threats against their designated successors. Potential challengers came not only from the military, but also from the aristocracy. Indeed, we find that the blood relatives of the emperors were more likely to experience a mild form of purges: deprivation of titles. These findings suggest that dictators are more likely to use purges to reduce existential threats. [ABSTRACT FROM AUTHOR]

This scientometric study aimed to provide a first comprehensive overview of the global research landscape of Metronomic Chemotherapy (MC) from 2000 to 2022 using a data-driven approach to identify key trends, collaborations, and potential opportunities. This study highlights the increasing prevalence of MC, with annual outputs increasing substantially over the same timeframe. The United States contributed the most to MC research, followed by Italy and China, while there was a lack of collaborative research efforts between countries and organizations. Through keyword co-occurrence analysis, we identified emerging interdisciplinary research areas, such as "nanoparticles," "immunotherapy," and "antitumor immunity." Our citation analysis identified the most influential authors, institutions, and journals, providing a comprehensive overview of the structure of knowledge and dissemination of MC research. Although the number of publications has decreased since 2019, the analysis indicates that this field has received substantial scholarly attention. These discoveries are extremely important for researchers, funding organizations, and policymakers because they highlight the need for more collaboration, interdisciplinary approaches, and resource allocation in underrepresented fields. This study concludes with recommendations for guiding future research and collaboration, resulting in a larger impact and fostering substantial advancements in MC research. • Comprehensive overview of global MC research trends from 2000 to 2023. • Identifies USA, Italy, and China as major contributors to MC research. • Highlights emerging areas: nanoparticles, immunotherapy, and antitumor immunity. • Citation analysis reveals influential authors and trends in MC research. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b. Both grin1a-/- and grin1b-/- zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a-/-; grin1b-/-), which lack all NMDAR-mediated synaptic transmission, survive until ~10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system. [ABSTRACT FROM AUTHOR]

Background: Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong.Methods: Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women's willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis.Results: The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper (p ≤ 0.05). Taking into account women's willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made.Conclusion: By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong. [ABSTRACT FROM AUTHOR]

Background: In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab‐paclitaxel (GnP) have been publicly funded for first‐line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real‐world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC. Methods: Patients receiving first‐line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population‐based databases. Overall survival (OS) was assessed using Kaplan‐Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models. Results: For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70‐0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P =.0001; Hospitalization: OR = 0.76, P =.002), whereas the risk of febrile neutropenia‐related hospitalization was significantly higher (OR = 2.12, P =.001). Outcomes for uLAPC and mPC were similar. Conclusion: In the real world, FFX had longer OS, less frequent all‐cause EDV and all‐cause hospitalization, but more febrile neutropenia‐related hospitalization compared to GnP. [ABSTRACT FROM AUTHOR]

In evaluating new oncology medicines, two common modeling approaches are state transition (e.g., Markov and semi-Markov) and partitioned survival. Partitioned survival models have become more prominent in oncology health technology assessment processes in recent years. Our experience in conducting and evaluating models for economic evaluation has highlighted many important and practical pitfalls. As there is little guidance available on best practices for those who wish to conduct them, we provide guidance in the form of 'Key steps for busy analysts,' who may have very little time and require highly favorable results. Our guidance highlights the continued need for rigorous conduct and transparent reporting of economic evaluations regardless of the modeling approach taken, and the importance of modeling that better reflects reality, which includes better approaches to considering plausibility, estimating relative treatment effects, dealing with post-progression effects, and appropriate characterization of the uncertainty from modeling itself. [ABSTRACT FROM AUTHOR]

Indices of aggressive or supportive end-of-life (EOL) care are used to evaluate health services quality. Disparities according to sex were previously described, with studies showing that male sex is associated with aggressive EOL care. This is a secondary analysis of 69,983 patients who died of a GI malignancy in Ontario between 2006 and 2018. Quality indices from the last 14–30 days of life and aggregate measures for aggressive and supportive EOL care were derived from administrative data. Hospitalizations, emergency department use, intensive care unit admissions, and receipt of chemotherapy were considered indices of aggressive care, while physician house call and palliative home care were considered indices of supportive care. Overall, a smaller proportion of females experienced aggressive care at EOL (14.3% vs. 19.0%, standardized difference = 0.13, where ≥0.1 is a meaningful difference). Over time, rates of aggressive care were stable, while rates of supportive care increased for both sexes. Logistic regression showed that younger females (ages 18–39) had increased odds of experiencing aggressive EOL care (OR 1.71, 95% CI 1.30–2.25), but there was no such association for males. Quality of EOL care varies according to sex, with a smaller proportion of females experiencing aggressive EOL care. [ABSTRACT FROM AUTHOR]

Aim: To assess this risk of SARS-CoV-2 infection among Ontario physicians by specialty and in comparison with nonphysician controls during the COVID-19 pandemic. Methods: In this retrospective cohort study, the primary outcome was incident SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR). Secondary outcomes were hospitalization, use of critical care, and mortality. Results: From March 1, 2020 to December 31, 2022, 6172/30 617 (20%) active Ontario physicians tested positive for SARS-CoV-2. Infection was less likely if physicians were older (OR 0.78 [0.76-0.81] per 10 years), rural residents (OR 0.70 [0.59-0.83]), and lived in more marginalized neighborhoods (OR 0.74 [0.62-0.89]), but more likely if they were female (OR 1.14 [1.07-1.22]), worked in long-term care settings (OR 1.16 [1.02-1.32]), had higher patient volumes (OR 2.05 [1.82-2.30] for highest vs lowest), and were pediatricians (OR 1.25 [1.09-1.44]). Compared with communitymatched controls (n = 29 763), physicians had a higher risk of infection during the first two waves of the pandemic (OR 1.38 [1.20-1.59]) but by wave 3 the risk was no longer significantly different (OR 0.93 [0.83-1.05]). Physicians were less likely to be hospitalized within 14 days of their first positive PCR test than non-physicians (P < 0.0001), but there was no difference in the use of critical care (P = 0.48) or mortality (P = 0.15). Conclusion: Physicians had higher rates of infection than community-matched controls during the first two waves of the pandemic in Ontario, but not from wave 3 onward. Physicians practicing in long-term care facilities and pediatricians were more likely to test positive for SARS-CoV-2 than other physicians. [ABSTRACT FROM AUTHOR]

Background: The soaring costs of anti‐cancer drugs pose a threat to the sustainability of cancer care. The pricing strategy chosen by manufacturers can impact the costs of oral anti‐cancer drugs during dose modifications, but this issue remains under‐recognized in the literature. In general, with the flat pricing strategy, there is a single fixed price for each tablet regardless of dosage strength, whereas with linear pricing, the price of each tablet increases with its dose. We hypothesize that flat pricing will have increased drug costs compared to linear pricing during dose reductions since the cost remains fixed despite decreased dose requirements. This practice may have significant financial implications considering the high costs, extensive utilization, and frequent occurence of dose reductions with anti‐cancer drugs. Methods: Oral anti‐cancer drugs reviewed by the pan‐Canadian Oncology Drug Review program between 2011 and 2018 were identified. The cost per mg and cost per 28‐day cycle were calculated for dose levels −2 to +2. The percent change in cost per mg and cost per cycle during dose modifications from the standard dose were calculated. We conducted Mann‐Whitney U and Fisher‐exact tests to compare the association between drug costs during dose reductions and pricing strategy. Results: In this study, 30 oral anti‐cancer drugs for use in 41 indications were analyzed; 44% of drugs used linear pricing and 56% used flat pricing. Dose reductions increased the mean cost per mg for drugs with linear pricing by 14.7% (range: 0%‐50%) at dose level −1 and 17.2% (range: 0%‐50%) at dose level −2 and flat pricing by 60.8% (range: 19%‐100%) at dose level −1 and 99.1% (range: 0%‐300%) at dose level −2. The cost per mg was significantly increased in drugs using flat pricing compared to linear pricing when dose reduction to either level ‐1 (P = 0.010) or level ‐2 (P = 0.006) occurred. The mean cost per cycle was decreased for drugs using linear pricing by 20.9% (range: −40% to 0%) at dose level −1 and 48.7% (range: −60% to −25%) at dose level −2 and flat pricing by 0.8% (range −6% to 0%) at dose level −1 and 11.0% (range: −50% to 100%) at dose level −2. The cost per cycle was significantly decreased in drugs with linear pricing compared to flat pricing when the standard dose is reduced to either dose level ‐1 (P = 0.005) or dose level ‐2 (P = 0.026). Conclusions: Overall, flat pricing had significantly greater costs compared to linear pricing during dose reductions of anti‐cancer drugs. While there is a general expectation that the cost of drugs should decrease with dose reduction, drugs with flat pricing were generally found to have increased cost per mg and no change in the cost per cycle. The resultant increased spending on drug acquisition (despite purchasing lower doses) lead to financial wastage, which has significant implications on cost‐effectiveness considerations and budgets. Future economic evaluations should take into consideration the hidden costs associated with dose reductions of flat priced drugs. [ABSTRACT FROM AUTHOR]

The association between obesity and survival in non-Hodgkin lymphoma is unclear. Using the Ontario Cancer Registry we conducted a retrospective analysis of incident cases of aggressive-histology B-cell lymphoma treated with a rituximab-containing regimen with curative intent between 2008–2016. 6246 patients were included. On multivariable analysis the rate of all-cause mortality was lower for the overweight body mass index (BMI 25–29.9 kg/m2) (HR 0.85; 95%CI 0.77–0.95) and obese BMI (≥30 kg/m2) (HR 0.75; 95%CI 0.67–0.85) groups compared to the normal weight group (18.5–24.9 kg/m2). Binomial logistic regression analysis revealed a lower odds ratio (OR) of admission to hospital during treatment in the overweight (OR 0.84; 95%CI 0.75–0.95) compared to normal weight BMI group. In the largest cohort to date of aggressive-histology B-cell lymphoma patients treated with rituximab, increased BMI is associated with a survival advantage, and the magnitude of this effect increases from overweight to obese BMI. [ABSTRACT FROM AUTHOR]

The rainfall distribution associated with landfalling tropical cyclones (TCs) along the South China coast are examined using radar data from Hong Kong Observatory (HKO). This preliminary study relates the landfall direction, and possible rotations/transitions of TC rainfall asymmetries before and after the landfall. Three types of landfalling TCs on the South China coast are categorized: from the east, normal to the coast and from the southwest. For those from the east, the rainfall maximum rotates anticyclonically from the southwest before later landfall to the northwest. TCs making landfall perpendicular to the coast have a rainfall maximum remaining in the southwest quadrant throughout the landfall process. For TCs making landfall from the southwest, the rainfall maximum rotates cyclonically from the southeast before later landfall to the northeast. The relative importance of the impact of land properties and vertical wind shear on these rainfall asymmetries is investigated by using a numerical model. Sensitivity tests show that the rotations/transitions of landfalling TC rainfall asymmetry appear to be insensitive to land properties (e.g. moisture availability, surface friction and topography), but result primarily from changes in the orientations of the vertical wind shear in the environment. However, the surface friction of the landmass appears to contribute to the enhancement of rainfall intensity. The rainfall distribution associated with landfalling tropical cyclones (TCs) along the South China coast are examined using radar data. Three types of landfalling TCs are categorized based on the landfall direction, and possible rotations/transitions of TC rainfall asymmetries before and after the landfall. The rotations/transitions of landfalling TC rainfall asymmetry appear to be insensitive to land properties (e.g. moisture availability, surface friction and topography), but result primarily from the orientations of the vertical wind shear in the environment. [ABSTRACT FROM AUTHOR]

Background: The cost of new anticancer drugs is rising. We aimed to assess the clinical benefit and price of anti‐cancer drugs approved by the US Food and Drug Administration (FDA) for advanced gastrointestinal cancers. Methods: Drugs approved between 2006 and 2017 for advanced GI malignancies were identified from FDA.gov, and their updated supporting trial data were searched. Incremental clinical benefit was quantified by using ESMO Magnitude of Clinical Benefit Scale version 1.1 (grade 0‐5) and ASCO Value Framework version 2 (score range −20 to 180). Higher scores indicate larger net benefit, and substantial benefit was defined as score 4 or 5 by the European Society for Medical Oncology (ESMO). The Micromedex REDBOOK was used to estimate the monthly average wholesale price (AWP) and total drug price (TDP) over the median treatment duration per patient. Clinical benefit, AWP and TDP of each drug class were assessed. Results: In total, 16 GI cancer drugs received FDA approval for 24 indications, including five monoclonal antibodies (mAbs), five oral targeted therapies (TT), two immunotherapeutics (IO), three cytotoxic chemotherapies (CT), and one recombinant fusion protein (aflibercept). Most supporting trials (82%) reported overall survival benefit of less than 3 months and no significant improvement in quality of life. Only five agents (including one TT and one IO) with 21% the of approved indications met the ESMO's threshold of substantial clinical benefit. Median incremental benefit scores of TT and IO were comparable to other drug classes. However their median TDP was much higher at $153 402 and $98 208, respectively, compared to $30 330 USD per patient for CT. The estimated TDP did not correlate with clinical benefit scores. Conclusion: Most FDA–approved gastrointestinal cancer drugs do not meet the ESMO threshold of substantial clinical benefit. TT and IO are estimated to carry significant drug costs, and further cost analysis of these drugs is urgently needed. [ABSTRACT FROM AUTHOR]

This paper presents a summary of several seminal observational and numerical studies on climatology and possible change mechanisms of the outer-core wind structure of a tropical cyclone (TC). This has generally been referred to as size, a term also used in this review despite various definitions being given in the literature. In all the ocean basins where TCs exist, TC size has been found to vary with season, year, decade, latitude and longitude. Such variations are related to the synoptic flow patterns in which the TCs are embedded. Several factors have been identified as responsible for changes in TC size, including: environmental humidity, vortex structure, sea surface temperature and planetary vorticity. Each of these factors can modify the transport of lower tropospheric angular momentum into the TC and cause changes in its size. The paper ends with a discussion of outstanding issues in the study of the outer-core wind structure of a TC. [ABSTRACT FROM AUTHOR]

Background Mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), but studies examining their association with mortality are lacking. Methods We conducted a population-based study using linked administrative health-care databases from Ontario, Canada. All patients with DLBCL 18 years of age or older treated with rituximab-based therapy between January 1, 2005, and December 31, 2017, were identified and followed until March 1, 2020. Mental disorders were defined as either preexisting or postdiagnosis (after lymphoma treatment initiation). Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) between mental disorders and 1-year and all-cause mortality while controlling for covariates. Results We identified 10 299 patients with DLBCL. The median age of the cohort was 67 years; 46% of patients were female, and 28% had a preexisting mental disorder. At 1-year follow-up, 892 (9%) had a postdiagnosis mental disorder, and a total of 2008 (20%) patients died. Preexisting mental disorders were not associated with 1-year mortality (adjusted HR = 1.06, 95% confidence interval [CI] = 0.96 to 1.17, P  = .25), but postdiagnosis disorders were (adjusted HR = 1.51, 95% CI = 1.26 to 1.82, P  = .0001). During a median follow-up of 5.2 years, 2111 (22%) patients had a postdiagnosis mental disorder, and 4084 (40%) patients died. Both preexisting and postdiagnosis mental disorders were associated with worse all-cause mortality (preexisting adjusted HR = 1.12, 95% CI = 1.04 to 1.20, P  = .0024; postdiagnosis adjusted HR = 1.63, 95% CI = 1.49 to 1.79, P  < .0001). Conclusions Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with postdiagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality. [ABSTRACT FROM AUTHOR]

The sensitivity of the simulation of tropical cyclone (TC) size to microphysics schemes is studied using the Advanced Hurricane Weather Research and Forecasting Model (WRF). Six TCs during the 2013 western North Pacific typhoon season and three mainstream microphysics schemes-Ferrier (FER), WRF Single-Moment 5-class (WSM5) and WRF Single-Moment 6-class (WSM6)-are investigated. The results consistently show that the simulated TC track is not sensitive to the choice of microphysics scheme in the early simulation, especially in the open ocean. However, the sensitivity is much greater for TC intensity and inner-core size. The TC intensity and size simulated using the WSM5 and WSM6 schemes are respectively higher and larger than those using the FER scheme in general, which likely results from more diabatic heating being generated outside the eyewall in rainbands. More diabatic heating in rainbands gives higher inflow in the lower troposphere and higher outflow in the upper troposphere, with higher upward motion outside the eyewall. The lower-tropospheric inflow would transport absolute angular momentum inward to spin up tangential wind predominantly near the eyewall, leading to the increment in TC intensity and size (the inner-core size, especially). In addition, the inclusion of graupel microphysics processes (as in WSM6) may not have a significant impact on the simulation of TC track, intensity and size. [ABSTRACT FROM AUTHOR]

In this first Asian study, the decision outcomes (decision conflict, decision regret, and anxiety) of 262 pregnant women offered noninvasive prenatal test (NIPT) for high-risk Down screening results were assessed. Decision conflict was experienced by 3.5% and level of decisional regret low (mean score 15.7, 95%CI 13.2-18.3). All 13 cases of decisional regret were NIPT acceptors. Elevated anxiety was experienced by 55.9% at the time of decision making about NIPT and persistent in 30.3%. Insufficient knowledge about NIPT was associated with elevated anxiety at decision making (p = .011) and with decisional regret (p = .016). Decisional regret was associated with prolonged anxiety (p = .010). [ABSTRACT FROM AUTHOR]

In this first Asian study, the decision outcomes (decision conflict, decision regret, and anxiety) of 262 pregnant women offered noninvasive prenatal test (NIPT) for high-risk Down screening results were assessed. Decision conflict was experienced by 3.5% and level of decisional regret low (mean score 15.7, 95%CI 13.2-18.3). All 13 cases of decisional regret were NIPT acceptors. Elevated anxiety was experienced by 55.9% at the time of decision making about NIPT and persistent in 30.3%. Insufficient knowledge about NIPT was associated with elevated anxiety at decision making (p = .011) and with decisional regret (p = .016). Decisional regret was associated with prolonged anxiety (p = .010). [ABSTRACT FROM AUTHOR]

This paper presents to date the most complete global climatology of the size of tropical cyclones (TCs) between 1999 and 2009 using the QuikSCAT satellite data. Here, TC size is defined as the azimuthal mean radius of 17ms-1 surface winds from the TC centre. While the TC size climatology for the Western North Pacific (WNP) and North Atlantic (NA) has been documented in previous studies, those for the Eastern North Pacific (ENP), South Indian Ocean (SI) and South Pacific (SP) have yet to be examined in detail, which is the objective of this study. Among all the basins, TCs over the WNP are the largest and have the largest variance, while those over the ENP are the smallest. In addition, TCs in the Northern Hemisphere (WNP, NA and ENP) have two seasonal size peaks, but those in the Southern Hemisphere (SI and SP) have only one. An important finding is that for all basins, the size of a TC does not necessarily increase with latitude monotonically, but reaches the maximum at some latitudinal region. Such a result agrees well with a recent theoretical study in terms of a balance between the inertial stability associated with the TC circulation and the import of angular momentum into the TC. [ABSTRACT FROM AUTHOR]

Docetaxel and cyclophosphamide ( TC) is a widely used breast cancer adjuvant regimen. We sought to compare the rates of febrile neutropenia ( FN) between patients receiving no primary prophylaxis ( PP) and those receiving PP with either granulocyte-colony stimulating factor (G- CSF) or antibiotics. We also analyzed cost-effectiveness of TC with and without either G- CSF or antibiotics. Charts were reviewed of all 340 patients who received adjuvant TC between January 2008 and December 2012 at two major cancer centers. Rates of FN in the three groups - no PP, PP with G- CSF and PP with antibiotics were compared. A Markov model was constructed comparing cost-effectiveness of PP with G- CSF, PP with antibiotics, and secondary prophylaxis ( SP) with G- CSF after an episode of FN in a previous cycle. Costs were based on actual resource utilization and supplemented by the published literature, adjusted to 2012 Canadian dollars. Of the 73 (21%) patients who did not receive any PP, 23 (32%) of patients developed FN. Of the 192 (57%) patients receiving PP with G- CSF alone, only two (1%; p < 0.0001) developed FN; and of the 53 (16%) receiving PP with antibiotics alone, six (11%; p < 0.01) developed FN. From a cost-standpoint, PP with G- CSF was less cost-effective than PP with antibiotics. The rate of FN with TC chemotherapy exceeds 30%, and American Society of Clinical Oncology guidelines recommend PP with G- CSF in this situation. PP with antibiotics is more cost-effective, and is a reasonable option in resource-limited settings or for patients who decline or do not tolerate G- CSF. [ABSTRACT FROM AUTHOR]

The safe use of Chinese materia medica (CMM) and products in traditional Chinese medicine (TCM) practice conventionally relies on correct pharmacognostic identification, good agricultural and manufacturing practices based on pharmacopoeia standards and rational/correct CMM combinations with TCM-guided clinical prescribing. These experience-based principles may not absolutely ensure safety without careful toxicological investigations when compared with development of new pharmaceutical drugs. Clinically observed toxicity reports remain as guidance for gathering toxicological evidence, though essential as pharmacovigilance, but are considered as late events for ensuring safety. The overview focuses on the following factors: global development of TCM that has affected conventional healthcare; examples of key toxic substances in CMM; reported adverse drug reactions (ADRs) consequential to taking CMM and TCM products; and proposals on rational approaches to integrate the knowledge of biomedical science and the principles of TCM practice for detecting early ADRs if both TCM products and orthodox drugs are involved. It is envisaged that good control of the quality and standards of CMM and proprietary Chinese medicines can certainly reduce the incidence of ADRs in TCM practice when these medications are used. [ABSTRACT FROM AUTHOR]

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho-CH cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono- N-protected amino acid (MPAA) ligands as a promoter. [ABSTRACT FROM AUTHOR]

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho-CH cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono- N-protected amino acid (MPAA) ligands as a promoter. [ABSTRACT FROM AUTHOR]

BACKGROUND A watch and wait (WW) strategy is the standard of care for patients with asymptomatic advanced-stage follicular lymphoma. Recent data have demonstrated an improvement in the time to progression with rituximab induction (RI) with or without rituximab maintenance (RM) in comparison with a WW strategy wait in such patients. It remains unclear whether this is a cost-effective strategy. METHODS A Markov decision analysis model was developed to compare the clinical outcomes, costs, and cost-effectiveness of RI (4 weekly doses) plus RM (12 doses every 2 months), RI (4 weekly doses), and a WW strategy for patients newly diagnosed with low-burden, asymptomatic advanced-stage follicular lymphoma over a lifetime horizon. Baseline probabilities and utilities were derived from a systematic review of published studies, and they were evaluated on a 6-month cycle. A Canadian public health payer's perspective was adopted, and costs were presented in 2012 Canadian dollars. RESULTS RI was the cheapest strategy. It was less costly at $59,953 versus $67,489 for the RM arm and $75,895 for the WW arm. It was also associated with a slightly lower quality-adjusted life expectancy at 6.16 quality-adjusted life years (QALYs) versus 6.28 QALYs for the RM strategy but was superior to WW (5.71 QALYs). In sensitivity analyses of key variables, this effectiveness was sensitive to the probability of first and second progression in the RI arm, and this indicated relatively neutral effectiveness between the 2 rituximab arms. CONCLUSIONS RI without maintenance for asymptomatic advanced-stage follicular lymphoma is the preferred strategy: it minimizes costs per patient over a lifetime horizon. Cancer 2015;121:2637-2645. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Reactivation of hepatitis B virus (HBV) during immunosuppressive therapy (IST) can lead to severe and even fatal hepatitis but can be largely prevented with prophylactic antiviral therapy. Screening for HBV prior to starting IST is recommended. Both risk-based and universal screening have been recommended by different societies. For effective risk-based screening, physicians must be aware of risk factors for chronic HBV infection. Methods: The HBV screening practices prior to starting IST of rheumatologists, medical and hematological oncologists were evaluated by survey and chart review. Country of origin, the primary risk factor for HBV exposure, was determined in all patients. Results: Of 140 rheumatology, 79 medical oncology and 53 hematology patients reviewed, 81%, 11% and 81% were deemed to be at high risk of HBV reactivation by their physicians respectively, however only 27%, 6% and 62% (p<0.0001) were actually screened for HBV prior to starting IST. For patients from HBV-endemic regions, more hematology patients (53%) were correctly identified by their physicians as being at high risk of reactivation than rheumatology patients (2.4%, p=0.0001) or medical oncology patients (15%, p=0.009). However actual screening rates were not increased in patients from endemic regions. A total of 81 patients were screened for HBsAg; 2 were positive. Of the 33 patients screened for anti-HBc, 10 (30%) were positive. Conclusions: Hematologists, rheumatologists and medical oncologists had low rates of screening for HBV prior to prescribing IST, largely due to poor identification of those at risk for infection. Risk-based screening strategies are unlikely to be effective and should be replaced by universal screening. [ABSTRACT FROM AUTHOR]

C--H arylation via a Pd(II)/Pd(IV) catalytic cycle has been one of the most extensively studied C--H activation reactions since the 1990s. Despite the rapid development of this reaction in the past two decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C--H bonds with aryl iodides using mono-N-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of chiral substrates. [ABSTRACT FROM AUTHOR]

The present study seeks to understand how the initial vortex intensity and outer winds influence tropical cyclone (TC) size, which is defined as the azimuthally averaged radius of the 10 m 17 m s−1 wind from the TC centre ( R17), using a full baroclinic model in a quiescent f-plane environment. The initial vortex intensity is found to influence the size growth rate in the developing phase of the vortex life cycle. However, when the vortex comes to the mature and/or decaying phase of the vortex life cycle, the initial vortex intensity (ranging between 20 and 40 m s−1 in this study) does not strongly affect TC size. On the other hand, vortex intensification or re-intensification resulting from inner-core dynamics is apparently favourable for size growth in most instances. In addition, the lower-tropospheric outer winds of a vortex (i.e. winds beyond R17; e.g. the environmental flows around the TC) are found to be an important factor governing size change. The outer winds closer to R17 are more effective and can influence the vortex size at an earlier stage, especially if the winds are strong. The impact of the initial lower-tropospheric outer winds on the TC size evolution appears to be more prominent than that of the initial vortex intensity. The size change is much more sensitive to the outer-core, rather than inner-core, dynamics. The higher the angular momentum (AM) beyond R17, the more the AM can be brought towards the centre and hence favour size growth, and vice versa. [ABSTRACT FROM AUTHOR]

This is a numerical modelling study to understand how the initial vortex size, which is defined as the azimuthally averaged radius from the tropical cyclone (TC) centre of the 10 m 17 m s−1 wind, and planetary vorticity ( f) influence TC size change. Results from 16 f-plane experiments in a quiescent environment suggest that both of them are important in determining TC size change. With a given initial intensity and on the same f-plane, an initially larger TC generally has a larger size at a later stage because it has a larger horizontal wind extent and higher winds outside the inner core. The larger vortex therefore possesses higher angular momentum (AM) in the lower troposphere to increase its size in the outer-core region through AM transport. However, an initially small TC may not be 'destined' to be small during its lifetime, which agrees with the observation that TC size has a positive relationship with TC lifetime. In addition, a vortex can apparently grow by itself in a resting environment through fluxes of AM. A vortex at a higher latitude is also found to be not necessarily larger. Furthermore, size change is controlled to some extent by the lower-tropospheric inertial stability associated with the vortex. Consistent with observations, TC size appears to have a maximum at some optimum latitudinal region (∼ 25°N in general). All the results agree well with the AM transport concept such that the outer-core symmetric relative AM flux and Coriolis torque in the lower troposphere (especially those at the boundary layer) are important factors that govern size change. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong. Methods: We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their “clinical actionability” based on established criteria. Results: Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p<0.001). Nineteen out of the 28 management recommendations are “evidence-based” on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12). Conclusion: The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing. [ABSTRACT FROM AUTHOR]

Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. Results: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50–1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons. [ABSTRACT FROM AUTHOR]

There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reactions of C(sp2)-H and C(sp3)-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)-H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp3)-H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids. [ABSTRACT FROM AUTHOR]

This paper is the second part of a comprehensive study on tropical cyclone (TC) size. In Part I, the climatology of TC size and strength over the western North Pacific (WNP) and the North Atlantic was established based on the Quick Scatterometer (QuikSCAT) data. In this second part, the mechanisms that are likely responsible for TC size changes are explored through analyses of angular momentum (AM) transports and synoptic flow patterns associated with the TC. Changes in AM transport in the upper and lower troposphere appear to be important factors that affect TC intensity and size, respectively. The change in TC intensity is positively related to the change in the upper-tropospheric AM export, while the change in TC size is positively proportional to the change in the lower-tropospheric AM import. An examination of the synoptic flow patterns associated with WNP TCs suggests that changes in the synoptic flow near the TC are important in determining the change in TC size, with developments of the lower-tropospheric anticyclonic flows (one to the east and one to the west) bordering the TC being favorable for TC growth and a weakening of the subtropical high to the southeast for TC size reduction. A recurving TC tends to grow if the lower-tropospheric westerlies to its west increase. Moreover, a northward TC movement is related to the change in TC size. For example, a higher northward-moving speed is found for a larger TC, which also agrees well with the AM transport concept. [ABSTRACT FROM AUTHOR]

In immunocompetent patients with primary central nervous system ( CNS) lymphoma, combined modality therapy ( CMT) using high-dose methotrexate and whole brain radiotherapy has improved response rates compared to chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity. A Markov decision-analytic model compared CMT to chemotherapy alone in patients with primary CNS lymphoma. Baseline probabilities were derived from a systematic literature review. Outcomes were life expectancy and quality-adjusted life expectancy. Sensitivity analyses were performed. The life expectancy was 2·69 years for CMT and 2·77 years for chemotherapy alone. The quality-adjusted life expectancies for the two strategies were 1·70 and 1·67 quality-adjusted life years ( QALYs) respectively. In younger patients <60 years of age, CMT yielded a quality-adjusted life expectancy of 2·71 QALYs, compared to 2·09 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0·62 QALYs or 7·4 quality-adjusted months. There was no difference between the strategies in the older group. The model was robust to key variables for the younger group. The preferred induction strategy for younger patients appears to be CMT, maximizing life expectancy, and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone. [ABSTRACT FROM AUTHOR]

Population-based quality indicators of either aggressive or supportive care at end of life (EOL), especially when specific to a cancer type, help to inform quality improvement efforts. This is a population-based, retrospective cohort study of gastrointestinal (GI) cancer decedents in Ontario from 1 January 2006–31 December 2018, using administrative data. Quality indices included hospitalizations, emergency department (ED) use, intensive care unit admissions, receipt of chemotherapy, physician house call, and palliative home care in the last 14–30 days of life. Previously defined aggregate measures of both aggressive and supportive care at end of life were also used. In our population of 69,983 patients who died of a GI malignancy during the study period, the odds of experiencing aggressive care at EOL remained stable, while the odds of experiencing supportive care at EOL increased. Most of our population received palliative care in the last year of life (n = 65,076, 93.0%) and a palliative care home care service in the last 30 days of life (n = 45,327, 70.0%). A significant number of patients also experienced death in an acute care hospital bed (n = 28,721, 41.0%) or had a new hospitalisation in the last 30 days of life (n = 33,283, 51.4%). The majority of patients received palliative care in the last year of life, and a majority received a palliative care home service within the last 30 days of life. The odds of receiving supportive care at EOL have increased over time. Differences in care exist according to income, age, and rurality. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic greatly impacted primary care and cancer care. We studied how primary care utilization in Ontario, Canada changed for patients who were newly diagnosed with cancer just prior to the COVID-19 pandemic compared to those diagnosed in non-pandemic years.Methods: This population-based, retrospective cohort study used linked healthcare databases to compare outcomes for patients with a new malignancy diagnosed within the year prior to the COVID-19 pandemic, between July 1 and September 30, 2019 (COVID-19 cohort) to those diagnosed in the same months in 2018 and 2017 (pre-pandemic cohort). We used Poisson regression models to compare rates of in-person and virtual visits to patients' usual primary care physician (PCP), emergency department (ED) visits, and hospitalizations, all reported per person-year of follow-up.Results: In-person visits to usual PCPs decreased from 4.07/person-year in the pre-pandemic cohort to 2.58 in the COVID-19 cohort (p < 0.0001). Virtual visits to usual PCPs increased from 0.00 to 1.53 (p < 0.0001). Combined in-person and virtual visits to patients' usual PCPs was unchanged from 4.07 to 4.12 (p = 0.89). The rate of ED visits decreased from 0.99/person-year to 0.88 (p < 0.0001). Non-elective hospitalizations remained unchanged, from 0.49/person-year to 0.47 (p = 0.1675).Conclusion: There was a sizeable shift in primary care visits for cancer patients from in-person to virtual during the pandemic, although there was no resultant increase in hospitalizations. This suggests that early in the pandemic, virtual care allowed for continuity in utilization of primary care, though further studies are required to confirm this persisted later in the pandemic. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate Canadian medical oncologists' perspectives on how barriers to accessing new expensive cancer drugs have affected their practice and their opinions on the drug approval and funding processes. Methods: Canadian medical oncologists treating colorectal cancer (CRC) were surveyed by means of a self-administered, cross-sectional survey. Results: Of the 164 eligible oncologists, there were 68 respondents (41.4% response rate). Only 29.4% of physicians felt they had been using the ideal first-line chemotherapy regimen for patients with metastatic CRC. Although all considered bevacizumab to be a component of the ideal first-line regimen, only 18% could use bevacizumab routinely, and less than half (44.8%) always discussed its role with their patients. In terms of accessing unfunded drugs, most physicians agreed that private payment should be allowed for drugs to be delivered at their own centers (76.1%) or private infusion clinics (52.2%). Ninety-seven percent of physicians reported major concerns about the drug approval and funding processes, and 85% of physicians supported the establishment of a national drug formulary. Conclusions: Canadian medical oncologists are struggling to provide optimal cancer care for their patients with metastatic CRC as a result of nonuniform access to preferred therapeutic drugs. In face of these challenges, physicians have had to use clinical trials and private infusion clinics and, at times, may avoid discussing drugs with limited access. Many oncologists are dissatisfied with the existing funding mechanism and approval processes and support private payment for unfunded drugs. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Studies on traditional Chinese medicine (TCM), like those of other systems of traditional medicine (TM), are very variable in their quality, content and focus, resulting in issues around their acceptability to the global scientific community. In an attempt to address these issues, an European Union funded FP7 consortium, composed of both Chinese and European scientists and named “Good practice in traditional Chinese medicine” (GP-TCM), has devised a series of guidelines and technical notes to facilitate good practice in collecting, assessing and publishing TCM literature as well as highlighting the scope of information that should be in future publications on TMs. This paper summarises these guidelines, together with what has been learned through GP-TCM collaborations, focusing on some common problems and proposing solutions. The recommendations also provide a template for the evaluation of other types of traditional medicine such as Ayurveda, Kampo and Unani. Materials and methods: GP-TCM provided a means by which experts in different areas relating to TCM were able to collaborate in forming a literature review good practice panel which operated through e-mail exchanges, teleconferences and focused discussions at annual meetings. The panel involved coordinators and representatives of each GP-TCM work package (WP) with the latter managing the testing and refining of such guidelines within the context of their respective WPs and providing feedback. Results: A Good Practice Handbook for Scientific Publications on TCM was drafted during the three years of the consortium, showing the value of such networks. A “deliverable – central questions – labour division” model had been established to guide the literature evaluation studies of each WP. The model investigated various scoring systems and their ability to provide consistent and reliable semi-quantitative assessments of the literature, notably in respect of the botanical ingredients involved and the scientific quality of the work described. This resulted in the compilation of (i) a robust scoring system and (ii) a set of minimum standards for publishing in the herbal medicines field, based on an analysis of the main problems identified in published TCM literature. Conclusion: Good quality, peer-reviewed literature is crucial in maintaining the integrity and the reputation of the herbal scientific community and promoting good research in TCM. These guidelines provide a clear starting point for this important endeavour. They also provide a platform for adaptation, as appropriate, to other systems of traditional medicine. [Copyright &y& Elsevier]

A comprehensive statistical climatology of the size and strength of the tropical cyclones (TCs) occurring over the western North Pacific (WNP; including the South China Sea) and the North Atlantic (NA; including the Gulf of Mexico and the Caribbean Sea) between 1999 and 2009 is constructed based on Quick Scatterometer (QuikSCAT) data. The size and strength of a TC are defined, respectively, as the azimuthally averaged radius of 17 m s−1 of ocean-surface winds (R17) and the azimuthally averaged tangential wind within 1°-2.5°-latitude radius from the TC center (outer-core wind strength, OCS). The mean TC size and strength are found to be 2.13° latitude and 19.6 m s−1, respectively, in the WNP, and 1.83° latitude and 18.7 m s−1 in the NA. While the correlation between size and strength is strong ( r ≈≈ 0.9), that between intensity and either size or strength is weak. Seasonally, midsummer (July) and late-season (October) TCs are significantly larger in the WNP, while the mean size is largest in September in the NA. The percentage frequency of TCs having large size or high strength is also found to vary spatially and seasonally. In addition, the interannual variation of TC size and strength in the WNP correlate significantly with the TC lifetimes and the effect of El Niño over the WNP. TC lifetime and seasonal subtropical ridge activities are shown to be potential factors that affect TC size and strength. [ABSTRACT FROM AUTHOR]

Abstract: Here we present a comparison of commonly used methodologies for the extraction and quantification of konjac glucomannan (KGM). Compositional analysis showed that the purified konjac flour (PKF) produced using a modified extraction procedure contained 92% glucomannan, with a weight average molecular weight (M w), polydispersity index (PDI) and degree of acetylation (DA) of 9.5±0.6×105 gmol−1, 1.2 and 2.8wt.%. These data, plus Fourier-transform infrared spectral (FTIR) and zero shear viscosity analyses of the extract (PKF) were all consistent with the literature. Comparison of three existing methodologies for the quantitative analysis of the KGM content of the PKF, namely 3,5-dinitrosalicylic acid (3,5-DNS), phenol–sulphuric acid and enzymatic colorimetric assays; indicated that the 3,5-DNS colorimetric assay was the most reproducible and accurate method, with a linear correlation coefficient of 0.997 for samples ranging from 0.5 to 12.5mg/ml, and recoveries between 97% and 103% across three spiking levels (250, 500 and 750μg/g) of starch. These data provide the basis of improved good laboratory practice (GLP) for the commercial extraction and analysis of this multifunctional natural polymer. [Copyright &y& Elsevier]

Epitaxial anatase TiO2 thin films were grown on (001) oriented SrTiO3 single crystal substrates by liquid phase deposition at 50°C. The film consisted of nanosized crystallites and exhibited a significant void fraction of 31 %. This contributed to the cracking of thicker films due to the generation of capillary stresses in the nanosized pores during drying. This porosity also comes in useful during the photodegradation of a methylene blue dye by an as-grown film. [ABSTRACT FROM AUTHOR]

Epitaxial cobalt doped TiO2anatase thin films were deposited on (001) oriented SrTiO3single crystal substrates at 120 °C by liquid phase deposition. X-Ray diffraction, photoelectron and absorption spectroscopies revealed that cobalt substituted Ti4+predominantly as low spin Co3+in the as formed films as a result of the oxidizing environment of the growth solution. Enhanced ferromagnetism was observed in films when annealed in vacuum and air as Co3+was reduced to Co2+with no evidence of cobalt metal clusters forming. The insulating nature of the films indicated that ferromagnetism was not carrier-mediated but due to percolation of bound magnetic polarons. [ABSTRACT FROM AUTHOR]