Self-calibrated atom-interferometer gyroscope by modulating atomic velocities.

Atom-interferometer gyroscopes have attracted much attention for their long-term stability and extremely low drift. For such high-precision instruments, self-calibration to achieve an absolute rotation measurement is critical. In this work, we propose and demonstrate the self-calibration of an atom-interferometer gyroscope. This calibration is realized by using the detuning of the laser frequency to control the atomic velocity, thus modulating the scale factor of the gyroscope. The modulation determines the order and the initial phase of the interference stripe, thus eliminating the ambiguity caused by the periodicity of the interferometric signal. This self-calibration method is validated through a measurement of the Earth's rotation rate, and a relative uncertainty of 162 ppm is achieved. Long-term stable and self-calibrated atom-interferometer gyroscopes have important applications in the fields of fundamental physics, geophysics, and long-time navigation.

Compact multi-channel radio frequency pulse-sequence generator with fast-switching capability for cold-atom interferometers.

Cold-atom interferometers have matured into a powerful tool for fundamental physics research, and they are currently moving from realizations in the laboratory to applications in the field. A radio frequency (RF) generator is an indispensable component of these devices for controlling lasers and manipulating atoms. In this work, we developed a compact RF generator for fast switching and sweeping the frequencies and amplitudes of atomic-interference pulse sequences. In this generator, multi-channel RF signals are generated using a field-programmable gate array (FPGA) to control eight direct digital synthesizers (DDSs). We further propose and demonstrate a method for pre-loading the parameters of all the RF pulse sequences to the DDS registers before their execution, which eliminates the need for data transfer between the FPGA and DDSs to change RF signals. This sharply decreases the frequency-switching time when the pulse sequences are running. Performance characterization showed that the generated RF signals achieve a 100 ns frequency-switching time and a 40 dB harmonic-rejection ratio. The generated RF pulse sequences were applied to a cold-atom-interferometer gyroscope, and the contrast of atomic interference fringes was found to reach 38%. This compact multi-channel generator with fast frequency/amplitude switching and/or sweeping capability will be beneficial for applications in field-portable atom interferometers.

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

Zoning of precipitation regimes on the Qinghai-Tibet Plateau and its surrounding areas responded by the vegetation distribution.

Compared with other factors influencing vegetation patterns, such as light and temperature, precipitation has relatively large variability, especially on the Qinghai-Tibet Plateau (QTP), where the natural environment is extremely fragile and sensitive. However, the impact of precipitation regimes, rather than precipitation amount, on vegetation has seldom been revealed. This study characterised the precipitation regimes by both the amount and temporal distribution of precipitation and zoned the QTP as different precipitation regimes accordingly. The response of vegetation to such precipitation regimes was then investigated. The results indicate that the vegetation patterns are quite consistent with zoning, that is, there is a certain type or a few dominant types of vegetation in each sub-region divided by the precipitation regimes. The areas where the precipitation became more uniform within a year were concentrated in grassland and bare land, which benefits the restoration and improvement of the ecological environment of the plateau. The increase in precipitation variability in the south-eastern part of the plateau may lead to natural disasters such as floods and mudslides. This study provides a novel perspective to understand the distribution of vegetation patterns.

Impact of the model of long-term follow-up care on adherence to guideline-recommended surveillance among survivors of adolescent and young adult cancers.

PURPOSE: Adolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long-term follow-up (LTFU) care on adherence to recommended surveillance. METHODS: We conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five-year survivors were identified from IMPACT, a database of patients aged 15-20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance. RESULTS: A total of 1574 survivors were followed for a mean of 9.2 years (range 4.3-13.9 years) from index (5-year survival). The highest level of LTFU attended in the first 2-years post-index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05-1.18) increase in the rate of becoming adherent. CONCLUSION: LTFU attendance and surveillance adherence are sub-optimal. SCC follow-up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence.

Expression analysis and tissue localization of IgZ in the grouper Epinephelus coioides after Vibrio alginolyticus infection and vaccination.

The orange-spotted grouper (Epinephelus coioides) is an important marine farmed fish in China. It is affected by the bacterial pathogen Vibrio alginolyticus, which causes high mortality and substantial economic losses. We studied the transcriptional changes of the IgZ gene in E. coioides following V. alginolyticus stimulation and investigated the distribution of IgZ in different tissues. The highest expression level of IgZ occurred in the head kidney. When fish were stimulated with live and inactivated V. alginolyticus, the expression levels of IgZ in the head kidney, spleen, intestine, gills and blood cells were significantly upregulated. In an in situ hybridization study, IgZ mRNA-positive cells were detected in the head kidney, spleen and gill, but positive signals were not detected in the liver and intestine. IgZ-labelled cells increased in the head kidney, spleen and gills post-infection with V. alginolyticus for 21 days. The present study provides additional evidence that IgZ is involved in mucosal immune responses and helps explain the role of IgZ in E. coioides defence against V. alginolyticus infection.

Health care costs associated with chronic hepatitis C virus infection in Ontario, Canada: a retrospective cohort study.

BACKGROUND: High-quality estimates of health care costs are required to understand the burden of illness and to inform economic models. We estimated the costs associated with hepatitis C virus (HCV) infection from the public payer perspective in Ontario, Canada. METHODS: In this population-based retrospective cohort study, we identified patients aged 18-105 years diagnosed with chronic HCV infection in Ontario from 2003 to 2014 using linked administrative data. We allocated the time from diagnosis until death or the end of follow-up (Dec. 31, 2016) to 9 mutually exclusive health states using validated algorithms: no cirrhosis, no cirrhosis (RNA negative) (i.e., cured HCV infection), compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, both decompensated cirrhosis and hepatocellular carcinoma, liver transplantation, terminal (liver-related) and terminal (non-liver-related). We estimated direct medical costs (in 2018 Canadian dollars) per 30 days per health state and used regression models to identify predictors of the costs. RESULTS: We identified 48 239 patients with chronic hepatitis C, of whom 30 763 (63.8%) were men and 35 891 (74.4%) were aged 30-59 years at diagnosis. The mean 30-day costs were $798 (95% confidence interval [CI] $780-$816) (n = 43 568) for no cirrhosis, $661 (95% CI $630-$692) (n = 6422) for no cirrhosis (RNA negative), $1487 (95% CI $1375-$1599) (n = 4970) for compensated cirrhosis, $3659 (95% CI $3279-$4039) (n = 3151) for decompensated cirrhosis, $4238 (95% CI $3480-$4996) (n = 550) for hepatocellular carcinoma, $8753 (95% CI $7130-$10 377) (n = 485) for both decompensated cirrhosis and hepatocellular carcinoma, $4539 (95% CI $3746-$5333) (n = 372) for liver transplantation, $11 202 (95% CI $10 645-$11 760) (n = 3201) for terminal (liver-related) and $8801 (95% CI $8331-$9271) (n = 5278) for terminal (non-liver-related) health states. Comorbidity was the most significant predictor of total costs for all health states. INTERPRETATION: Our findings suggest that the financial burden of HCV infection is substantially higher than previously estimated in Canada. Our comprehensive, up-to-date cost estimates for clinically defined health states of HCV infection should be useful for future economic evaluations related to this disorder.

Mutant-selective degradation by BRAF-targeting PROTACs.

Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.

Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.

Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in NF1. SIGNIFICANCE: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those naïve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.

Leveraging Systematic Functional Analysis to Benchmark an In Silico Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation.See related commentary by Whitehead and Sebolt-Leopold, p. 4042.

Identification of Leaf Rust Resistance Genes in Bread Wheat Cultivars from Ethiopia.

Wheat leaf rust, caused by Puccinia triticina (Pt), is a widespread disease of bread wheat worldwide. In the present study, 50 wheat cultivars from Ethiopia and 34 differential lines, mostly near-isogenic lines (NILs) in the background of Thatcher with known resistance genes to leaf rust (Lr), were tested with 14 Pt races in the greenhouse to postulate Lr genes at the seedling stage. Field experiments were also conducted to identify adult plant responses to leaf rust in Baoding in the 2017-2018 and 2018-2019 growing seasons and in Zhoukou in the 2018-2019 growing season. Thirteen Lr genes (Lr1, Lr18, Lr3ka, Lr15, Lr26, Lr20, Lr14a, Lr30, Lr2a, Lr11, Lr34, Lr46, and Lr68) either singly or in combination were found in 39 cultivars. Known Lr genes were not present in the remaining 11 cultivars. Lr1 and Lr46, each in 13 cultivars, and Lr34 in 12 cultivars were the most commonly identified resistance genes. Less frequently identified genes included Lr26 (five cultivars); Lr30 and Lr18 (each present in four cultivars); Lr15, Lr3ka, and Lr2a (each identified in three cultivars); and Lr68 (two cultivars). Evidence for the existence of Lr11, Lr20, and Lr14a (each in one cultivar) was also obtained. Twenty-one cultivars were found to have slow rusting resistance to leaf rust in the field tests. The results should be valuable for cultivar selection with combinations of effective Lr genes and used in breeding new cultivars with improved resistance to leaf rust in Ethiopia and China.

RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors.

The mutation of K-RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K-RAS mutations. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C-RAF and with the reactivation of mitogen-activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB-283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small-cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B-RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF-dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K-RAS-mutated cells. This synergistic effect was also observed in several K-RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.

Frequency of repeat antinuclear antibody testing in Ontario: a population-based descriptive study.

BACKGROUND: Repeat antinuclear antibody (ANA) testing may be unnecessary, potentially harmful and costly. Our aim was to assess the frequency and correlates of repeat ANA testing in Ontario. METHODS: We performed a retrospective descriptive study identifying ANA tests performed over 2008-2015 among adults within the Ontario Laboratories Information System. Our primary outcome was any ANA test performed within 1 year of a previous ANA test. Our secondary outcome was any repeat test after a previous positive result. Repeat testing overall (regardless of who performed the previous test) and repeat testing by the same provider who performed the previous test were determined separately. We assessed correlates of repeat testing (e.g., patient and physician characteristics) and of repeat testing after a positive result using separate logistic regression models by means of generalized estimating equations to account for clustering of repeat testing within patients and within physician practices. RESULTS: In total, 587 357 ANA tests were performed in 437 966 patients over the study period, of which 126 322 (21.5%) gave a positive result and 164 913 (28.1%) were repeat tests. Family physicians ordered 358 422 tests (61.0%), and rheumatologists ordered 65 071 tests (11.1%). Of the repeat tests, 82 332 (49.9%) were ordered within 12 months of the previous test. Among the 73 961 repeat tests ordered by the same practitioner within 12 months, the previous test result was positive for 22 657 (30.6%). A higher proportion of rheumatologists than other physicians ordered repeat tests within 12 months (36.1% v. 11.3%). The most significant correlate of potentially redundant testing was testing among patients with suspected or confirmed connective tissue disease. INTERPRETATION: Over a quarter of ANA tests in Ontario were repeat tests; rheumatologists were most likely to order repeat testing. Our findings may be useful to inform quality-improvement initiatives related to the appropriateness of ANA testing.

Incidence of chronic obstructive pulmonary disease in people with HIV in Ontario, 1996-2015: a retrospective population-based cohort study.

BACKGROUND: Because of high smoking rates and HIV-related factors, people with HIV may be at high risk for chronic obstructive pulmonary disease (COPD); however, population-based estimates of the incidence of COPD among people with HIV are lacking, particularly for women. We compared the incidence of COPD among Ontario adults aged 35 years or more with and without HIV between Jan. 1, 1996, and Dec. 31, 2015. METHODS: We conducted a population-based study using Ontario's health administrative databases. We compared the incidence of COPD between people with and without HIV using standardized incidence ratios and generalized estimating equations with a log link function. RESULTS: We identified 1849 people with HIV and 1 168 727 HIV-negative people who were newly diagnosed with COPD between 1996 and 2015. People with HIV were younger than HIV-negative people (mean age 49.7 [standard deviation 10.4] yr v. 62.2 [standard deviation 14.8] yr; standardized difference 0.98). Rates of COPD were higher among people with HIV than among HIV-negative people (10.4 v. 9.0 cases per 1000 person-years; standardized incidence ratio 1.16, 95% confidence interval [CI] 1.10 to 1.21; adjusted rate ratio 1.34, 95% CI 1.27 to 1.41). In sex-stratified analyses, rates of COPD were higher among men with HIV (adjusted rate ratio 1.32, 95% CI 1.24 to 1.40) and women with HIV (adjusted rate ratio 1.54, 95% CI 1.37 to 1.72) than among men and women without HIV. In a sensitivity analysis, smoking explained observed differences in COPD incidence. INTERPRETATION: People with HIV had higher rates of incident COPD than HIV-negative people. This may reflect the disproportionately higher prevalence of smoking among the former.

Fractionation in adjuvant radiotherapy for invasive breast cancer and ductal carcinoma in situ in Ontario, Canada from 2009 to 2015.

The use of hypofractionated radiotherapy (HFRT) in patients with breast cancer and ductal carcinoma in situ (DCIS) in Ontario, Canada, from 2009 to 2015 was reported. A retrospective cohort study was conducted using data from the Institute for Clinical Evaluative Sciences (ICES). Patients with a breast cancer or DCIS diagnosis between 2009 and 2015 who received adjuvant breast or chest wall radiation were included. Trends in HFRT use (≤16 fractions) and factors associated with HFRT use in a multivariable logistic regression model with physician-level random effect were reported. The approximate number of hours that could be saved if all patients were to receive HFRT was calculated. A total of 42 072 patients were included. All included characteristics were significantly associated with HFRT use. Hypofractionated radiotherapy use in patients with breast cancer and DCIS increased to around 75% in 2015. In stage I/II patients with mastectomy and chest wall radiation, HFRT use increased to 40% in 2015. Hypofractionated radiotherapy use in patients with regional nodal radiation or reconstruction has increased but remains under 20%. For breast cancer patients with breast-conserving surgery (BCS) and breast radiation, 56 265 visits corresponding to 7200 hours of treatment or 3500 additional HFRT courses could have been saved. In conclusion, HFRT use in Ontario has increased in all patient populations but is nonuniform among physicians and institutions. Use of HFRT in chest wall and regional nodal radiation remains relatively lower than in breast cancer and DCIS patients with BCS.

Smoking, drinking, diet and physical activity-modifiable lifestyle risk factors and their associations with age to first chronic disease.

BACKGROUND: This study examined the incidence of a person's first diagnosis of a selected chronic disease, and the relationships between modifiable lifestyle risk factors and age to first of six chronic diseases. METHODS: Ontario respondents from 2001 to 2010 of the Canadian Community Health Survey were followed up with administrative data until 2014 for congestive heart failure, chronic obstructive respiratory disease, diabetes, lung cancer, myocardial infarction and stroke. By sex, the cumulative incidence function of age to first chronic disease was calculated for the six chronic diseases individually and compositely. The associations between modifiable lifestyle risk factors (alcohol, body mass index, smoking, diet, physical inactivity) and age to first chronic disease were estimated using cause-specific Cox proportional hazards models and Fine-Gray competing risk models. RESULTS: Diabetes was the most common disease. By age 70.5 years (2015 world life expectancy), 50.9% of females and 58.1% of males had at least one disease and few had a death free of the selected diseases (3.4% females; 5.4% males). Of the lifestyle factors, heavy smoking had the strongest association with the risk of experiencing at least one chronic disease (cause-specific hazard ratio = 3.86; 95% confidence interval = 3.46, 4.31). The lifestyle factors were modelled for each disease separately, and the associations varied by chronic disease and sex. CONCLUSIONS: We found that most individuals will have at least one of the six chronic diseases before dying. This study provides a novel approach using competing risk methods to examine the incidence of chronic diseases relative to the life course and how their incidences are associated with lifestyle behaviours.

Trends of intentional drug overdose among youth: a population-based cohort study.

Background: Intentional overdose is the commonest form of self-harm in adolescents globally. We explored temporal trends in intentional overdose among youth.Methods: Using multiple linked healthcare databases, we conducted a population-based cohort study in Ontario, Canada, from 2002 to 2015. We included all patients aged 8 to 19 years who presented to an emergency department (ED) or were hospitalized for intentional overdose, stratifying by age and agent(s) consumed. We determined the annual rate of intentional overdose over time. For context, we contrasted these data against the annual rate of select unintentional injuries (laceration of face or scalp, upper extremity fracture, and accidental burn) in the same group over the same period.Results: We identified 31,419 unique intentional overdose events in youth, with a striking U-shaped trend apparent over the study period. From 2002 to 2010, hospital presentations for intentional overdose gradually declined. However, from 2010 to 2015, ED visits increased by 75% and hospital admissions doubled. The sharpest increases were observed in adolescents aged 14 to 17 years, and the most commonly implicated substances were acetaminophen, antidepressants and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Over the study period, intentional overdoses involving antidepressants nearly doubled and those involving acetaminophen increased by 50%. In contrast, we observed steady and sustained declines in rates of hospital care for unintentional injuries in the same population over the same period.Conclusions: Since 2010, intentional overdoses have increased among youth, while other forms of unintentional injury have continued to decline. Further research is needed to understand the reasons for the unexpected rise in intentional overdose in adolescents, and strategies developed to mitigate this phenomenon.

The risk of death within 5 years of first hospital admission in older adults.

BACKGROUND: The risk of death in people after their first admission to hospital or first presentation to the emergency department for any reason is not known. The objective of this study was to estimate the risk of death among older adults who had had no admissions to hospital or emergency department visits in the preceding 5 years. METHODS: We used administrative data from Ontario, Canada, from 2007 to 2017 to measure the 5-year risk of death in community-dwelling adults aged 66 years and older after their first planned or unplanned hospital admission or emergency department visit, and among those who were neither admitted to hospital nor presented to the emergency department. We describe how this risk varied by age. RESULTS: Among 922 074 community-dwelling older adults, 12.7% died (116 940 deaths) over a follow-up of 3 112 528 person-years (standardized mortality rate 53.8 per 1000 person-years). After the first unplanned hospital admission, 39.7% died (59 234 deaths, standardized mortality rate 127.6 per 1000 person-years). After the first planned hospital admission, 13.0% died (10 775 deaths, standardized mortality rate 44.6 per 1000 person-years). After the first visit to the emergency department, 10.9% died (35 663 deaths, standardized mortality rate 36.2 per 1000 person-years). Among those with neither an emergency department visit nor hospital admission during follow-up, 3.1% died (11 268 deaths, standardized mortality rate 29.6 per 1000 person-years). Slightly more than half of all deaths were in those with first unplanned hospital admission (50.7%). INTERPRETATION: Death within 5 years of first unplanned hospital admission for older adults is frequent and common. Knowledge of this risk may influence counselling and patient preferences and may be useful in research and analyses for health system planning.

Development and Validation of a Score to Predict Acute Care Use After Initiation of Systemic Therapy for Cancer.

Importance: Emergency department visits and hospitalizations after starting systemic therapy for cancer are frequent, undesirable, and costly. A score to quantify the risk of needing acute care can inform decision-making and facilitate the development of preventive interventions. Objective: To develop and validate a score to predict early use of acute care after initiating systemic therapy for cancer. Design, Setting, and Participants: A retrospective population-based cohort study was conducted between July 1, 2014, and June 30, 2015. Patients with cancer were eligible if they started a new systemic therapy for cancer, regardless of line of therapy. A total of 12 162 patients in Southwestern Ontario, Canada, formed the development cohort and 15 845 patients in Northeastern Ontario formed the validation cohort. Data analysis was conducted from December 1, 2016, to August 10, 2019. Exposures: The Prediction of Acute Care Use During Cancer Treatment (PROACCT) score was created based on logistic regression in the development cohort. Combinations of cancer type and regimens were grouped into quintiles based on risk of needing acute care. The score was assessed in the validation cohort. Main Outcomes and Measures: At least 1 emergency department visit or hospitalization within 30 days after starting systemic therapy for cancer identified from administrative databases. Results: Among the 12 162 patients in the development cohort, 6903 were women and 5259 were men (mean [SD] age, 62.9 [12.6] years); among the 15 845 patients in the validation cohort, 9025 were women and 6820 were men (mean [SD] age, 62.9 [12.6] years). Use of acute care occurred within 30 days after initiation of systemic therapy in 3039 patients (25.0%) in the development cohort and 4212 patients (26.6%) in the validation cohort. Three characteristics predicted early use of acute care and formed the PROACCT score: combination of cancer type and treatment regimen, age, and emergency department visits in the prior year (C statistic, 0.67; 95% CI, 0.66-0.69; P < .001). Other characteristics including patient-reported symptoms did not improve performance. In the validation cohort, the PROACCT score was associated with use of acute care (odds ratio per point increase, 1.22; 95% CI, 1.20-1.24; P < .001), had a C statistic of 0.61 (95% CI, 0.60-0.62; P < .001), was reasonably calibrated, and provided net benefit in decision curve analysis. Conclusions and Relevance: The PROACCT score predicted the risk of early use of acute care in patients starting systemic treatment for cancer and could be incorporated at the point of care to select patients for preventive interventions. Future studies should validate the PROACCT score in other settings.

Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.

PURPOSE: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy. EXPERIMENTAL DESIGN: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3). RESULTS: Forty patients with oncogenic non-V600 BRAF-mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14). CONCLUSIONS: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment.See related commentary by Fontana and Valeri, p. 6896.