While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to ...assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC.
A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations.
In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib.
Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.
Background
Substance use-related emergency department (ED) visits have increased substantially in North America. Screening for substance use in EDs is recommended; best approaches are unclear. This ...systematic review synthesizes evidence on diagnostic accuracy of ED screening tools to detect harmful substance use.
Methods
We included derivation or validation studies, with or without comparator, that included adult (≥ 18 years) ED patients and evaluated screening tools to identify general or specific substance use disorders or harmful use. Our search strategy combined concepts
Emergency Department
AND
Screening
AND
Substance Use
. Trained reviewers assessed title/abstracts and full-text articles for inclusion, extracted data, and assessed risk of bias (QUADAS-2) independently and in duplicate. Reviewers resolved disagreements by discussion. Primary investigators adjudicated if necessary. Heterogeneity precluded meta-analysis. We descriptively summarized results.
Results
Our search strategy yielded 2696 studies; we included 33. Twenty-one (64%) evaluated a North American population. Fourteen (42%) applied screening among general ED patients. Screening tools were administered by research staff (
n
= 21), self-administered by patients (
n
= 10), or non-research healthcare providers (
n
= 1). Most studies evaluated alcohol use screens (
n
= 26), most commonly the Alcohol Use Disorders Identification Test (AUDIT;
n
= 14), Cut down/Annoyed/Guilty/Eye-opener (CAGE;
n
= 13), and Rapid Alcohol Problems Screen (RAPS/RAPS4/RAPS4-QF;
n
= 12). Four studies assessing six tools and screening thresholds for alcohol abuse/dependence in North American patients (AUDIT ≥ 8; CAGE ≥ 2; Diagnostic and Statistical Manual of Mental Disorders, 4th Edition DSM-IV-2 ≥ 1; RAPS ≥ 1; National Institute on Alcohol Abuse and Alcoholism NIAAA; Tolerance/Worry/Eye-opener/Amnesia/K-Cut down TWEAK ≥ 3) reported both sensitivities and specificities ≥ 83%. Two studies evaluating a single alcohol screening question (SASQ) (
When was the last time you had more than X drinks in 1 day?, X
=
4 for women; X
=
5 for men)
reported sensitivities 82–85% and specificities 70–77%. Five evaluated screening tools for general substance abuse/dependence (Relax/Alone/Friends/Family/Trouble RAFFT ≥ 3, Drug Abuse Screening Test DAST ≥ 4, single drug screening question, Alcohol, Smoking and Substance Involvement Screening Test ASSIST ≥ 42/18), reporting sensitivities 64%-90% and specificities 61%-100%. Studies’ risk of bias were mostly high or uncertain.
Conclusions
Six screening tools demonstrated both sensitivities and specificities ≥ 83% for detecting alcohol abuse/dependence in EDs. Tools with the highest sensitivities (AUDIT ≥ 8; RAPS ≥ 1) and that prioritize simplicity and efficiency (SASQ) should be prioritized.
The International Extranodal Lymphoma Study Group-32 (IELSG32) randomized patients with primary central nervous system lymphoma (PCNSL) for induction treatment with methotrexate-cytarabine, ...methotrexate-cytarabine-rituximab, or methotrexate-cytarabine-thiotepa-rituximab (MATRix) and reported significantly improved complete remission with the MATRix regimen. This study assessed cost-effectiveness among these three induction strategies for PCNSL. A Markov model was developed based on the IELSG32 trial over a 20 year time horizon from the Canadian health care system perspective. Costs for induction, consolidation, inpatient treatment administration, follow-up, adverse events, relapsed disease, and palliative care were included. Methotrexate-cytarabine-rituximab was subject to extended dominance by the other two strategies. The MATRix regimen compared to methotrexate-cytarabine produced 3.05 quality-adjusted life year (QALY) gains at added costs of $75,513, resulting in an incremental cost-effectiveness ratio of $24,758/QALY gained. The MATRix regimen was the optimal strategy in the majority of simulations (98% probability at willingness-to-pay of $50,000/QALY gained) and results appeared robust across sensitivity analyses.
The pan-Canadian Oncology Drug Review (pCODR) evaluates new cancer drugs for public funding recommendations. While pCODR's deliberative framework evaluates overall clinical benefit and includes ...considerations for exceptional circumstances, rarity of indication is not explicitly addressed. Given the high unmet need that typically accompanies these indications, we explored the impact of rarity on oncology HTA recommendations and funding decisions.
We examined pCODR submissions with final recommendations from 2012 to 2017. Incidence rates were calculated using pCODR recommendation reports and statistics from the Canadian Cancer Society. Indications were classified as rare if the incidence rate was lower than 1/100,000 diagnoses, a definition referenced by the Canadian Agency for Drugs and Technologies in Health. Each pCODR final report was examined for the funding recommendation/justification, level of supporting evidence (presence of a randomized control trial RCT), and time to funding (if applicable).
Of the ninety-six pCODR reviews examined, 16.6 percent were classified as rare indications per above criteria. While the frequency of positive funding recommendations were similar between rare and nonrare indication (78.6 vs. 75 percent), rare indications were less likely to be presented with evidence from RCT (50 vs. 90 percent). The average time to funding did not differ significantly across provinces.
Rare indications appear to be associated with weaker clinical evidence. There appears to be no association between rarity, positive funding recommendations, and time to funding. Further work will evaluate factors associated with positive recommendations and the real-world utilization of funded treatments for rare indications.
The Gothic novel, usually considered a set of imitative devices to evoke terror, should be reconsidered, not on the basis of its methods but on the particularized response it evokes. The Gothic novel ...creates an effect of fear, characterized by the vague presentiment of danger and evil, by the intensity of its effect, by a pervasive ominous atmosphere. This fear is also developed by the frightening supremacy of power over weakness. The traditional trappings are not the defining elements of the Gothic; rather the traditional Gothic novels, from Walpole to Maturin, use different devices but produce a common effect. This common effect can also be noted in novels of later vintage. In these later novels, of the Brontes, Dickens, Conrad, Faulkner, the Gothic response is employed as a thematic metaphor revealing the author's judgment of the nature of existence in the world about which he writes. In the contemporary novel, the Gothic serves more and more as a metaphor, like the absurd, for the current horrors of modern life. (JMK)
Tha English reading public, during tha greater part of the nineteenth century, encountered a new novel in a different format from the compact one-volume book of today. The latest in original fiction ...then appeared in three forma: the three-decker, a set of three post-octavo volumes sailing for a guinea and a half; the part issue, the aggregate of several weekly or monthly installments; the magazine serial. Novelists, working under artistic limitations completely unknown today, were forced to accommodate their work to tha three acceptable publishing formats, enlarging, squeezing, or pruning their material to make it fit.Examination of the nineteenth-century novel in relation to these publishing forms, their history, development, and effect upon specific novels, reveals that they profoundly influenced the size, structure, contents, and artistic technique of the novel. Contemporary critical consideration of these effects is brief and scattered; but the correspondence, memoirs, and commentary of nineteenth-century novelists and publishers, and the internal evidence provided by the novels themselves, collectively illustrate the problems of writing for carefully specified publishing formats.The three-volume format, created by the success of Sir Walter Scott's novels in this form, was favored by the circulating libraries; iv and their immense purchasing power caused publishers to demand that authors supply novels in three volumes. The nine hundred pages, or approximately 167,000 words, necessary to fill these volumes ware obtained by multiplication of characters and subplots, elaborate descriptions, digressions, superfluous dialogue, and the ingenious tricks of the printer. The three-decker frequently followed a sort of three-act structure, and it often dealt with a specialized subject matter designed to appeal to the subscribers of the circulating libraries.The part-issue novel, originated by Charles Dickens in the early 1830*s in an attempt to offer novels to the public at a cheaper price, and the serial novel, which became a significant vehicle for issuing novels with tha appearance of the shilling magazines in the late 1850's, were even longer than the three-decker. Often extending to 31*0,000 words or more, installment novels were also padded with unnecessary characters, episodes, and wordy digressions. The set length of their component parts and the necessity of a climax in every issue frequently rendered them episodic. Often such novels ware hurriedly and carelessly written. Frequently composed piecemeal during the course of publication, they offered novelists the opportunity to accentuate elements which stimulated sales and to satisfy an appreciative public's expression of the desired treatment of character and plot. In addition, subtlety in characterization was often sacrificed to the exigencies of installment publication.These three publishing formats exerted an influence upon the novel for almost three-quarters of a century. Although the serial, appearing in a magazine which offered the reader more for his money, had put an end to the part-issue novel by the 1880's, the three volume format and the serial existed as important formats until the early l89Q,s. Only than, with the successful establishment of the one-volume novel, was the novelist offered the artistic freedom to control his material as he desired. An awareness, therefore, of the unique writing requirements of the nineteenth century and the affects they had upon its fiction can open new avenues of critical evaluation of the novels of the last century.
NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.
...We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay ELISA units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35.
After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively).
At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).
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