We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Surrogate endpoints are increasingly being used in the pivotal trials of cancer drugs to underpin (conditional) regulatory approval. We examined the relationship between the use of surrogate measures in pivotal trials underpinning cancer drug approvals by the European Medicines Agency (EMA) between 2017 and 2022 and health technology assessment (HTA) recommendations made by the National Centre for Pharmacoeconomics in Ireland (NCPE).
Methods
A previously published methodology was used to identify cancer drug indications that received (conditional) marketing authorization between 2017 and 2022, inclusive. EMA-approved cancer drugs were categorized using the following benefit categories, based on pivotal trial endpoints: overall survival (OS), progression-free survival (PFS), disease response (DR), and single-arm trials (SATs). The NCPE website was searched to identify indications that had undergone, at least, a rapid review (RR) assessment. The NCPE recommendation for each assessment was recorded. Additional data including the incremental quality-adjusted life years (QALY) gain reported in cost-effectiveness analyses were extracted for indications that had undergone a full HTA.
Results
One hundred and eight cancer drug indications were identified, comprising 68 cancer drugs. In 2017, OS, PFS, and SAT benefit underpinned equal proportions of approvals (28.6% each). In 2022, SAT underpinned the largest proportion of approvals (53.6%). As of June 2023, 77 indications (71.3%) had undergone at least a RR assessment; 31 indications had completed a full HTA appraisal. All of the indications underpinned by SAT evidence (n=7) received a conditional negative recommendation. Indications with SAT evidence had a mean incremental QALY gain of 1.88 (standard deviation [SD] 1.20), whereas indications with an OS benefit had a mean incremental QALY gain of 0.81 (SD 0.36).
Conclusions
The proportion of cancer drug indications receiving regulatory approval on the basis of SAT evidence, where no direct comparative evidence is available, is increasing. This results in additional uncertainty in the comparative benefit of cancer drugs supported by SAT evidence. The study is limited by the sample size of HTA appraisals included. Further in-depth analysis of factors influencing NCPE recommendations is needed.
Ruth Glacier is situated in the Central Alaska Range, with the Don Sheldon Amphitheater comprising much of its broad accumulation area, directly adjacent to North America's tallest mountain, Denali. From there it funnels through the ‘Great Gorge,’ flanked by steep valley walls reaching over 1500 m. We combine airborne and ground-based radar measurements of ice thickness with satellite-derived surface velocities to constrain ice flux above and below the gorge, and employ a mass conservation approach to estimate the glacier's thickness within the gorge. We measure ice thickness in the amphitheater to reach 950 m, and estimate centerline thickness in the gorge to range from 610 to 960 m. Our estimates are up to two times greater than those suggested by global models, and allow us to confirm that the Great Gorge rivals Hells Canyon as the deepest gorge in North America. We found that the geometry of the gorge prevents radar measurements of ice thickness there since returns from the subglacial valley walls would precede and potentially occlude nadir bed returns. The same may be true of other unmapped mountain glaciers; however, thickness may be determined using appropriately located flux gates where radar sounding is feasible, combined with mass conservation methods.
Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months, intended for the treatment of schizophrenia and maintenance monotherapy treatment of bipolar I disorder (BP-I). This 32-week trial evaluated the safety, tolerability, and pharmacokinetic profile of multiple-dose gluteal administration of Ari 2MRTU 960 in clinically stable adult patients with a diagnosis of schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the treatment of schizophrenia and maintenance monotherapy treatment of BP-I).
Methods
This was an open-label, multiple-dose, randomized, parallel-arm trial conducted at 16 sites in the US. Eligible patients (N=266) were randomized to receive Ari 2MRTU 960 every 56±2 days (n=132; 4 injections in total) or AOM 400 every 28±2 days (n=134; 8 injections in total). Safety and tolerability were evaluated throughout the study; assessments included adverse event reporting, patient reporting of injection site pain, and monitoring of extrapyramidal symptoms.
Results
In the Ari 2MRTU group, 102 patients (77.3%) completed the study; in the AOM 400 group, 92 patients (68.7%) completed the study. The overall incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 and AOM 400 (71.2% versus 70.9%, respectively). The most frequently reported TEAEs were increased weight (22.7% for Ari 2MRTU 960 versus 20.9% for AOM 400) and injection site pain (18.2% for Ari 2MRTU 960 versus 9.0% for AOM 400), none of which were assessed as serious or severe by the investigators. All injection site pain events in the Ari 2MRTU 960 group were assessed as mild or moderate in severity; most (15.9%) coincided with the first injection and resolved within 5 days. Extrapyramidal symptom scores remained unchanged in both treatment groups.
Conclusions
Multiple-dose administration of Ari 2MRTU 960 was generally well tolerated in patients with schizophrenia or BP-I and did not show any new safety concerns.
Funding
Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark)
The present study investigates how group-cooperation heuristics boost voluntary contributions in a repeated public goods game. We manipulate two separate factors in a two-person public goods game: i) group composition (Selfish Subjects vs. Conditional Cooperators) and ii) common knowledge about group composition (Information vs. No Information). In addition, we let the subjects signal expectations of the other’s contributions in the experiment’s second phase. Common knowledge of Selfish type alone slightly dampens contributions but dramatically increases contributions when signaling of expectations is allowed. The results suggest that group-cooperation heuristics are triggered when two factors are jointly salient to the agent: (i) that there is no one to free-ride on; and (ii) that the other wants to cooperate because of (i). We highlight the potential effectiveness of group-cooperation heuristics and propose solution thinking as the schema of reasoning underlying the heuristics. The high correlation between expectations and actual contributions is compatible with the existence of default preference to satisfy others’ expectations (or to avoid disappointing them), but the stark end-game effect suggests that group-cooperation heuristics, at least among selfish players, function ultimately to benefit material self-interest rather than to just please others.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.
This study evaluates the cost-effectiveness of tisagenlecleucel (a CAR T-cell therapy), versus blinatumomab, for the treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) in the Irish healthcare setting. The value of conducting further research, to investigate the value of uncertainty associated with the decision problem, is assessed by means of expected value of perfect information (EVPI) and partial EVPI (EVPPI) analyses.
Methods
A three-state partitioned survival model was developed. A short-term decision tree partitioned patients in the tisagenlecleucel arm according to infusion status. Survival was extrapolated to 60 months; general population mortality with a standardized mortality ratio was then applied. Estimated EVPI and EVPPI were scaled up to population according to the incidence of the decision.
Results
At list prices, the incremental cost-effectiveness ratio was EUR 73,086 per quality-adjusted life year (QALY) (incremental costs EUR 156,928; incremental QALYs 2.15). The probability of cost-effectiveness, at the willingness-to-pay threshold of EUR 45,000 per QALY, was 16 percent. At this threshold, population EVPI was EUR 314,455; population EVPPI was below EUR 100,000 for each parameter category.
Conclusions
Tisagenlecleucel is not cost effective, versus blinatumomab, for the treatment of pediatric and young adult patients with R/R ALL in Ireland (at list prices). Further research to decrease decision (parameter) uncertainty, at the defined willingness-to-pay threshold, may not be of value. However, there is a high degree of uncertainty underpinning the analysis, which may not be captured by EVPI analysis.
A growing number of older men are living alone. They are often referred to as an at-risk group in health-care systems. The purpose of this article is to establish an overview of these men's health and health-care utilisation. We do so by drawing on three sources: an online survey with health-care professionals, data from a national self-report health study and register-based data on health-care utilisation. The results show that older men living alone generally have lower health scores than older men co-habiting and that, among older men living alone, lower educational level is associated with lower health scores but also a greater use of free-of-charge health-care services. Health-care professionals conducting preventive home visits consider older men's social needs the most pronounced problem for the men's wellbeing and call for new services to be custom made for them. In this article, we discuss differences between older men living in rural and urban areas and between those who are single, divorced or widowed. We conclude that health and social care systems must differentiate between sub-groups of older men living alone when developing new services and that free-of-charge services, such as general practitioners and home care, should be considered as vehicles for addressing health inequities.
We develop the concept of character level for the complex irreducible characters of finite, general or special, linear and unitary groups. We give characterizations of the level of a character in terms of its Lusztig label and in terms of its degree. Then we prove explicit upper bounds for character values at elements with not-too-large centralizers and derive upper bounds on the covering number and mixing time of random walks corresponding to these conjugacy classes. We also characterize the level of the character in terms of certain dual pairs and prove explicit exponential character bounds for the character values, provided that the level is not too large. Several further applications are also provided. Related results for other finite classical groups are obtained in the sequel [Guralnick et al. ‘Character levels and character bounds for finite classical groups’, Preprint, 2019, arXiv:1904.08070] by different methods.
Governments are often punished for negative events such as economic downturns and financial shocks. However, governments can address such shocks with salient policy responses that might mitigate public punishment. We use three high-quality nationally representative surveys collected around a key event in the history of the Dutch economy, namely the outbreak of the financial crisis in 2008, to examine how voters responded to a salient government bailout. The results illustrate that governments can get substantial credit for pursuing a bailout in the midst of a financial crisis. Future research should take salient policy responses into account to fully understand the public response to the outbreak of financial and economic crises.
To assess variability in antimicrobial use and associations with infection testing in pediatric ventilator-associated events (VAEs).
Design
Descriptive retrospective cohort with nested case-control study.
Setting
Pediatric intensive care units (PICUs), cardiac intensive care units (CICUs), and neonatal intensive care units (NICUs) in 6 US hospitals.
Patients
Children≤18 years ventilated for≥1 calendar day.
Methods
We identified patients with pediatric ventilator-associated conditions (VACs), pediatric VACs with antimicrobial use for≥4 days (AVACs), and possible ventilator-associated pneumonia (PVAP, defined as pediatric AVAC with a positive respiratory diagnostic test) according to previously proposed criteria.
Results
Among 9,025 ventilated children, we identified 192 VAC cases, 43 in CICUs, 70 in PICUs, and 79 in NICUs. AVAC criteria were met in 79 VAC cases (41%) (58% CICU; 51% PICU; and 23% NICU), and varied by hospital (CICU, 20–67%; PICU, 0–70%; and NICU, 0–43%). Type and duration of AVAC antimicrobials varied by ICU type. AVAC cases in CICUs and PICUs received broad-spectrum antimicrobials more often than those in NICUs. Among AVAC cases, 39% had respiratory infection diagnostic testing performed; PVAP was identified in 15 VAC cases. Also, among AVAC cases, 73% had no associated positive respiratory or nonrespiratory diagnostic test.
Conclusions
Antimicrobial use is common in pediatric VAC, with variability in spectrum and duration of antimicrobials within hospitals and across ICU types, while PVAP is uncommon. Prolonged antimicrobial use despite low rates of PVAP or positive laboratory testing for infection suggests that AVAC may provide a lever for antimicrobial stewardship programs to improve utilization.
Reduced absorption capacity in patients with intestinal resections (IR) could result in malabsorption of fat-soluble components like carotenoids, which are of clinical interest in relation to visual health. In this case cohort, we investigated the association between IR and serum lutein, zeaxanthin, β-carotene and macular pigment optical density, when compared with healthy controls. Ten patients with IR and twelve healthy controls were included in the study. Baseline characteristics were comparable between groups, except for higher serum TAG (P < 0·05) and shorter bowel length (P < 0·0001) in the group with IR. Serum lutein, zeaxanthin, β-carotene and macular pigment optical density were >15 % lower in the patient group compared with healthy controls (P < 0·05, adjusted for age) and, in the case of serum lutein and zeaxanthin, also for dietary intake of carotenoids. Results suggest that for a test of macular carotenoid supplementation, subjects with a potentially clinically significant carotenoid deficit could be recruited among patients with IR.
Adult ventilator-associated event (VAE) definitions include ventilator-associated conditions (VAC) and subcategories for infection-related ventilator-associated complications (IVAC) and possible ventilator-associated pneumonia (PVAP). We explored these definitions for children.
DESIGN
Retrospective cohort
SETTING
Pediatric, cardiac, or neonatal intensive care units (ICUs) in 6 US hospitals
PATIENTS
Patients ≤18 years old ventilated for ≥1 day
METHODS
We identified patients with pediatric VAC based on previously proposed criteria. We applied adult temperature, white blood cell count, antibiotic, and culture criteria for IVAC and PVAP to these patients. We matched pediatric VAC patients with controls and evaluated associations with adverse outcomes using Cox proportional hazards models.
RESULTS
In total, 233 pediatric VACs (12,167 ventilation episodes) were identified. In the cardiac ICU (CICU), 62.5% of VACs met adult IVAC criteria; in the pediatric ICU (PICU), 54.2% of VACs met adult IVAC criteria; and in the neonatal ICU (NICU), 20.2% of VACs met adult IVAC criteria. Most patients had abnormal white blood cell counts and temperatures; we therefore recommend simplifying surveillance by focusing on “pediatric VAC with antimicrobial use” (pediatric AVAC). Pediatric AVAC with a positive respiratory diagnostic test (“pediatric PVAP”) occurred in 8.9% of VACs in the CICU, 13.3% of VACs in the PICU, and 4.3% of VACs in the NICU. Hospital mortality was increased, and hospital and ICU length of stay and duration of ventilation were prolonged among all pediatric VAE subsets compared with controls.
CONCLUSIONS
We propose pediatric AVAC for surveillance related to antimicrobial use, with pediatric PVAP as a subset of AVAC. Studies on generalizability and responsiveness of these metrics to quality improvement initiatives are needed, as are studies to determine whether lower pediatric VAE rates are associated with improvements in other outcomes.
Let $w_{1}$ and $w_{2}$ be nontrivial words in free groups $F_{n_{1}}$ and $F_{n_{2}}$, respectively. We prove that, for all sufficiently large finite nonabelian simple groups $G$, there exist subsets $C_{1}\subseteq w_{1}(G)$ and $C_{2}\subseteq w_{2}(G)$ such that $|C_{i}|=O(|G|^{1/2}\log ^{1/2}|G|)$ and $C_{1}C_{2}=G$. In particular, if $w$ is any nontrivial word and $G$ is a sufficiently large finite nonabelian simple group, then $w(G)$ contains a thin base of order $2$. This is a nonabelian analog of a result of Van Vu [‘On a refinement of Waring’s problem’, Duke Math. J. 105(1) (2000), 107–134.] for the classical Waring problem. Further results concerning thin bases of $G$ of order $2$ are established for any finite group and for any compact Lie group $G$.