The ethics of animal research: a survey of the public and scientists in North America

Background: To determine whether the public and scientists consider common arguments (and counterarguments) in support (or not) of animal research (AR) convincing. Methods: After validation, the survey was sent to samples of public (Sampling Survey International (SSI; Canadian), Amazon Mechanical Turk (AMT; US), a Canadian city festival and children’s hospital), medical students (two second-year classes), and scientists (corresponding authors, and academic pediatricians). We presented questions about common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses were compared using Chi-square with Bonferonni correction. Results: There were 1220 public [SSI, n = 586; AMT, n = 439; Festival, n = 195; Hospital n = 107], 194/331 (59 %) medical student, and 19/319 (6 %) scientist [too few to report] responses. Most public respondents were(65 %), had some College/University education (83 %), and had never done AR (92 %). Most public and medical student respondents considered ‘benefits arguments’ sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same ‘benefits arguments’ do not apply to using humans in research, significantly weakened ‘benefits arguments’. Almost all were not convinced of the moral permissibility of AR by ‘characteristics of non-human-animals arguments’, including that non-human-animals are not sentient, or are property. Most were not convinced of the moral permissibility of AR by ‘human exceptionalism’ arguments, including that humans have more advanced mental abilities, are of a special ‘kind’, can enter social contracts, or face a ‘lifeboat situation’. Counterarguments explained much of this, including that not all humans have these more advanced abilities [‘argument from species overlap’], and that the notion of ‘kind’ is arbitrary [e.g., why are we not of the ‘kind’ ‘sentient-animal’ or ‘subject-of-a-life’?]. Medical students were more supportive (80 %) of AR at the end of the survey (p \u3c 0.05). Conclusions: Responses suggest that support for AR may not be based on cogent philosophical rationales, and more open debate is warranted

COSMOS-Web: Intrinsically Luminous z≳\gtrsim10 Galaxy Candidates Test Early Stellar Mass Assembly

We report the discovery of 15 exceptionally luminous $10\lesssim z\lesssim14$ candidate galaxies discovered in the first 0.28 deg$^2$ of JWST/NIRCam imaging from the COSMOS-Web Survey. These sources span rest-frame UV magnitudes of $-20.5>M_{\rm UV}>-22$, and thus constitute the most intrinsically luminous $z\gtrsim10$ candidates identified by JWST to-date. Selected via NIRCam imaging with Hubble ACS/F814W, deep ground-based observations corroborate their detection and help significantly constrain their photometric redshifts. We analyze their spectral energy distributions using multiple open-source codes and evaluate the probability of low-redshift solutions; we conclude that 12/15 (80%) are likely genuine $z\gtrsim10$ sources and 3/15 (20%) likely low-redshift contaminants. Three of our $z\sim12$ candidates push the limits of early stellar mass assembly: they have estimated stellar masses $\sim5\times10^{9}\,M_\odot$, implying an effective stellar baryon fraction of $\epsilon_{\star}\sim0.2-0.5$, where $\epsilon_{\star}\equiv M_{\star}/(f_{b}M_{halo})$. The assembly of such stellar reservoirs is made possible due to rapid, burst-driven star formation on timescales $<$100\,Myr where the star-formation rate may far outpace the growth of the underlying dark matter halos. This is supported by the similar volume densities inferred for $M_\star\sim10^{10}\,M_\odot$ galaxies relative to $M_\star\sim10^{9}\,M_\odot$ -- both about $10^{-6}$ Mpc$^{-3}$ -- implying they live in halos of comparable mass. At such high redshifts, the duty cycle for starbursts would be of order unity, which could cause the observed change in the shape of the UVLF from a double powerlaw to Schechter at $z\approx8$. Spectroscopic redshift confirmation and ensuing constraints of their masses will be critical to understanding how, and if, such early massive galaxies push the limits of galaxy formation in $\Lambda$CDM.Comment: 30 pages, 9 figures; ApJ submitte

Assessing the Quality of Decision Support Technologies Using the International Patient Decision Aid Standards instrument (IPDASi)

Objectives To describe the development, validation and inter-rater reliability of an instrument to measure the quality of patient decision support technologies (decision aids). Design Scale development study, involving construct, item and scale development, validation and reliability testing. Setting There has been increasing use of decision support technologies – adjuncts to the discussions clinicians have with patients about difficult decisions. A global interest in developing these interventions exists among both for-profit and not-for-profit organisations. It is therefore essential to have internationally accepted standards to assess the quality of their development, process, content, potential bias and method of field testing and evaluation. Methods Scale development study, involving construct, item and scale development, validation and reliability testing. Participants Twenty-five researcher-members of the International Patient Decision Aid Standards Collaboration worked together to develop the instrument (IPDASi). In the fourth Stage (reliability study), eight raters assessed thirty randomly selected decision support technologies. Results IPDASi measures quality in 10 dimensions, using 47 items, and provides an overall quality score (scaled from 0 to 100) for each intervention. Overall IPDASi scores ranged from 33 to 82 across the decision support technologies sampled (n = 30), enabling discrimination. The inter-rater intraclass correlation for the overall quality score was 0.80. Correlations of dimension scores with the overall score were all positive (0.31 to 0.68). Cronbach's alpha values for the 8 raters ranged from 0.72 to 0.93. Cronbach's alphas based on the dimension means ranged from 0.50 to 0.81, indicating that the dimensions, although well correlated, measure different aspects of decision support technology quality. A short version (19 items) was also developed that had very similar mean scores to IPDASi and high correlation between short score and overall score 0.87 (CI 0.79 to 0.92). Conclusions This work demonstrates that IPDASi has the ability to assess the quality of decision support technologies. The existing IPDASi provides an assessment of the quality of a DST's components and will be used as a tool to provide formative advice to DSTs developers and summative assessments for those who want to compare their tools against an existing benchmark

Uncovering a Massive z~7.65 Galaxy Hosting a Heavily Obscured Radio-Loud QSO Candidate in COSMOS-Web

In this letter, we report the discovery of the highest redshift, heavily obscured, radio-loud QSO candidate selected using JWST NIRCam/MIRI, mid-IR, sub-mm, and radio imaging in the COSMOS-Web field. Using multi-frequency radio observations and mid-IR photometry, we identify a powerful, radio-loud (RL), growing supermassive black hole (SMBH) with significant spectral steepening of the radio SED ($f_{1.32 \mathrm{GHz}} \sim 2$ mJy, $q_{24\mu m} = -1.1$, $\alpha_{1.32-3\mathrm{GHz}}=-1.2$, $\Delta \alpha = -0.4$). In conjunction with ALMA, deep ground-based observations, ancillary space-based data, and the unprecedented resolution and sensitivity of JWST, we find no evidence of QSO contribution to the UV/optical/NIR data and thus infer heavy amounts of obscuration (N$_{\mathrm{H}} > 10^{23}$ cm$^{-2}$). Using the wealth of deep UV to sub-mm photometric data, we report a singular solution photo-z of $z_\mathrm{phot}$ = 7.65$^{+0.4}_{-0.3}$ and estimate an extremely massive host-galaxy ($\log M_{\star} = 11.92 \pm 0.06\,\mathrm{M}_{\odot}$). This source represents the furthest known obscured RL QSO candidate, and its level of obscuration aligns with the most representative but observationally scarce population of QSOs at these epochs.Comment: Submitted to ApJL, Comments welcom

A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD2 rates between arms, the log of the PFS hazard ratio decreased by 20.188 (95% confidence interval, 20.321 to 20.055; P 5 .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 J