Missing observations in regression: a conditional approach.

This note presents an alternative to multiple imputation and other approaches to regression analysis in the presence of missing covariate data. Our recommendation, based on factorial and fractional factorial arrangements, is more faithful to ancillarity considerations of regression analysis and involves assessing the sensitivity of inference on each regression parameter to missingness in each of the explanatory variables. The ideas are illustrated on a medical example concerned with the success of hematopoietic stem cell transplantation in children, and on a sociological example concerned with socio-economic inequalities in educational attainment.

Regression Reconstruction from a Retrospective Sample.

The simplest form of retrospective study allows the reconstruction of the dependence between a binary outcome, Y , representing the contrast between cases and controls, and one or more explanatory variables. A different objective for such situations is considered, in which there are distinct explanatory variables, say ( W , X ) determining Y . Reconstruction of the originating distribution of ( W , X ) from the case-control data is considered for both continuous and binary variables. Emphasis is on the linear regression coefficient of W on X . That coefficient, but not the relevant intercept, shows considerable stability, as shown by theory and simulations. An approximation to the value of the coefficient not conditioning on Y is given.

A propensity score-weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer.

PURPOSE: A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. METHODS: Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. RESULTS: Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. CONCLUSION: PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Assessment of on-treatment platelet reactivity at high and low shear stress and platelet activation status after the addition of dipyridamole to aspirin in the early and late phases after TIA and ischaemic stroke.

BACKGROUND: Data are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin. AIMS: To assess inhibition of platelet function/reactivity and platelet activation with dipyridamole in CVD. METHODS: This prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. 'Dipyridamole-high on-treatment platelet reactivity (HTPR)' was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin. RESULTS: Dipyridamole-HTPR was identified in 71.4-75% of patients on PFA-100 C-ADP, 83.9-86.8% of patients on VerifyNow P2Y12, and 81.5-83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR. DISCUSSION: Additional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.

Majority of artificially lit Earth surface associated with the non-urban population.

Key to understanding the negative impacts of artificial light at night (ALAN) on human health and the natural environment is its relationship with human density. ALAN has often primarily been considered an urban issue, however although over half of the population is urbanized, the 46 % that are not inhabit a dispersed array of smaller settlements. Here, we determine the global relationships between two dimensions of ALAN, namely direct emissions (radiance) and skyglow, and human density, and how these relationships vary across continents. We correct the Visible Infrared Imaging Radiometer Suite Day/Night Band (VIIRS DNB) product for albedo, skyglow, airglow, the aurora and permanent snow and ice to represent upward radiance overland at 1.61 ∗ 2.12 km resolution from artificial sources only. For skyglow we use the World Atlas of Artificial Sky Brightness. Globally (between 59°N and 55°S), direct emissions were detected over 26.5 % and skyglow over 46.9 % of land area. Over half of all cumulative direct emissions (54.9 %) were emitted at low levels by the non-urban population, whilst these populations experienced the negative impacts of over two-thirds of all cumulative skyglow (69.8 %). This emphasises the extent of ALAN outside of urban areas, and its similarity in this regard to a number of other forms of pollution. Although powerful sources of rural direct emissions (e.g., industry, recreation) are important contributors of light pollution, cumulatively they only contributed 10 % to total direct emissions. The relationship between each dimension of ALAN and population density varied across continents, driven by powerful rural emissions, non-urban populations and urban design. These relationships reflect the unique socio-economic and geographical make-up of each region and inform on where best to target light pollution mitigation strategies, not only in urban areas but also in rural ones.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

[Impact of NGS results on patient outcome with a multiform glioblastoma]. / Analyse de l'impact des résultats du séquençage de nouvelle génération chez les patients atteints de glioblastome.

PURPOSE: Although some genetic alterations in glioblastoma (GBM) have been characterized, the prognostic value of these gene mutations is not yet established in patients treated with standard therapy. PATIENTS AND METHOD: 40 patients with newly diagnosed GBM, treated between July 2017 and December 2019, and who had genomic analysis were analyzed. Next-generation sequencing techniques (NGS) were used with a panel of 26 genes. Patients were grouped according to MGMT status, the presence or absence of at least one mutated gene on the panel, and p53 expression by immunohistochemistry. RESULTS: the median follow-up was 11.5 months (1.0-37). For all patients, the median duration of progression-free survival was 8 months (95% CI, 5.3-10.7) and the median overall survival (OS) was 17 months (95% CI, 7.5-26.5). Progression-free and overall survival were significantly different according to MGMT status but not according to NGS and p53 status. Three groups of patients according to different combined status could be distinguished due to significant differences in overall survival. CONCLUSION: we have shown that the presence of MGMT promoter methylation is a good prognostic factor. By grouping the patients according to their MGMT, NGS and p53 status, three groups of patients could be separated according to their overall survival. However, these results must be confirmed on a larger number of patients.

A multi-centred sequential trial comparing PEGASUS, an intervention to promote shared decision making about breast reconstruction with usual care.

Decision making about breast reconstruction (BR) is complex. The Patients' Expectations and Goals: Assisting Shared Understanding of Surgery (PEGASUS) intervention aims to support shared decision making by helping women and clinicians clarify and discuss their expectations around reconstructive surgery. We conducted a multi-centred sequential trial comparing PEGASUS (n = 52) with usual care (UC) (n = 86) in women considering reconstruction, who completed outcome measures at baseline, and 3, 6 and 12 months post-surgery. The primary outcome was BR-specific quality of life (Breast-Q) 6 months post-intervention. Secondary outcomes were health-related quality of life (EQ-5D-5L), capabilities (ICECAP-A) and decisional regret, compared using t-tests and Cohen's d. Comparative analyses revealed no significant differences between groups in Breast-Q scores at any time point, except for a favourable effect for UC on psychological well-being at 3 months (t = -2.41, p = .019, d= -0.59). Intervention participants reported significantly higher, therefore improved, ICECAP-A (t = -2.13, p = .037, d = -0.45) and EQ VAS (t = -2.28, p = .026, d = -0.49) scores at 12 months compared to UC. Decisional regret was significantly lower in the PEGASUS group compared to the UC group at 6 months (t =2.06, p = .044, d= -0.51), but this was not sustained at 12 months. In conclusion, the PEGASUS intervention offers some benefits to women considering BR. At times, women experienced less decisional regret, improved health-related quality of life and capability well-being. Findings are discussed in the light of fidelity testing and embedding PEGASUS into practice.

4D-imaging of drip-line radioactivity by detecting proton emission from 54mNi pictured with ACTAR TPC.

Proton radioactivity was discovered exactly 50 years ago. First, this nuclear decay mode sets the limit of existence on the nuclear landscape on the neutron-deficient side. Second, it comprises fundamental aspects of both quantum tunnelling as well as the coupling of (quasi)bound quantum states with the continuum in mesoscopic systems such as the atomic nucleus. Theoretical approaches can start either from bound-state nuclear shell-model theory or from resonance scattering. Thus, proton-radioactivity guides merging these types of theoretical approaches, which is of broader relevance for any few-body quantum system. Here, we report experimental measurements of proton-emission branches from an isomeric state in 54mNi, which were visualized in four dimensions in a newly developed detector. We show that these decays, which carry an unusually high angular momentum, ℓ = 5 and ℓ = 7, respectively, can be approximated theoretically with a potential model for the proton barrier penetration and a shell-model calculation for the overlap of the initial and final wave functions.

Diel niche variation in mammals associated with expanded trait space.

Mammalian life shows huge diversity, but most groups remain nocturnal in their activity pattern. A key unresolved question is whether mammal species that have diversified into different diel niches occupy unique regions of functional trait space. For 5,104 extant mammals we show here that daytime-active species (cathemeral or diurnal) evolved trait combinations along different gradients from those of nocturnal and crepuscular species. Hypervolumes of five major functional traits (body mass, litter size, diet, foraging strata, habitat breadth) reveal that 30% of diurnal trait space is unique, compared to 55% of nocturnal trait space. Almost half of trait space (44%) of species with apparently obligate diel niches is shared with those that can switch, suggesting that more species than currently realised may be somewhat flexible in their activity patterns. Increasingly, conservation measures have focused on protecting functionally unique species; for mammals, protecting functional distinctiveness requires a focus across diel niches.

Exploring the active ingredients of workplace physical and psychological wellbeing programs: a systematic review.

Previous reviews have established that workplace wellbeing initiatives are effective at promoting wellbeing, but less is known about which intervention characteristics or "active ingredients" underpin this effectiveness (i.e., behavior change techniques [BCTs]). This review aims to illuminate the connections between the types of BCTs and the level of intervention intensity with intervention effectiveness. A systematic search for peer-reviewed studies evaluating a workplace wellbeing initiative was undertaken across five databases: Medline, Scopus, PsycInfo, and CINAHL (Ovid Emcare). Eligible studies included those that evaluated the effect of a workplace wellbeing initiative on participants' physical wellbeing (e.g., physical activity and quality of life) and psychological wellbeing (e.g., mental health and stress), were published between 2009 and September 2019, and utilized a comparator (e.g., control group or prepost change). Studies were screened in independent duplicate to minimize bias. Effect sizes were calculated. Following removal of duplicates, 1,541 studies were identified and screened for eligibility. Of these, 23 studies reporting 28 comparisons were deemed to meet eligibility criteria. Just over 50% of these studies reported evidence of either a strong or moderate effect across a physical and a psychological outcome, providing a positive indication that workplace wellbeing programs can promote physical and psychological wellbeing in workers. Interventions tended to employ multiple BCTs (mean range 8.1-9.4), however, no discernible patterns between the types or numbers of BCTs employed and intervention effectiveness was found. Further experimental work is required that compares and contrasts workplace wellbeing initiatives to enable a better understanding of how to develop and implement highly effective programs.

Spectroscopy along Flerovium Decay Chains: Discovery of

A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions ^{48}Ca+^{242}Pu and ^{48}Ca+^{244}Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to ^{286}Fl and ^{288}Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely ^{282}Cn. Spectroscopy of ^{288}Fl decay chains fixed Q_{α}=10.06(1) MeV. In one case, a Q_{α}=9.46(1)-MeV decay from ^{284}Cn into ^{280}Ds was observed, with ^{280}Ds fissioning after only 518 µs. The impact of these findings, aggregated with existing data on decay chains of ^{286,288}Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.

The role of rhinovirus infections in young children with cystic fibrosis.

Rhinovirus (RV) is an important virus in children with chronic respiratory conditions such as asthma; however, little is known about its role in CF. Our aim was to examine the prevalence and clinical impact of different RV species in young children with CF. We collected clinical data and nasal swabs on patients at home and in the hospital setting. Parents filled out symptom diaries and collected nasal swabs when their children were symptomatic and asymptomatic. A novel RV typing PCR assay was used to determine the RV species present. We collected 55 nasal swab samples from ten preschool CF patients over a six month period. The quality of parent collected samples at home was sufficient for PCR analysis. RV was the most common virus detected in young children with CF. There was no difference in the frequency of RV species between symptomatic and asymptomatic subjects. However, parental home-sampling is an acceptable and feasible approach to monitoring young children with CF.

Relationship between 'on-treatment platelet reactivity', shear stress, and micro-embolic signals in asymptomatic and symptomatic carotid stenosis.

BACKGROUND: Assessment of 'high on-treatment platelet reactivity (HTPR)' could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on antiplatelet therapy. METHODS: This prospective, multi-centre study assessed antiplatelet-HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50-99% carotid stenosis. Platelet function/reactivity was assessed under 'moderately high shear stress' with the PFA-100® and 'low shear stress' with VerifyNow® and Multiplate® analysers. Bilateral 1-h transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES + ve or MES - ve. RESULTS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 patients in the 'late phase' (≥ 3 months) after TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg; P < 0.001), but not late symptomatic (75 mg; P = 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin-HTPR in early (28.6%; P = 0.028), but not late symptomatic (38.9%; P = 0.22) compared with asymptomatic patients (56.7%) on the PFA-100®, but not on the VerifyNow® or Multiplate® (P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin-HTPR on the PFA-100® (28.6%) vs. VerifyNow® (9.5%; P = 0.049), but not Multiplate® assays (11.9%, P = 0.10). There was no difference in aspirin-HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES - ve subgroup. DISCUSSION: Recently symptomatic moderate-severe carotid stenosis patients had a lower prevalence of aspirin-HTPR than their asymptomatic counterparts on the PFA-100®, likely related to higher aspirin doses. The prevalence of antiplatelet-HTPR was positively influenced by higher shear stress levels, but not MES status.

Gas flow and accretion via spiral streamers and circumstellar disks in a young binary protostar.

The majority of stars are part of gravitationally bound stellar systems, such as binaries. Observations of protobinary systems constrain the conditions that lead to stellar multiplicity and subsequent orbital evolution. We report high-angular resolution observations of the circumbinary disk around [BHB2007] 11, a young binary protostar system. The two protostars are embedded in circumstellar disks that have radii of 2 to 3 astronomical units and probably contain a few Jupiter masses. These systems are surrounded by a complex structure of filaments connecting to the larger circumbinary disk. We also observe accretion and radio jets associated with the protobinary system. The accretion is preferentially onto the lower-mass protostar, consistent with theoretical predictions.

The Prevalence of Pseudomonas Aeruginosa Infection Over a Ten-Year Period in Children with Cystic Fibrosis

Background Pseudomonas aeruginosa (PA) infection is associated with an increased morbidity and adverse prognosis in children with Cystic Fibrosis(CF). The aim of the study was to evaluate the prevalence and characteristics of PA over a ten year period at a single paediatric tertiary referral centre in Ireland. Methods This was a retrospective cross-sectional study. Patient's case notes, microbiology laboratory results and CF Registry of Ireland(CFRI) data were used to collect the data. Results The overall chronic PA infection prevalence was 28.1%(45/160) in 2004 and 21.3%(35/164) in 2014. In 2004, 54/160(33.8%) patients were never infected with PA, 27/160(16.9%) were free for 12 months and 34/160(21.3%) were intermittently infected. In 2014; 80/164(49%) patients, 38/164(23.2%) and 11/164(6.7%) were never infected, free for 12 months and intermittently infected respectively. Conclusion There has been a decline in the overall prevalence of PA infection and a change in the pattern of prevalence over the last decade at our Centre.

Near-Field Scanning Microwave Microscopy in the Single Photon Regime.

The microwave properties of nano-scale structures are important in a wide variety of applications in quantum technology. Here we describe a low-power cryogenic near-field scanning microwave microscope (NSMM) which maintains nano-scale dielectric contrast down to the single microwave photon regime, up to 109 times lower power than in typical NSMMs. We discuss the remaining challenges towards developing nano-scale NSMM for quantum coherent interaction with two-level systems as an enabling tool for the development of quantum technologies in the microwave regime.

On the linear in probability model for binary data.

The analysis of binary response data commonly uses models linear in the logistic transform of probabilities. This paper considers some of the advantages and disadvantages of simple least-squares estimates based on a linear representation of the probabilities themselves, this in particular sometimes allowing a more direct empirical interpretation of underlying parameters. A sociological study is used in illustration.