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Abstract Background The proportion of patients with breast cancer and obesity is increasing. While the therapeutic landscape of breast cancer has been expanding, we lack knowledge about the potential differential efficacy of most drugs according to the body mass index (BMI). Here, we conducted a systematic review on recent clinical drug trials to document the dosing regimen of recent drugs, the reporting of BMI and the possible exclusion of patients according to BMI, other adiposity measurements and/or diabetes (leading comorbidity of obesity). We further explored whether treatment efficacy was evaluated according to BMI. Methods A search of Pubmed and ClinicalTrials.gov was performed to identify phase I-IV trials investigating novel systemic breast cancer treatments. Dosing regimens and exclusion based on BMI, adiposity measurements or diabetes, documentation of BMI and subgroup analyses according to BMI were assessed. Results 495 trials evaluating 26 different drugs were included. Most of the drugs (21/26, 81%) were given in a fixed dose independent of patient weight. BMI was an exclusion criterion in 3 out of 495 trials. Patients with diabetes, the leading comorbidity of obesity, were excluded in 67/495 trials (13.5%). Distribution of patients according to BMI was mentioned in 8% of the manuscripts, subgroup analysis was performed in 2 trials. No other measures of adiposity/body composition were mentioned in any of the trials. Retrospective analyses on the impact of BMI were performed in 6 trials. Conclusions Patient adiposity is hardly considered as most novel drug treatments are given in a fixed dose. BMI is generally not reported in recent trials and few secondary analyses are performed. Given the prevalence of patients with obesity and the impact obesity can have on pharmacokinetics and cancer biology, more attention should be given by investigators and study sponsors to reporting patient’s BMI and evaluating its impact on treatment efficacy and toxicity.

Abstract Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.

Abstract Invasive lobular breast cancer (ILC) differs from invasive breast cancer of no special type in many ways. Evidence on treatment efficacy for ILC is, however, lacking. We studied the degree of documentation and representation of ILC in phase III/IV clinical trials for novel breast cancer treatments. Trials were identified on Pubmed and clinicaltrials.gov. Inclusion/exclusion criteria were reviewed for requirements on histological subtype and tumor measurability. Documentation of ILC was assessed and ILC inclusion rate, central pathology and subgroup analyses were evaluated. Inclusion restrictions concerning tumor measurability were found in 39/93 manuscripts. Inclusion rates for ILC were documented in 13/93 manuscripts and varied between 2.0 and 26.0%. No central pathology for ILC was reported and 3/13 manuscripts had ILC sub-analyses. ILC is largely disregarded in most trials with poor representation and documentation. The current inclusion criteria using RECIST v1.1, fall short in recognizing the unique non-measurable metastatic infiltration of ILC.

Abstract Late-life depression has been consistently associated with lower gray matter volume, the origin of which remains largely unexplained. Recent in-vivo PET findings in early-onset depression and Alzheimer’s Disease suggest that synaptic deficits contribute to the pathophysiology of these disorders and may therefore contribute to lower gray matter volume in late-life depression. Here, we investigate synaptic density in vivo for the first time in late-life depression using the synaptic vesicle glycoprotein 2A receptor radioligand 11C-UCB-J. We included 24 currently depressed adults with late-life depression (73.0 ± 6.2 years, 16 female, geriatric depression scale = 19.5 ± 6.8) and 36 age- and gender-matched healthy controls (70.4 ± 6.2 years, 21 female, geriatric depression scale = 2.7 ± 2.9) that underwent simultaneous 11C-UCB-J positron emission tomography (PET) and 3D T1- and T2-FLAIR weighted magnetic resonance (MR) imaging on a 3-tesla PET-MR scanner. We used analyses of variance to test for 11C-UCB-J binding and gray matter volumes differences in regions implicated in depression. The late-life depression group showed a trend in lower gray matter volumes in the hippocampus (p = 0.04), mesial temporal (p = 0.02) and prefrontal cortex (p = 0.02) compared to healthy control group without surviving correction for multiple comparison. However, no group differences in 11C-UCB-J binding were found in these regions nor were any associations between 11C-UCB-J and depressive symptoms. Our data suggests that, in contrast to Alzheimer’s Disease, lower gray matter volume in late-life depression is not associated with synaptic density changes. From a therapeutic standpoint, preserved synaptic density in late-life depression may be an encouraging finding.

Primary tumors with a mixed invasive breast carcinoma of no-special type (IBC-NST) and invasive lobular cancer (ILC) histology are present in approximately five percent of all patients with breast cancer and are understudied at the metastatic level. Here, we characterized the histology of metastases from two patients with primary mixed IBC-NST/ILC from the postmortem tissue donation program UPTIDER (NCT04531696). The 14 and 43 metastatic lesions collected at autopsy had morphological features and E-cadherin staining patterns consistent with pure ILC. While our findings still require further validation, they may challenge current clinical practice and imaging modalities used in these patients.

Abstract Background There is increasing interest in incorporating clinical decision support (CDS) into electronic healthcare records (EHR). Successful implementation of CDS systems depends on acceptance of them by healthcare workers. We used a mix of quantitative and qualitative methods starting from Qsort methodology to explore expectations and perceptions of practicing physicians on the use of CDS incorporated in EHR. Methods The study was performed in a large tertiary care academic hospital. We used a mixed approach with a Q-sort based classification of pre-defined reactions to clinical case vignettes combined with a thinking-aloud approach, taking into account COREQ recommendations The open source software of Ken-Q Analysis version 1.0.6. was used for the quantitative analysis, using principal components and a Varimax rotation. For the qualitative analysis, a thematic analysis based on the four main themes was performed based on the audiotapes and field notes. Results Thirty physicians were interviewed (7 in training, 8 junior staff and 15 senior staff; 16 females). Nearly all respondents were strongly averse towards interruptive messages, especially when these also were obstructive. Obstructive interruption was considered to be acceptable only when it increases safety, is adjustable to user expertise level and/or allows deviations when the end-user explains why a deviation is desirable in the case at issue. Transparency was deemed an essential feature, which seems to boil down to providing sufficient clarification on the factors underlying the recommendations of the CDS, so that these can be compared against the physicians’ existing knowledge, beliefs and convictions. Conclusion Avoidance of disruptive workflows and transparency of the underlying decision processes are important points to consider when developing CDS systems incorporated in EHR.

Abstract Research regarding the drivers of acceptance of clinical decision support systems (CDSS) by physicians is still rather limited. The literature that does exist, however, tends to focus on problems regarding the user-friendliness of CDSS. We have performed a thematic analysis of 24 interviews with physicians concerning specific clinical case vignettes, in order to explore their underlying opinions and attitudes regarding the introduction of CDSS in clinical practice, to allow a more in-depth analysis of factors underlying (non-)acceptance of CDSS. We identified three general themes from the results. First, ‘the perceived role of the AI’, including items referring to the tasks that may properly be assigned to the CDSS according to the respondents. Second, ‘the perceived role of the physician’, referring to the aspects of clinical practice that were seen as being fundamentally ‘human’ or non-automatable. Third, ‘concerns regarding AI’, including items referring to more general issues that were raised by the respondents regarding the introduction of CDSS in general and/or in clinical medicine in particular. Apart from the overall concerns expressed by the respondents regarding user-friendliness, we will explain how our results indicate that our respondents were primarily occupied by distinguishing between parts of their job that should be automated and aspects that should be kept in human hands. We refer to this distinction as ‘the division of clinical labor.’ This division is not based on knowledge regarding AI or medicine, but rather on which parts of a physician’s job were seen by the respondents as being central to who they are as physicians and as human beings. Often the respondents’ view that certain core parts of their job ought to be shielded from automation was closely linked to claims concerning the uniqueness of medicine as a domain. Finally, although almost all respondents claimed that they highly value their final responsibility, a closer investigation of this concept suggests that their view of ‘final responsibility’ was not that demanding after all.

The combination of “Big Data” and Artificial Intelligence (AI) is frequently promoted as having the potential to deliver valuable health benefits when applied to medical decision-making. However, the responsible adoption of AI-based clinical decision support systems faces several challenges at both the individual and societal level. One of the features that has given rise to particular concern is the issue of explainability, since, if the way an algorithm arrived at a particular output is not known (or knowable) to a physician, this may lead to multiple challenges, including an inability to evaluate the merits of the output. This “opacity” problem has led to questions about whether physicians are justified in relying on the algorithmic output, with some scholars insisting on the centrality of explainability, while others see no reason to require of AI that which is not required of physicians. We consider that there is merit in both views but find that greater nuance is necessary in order to elucidate the underlying function of explainability in clinical practice and, therefore, its relevance in the context of AI for clinical use. In this paper, we explore explainability by examining what it requires in clinical medicine and draw a distinction between the function of explainability for the current patient versus the future patient. This distinction has implications for what explainability requires in the short and long term. We highlight the role of transparency in explainability, and identify semantic transparency as fundamental to the issue of explainability itself. We argue that, in day-to-day clinical practice, accuracy is sufficient as an “epistemic warrant” for clinical decision-making, and that the most compelling reason for requiring explainability in the sense of scientific or causal explanation is the potential for improving future care by building a more robust model of the world. We identify the goal of clinical decision-making as being to deliver the best possible outcome as often as possible, and find—that accuracy is sufficient justification for intervention for today’s patient, as long as efforts to uncover scientific explanations continue to improve healthcare for future patients.

Background: The heterogeneity of rectal biopsy techniques has encouraged us to search for a surgical and pathological standardisation of this diagnostic technique to exclude Hirschsprung’s disease. The different amounts of information on the anatomopathology report prompted us to compile a template for the anatomopathology report for diagnostic rectal biopsies for surgical colleagues and pathologists working on Hirschsprung’s disease. Methods: We gathered the anonymous biopsy information and its pathology information from five hospitals for all patients in which rectal biopsies were taken to diagnose Hirschsprung’s disease over two years (2020–2021). Results: Of the 82 biopsies, 20 suction (24.4%), 31 punch (37.8%) and 31 open biopsies (37.8%) were taken. Of all biopsies, 69 were conclusive (84.2%), 13 were not (15.8%). In the suction biopsy group, 60% were conclusive and 40% were not; for punch biopsy, the values were 87% and 13%, respectively and for open biopsy, 97% and 3%. Inconclusive results were due to insufficient submucosa in 6/8 suction biopsies, 4/4 punch biopsies and 0/1 open biopsies. An insufficient amount of submucosa was the reason for an inconclusive result in 6/20 cases (30%) after suction biopsy, 4/31 (12.9%) cases after punch biopsy and 0 cases (0%) after open biopsy. We had one case with major postoperative bleeding post suction biopsy; there were no further adverse effects after biopsy. Conclusions: Diagnostic rectal biopsies in children are safe. Non-surgical biopsies are more likely to give inconclusive results due to smaller amounts of submucosa present in the specimen. Open biopsies are especially useful when previous non-surgical biopsies are inconclusive. An experienced pathologist is a key factor for the result. The anatomopathology report should specify the different layers present in the specimen, the presence of ganglion cells and hypertrophic nerve fibres, their description and a conclusion.

Abstract Psychomotor dysfunction (PMD) is a core element and key contributor to disability in late life depression (LLD), which responds well to electroconvulsive therapy (ECT). The neurobiology of PMD and its response to ECT are not well understood. We hypothesized that PMD in LLD is associated with lower striatal volume, and that striatal volume increase following ECT explains PMD improvement. We analyzed data from a two-center prospective cohort study of 110 LLD subjects (>55 years) receiving ECT. Brain MRI and assessment of mood, cognition, and PMD was performed 1 week before, 1 week after, and 6 months after ECT. Volumetry of the caudate nucleus, putamen, globus pallidus, and nucleus accumbens was derived from automatically segmented brain MRIs using Freesurfer®. Linear multiple regression analyses were used to study associations between basal ganglia volume and PMD. Brain MRI was available for 66 patients 1 week post ECT and in 22 patients also six months post ECT. Baseline PMD was associated with a smaller left caudate nucleus. One week after ECT, PMD improved and volume increases were detected bilaterally in the caudate nucleus and putamen, and in the right nucleus accumbens. Improved PMD after ECT did not relate to the significant volume increases in these structures, but was predicted by a nonsignificant volume change in the right globus pallidus. No volume differences were detected 6 months after ECT, compared to baseline. Although PMD is related to lower striatal volume in LLD, ECT-induced increase of striatal volume does not explain PMD improvement.

Abstract Background Major depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved. Methods This is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [11C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [18F]MK-6240, and cerebral amyloid using [18F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function. Discussion The main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT. Trial registration ClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.

Introduction: Breaking bad news (BBN) in the emergency department (ED) represents a challenging and stressful situation for physicians. Many medical students and residents feel stressed and uncomfortable with such situations because of insufficient training. Our randomized controlled study aimed to assess the efficacy of a four-hour BBN simulation-based training on perceived self-efficacy, the BBN process, and communication skills. Methods: Medical students and residents were randomized into a 160-hour ED clinical rotation without a formal BBN curriculum (control group [CG], n = 31) or a 156-hour ED clinical rotation and a four-hour BBN simulation-based training (training group [TG], n = 37). Both groups were assessed twice: once at the beginning of the rotation (pre-test) and again four weeks later. Assessments included a BBN evaluation via a simulation with two actors playing family members and the completion of a questionnaire on self-efficacy. Two blinded raters assessed the BBN process with the SPIKES (a delivery protocol for delivering bad news) competence form and communication skills with the modified BBN Assessment Schedule. Results: Group-by-time effects adjusted by study year revealed a significant improvement in TG as compared with CG on self-efficacy (P < 0.001), the BBN process (P < 0.001), and communication skills (P < 0.001). TG showed a significant gain regarding the BBN process (+33.3%, P < 0.001). After the training, students with limited clinical experience prior to the rotation showed BBN performance skills equal to that of students in the CG who had greater clinical experience. Conclusion: A short BBN simulation-based training can be added to standard clinical rotations. It has the potential to significantly improve self-efficacy, the BBN process, and communication skills.

Jean-Louis Corhay, Delphine Nguyen Dang, Hélène Van Cauwenberge, Renaud Louis Department of Pneumology, Centre Hospitalier Universitaire du Sart-Tilman Liège, Liège, Belgium Abstract: Chronic obstructive pulmonary disease (COPD) is an obstructive and progressive airway disease associated with an important reduction in daily physical activity and psychological problems that contribute to the patient's disability and poor health-related quality of life (HRQoL). Nowadays, pulmonary rehabilitation (PR) plays an essential role in the management of symptomatic patients with COPD, by breaking the vicious circle of dyspnea–decreased activity–deconditioning–isolation. Indeed the main benefits of comprehensive PR programs for patients with COPD include a decrease in symptoms (dyspnea and fatigue), improvements in exercise tolerance and HRQoL, reduction of health care utilization (particularly bed-days), as well as an increase in physical activity. Several randomized studies and meta-analyses greatly established the benefits of PR, which additionally, is recommended in a number of influential guidelines. This review aimed to highlight the impact of PR on COPD patients, focusing on the clinical usefulness of PR, which provides patients a good support for change. Keywords: chronic obstructive pulmonary disease, exercise training, physical activity, quality of life

There is need for better understanding of how mobility management interventions work and how they affect the individuals’ modal choice decisions, as well as need for robust evaluation techniques allowing any behavioural changes to be observed. Changing individual’s behaviour is not a one-step process and any evaluation methodology should account for this. A new standardized expert evaluation resource MaxSUMO takes this step-wise process into account. MaxSUMO is based on a new theoretical behavioural change model MaxSEM which measures individuals’ stage positions (their susceptibility to change behaviour) and stage movement (progression towards actual behavioural change). This paper illustrates the use of MaxSUMO by the evaluation of the mobility campaign “I keep moving, even without my car” undertaken by the City of Ghent.

Dans son film de montage Le fond de l’air est rouge, Chris Marker compile un ensemble de représentations hétérogènes issues d’une décennie de luttes (ouvrières, étudiantes, indépendantistes, etc.) dans le monde. Par l’assemblage de ces images, le cinéaste déploie une historiographie a priori mélancolique et défaitiste. Le présent texte entend dépasser cette interprétation unilatérale de la critique politique des images pour y identifier les traces d’un retour chronique à l’espoir militant.

A case study of a Belgian 3-year-old girl with Kabuki make-up syndrome found she had normal receptive skills and good expressive vocabulary but poor morphosyntactic abilities. She was capable of producing most of the sounds of her native language but demonstrated high variability in production of the sounds. (Contains references.) (Author/CR)

In March 2011, the European Commission launched a proposal for a Common Consolidated Corporate Tax Base (CCCTB). However, a Common Corporate Tax Base (CCTB), leaving consolidation and apportionment out of consideration, appears to be a more realistic proposition for corporate tax harmonization in Europe. Using the European Tax Analyzer (ETA), we simulate the impact of the CCTB on the effective tax burden in Belgium. The results show that the adoption of the CCTB increases the Belgian effective tax burden by 16%. This remarkable increase is mainly driven by the fact that national tax deductions are not allowed under CCTB. This study allows policymakers to gain insight into the size effects of certain corporate tax measures and contributes to the current discussion on corporate tax harmonization in Europe.

In this paper we use firm level data from a listed multinational to investigate how several designs for the Common Consolidated Corporate Tax Base (CCCTB) formula could affect the allocation of the consolidated tax base. The design is relevant in the light of member states’ concern for protecting their tax revenues, as well as for the multinational companies’ tax minimizing possibilities. Moreover, it plays an important role in achieving an efficient and simple tax system. Simulating different apportionment formulas, the results show that including more factors and using more equal weights distributes the common tax base more equally, which could reduce the incentive to shift factors from high to low tax countries. The results also indicate that simplifying the factor definitions, leads to rather minor changes in the allocation. Using unpublished data, this study allows to investigate the consequences of different formulas in detail, which contributes to the current discussion on corporate tax harmonization in the EU.

The 2007 global financial crisis led to a chaotic financial environment characterized by highly uncertain and volatile stock markets. This created additional uncertainty about the fundamental value of shares and potentially increased the benefit of inside information. In this paper, we use event study methodology to examine whether Belgian corporate insiders were able to benefit from these turbulent market conditions. Given the large weight of financial institutions, the Belgian stock market was especially vulnerable to the financial crisis and provides an interesting environment to test this hypothesis. Our results show that, while insiders are generally able to earn abnormal returns, these returns are significantly higher during the years of the financial crisis. First published online: 19 Oct 2012

"Erratum on the article ‘The impact of the financial crisis on insider trading profitability in Belgium’ (doi: 10.3846/16111699.2011.652980)." Journal of Business Econimics and Management, 14(2), p. 432 First published online: 04 Mar 2013

BACKGROUND: Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. METHODS/PRINCIPAL FINDINGS: NOD/shi-scid/γ(c)null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. CONCLUSIONS/SIGNIFICANCE: This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.