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Background Bulk segregant analysis (BSA) can help identify quantitative trait loci (QTLs), but this may result in substantial bycatch of functionally irrelevant genes. Results Here we develop a Gene Ontology-mediated approach to zoom in on specific genes located inside QTLs identified by BSA as implicated in a continuous trait. We apply this to a novel experimental system: flowering time in the giant woody Jersey kale, which we phenotyped in four bulks of flowering onset. Our inferred QTLs yielded tens of thousands of candidate genes. We reduced this by two orders of magnitude by focusing on genes annotated with terms contained within relevant subgraphs of the Gene Ontology. A pathway enrichment test then led to the circadian rhythm pathway. The genes that enriched this pathway are attested from previous research as regulating flowering time. Within that pathway, the genes CCA1 , FT , and TSF were identified as having functionally significant variation compared to Arabidopsis . We validated and confirmed our ontology-mediated results through genome sequencing and homology-based SNP analysis. However, our ontology-mediated approach produced additional genes of putative importance, showing that the approach aids in exploration and discovery. Conclusions Our method is potentially applicable to the study of other complex traits and we therefore make our workflows available as open-source code and a reusable Docker container.

We estimated the genetic basis for variation in floral traits and the phenotypic and genetic correlations between these traits using clonal propagation in Echium vulgare (Boraginaceae). For all floral traits measured (nectar volume, nectar sugar concentration, sugar production, corolla size, style length, stamen length) we found significant clonal repeatabilities in a greenhouse experiment. Variation among clonal families in nectar volume was surprisingly high (seven-fold difference between the highest and lowest family mean) and not correlated with flower size. Variation among clonal families in pollen production was even higher (28-fold) and correlated to flower size traits. Corolla length, style length and stamen length were all highly correlated. Flower size is not a good predictor for nectar production rate, while it is for the number of pollen grains produced.

Ragwort plants were damaged experimentally by removing the whole shoot. Within about 1 month the original allocation pattern of biomass to root and shoot was reestablished to a large extent. If left undisturbed for a longer period, plant growth accelerated into compensatory growth. Intraspecific variation in storage and tolerance (shoot weight), 1 month after damage, was significant. We could not detect a trade-off between storage or tolerance and relative growth rate of control plants. Consequently there are no indications for costs involved in storage of resources or in tolerating damage. Although tolerance is thought to be dependent upon storage of resources, we detected no effect of storage on tolerance after one event of damage. Storage is genotype specific, but at the same time highly plastic. We hypothesize that the value of storage in ragwort only becomes evident after repeated disturbances. Competition, history of herbivory and change of season all affected storage radically.

Establishing irremediability of suffering is a central challenge in determining the appropriateness of medical assistance in dying (MAiD) for patients with a psychiatric disorder. We sought to evaluate how experienced psychiatrists define irremediable psychiatric suffering in the context of MAiD and what challenges they face while establishing irremediable psychiatric suffering. We conducted a qualitative study of psychiatrists in the Netherlands with experience assessing irremediable psychiatric suffering in the context of MAiD. We collected data from in-depth, semistructured interviews focused on the definition of irremediable psychiatric suffering and on the challenges in establishing irremediability. We analyzed themes using a modified grounded theory approach. The study included 11 psychiatrists. Although irremediable psychiatric suffering is a prospective concept, most participants relied on retrospective dimensions to define it, such as a history of failed treatments, and expressed that uncertainty was inevitable in this process. When establishing irremediable psychiatric suffering, participants identified challenges related to diagnosis and treatment. The main diagnostic challenge identified was the frequent co-occurrence of more than 1 psychiatric diagnosis. Important challenges related to treatment included assessing the quality of past treatments, establishing when limits of treatment had been reached and managing “treatment fatigue.” Challenges regarding the definition, diagnosis and treatment of irremediable psychiatric suffering complicate the process of establishing it in the context of MAiD. Development of consensus clinical criteria for irremediable psychiatric suffering in this context and further research to understand “treatment fatigue” among patients with psychiatric disorders may help address these challenges. Registration: This study was preregistered under osf.io/2jrnd.

PurposeConsidering the comparable prognosis in early-stage breast cancer after breast-conserving therapy (BCT) and mastectomy, quality of life should be a focus in treatment decision(s). We retrospectively collected PROs and analyzed differences per type of surgery delivered. We aimed to obtain reference values helpful in shared decision-making.Patients and MethodspTis-T3N0-3M0 patients operated between January 2005 and September 2016 were eligible if: (1) no chemotherapy was administered < 6 months prior to enrolment, and (2) identical surgeries were performed in case of bilateral surgery. After consent, EQ-5D-5L, EORTC-QLQ-C30/BR23, and BREAST-Q were administered. PROs were evaluated per baseline characteristics using multivariable linear regression models. Outcomes were compared for different surgeries as well as for primary (PBC) and second primary or recurrent (SBC) breast cancer patients using analyses of variance (ANOVAs).ResultsThe response rate was 68%. PROs in 612 PBC patients were comparable to those in 152 SBC patients. Multivariable analyses showed increasing age to be associated with lower “physical functioning” [β − 0.259, p < 0.001] and “sexual functioning” [β − 0.427, p < 0.001], and increasing time since surgery with less “fatigue” [β − 1.083, p < 0.001]. Mastectomy [β − 13.596, p = 0.003] and implant reconstruction [β − 13.040, p = 0.007] were associated with lower “satisfaction with breast” scores than BCT. Radiation therapy was associated with lower satisfaction scores than absence of radiotherapy.DiscussionPRO scores were associated with age, time since surgery, type of surgery, and radiation therapy in breast cancer patients. The scores serve as a reference value for different types of surgery in the study population and enable prospective use of PROs in shared decision-making.

In vitiligo, cytotoxic T cells infiltrating the perilesional margin are suspected to be involved in the pathogenesis of the disease. However, it remains to be elucidated whether these T cells are a cause or a consequence of the depigmentation process. T cells we obtained from perilesional skin biopsies, were significantly enriched for melanocyte antigen recognition, compared with healthy skin-infiltrating T cells, and were reactive to melanocyte antigen-specific stimulation. Using a skin explant model, we were able to dissect the in situ activities of perilesional T cells in the effector phase of depigmentation. We show that these T cells could infiltrate autologous normally pigmented skin explants and efficiently kill melanocytes within this microenvironment. Interestingly, melanocyte apoptosis was accompanied by suprabasal keratinocyte apoptosis. Perilesional T cells did, however, not induce apoptosis in lesional skin, which is devoid of melanocytes, indicating the melanocyte-specific cytotoxic activity of these cells. Melanocyte killing correlated to local infiltration of perilesional T cells. Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.

The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy introduced updates to the prescription of inhaled medication, including withdrawing recommendation of long-acting beta-agonist/inhaled corticosteroids (LABA/ICS) as double therapy, restricting ICS use to patients with exacerbations, and recommending earlier escalation to triple therapy. These changes are expected to have a substantial impact on clinical practice. This study aims to describe how well clinicians adhere to the GOLD strategy in daily practice, and to explore the extent to which the 2023 update has changed prescribing patterns. Data were collected from a real-world cohort at a teaching hospital in the Netherlands in 2022, and the same cohort was reassessed in 2023. To determine guideline adherence, each patient's treatment was assessed against the applicable GOLD strategy at that time. Subgroups that did not receive treatment according to the GOLD strategy were identified. Finally, a more detailed assessment of ICS prescriptions and their indications was conducted. A total of 1318 patients were included in 2022. In 2022, 51.6% received inhaled medication in line with the applicable GOLD strategy, compared to 57.3% in 2023 in accordance with that year's GOLD strategy. Patients with low eosinophils, those without exacerbations, and those with less severe GOLD classification were less frequently treated in accordance with the 2023 strategy. Overtreatment with ICS was common (25.4%). A substantial proportion of patients with COPD are not treated in accordance with GOLD recommendations. While there may be valid reasons for deviating from the recommendations, these findings should prompt physicians to consider whether their patients' current treatment is optimal. Clear criteria exist for initiating ICS treatment. However, there is no data-driven evidence or consensus on how to manage ICS treatment once a patient has stabilised. Identifying and discussing the barriers for implementation of the GOLD strategy is essential.