Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Photo-supported conversations about well-being (BeWell) for patients with exhaustion disorders - a controlled clinical intervention study.

Introduction: Health-promotion approaches to address stress-related exhaustion disorders, reduce personal suffering, improve coping and participation in everyday life are needed in primary care. The aim of this study was to investigate self-reported health and well-being before and after an intervention focusing on well-being with photo-supported conversations (BeWell).

Material And Methods: Eighty-one patients (69 women), 20-67 years old, with exhaustion disorders were recruited at Swedish primary health care centres (PHCC) to a controlled clinical study.

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

Balancing on a slack line - Staffs' experiences of talking about sexuality and sexual health with patients cared for in forensic psychiatry in Sweden.

Sexuality is a central part of being human, however, talking about sexual health is generally avoided in forensic psychiatry. The aim of this qualitative study was to explore how healthcare professionals experience talking about sexuality and sexual health with patients cared for in forensic psychiatry. Individual interviews were conducted with eighteen healthcare professionals from ten different forensic psychiatry care units in Sweden.

Occupational therapists' experiences of photo-supported conversations - An intervention in primary health care.

Background: The health-promoting intervention BeWell, which includes photo-supported conversations, is intended for people with stress-related illnesses. Its focus is on improving the individual's health and well-being by addressing what contributes to well-being from the patient's own perspective. There is no current knowledge of the experiences of occupational therapists of using BeWell in primary health care.

Employers' requests when advertising for nurses-A national mapping of recruitment advertising for nurses in Sweden.

Introduction: There is a shortage of nurses and many are leaving the profession. Maintaining sufficient nursing staff is a major healthcare challenge for societies worldwide. Work conditions, job orientation, and career opportunities all factor into nurses' rates of attrition, exit, and turnover.

InCHARGE: Co-creating, implementing and evaluating interventions to utilize nurses' competence and achieve person-centred fundamental care-A research protocol describing an action research approach.

Aim And Objectives: This research protocol presents an action research project with the aim to demonstrate the value of person-centred fundamental care to nurses and nurse managers in surgical care units to encourage a far-reaching change in this direction. The objectives are to describe this process and to evaluate the effects on missed nursing care and person-centred fundamental care.

Methods: In a novel collaboration between nursing science and medical humanities the action research design will be used to interact with nursing staff and leaders in three surgical care units and design interventions with the purpose to affect the direction of nursing.

Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR.

To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine as a starting point.

Missed nursing care in surgical care- a hazard to patient safety: a quantitative study within the inCHARGE programme.

Background: Missed nursing care occurs globally, and the consequences are severe for the patients when fundamental care needs are not fulfilled, nor delivered in a person-centred way. This study aimed to investigate the occurrence and cause of missed nursing care, and the relationship between registered nurses' and nursing assistants' perceptions of missed nursing care, in a surgical care context.

Methods: A quantitative study was performed using the MISSCARE survey, measuring missed nursing care and associated reasons, in three surgical wards with registered nurses and nursing assistants as the participants (n = 118), during May-November in 2022.

Being in a meaningful context. Nature and animal-assisted activities as perceived by adults with autism.

Introduction: Animal-assisted and nature-based interventions in psychosocial treatment for various groups of clients have been studied internationally. However, there is little knowledge about how young adults with autism experience participation in such types of interventions. This clinical study aimed to describe the feasibility of animal-assisted and nature-based activities on a farm as a complementary intervention for young adults with autism and social withdrawal.

Nesting behavior of greater eelpout (Lycodes esmarkii), identified through a predation event by spotted wolffish (Anarhichas minor).

The stomach of a spotted wolffish (Anarhichas minor) caught in Icelandic waters was found to contain ~727 greater eelpout larvae (Lycodes esmarkii). All the larvae were of similar size and at a similar state of digestion, indicating they were all consumed together. The likely explanation for this observation is that greater eelpout lay their eggs in a nest, with the larvae remaining in the nest for a short period after hatching.

Is there any job for me? Qualitative exploration of support needs among young Swedish adults with psychosis envisioning productive activities.

Background: Unemployment is high not only among people with mental illness, but also among young adults in general. The combination of having a severe mental illness and being young entails a particularly problematic situation for young people with psychosis. This study aimed to understand how this group envision their future possibilities for entering the labour market or engaging in other productive activities.

Oral health and oral care in patients in a surgical context: A quantitative study comparing patients' and nurses' assessments.

Aims: To investigate fundamental care delivery regarding oral care in a surgical context, and to compare patients' self-reported oral health with registered nurse assessments.

Design: A descriptive and comparative study, with a consecutive selection.

Methods: A patient oral health rating tool, including questions about performed oral care, was distributed to patients (n = 50), at four surgical wards in Sweden.

Creating Designer Engineered Extracellular Vesicles for Diverse Ligand Display, Target Recognition, and Controlled Protein Loading and Delivery.

Efficient and targeted delivery of therapeutic agents remains a bottleneck in modern medicine. Here, biochemical engineering approaches to advance the repurposing of extracellular vesicles (EVs) as drug delivery vehicles are explored. Targeting ligands such as the sugar GalNAc are displayed on the surface of EVs using a HaloTag-fused to a protein anchor that is enriched on engineered EVs.

A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.

The disruption of the protein-protein interaction (PPI) between Nrf2 and Keap1 is an attractive strategy to counteract the oxidative stress that characterises a variety of severe diseases. Peptides represent a complementary approach to small molecules for the inhibition of this therapeutically important PPI. However, due to their polar nature and the negative net charge required for binding to Keap1, the peptides reported to date exhibit either mid-micromolar activity or are inactive in cells.

Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism.

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation.

Selfcare Strategies Shown to Be Useful in Daily Life for Adults Diagnosed with Attention Deficit Hyperactivity Disorder - A Systematic Review.

Adults with ADHD experience a wide range of difficulties in daily life, and RNs and other healthcare professionals need to know how to support them. The aim was to conduct a systematic review of which selfcare strategies adults with ADHD use and need in order to manage daily life. A literature review based on the PRISMA model was performed, and seven articles with a qualitative design were found.

Serum neurofilament light as a predictor of outcome in subarachnoid haemorrhage.

Background: Prognostication of clinical outcome in patients suffering from aneurysmal subarachnoid haemorrhage (SAH) is a challenge. There are no biochemical markers in routine use that can aid in prognostication. Neurofilament light (NFL) measured in cerebrospinal fluid (CSF) has been associated with clinical outcome in previous studies.

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery.

The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties of such heterobifunctional molecules. Molecules occupying this "beyond rule of five" space often demonstrate limited oral bioavailability due to the compounding effects of elevated molecular weight and hydrogen bond donor count (among other properties), but it is possible to achieve sufficient oral bioavailability through physicochemical optimization. Herein, we disclose the design and evaluation of a low hydrogen bond donor count (≤1 HBD) fragment screening set to aid hit generation of PROTACs intended for an oral route of delivery.

'Everything that's said comes from me': New fathers' experiences of individual conversations with the child health nurse.

Aim: Swedish Child Health Services provide regular health surveillance of children 0-5 years and support to parents, with the aim to contribute to equitable child healthcare and to promote physical, emotional, and social health for children. Individual conversations with the child health nurse, including screening for postnatal depression, have been recommended and well implemented for mothers, whereas routines for a visit specifically for the nonbirthing parent vary and are not well studied. The aim of this study was therefore to explore how nonbirthing parents experienced individual conversations with their child health nurse, held 3 months after the birth of their child.

Biobank-scale inference of ancestral recombination graphs enables genealogical analysis of complex traits.

Genome-wide genealogies compactly represent the evolutionary history of a set of genomes and inferring them from genetic data has the potential to facilitate a wide range of analyses. We introduce a method, ARG-Needle, for accurately inferring biobank-scale genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies to perform association and other complex trait analyses. We use these methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and test for association across seven complex traits.

Quality of life, sense of coherence and occupational balance one year after an occupational therapy intervention for people with depression and anxiety disorders.

Background: Quality of life (QOL), sense of coherence (SOC) and occupational balance (OB) have been found to increase after rehabilitation among people living with depression and anxiety. However, these aspects have not been investigated over time in participants with different paid work situations, such as being on sick leave or not.

Objective: To describe and compare the self-rated QOL, SOC and OB after participation in occupational therapy in three groups of people with depression and anxiety disorders based on their work situation during the study period: continuous sick leave, return to work and continuous work.

Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication.

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that binds DNA and assembles co-regulator complexes to regulate gene transcription. GR agonists are widely prescribed to people with inflammatory and autoimmune diseases. Here we present high-resolution, multidomain structures of GR in complex with ligand, DNA and co-regulator peptide.