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The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC).Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology.As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training-carefully monitored for intensity-might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments. image

The delivery of effective healthcare entails the configuration and resourcing of health economies to address the burden of disease, including acute and chronic heart failure, that affects local populations. Increasing migration is leading to more multicultural and ethnically diverse societies worldwide, with migration research suggesting that minority populations are often subject to discrimination, socio-economic disadvantage, and inequity of access to optimal clinical support. Within these contexts, the provision of person-centred care requires medical and nursing staff to be aware of and become adept in navigating the nuances of cultural diversity, and how that can impact some individuals and families entrusted to their care. This paper will examine current evidence, provide practical guidance, and signpost professionals on developing cultural competence within the setting of patients with advanced heart failure who may benefit from palliative care.

Introduction Two ethical challenges of nursing home nurses during the COVID-19 pandemic in Sweden are discussed in this paper. Background Historically, the nurses primary concern is for the person who is ill, which is the core of nurses moral responsibility and identity. In Sweden, person-centered care is generally deemed important in nursing older nursing home residents. Objective To chart moral responsibilities of nursing home nurses in two cases involving older residents during the COVID-19 pandemic in Sweden. Methods We used Margaret Urban Walkers framework for moral responsibilities and the International Council of Nurses (ICN) code of ethics for nurses (2021) for our normative analysis. Ethical considerations Written and verbal consent was obtained before the interviews, and information was given that participation was entirely voluntary and possible to cancel at any time before the work was published. The Swedish Ethical Review Agency gave an advisory opinion stating that there were no ethical objections to this research project (Dnr. 2020-05649). Findings Case #1: a palliative older nursing home resident who was coercively tested for COVID-19, and case #2: a COVID-19-infected resident with dementia who was isolated using sedation. The decision that was finally made in the respective case was analyzed in the light of either consequentialist/utilitarian or non-consequentialist/deontological reasons. Discussion Empowerment of nurses as moral agents is required for the application of practical wisdom in the balancing of different care relationships (responsibilities), moral identities (professional virtues), and competing moral values. This requires resources and opens possibilities for profound ethical reflection in nursing education and at work. Conclusion During the COVID-19 pandemic, the moral and professional responsibility of nursing home nurses to deliver person-centered care was sometimes problematically abandoned in favor of a more utilitarian manner of

INTRODUCTION: Approximately 2 million babies are stillborn annually worldwide, most in low- and middle-income countries. Present review studies of the parental and healthcare providers' experiences of stillbirth often include a variety of settings, which may skew the findings as the available resources can vary considerably. In high-income countries, the prevalence of stillbirth is low, and support programs are often initiated immediately when a baby with no signs of life is detected. There is limited knowledge about what matters to parents, siblings, and healthcare providers when a baby is stillborn in high-income countries. OBJECTIVES: This systematic review and interpretive meta-synthesis aim to identify important aspects of care and support for parents, siblings, and healthcare professionals in high-income countries from the diagnosis of stillbirth throughout the birth and postpartum period. METHODS: A systematic review and qualitative meta-synthesis were conducted to gain a deeper and broader understanding of the available knowledge about treatment and support when stillbirth occurred. Relevant papers were identified by systematically searching international electronic databases and citation tracking. The quality of the included studies was assessed, and the data was interpreted and synthesised using Gadamer's hermeneutics. The review protocol, including qualitative and quantitative study approaches, was registered on PROSPERO (CRD42022306655). RESULTS: Sixteen studies were identified and included in the qualitative meta-synthesis. Experiences of care and support were interpreted and identified as four fusions. First, Personification is of central importance and stresses the need to acknowledge the baby as a unique person. The parents became parents even though their baby was born dead: The staff should also be recognised as the individuals they are with their personal histories. Second, the personification is reinforced by a respectful attitude where the paren

It is uncontroversial to claim that the extent to which health care interventions benefit patients is a relevant consideration for health care priority setting. However, when effects accrue to the individual patient, effects of a more indirect kind may accrue to other individuals as well, such as the patients children, friends, or partner. If, and if so how, such relational effects should be considered relevant in priority setting is contentious. In this paper, we illustrate this question by using disease-modifying drugs for Alzheimers disease as a case in point. The ethical analysis begins by sketching the so-called prima facie case for ascribing moral weight to relational effects and then moves on to consider a number of objections to it. We argue that, whereas one set of objections may be dismissed, there is another set of arguments that poses more serious challenges for including relational effects in priority setting., Funding Agencies|Swedish Research Council [2021-01266]

Current hardware limitations make it impossible to train convolutional neural networks on gigapixel image inputs directly. Recent developments in weakly supervised learning, such as attention-gated multiple instance learning, have shown promising results, but often use multi-stage or patch-wise training strategies risking suboptimal feature extraction, which can negatively impact performance. In this paper, we propose to train a ResNet-34 encoder with an attention-gated classification head in an end-to-end fashion, which we call StreamingCLAM, using a streaming implementation of convolutional layers. This allows us to train end-to-end on 4-gigapixel microscopic images using only slide-level labels.We achieve a mean area under the receiver operating characteristic curve of 0.9757 for metastatic breast cancer detection (CAMELYON16), close to fully supervised approaches using pixel-level annotations. Our model can also detect MYC-gene translocation in histologic slides of diffuse large B-cell lymphoma, achieving a mean area under the ROC curve of 0.8259. Furthermore, we show that our model offers a degree of interpretability through the attention mechanism., Funding Agencies|Innovative Medicines Initiative 2 Joint Undertaking [945358]; European Union; EFPIA, Belgium

The objective of this paper was to investigate if socioeconomic status (SES), measured by maternal education and household income, influenced the risk of developing autoimmune disease (Type 1 Diabetes, Celiac disease, Juvenile Idiopathic Arthritis, Crohns disease, Ulcerative colitis, and autoimmune thyroid disease), or age at diagnosis, and to analyse pathways between SES and autoimmune disease. We used data from the All Babies in Southeast Sweden (ABIS) study, a population-based prospective birth cohort, which included children born 1997-1999. Diagnoses of autoimmune disease was collected from the Swedish National Patient Register Dec 2020. In 16,365 individuals, low maternal education, but not household income, was associated with increased risk of Type 1 Diabetes; middle education RR 1.54, 95% CI 1.06, 2.23; P 0.02, low education RR 1.81, 95% CI 1.04, 3.18; P 0.04. Maternal education and household income was not associated with any other autoimmune disease and did not influence the age at diagnosis. Part of the increased risk of Type 1 Diabetes by lower maternal education was mediated by the indirect pathway of higher BMI and higher risk of Serious Life Events (SLE) at 5 years of age. The risk of developing Type 1 Diabetes associated to low maternal education might be reduced by decreasing BMI and SLE during childhood., Funding Agencies|Linkoeping University; County Council of Ostergot-land, Forskningsradet i Sydoestra Sverige, Vetenskapsradet [K2005-72X-11242-11A]; Knut och Alice Wallenbergs Stiftelse [K 98-99D-12813-01A]; Forskningsradet foer Arbetsliv och Socialvetenskap [FAS20041775]; Barndiabetesfonden; Juvenile Diabetes Research Foundation International; Ostgota Brandstodsbolag

In a seminal paper, Frederick et al. (J Consum Res 36:553-561, 2009) showed that peoples willingness to purchase a consumer good declined dramatically when opportunity costs were made more salient (Cohens d = 0.45-0.85). This finding suggests that people normally do not pay sufficient attention to opportunity costs and as a result make poorer and less efficient decisions, both in private and public domains. To critically assess the strength of opportunity cost neglect, we carried out a systematic review and a meta-analysis including published and non-published experimental work. In total, 39 experimental studies were included in the meta-analysis (N = 14,005). The analysis shows a robust significant effect (Cohens d = 0.22; p < 0.001) of opportunity cost neglect across different domains, albeit the effect is considerably smaller than what was originally estimated by Frederick et al. (2009). Our findings highlight the importance of meta-analyses and replications of initial findings., Funding Agencies|Linkoping University; Swedish Research Council [2018.01755]; Swedish Research Council for Health, Working Life and Welfare (Forte) [202000864]

Although numerous studies have examined the effects of internet-delivered cognitive behavioral therapy (iCBT) for depression and anxiety on quality of life, no meta-analysis has yet been conducted to integrate the results of these studies. We conducted systematic searches in PubMed, Cochrane, and PsycInfo, which included terms for treatment type, modality of delivery, condition, and main outcome. We included studies that met the following inclusion criteria: (a) randomized controlled trials, (b) patients allocated to some form of the control condition, (c) patients receiving some type of treatment of anxiety and/or depression involving Internet-delivered Cognitive Behavioral Therapy, (d) use of a validated outcome measure assessing the level of quality of life, (e) conducted with adult participants diagnosed with anxiety disorder and/or unipolar depression, (f) papers written in English. We analyzed 40 randomized controlled trials with a total of 4289 participants that met inclusion criteria. The pooled between-group effect size for the quality of life overall score was small (g = 0.35, 95 % CI: 0.26-0.44, p = .0001), favoring iCBT over the control conditions. Regarding the distinct quality of life domains measured by the World Health Organization Quality of Life Assessment, a statistically significant difference between iCBT and control conditions was found only for the physical health domain (g = 0.56, 95 % CI: 0.06-1.07, p = .029), in favor of iCBT. In both cases, heterogeneity was moderate. While the effect on the quality of life is small (the overall quality of life score) to moderate (the physical health domain score), we conclude that iCBT for depression and anxiety may be a promising approach for improving the quality of life of patients., Funding: Ministry of Science and Higher Education subsidies for maintaining and developing the didactic and research po-tential of the Institute of Psychology of the SWPS University of Social Sciences and Humanities; [SUB/IPsy/2019/22]

Introduction: Migrants, especially from the Middle East, experience poorer health outcomes and face greater difficulties in accessing healthcare compared to native populations and there is a need for culturally appropriate education for this vulnerable group. The purpose of this study is to describe the process of developing a culturally appropriate tool to support self-care in migrants with type 2 diabetes.Methods: In this Co-design study, a tool for supporting self-care in migrants with type 2 diabetes was developed. Migrant patients with type 2 diabetes, healthcare providers and researchers participated in the process, which was based on six elements; engage, plan, explore, develop, decide and change. From February 2021 to December 2022, idea groups were conducted, and a tool was developed through brainstorming, prioritizing and prototyping.Results: In total, 14 migrant patients, ten health care providers and four researchers participated in the Co-design process. The patients wished to receive information about type 2 diabetes self-care behaviour in their own languages. The healthcare providers asked for clear instructions on where to guide their patients regarding reliable information about diabetes in the patients own language. All participants agreed that information can be presented in different formats, either: text (paper or online), audio-visual via recorded videos and/or lectures and pictures.Discussion: The Co-design process led to several important insights and experiences related to the importance of diverse cultural backgrounds. When conducting a Co-design study with end-users as stakeholders, it is significant that the stakeholders have a diverse background in experiences, both as patients as well as those who deliver or implement the health service. In this study it was of great importance to include patients with diverse backgrounds regarding; gender, age, health literacy, occupation, years living in Sweden and duration of diabetes.

Background: Individual face-to-face cognitive behavioral therapy is known to be effective for bulimia nervosa (BN). Since foods vary considerably between regions and cultures in which patients live, cultural adaptation of the treatment program is particularly important in cognitive behavioral therapy for BN. Recently, an internet-based cognitive behavioral therapy (ICBT) program was developed for Japanese women with BN, adapted to the Japanese food culture. However, no previous randomized controlled trial has examined the effectiveness of ICBT.Objective: This paper presents a research protocol for strategies to examine the effects of guided ICBT.Methods: This study is designed as a multicenter, prospective, assessor-blinded randomized controlled trial. The treatment groups will be divided into treatment as usual (TAU) alone as the control group and ICBT combined with TAU as the intervention group. The primary outcome is the total of binge eating and purging behaviors assessed before and after treatment by an independent assessor. Secondary outcomes will include measures of eating disorder severity, depression, anxiety, quality of life, treatment satisfaction, and working alliances. Treatment satisfaction and working alliances will be measured post assessment only. Other measures will be assessed at baseline, post intervention, and follow-up, and the outcomes will be analyzed on an intention-to-treat basis.Results: This study will be conducted at 7 different medical institutions in Japan from August 2022 to October 2026. Recruitment of participants began on August 19, 2022, and recruitment is scheduled to continue until July 2024. The first participants were registered on September 8, 2022.Conclusions: This is the first multicenter randomized controlled trial in Japan comparing the effectiveness of ICBT and TAU in patients with BN., Funding Agencies|Japan Society for the Promotion of Science [JP22H00985]; Lotte Research Promotion Grant; Asian Children With Developmental Disorders: MEXT Policy Initiative FY2022, under joint research conducted through the initiative

Many legal, ethical, and regulatory frameworks allow de-identified health data to be shared for research without patients opt-in consent. However, there may be public concerns about this practice, as people may feel they should have some say in how such data is used. This paper introduces the concept of the "inalienability of deidentified data," to describe a key assumption underlying that public concern and preference. The assumption, derived from ethnographic research with public and professional stakeholders in AI driven medical image analysis over the past two years, refers to a sense of felt ownership over de-identified health data, even where the subject has been obscured as referent and no clear legal rights of data ownership otherwise exist. The concept is important to medical ethics because it underpins public expectations regarding the rights people should have over the sharing of medical data (including expectations for consent). We note that where those expectations go counter to current legal and bioethical frameworks for de-identified data sharing, they provide a challenge for public support of big data and artificial intelligence driven health research., Funding Agencies|Data to Early Diagnosis and Precision Medicine strand of the UK governments Industrial Strategy Challenge Fund [104687]; Li Ka Shing Foundation; Wellcome Trust [203132]

Introduction: This paper describes the development of “Swedish Guidelines for OSA treatment” and the underlying managed care process. The Apnea Hypopnea Index (AHI) is traditionally used as a single parameter for obstructive sleep apnea (OSA) severity classification, although poorly associated with symptomatology and outcome. We instead implement a novel matrix for shared treatment decisions based on available evidence. Methods: A national expert group including medical and dental specialists, nurses, and patient representatives developed the knowledge-driven management model. A Delphi round was performed amongst experts from all Swedish regions (N = 24). Evidence reflecting treatment effects was extracted from systematic reviews, meta-analyses, and randomized clinical trials. Results: The treatment decision in the process includes a matrix with five categories from a “very weak”” to “very strong” indication to treat, and it includes factors with potential influence on outcome, including (A) OSA-related symptoms, (B) cardiometabolic comorbidities, (C) frequency of respiratory events, and (D) age. OSA-related symptoms indicate a strong incitement to treat, whereas the absence of symptoms, age above 65 years, and no or well-controlled comorbidities indicate a weak treatment indication, irrespective of AHI. Conclusions: The novel treatment matrix is based on the effects of treatments rather than the actual frequency of respiratory events during sleep. A nationwide implementation of this matrix is ongoing, and the outcome is monitored in a prospective evaluation by means of the Swedish Sleep Apnea Registry (SESAR).

How should scarce healthcare resources be distributed? This is a contentious issue that became especially pressing during the pandemic. It is often emphasised that studies exploring public views about this question provide valuable input to the issue of healthcare priority setting. While there has been a vast number of such studies it is rarely articulated, more specifically, what the results from these studies would mean for the justification of principles for priority setting. On the one hand, it seems unreasonable that public values would straightforwardly decide the ethical question of how resources should be distributed. On the other hand, in a democratic society, it seems equally unreasonable that they would be considered irrelevant for this question. In this paper we draw on the notion of reflective equilibrium and discuss the relevance and roles that empirical studies may plausibly have for justification in priority setting ethics. We develop a framework for analysing how different kinds of empirical results may have different kinds of implications for justification.

Bioelectronic medicine can treat diseases and disorders in humans by electrically interfacing with peripheral nerves. Multielectrode cuffs can be used for selective stimulation of portions of the nerve, which is advantageous for treatment specificity. The biocompatibility and conformability of cuffs can be improved by reducing the mechanical mismatch between nerve tissue and cuffs, but selective stimulation of nerves has yet to be achieved with soft and stretchable cuff electrodes. Here, this paper reports the development of a soft and stretchable multielectrode cuff (sMEC) for selective nerve stimulation. The device is made of 50 mu m thick silicone with embedded gold nanowire conductors, which renders it functional at 50% strain, and provides superior conformability for wrapping nerves. By using different stimulation protocols, high functional selectivity is achieved with the sMECs eight stimulation electrodes in a porcine sciatic nerve model. Finite element modeling is used to predict the potential distribution within the nerve, which correlate well with the achieved stimulation results. Recent studies are showing that mechanical softness is of outermost importance for reducing foreign body response. It is therefore believed that the soft high-performance sMEC technology is ideal for future selective peripheral nerve interfaces for bioelectronic medicine., Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council [2019-04424]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoeping University (Faculty Grant SFO Mat LiU) [2009 00971]; European Research Council, "e-NeuroPharma" ERC-2018-ADG [834677]

PurposeAt the outbreak of the COVID-19 pandemic, health care was at the centre of the crisis. New demands made existing organizational practices and services obsolete. Primary health care had a great deal of responsibility for COVID-19-related care. The pandemic demanded effective leadership to manage the new difficulties. This paper aims to explore experiences and perceptions of managers in primary health care in relation to their efforts to manage the COVID-19 crisis in their everyday work. Design/methodology/approachThe authors used a qualitative approach based on 14 semi-structured interviews with managers in primary health care from four regions in Sweden. The interviews were conducted during September to December 2020. Data were analysed using conventional qualitative content analysis. FindingsData analysis yielded three categories: lonely in decision-making; stretched to the limit; and proud to have coped. The participants felt lonely in their decision-making, and they were stretched to the limit of their own and the organizations capacity. The psychosocial working conditions in primary care worsened considerably during the pandemic because demands on leaders increased while their ability to control the work situation decreased. However, they also expressed pride that they and their employees had managed the situation by being flexible and having a common focus. Originality/valueLooking ahead and using lessons learnt, and apart from making wise decisions under pressure, an important implication for primary health-care leaders is to not underestimate the power of acknowledging the virtues of humanity and justice during a crisis. Continuing professional education for leaders focusing on crisis leadership could help prepare leaders for future crises.

Background: Over a decade, tissues dissected adjacent to primary tumors have been considered "normal " or healthy samples (NATs). However, NATs have recently been discovered to be distinct from both tumorous and normal tissues. The ability to predict the survival rate of cancer patients using NATs can open a new door to selecting optimal treatments for cancer and discovering biomarkers. Methods: This paper introduces an artificial intelligence (AI) approach that uses NATs for predicting the 5-year survival of pre-operative radiotherapy patients with rectal cancer. The new approach combines pre-trained deep learning, nonlinear dynamics, and long short-term memory to classify immunohistochemical images of RhoB protein expression on NATs. Results: Ten-fold cross-validation results show 88% accuracy of prediction obtained from the new approach, which is also higher than those provided from baseline methods. Conclusion: Preliminary results not only add objective evidence to recent findings of NATs molecular characteristics using state-of-the-art AI methods, but also contribute to the discovery of RhoB expression on NATs in rectal-cancer patients. Clinical impact: The ability to predict the survival rate of cancer patients is extremely important for clinical decision-making. The proposed AI tool is promising for assisting oncologists in their treatments of rectal cancer patients.

Texts about theory in nursing often refer to theory construction by using inductive methods in a rigid way. In this paper, it is instead argued that theories are created, which is in line with most philosophers of science. Theory creation is regarded as a creative process that does not follow a specific method or logic. As in any creative endeavour, the inspiration for theory creation can come from many sources, including previous research and existing theory. The main idea put forward is that deductive qualitative research approaches should play a key role in theory creation. Furthermore, there is a need to differentiate between theory creation and theory justification. A model that emphasizes the creative aspects of theory creation and theory justification using qualitative approaches is presented. The model suggests that knowledge development is a deductive trial-and-error process where theory creation is followed by testing. Scientific theory creation and justification are presented as an iterative process that is deductive in that a testable hypothesis is derived from the theory. If the hypothesis is falsified, then the theory needs modification or might be altogether wrong. Several factors can block the creative process, both in theory development and in finding ways to test a theory in the justification phase. Some of these blockers are the idea of 'building blocks' and the inductive view of science often brought forward in nursing. Other blockers include striving for consensus and adherence to existing nursing philosophies and existing theories. Research and knowledge development are creative processes, and following predefined methods is not enough to ensure scientific rigour in qualitative nursing research.

In this paper, the question of theodicy is viewed from the perspective of time. It is argued that even a very shallow analysis reveals that the concept of "long time" is deeply anthropocentric. We do not know what time is to God, but it seems that the only reason why we call billions of years a long period is because we use ourselves as measuring rods. What if the time questions we ask in this context say more about our temporal smallness than about reality itself? Three possible objections are answered: 1) It is acknowledged that this is of course not meant to be a definite answer to the problem of evil. It is merely offered as a reframing that seems strangely absent from the discussion. 2) The question of pastoral relevance is briefly discussed. 3) The troubling problem of why God created sequentially over time and not "instantaneously" is explored. It is concluded that perhaps our appraisal of time might not be ontologically valid at all. This does not make suffering easy to bear, but perhaps thoughts like these can provide a little hope and endurance-at least for those of us who are philosophically and theologically inclined.

Background Healthcare students must learn how to collaborate with colleagues from different professional backgrounds and organisational units. Research has showed what students themselves think they gain from interprofessional education. Less is known about what knowledge students share when doing interprofessional education. Purpose This paper aims to study students’ knowledge sharing when working together as an interprofessional team at an interprofessional training ward. Method The study was conducted using a focused ethnographic approach. Field observations were carried out at two different interprofessional training wards. Fieldnotes, drawings and informal interviews constitute data. Data was analysed iteratively with ‘practice architectures’ as theoretical lens. Discussion/conclusion We found that students share knowledge in different ways during ward rounds, at the student team room and during the reflection session. The ward rounds are more formal and structured; at the student team room, things are buzzing; and the reflection session is weary.

The importance of patients taking an active role in their healthcare is recognized internationally, to improve safety and effectiveness in practice. There is still, however, some ambiguity about the conceptualization of that patient role; it is referred to interchangeably in the literature as engagement, involvement, and participation. The aim of this discussion paper is to examine and conceptualize the concepts of patient engagement, involvement, and participation within healthcare, particularly nursing. The concepts were found to have semantic differences and similarities, although, from a nursing perspective, they can be summoned to illustrate the establishment of a mutual partnership between a patient and a nurse. The individualization of such processes requires the joint effort of engagement, involvement, or participation, represented by interactive actions of both the patient (asking questions, telling/speaking up, knowledge acquisition, learning, and decision-making) and the nurse (recognizing, responding, information sharing, teaching, and collaborating). Suggesting that the concepts can be used interchangeably comes with some caution, requiring that nurses embrace patients playing a role in their health and healthcare. Further research and practice development should focus on how patients and nurses receive and respond to each other to establish patient engagement, involvement, and participation.

Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.

Soon approaching its 50th anniversary, Journal of Analytical Toxicology (JAT) is an international scholarly publication specializing in analytical and forensic aspects of toxicology. Science Citation Index (SCI) and Journal Citation Reports (JCR), both of which are part of the Web-of-Science (WOS) database, were used to make a bibliometric evaluation of JAT articles. Between 1977 (volume 1) and 2023 (volume 47), a total of n = 4,785 items were published in JAT; the top-ten most highly cited articles and the most prolific authors were identified. Changes in the journal impact factor (JIF) were studied between 1997 and 2022, and this metric varied from a low of 1.24 (2006) to a high of 3.36 (2020).The most recent JIF (2022) dropped to 2.5 and the corresponding 5 year JIF was 2.6. JATs most highly cited article (590 cites) was a working group (SWGTOX) report dealing with standard practices for the validation of analytical methods in forensic toxicology laboratories. JAT published 62 articles each of which were cited over 100 times and the H-index for JAT was 89. The most prolific author of JAT articles was credited with 119 items, the first in 1980 (volume 4) and the latest in 2023 (volume 47). JAT articles were cited 4,537 times in 2022 by all journals in the JCR database, although 520 of these were self-citations (11.5%). Bibliometric methods are increasingly used to evaluate the published work of individual scientists, university departments, entire universities and whole countries. Highly cited articles are considered more influential and authoritative compared with papers that are seldom or never cited.

Wnt signaling orchestrates gene expression via its effector, (3-catenin. However, it is unknown whether (3-cat-enin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT & RUN against (3-catenin, ATAC-seq, and perturba-tion assays in different cell types, we show that Wnt/(3-catenin physical targets are tissue-specific, (3-catenin "moves"on different loci over time, and its association to DNA accompanies changing chromatin accessi-bility landscapes that determine cell behavior. In particular, Wnt/(3-catenin progressively shapes the chro-matin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as "plastic."In HEK293T cells, on the other hand, Wnt/(3-catenin drives a transient chromatin open-ing, followed by re-establishment of the pre-stimulation state, a response that we define as "elastic."Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints. A record of this papers transparent peer review process is included in the supplemental information., Funding Agencies|Cancerfonden [CAN 2018/542, 21 1572]; Swedish Research Council, Vetenskapsradet [2021- 03075]; Knut and Alice Wallenberg Foundation; WCMM at Linkoeping University; Swedish Research Council; [2018-05973]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than three vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group of the European Renal Association (ERA-IWG) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2-infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients.

Fair priority setting is based on morally sound criteria. Still, there will be cases when these criteria, our primary considerations, are tied and therefore do not help us in choosing one allocation over another. It is sometimes suggested that such cases can be handled by tiebreakers. In this paper, we discuss two versions of tiebreakers suggested in the literature. One version is to preserve fairness or impartiality by holding a lottery. The other version is to allow secondary considerations, considerations that are not part of our primary priority setting criteria, to be decisive. We argue that the argument for preserving impartiality by holding a lottery is sound, while the argument for using tiebreakers as secondary considerations is not. Finally, we argue that the instances where a tiebreaker seems necessary are precisely the situations where we have strong reasons for preferring a lottery. We conclude that factors that we consider valuable should all be included among the primary considerations, while ties should be settled by lotteries., Funding Agencies|Norges Forskningsrad [303724]

Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes., Funding Agencies|DST Inspire research student grant [190963]; Chettinad academy of Research and Education [004/Regr/AR-Research/2022-05]

When increasing the quality in clinical laboratories by decreasing measurement uncertainty, reliable methods are needed not only to quantify the performance of measuring systems, but also to set goals for the performance. Sigma metrics used in medical laboratories for documenting and expressing levels of performance, are evidently totally dependent on the "total permissible error" used in the formulas. Although the conventional biological variation (BV) based model for calculation of the permissible (or allowable) total error is commonly used, it has been shown to be flawed. Alternative methods are proposed, mainly also based on the within-subject BV. Measurement uncertainty models might offer an alternative to total error models. Defining the limits for analytical quality still poses a challenge in both models. The aim of the present paper is to critically discuss current methods for establishing performance specifica-tions by using the measurement of sodium concentrations in plasma or serum. Sodium can be measured with high accuracy but fails by far to meet conventional performance specifications based on BV. Since the use of sodium concentrations is well established for supporting clinical care, we question the concept that quality criteria for sodium and similar analytes that are under strict homeostatic control are best set by biology.

Objectives: Osteoarthritis (OA) and chronic low back pain (CLBP) are common musculoskeletal disorders with substantial patient and societal burden. Nordic administrative registers offer a unique opportunity to study the impact of these conditions in the real-world setting. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study was designed to study disease prevalence and the societal and economic burden in broad OA and CLBP populations. Methods: Patients in Sweden, Norway, Finland and Denmark with diagnoses of OA or CLBP (low back pain record plus >= 2 pain relief prescriptions to indicate chronicity) were identified in specialty care, in primary care (Sweden and Finland) and in a quality-of-care register (Sweden). Matched controls were identified for the specialty care cohort. Longitudinal data were extracted on prevalence, treatment patterns, patient-reported outcomes, social and economic burden. Results: Almost 1.4 million patients with OA and 0.4 million with CLBP were identified in specialty care, corresponding to a prevalence in the Nordic countries of 6.3 and 1.9%, respectively. The prevalence increased to 11-14% for OA and almost 6% for CLBP when adding patients identified in primary care. OA patients had a higher Elixhauser comorbidity index (0.66 vs. 0.46) and were using opioids (44.7 vs. 10.2%) or long-term nonsteroidal anti-inflammatory drug (NSAIDs) (20.9 vs. 4.5%) more than four times as often as compared to controls. The differences were even larger for CLBP patients compared to their controls (comorbidity index 0.89 vs. 0.39, opioid use 77.7 vs. 9.4%, and long-term NSAID use 37.2 vs. 4.8%). Conclusions: The BISCUITS study offers an unprecedented, longitudinal healthcare data source to quantify the real-world burden of more than 1.8 million patients with OA or CLBP across four countries. In subsequent papers we aim to explor, Funding Agencies|Pfizer; Eli Lilly Company

Aim: The process of biomarker discovery is being accelerated with the application of artificial intelligence (AI), including machine learning. Biomarkers of diseases are useful because they are indicators of pathogenesis or measures of responses to therapeutic treatments, and therefore, play a key role in new drug development. Proteins are among the candidates for biomarkers of rectal cancer, which need to be explored using state-of-the-art AI to be utilized for prediction, prognosis, and therapeutic treatment. This paper aims to investigate the predictive power of Ras homolog family member B (RhoB) protein in rectal cancer. Methods: This study introduces the integration of pretrained convolutional neural networks and support vector machines (SVMs) for classifying biopsy samples of immunohistochemical expression of protein RhoB in rectal-cancer patients to validate its biologic measure in biopsy. Features of the immunohistochemical expression images were extracted by the pretrained networks and used for binary classification by the SVMs into two groups of less and more than 5-year survival rates. Results: The fusion of neural search architecture network (NASNet)-Large for deep-layer feature extraction and classifier using SVMs provided the best average classification performance with a total accuracy = 85%, prediction of survival rate of more than 5 years = 90%, and prediction of survival rate of less than 5 years = 75%. Conclusions: The finding obtained from the use of AI reported in this study suggest that RhoB expression on rectal-cancer biopsy can be potentially used as a biomarker for predicting survival outcomes in rectal-cancer patients, which can be informative for clinical decision making if the patient would be recommended for preoperative therapy.

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self -apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value-and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (20182021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

Objective To evaluate whether a change of head coach or other head staff before or during a season is correlated to hamstring injury (HI) burden in male elite-level football (soccer) in Europe.Methods The survey was conducted using a questionnaire reporting any staff change within the team. Data about the head staff changes and hamstring injury burdens were collected from 14 teams participating in the Elite Club Injury Study (ECIS) during the 2019/2020, 2020/2021 and 2021/2022 seasons.Results On average, replacing the head coach before or during a season happens in every second season. All changes, except for the change of the head coach during a season, indicate an association with an increase in HI burden (ranging from 10% to 81%). However, only changes in the fitness coach and team doctor roles reached statistical significance. The HI burden seems to be influenced by adding new staff members, such as the head of fitness/performance coach in 36% of the teams and the team doctor in 17%. New head coaches starting the season with their own, for the team new, fitness/performance coach was highly associated with increased HI burden (p<0.001).Conclusions Bringing their own fitness/performance coaches is common for managers entering a new elite male football club. However, this paper has highlighted that this trend seems to lead to a three times increase in HI burden. Similarly, replacing the team doctor was also associated with increased HI burden. Instability among head staff members in male elite-level football teams seems associated with increased HI burden during the season., Funding Agencies|The authors thank the participating clubs for their participation in the study. A special thanks to Bruno Vanhecke, CMO, at Club Brugge KV, Ricard Pruna, CMO, at FC Barcelona and Maikel van Wijk, Sports Physician at AFC Ajax, for valuable comments on this

AimThis paper describes the trajectory during 1 year of four patient-reported outcomes (PROs), namely, sleep, depressive symptoms, health-related quality of life (HrQoL), and well-being, in patients with heart failure (HF), their relationship and the patient characteristics associated with changes in these PROs.Methods and resultsData analyses of PROs from 603 patients (mean age 67 years; 29% female, 60% NYHA II) enrolled in the HF-Wii study. On short term, between baseline and 3 months, 16% of the patients experienced continuing poor sleep, 11% had sustained depressive symptoms, 13% had consistent poor HrQoL, and 13% consistent poor well-being. Across the entire 1-year period only 21% of the patients had good PRO scores at all timepoints (baseline, 3, 6, and 12 months). All others had at least one low score in any of the PROs at some timepoint during the study. Over the 12 months, 17% had consistently poor sleep, 17% had sustained symptoms of depression, 15% consistently rated a poor HrQoL, and 13% poor well-being. Different patient characteristics per PRO were associated with a poor outcomes across the 12 months. Age, education, New York Heart Association, and length of disease were related to two PRO domains and submaximal exercise capacity (6 min test), co-morbidity, and poor physical activity to one.ConclusionIn total, 79% of the patients with HF encountered problems related to sleep, depressive symptoms, HrQoL, and well-being at least once during a 1-year period. This underscores the need for continuous monitoring and follow-up of patients with HF and the need for dynamic adjustments in treatment and care regularly throughout the HF trajectory., Funding Agencies|Swedish National Science Council [K2013-69X-22302-01-3, 2016-01390]; Swedish National Science Council/Swedish Research Council for Health, Working Life and Welfare, VR-FORTE [2014-4100]; Swedish Heart and Lung Association [E085/12]; Swedish Heart and Lung Foundation [20130340, 20160439]; Vardal Foundation [2014-0018]; Medical Research Council of Southeast Sweden (FORSS) [474681]

BackgroundHealth and Sense of Coherence (SOC) has been shown to be intertwined and argued to have a reciprocal relationship. The theory of SOC implies relatively stable scores during adulthood, however there are few longitudinal studies on the association between SOC and mental and somatic health. The main aim of the present study was to examine how SOC and self-rated health (SRH) are related during 25 years of follow-up.MethodsUsing paper questionnaires distributed by postal services, 415 mothers were followed from childbirth and 25 years prospectively. SOC was measured at three, 12 and 25 years after inclusion. Self-reports on health status were obtained at the 25-year follow-up. The association between SOC and self-reported health as well as the effect of sociodemographic factors and experience of stressful life events was assessed through regression models.ResultsSOC scores increased between three and 12 years after inclusion, and slightly decreased at the 25-year follow-up. Women of good health had a higher SOC-score at all three measurements compared to women of poor health. Multiple logistic regression showed that the likelihood of reporting good health increased with the number of times the women had reported SOC-scores above the 75th percentile. Moreover, women who had not been through a divorce were close to 60% more likely to report good health compared to women who had been through a divorce, whereas women not reporting stressful life events during the past two years were more than twice as likely to report good health. Symptoms below cut-off for postpartum depression and not having been through a divorce were associated with SOC scores above the 75th percentile.ConclusionThis 25-year follow-up study of a cohort of women reports good stability of SOC assessments in the vast majority of women. There was a stronger and more stable SOC in women with better health. The findings are in line with other studies on the predictive value of SOC and self-perceived, Funding Agencies|Skandia Research; Linkoeping University

Background: Artificial intelligence (AI) has the potential in health care to transform patient care and administrative processes, yet health care has been slow to adopt AI due to many types of barriers. Implementation science has shown the importance of structured implementation processes to overcome implementation barriers. However, there is a lack of knowledge and tools to guide such processes when implementing AI-based applications in health care. Objective: The aim of this protocol is to describe the development, testing, and evaluation of a framework, "Artificial Intelligence-Quality Implementation Framework" (AI-QIF), intended to guide decisions and activities related to the implementation of various AI-based applications in health care.Methods: The paper outlines the development of an AI implementation framework for broad use in health care based on the Quality Implementation Framework (QIF). QIF is a process model developed in implementation science. The model guides the user to consider implementation-related issues in a step-by-step design and plan and perform activities that support implementation. This framework was chosen for its adaptability, usability, broad scope, and detailed guidance concerning important activities and considerations for successful implementation. The development will proceed in 5 phases with primarily qualitative methods being used. The process starts with phase I, in which an AI-adapted version of QIF is created (AI-QIF). Phase II will produce a digital mockup of the AI-QIF. Phase III will involve the development of a prototype of the AI-QIF with an intuitive user interface. Phase IV is dedicated to usability testing of the prototype in health care environments. Phase V will focus on evaluating the usability and effectiveness of the AI-QIF. Cocreation is a guiding principle for the project and is an important aspect in 4 of the 5 development phases. The cocreation process will enable the use of both on research-based and practice, Funding Agencies|Swedish Innovation Agency; Knowledge Foundation

Neonatal palliative care aims to provide multidisciplinary support to families and neonates suffering from life-threatening or life-limiting diseases. Many countries worldwide have recognized the importance of enhancing the quality of life in critically ill neonates and thus have created and systematically implemented palliative care protocols in neonatal intensive care units (NICUs). Europe has a very low neonatal mortality rate, which has been steadily decreasing over the last 30 years. Greece in particular, a country located in Southeast Europe, reported a neonatal mortality rate of 2.29/1,000 live births in 2020. Nevertheless, neonatal palliative care facilities are scarce on a national level. In this paper, several reasons are presented to support the integration of neonatal palliative care in the Greek national healthcare system with the vision to ensure that all neonates and their families will receive in the near future the care, support, and dignity they deserve when facing life-threatening or life-limiting illnesses.

Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (

Cancer is a serious disease expected to be the world-leading cause of death in the 21st century. The use of harsh chemotherapies is motivated and accepted but, unfortunately, is often accompanied by severe toxicity and adverse drug reactions (ADRs). These occur because the classical chemotherapies’ common modes of action effectively kill and/or reduce the growth rate not only of tumour cells, but also of many other rapidly dividing healthy cells in the body. There are also considerable interindividual differences in ADRs, even between patients with similar cancers and disease stage treated with equal doses; some experience severe to life-threatening ADRs after one dose, leading to treatment delays, adjustments, or even discontinuation resulting in suboptimal treatment, while others remain unaffected through all treatment cycles. Being able to predict which patients are at high or low risk of ADRs, and to adjust doses accordingly before treatment, would probably decrease toxicity and patient suffering while also increasing treatment tolerability and effects. In this thesis, we have used next-generation sequencing (NGS) and bioinformatics for the prediction of myelosuppressive ADRs in lung and ovarian cancer patients treated with gemcitabine/carboplatin and paclitaxel/carboplatin. Paper I shows that ABCB1 and CYP2C8 genotypes have small effects inadequate for stratification of paclitaxel/carboplatin toxicity. This supports the transition to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Papers II and IV, respectively, use WES and WGS, and demonstrate that genetic variation in or around genes involved in blood cell regulation and proliferation, or genes differentially expressed at chemotherapy exposure, can be used in polygenic prediction models for stratification of gemcitabine/carboplatininduced myelosuppression. Paper III reassuringly shows that WES and WGS are concordant and mostly yield comparable genotypes across the exome. Paper V proves that si

There is a large and unmet need for diagnostic tool that can be used to characterize chronic liver diseases (CLD). In the earlier stages of CLD, much of the diagnostics involves performing biopsies, which are evaluated by a histopathologist for the presence of e.g. fat, iron, inflammation, and fibrosis. Performing biopsies, however, have two downsides: i) biopsies are invasive and carries a small but non-negligible risk for serious complications, ii) biopsies only represents a tiny portion of the liver and are thus prone to sampling error. Moreover, in the later stages of CLD, when the disease has progressed far enough, the ability of the liver to perform its basic function will be compromised. In this stage, there is a need for better methods for accurately measuring liver function. Additionally, measures of liver function can also be used when developing new drugs, as biomarkers for drug-induced liver injury (DILI), which is a serious drug-safety issue. Magnetic resonance imaging (MRI) is a non-invasive medical imaging modality, which have shown much promise with regards to characterizing liver disease in all of the abovementioned aspects. The aim of this PhD project was to develop and validate MR-based methods that can be used to non-invasively characterize liver disease. Paper I investigated if R2* mapping, a MR-method for measuring liver iron content, can be confounded by liver fat. The results show fat does affect R2*. The conclusion was therefore that fat must be taken into account when measuring small amounts of liver iron, as a small increase in R2* could be due to either small amounts of iron or large amounts of fat. Paper II examined whether T1 mapping, which is another MR-method, can be used for staging liver fibrosis. The results of previous research have been mixed; some studies have been very promising, whereas other studies have been less promising. Unfortunately, the results in Paper II belongs to the less promising studies. Paper III focused on mea

Background: Time utilisation among primary care professionals has been affected by structural changes and reorganisation performed in Swedish primary care over several decades. The work situation is complex with a heavy administrative work load. The overall aim with this thesis was to describe time utilisation among staff in Swedish primary care and to investigate associations with perceived psychosocial work environment and legitimacy of work tasks. Methods: A multicentre, descriptive, cross-sectional study design was used including all staff categories in primary care i.e. registered nurses, primary care physicians, care administrators, nurse assistants and allied professionals (physiotherapists, occupational therapists, psychologists, counsellors, dieticians and chiropodists) at eleven primary care centres located in southeast Sweden. The data collection consisted of a questionnaire including a subjective estimate of workload, the Bern Illegitimate Tasks Scale (BITS) and the Copenhagen Psychosocial Questionnaire (COPSOQ). Also, a time study was performed, where the participants reported their work time based on three main categories; direct patient work tasks, indirect patient work tasks and other work tasks, each with a number of subcategories. The participants reported time spent on different work tasks, day by day during two separate weeks. Response rates were 75% for the questionnaire and 79% for the time study. Results: In paper I the time study revealed that health professionals at the primary care centres spent 37% of their work time with direct patient work tasks. All professions estimated a higher proportion of time spent directly with patients than they reported in the time study. Physicians scored highest on the psychosocial scales of quantitative demands, stress and role conflicts. The proportion of administrative work tasks was associated with role conflicts, the more administration the more role conflicts. Findings in paper II were that more than a, Bakgrund: Under de senaste decennierna har det i svensk primärvård varit omfattande omorganisationer, vilket har påverkat arbetstidens innehåll. Arbetssituationen är komplex och omfattningen av administration har ökat. Det övergripande syftet med föreliggande studie var att beskriva arbetstidens innehåll bland personal i svensk primärvård och att undersöka samband mellan upplevd psykosocial arbetsmiljö och arbetsuppgifternas legitimitet. Metod: Studien har genomförts som en deskriptiv multicenterstudie med tvärsnittsdesign och inkluderade sjuksköterskor, läkare, vårdadministratörer, undersköterskor och övriga professioner (fysioterapeuter, arbetsterapeuter, psykologer, kuratorer, dietister och fotvårdsspecialister) vid elva vårdcentraler i sydöstra Sverige. Studien inleddes med att deltagarna ombads att besvara ett frågeformulär vars första del bestod av en skattning av hur arbetsuppgifterna var fördelade. Frågeformuläret innehöll också frågor om illegitima arbetsuppgifter; Bern Illegitimate Tasks Scale (BITS) och psykosocial arbetsmiljö; Copenhagen Psychosocial Questionnaire (COPSOQ). Därefter gjordes en tidsstudie där deltagarna fick registrera tidsåtgången för olika arbetsuppgifter, varje dag under två separata veckor. Arbetsuppgifterna delades upp i tre huvudkategorier; direkt patientarbete, indirekt patientarbete och övrigt arbete. Varje huvudkategori hade flera underkategorier. Svarsfrekvensen var 75% för frågeformuläret och 79% för tidsstudien. Resultat: Resultatet från delarbete I visar att personal i primärvård ägnade 37% av arbetstiden direkt med patienter. Alla professioner skattade den direkta patienttiden till större andel än vad tidsstudien visade. Läkare upplevde sämst psykosocial arbetsmiljö avseende kvantitativa krav, stress och rollkonflikter. Det förelåg ett samband mellan andelen administrativa arbetsuppgifter och rollkonflikter, ju mer administration desto mer rollkonflikter. I delstudie II visade resultatet att mer än en fjärdedel av läkarna up

Fractures in humans most commonly occur near the joints, in the metaphyseal bone area mainly consisting of cancellous bone. Despite this, mainly cortical fractures, located in the diaphyseal bone area, have been studied in experimental models of bone healing. It is known from previous studies that the diaphyseal fracture is sensitive to anti-inflammatory treatment, while metaphyseal bone healing is more resistant. The aim of this thesis is to study the inflammatory response to bone trauma in cancellous and cortical bone. A flow cytometric method was established for the purpose of examining the cellular composition of the inflammatory process in models of bone healing In paper I the cellular composition of metaphyseal bone healing was studied with flow cytometry. The proximal tibia was traumatized and then studied at day 1, 3, 5 and 10 afterwards and compared to healthy mice. The contralateral proximal tibia was also studied at the same time points to delineate the trauma site specific inflammation. A few changes could be noted that seemed specific to the trauma site in macrophage phenotype development. However, the cellular composition was similar at the trauma site and in the contralateral proximal tibia. This notion of a general skeletal response was confirmed with analysis of the humerus at day 5. In paper II a model of cortical bone healing apt for flow cytometry was developed and compared to cancellous bone healing. A furrow was milled along the femoral cortex and the healing bone tissue analyzed. The earliest time point that enough cells were present for flow cytometry was day 3. The cortical and cancellous model of bone healing was compared at day 3 and 5 to study how they evolve in comparison to each other. It was noted that they were similar in cellular composition at day 3, but had diverged at day 5. The cancellous model increased in neutrophilic granulocytes, whereas the cortical model increased in lymphocytes. In paper III the cancellous and cortical mod, En felaktig länk till posten förekom i den tryckta avhandlingen. Denna är ändrad i den elektroniska versionen / There was an icorrect link to this record in the printed version of the thesis. This is corrected in the electronic version

Background: The purpose of psychiatric forensic care is to provide treatment for mentally ill offenders and to prevent future acts of violence and other adverse events. During care, the type of restrictions of freedom, the patient’s continuous need for involuntary treatment and readiness for discharge, are continuously evaluated based on the assessment of risk the patient pose to themselves and others as well as the progress achieved with treatment. The use of structured risk assessment instruments is recommended in clinical guidelines to assess such risks. However, unstructured clinical assessments, considered to be less valid, are often used in clinical practice. There is insufficient research evidence concerning several aspects related to the clinical use of structured risk assessment instruments in terms of guiding the planning and realization of care and risk management interventions. There is also a lack of knowledge about what patients themselves perceive to be mediating factors for their use of violence. Overall aim: The overarching aim of this thesis was to investigate the implementation and use of structured risk assessment instruments to prevent violence and other adverse events in forensic settings and to improve understanding of the factors that influence such events among forensic patients. Methods: Several methods were used for data collection and data were analysed by different types of content analysis. In the first paper, a systematic review of previous research studies on implementation determinants for structured risk assessment instruments in forensic settings was conducted to investigate implementation determinants for such instruments. The second paper evaluates a pilot project of the implementation of a structured risk assessment instrument at a forensic clinic in Östergötland using focus group interviews with staff members who had used the instrument. Their perceptions of the instrument and barriers and facilitators to its implementation and

Since its introduction in the 1970’s CT has emerged as a modality of choice because of its high sensitivity in producing accurate diagnostic images. A third of all Computed Tomography (CT) examinations are abdominal CTs which deliver one of the highest doses among common examinations. An increase in the number of CT examinations has raised concerns about the negative effects of ionising radiation as the dose is cumulative over the life span of the individual. Image quality in CT is closely related to the radiation dose, so that a certain dose with an associated small, but not negligible, risk is a prerequisite for high image quality. Typically, dose reduction in CT results in higher noise and a decrease in low contrast resolution which can be detrimental to the image quality produced. New technology presents a wide range of dose reduction strategies, the latest being iterative reconstruction (IR).The aim of this thesis was to evaluate two different classes of iterative reconstruction algorithms: statistical (SAFIRE) and model-based (ADMIRE) as well as to explore the diagnostic value of a low-dose abdominal CT for optimisation purposes. This thesis included a total of 140 human subjects in four image quality evaluation studies, three of which were prospective studies (Papers I, II and IV) and one retrospective study (Paper III). Visual grading experiments to determine the potential dose reductions, were performed with pairwise comparison of image quality in the same patient at different tube loads (dose) and reconstructed with Filtered back projection (FBP) and SAFIRE strength 1 in a low-dose abdominal CT (Paper I) and FBP and ADMIRE strengths 3 and 5 in a standard dose abdominal CT (Paper II). Paper IV evaluated the impact of slice thicknesses in CT images reconstructed with ADMIRE strengths 3 and 5 when comparing multiplanar reconstruction (MPR) formatted images in a standard dose abdominal CT. Paper III, on the other hand, was an absolute assessment of image quali, Datortomografi (DT) används i allt större omfattning vid bilddiagnostik och ger en viss stråldos till patienten. DT är en viktig, snabb och patientvänlig undersökningsteknik. En fördel med denna teknik är att bildmaterialet kan rekonstrueras i olika format för att åskådliggöra anatomin på bästasätt beroende på vilken frågeställning som ska besvaras. Joniserande strålning från dessa undersökningar anses öka risken för negativa effekter även om risken för den enskilde patient är mycket liten. Antalet datortomografiundersökningar ökar från år till år vilket kan leda till ökade stråldoser tillbefolkningen. Optimering av undersökningsteknik och val av undersökning för att minska negativa effekter av röntgenstrålning är därför nödvändig. Det övergripande målet med avhandlingen var att utvärdera bildkvalitetvid en DT-undersökning av buken (då dessa medför en av de högstastråldoserna bland de vanliga röntgenundersökningarna), att kvantifieramöjlig stråldosminskning med hjälp av iterativa rekonstruktionsalgoritmer och att utvärdera diagnostiska värdet av lågdosundersökningsteknik vid DT-buk. Av de fyra delstudierna var delarbeten I, II och IV prospektiva och delarbete III retrospektivt. För de prospektiva studierna, samlades bildmaterial in vid en kliniskberättigad undersökning av lågdos-DT av buken (delarbetet I), eller standarddos-DT av buken (delarbetet II och IV). Bilder rekonstruerades meden standard bildrekonstruktionsalgoritm, filtrerad återprojektion (FBP), och med styrka 1 av den iterativa algoritmen SAFIRE (delarbetet I). I delarbeten II och IV, gjordes bildrekonstruktioner med FBP och med styrka 3 och 5 av den iterativa algoritmen ADMIRE. Avidentifierade bildmaterialför varje patient visades parvis i slumpmässig ordning för ett antal granskare och bildkvaliteten bedömdes med hjälp av europeiska bildkriterier. I den retrospektiva studien, delarbete III, hämtades bildmaterialet från utförda DT-urografiundersökningar från bildarkivet. För varje undersökning visades b

Background. Firefighting is one of the most physically demanding occupations and it requires a high cardiorespiratory fitness level. Pre-duty medical evaluation of firefighters includes fitness testing and assessment of cardiac health to ensure that firefighters meet the minimum physical fitness standard and to ensure that they are not at increased risk of cardiac events. The medical evaluation methods for Swedish firefighters are regulated by the Swedish Work Environment Authority and include a 6 min constant workload treadmill (TM) test for fitness evaluation in which the firefighter wears full smoke diving equipment and a maximal effort exercise electrocardiography test (ExECG) at cycle ergometer (CE) for assessment of cardiac health. Previously, fitness was also evaluated by cycle ergometry. The standard parameter for evaluation of ischaemic heart disease (IHD) is exercise-induced ST depression. In general, exercise testing of asymptomatic low-risk individuals is discouraged due to low sensitivity and specificity for IHD, generating both false-positive and false-negative test results. Heart rate (HR) adjustment of the ST-segment response has been shown to be superior to simple ST depression to evaluate cardiac ischaemia in some populations, but has not been extensively evaluated in an occupational setting. Methods. We retrospectively analysed a cohort of 774 firefighters who were asymptomatic at the time of the testing. In paper I, test approval, HR response, and calculated oxygen uptake from TM tests and CE tests for 424 firefighters (44±10 years) were compared. Paper II methodologically described the process for data extraction, processing, and calculation of ExECG data from a clinical database. Procedures for noise assessment, error checking, and computerized calculation of ST/HR parameters were described. In paper III, ExECG and medical records of 521 male firefighters (44±10 years) were studied. During 8.4 ± 2.1 years of follow-up, IHD was verified angiogra

Background: Many studies have been performed to identify important prognostic factors for outcomes after rehabilitation of patients with chronic pain, and there is a need to synthesize them through systematic review. In this process, it is important to assess the study quality and risk of bias. The "Quality In Prognosis Studies" (QUIPS) tool has been developed for this purpose and consists of several prompting items categorized into six domains, and each domain is judged on a three-grade scale (low, moderate or high risk of bias). The aim of the present study was to determine the interrater agreement of the risk of bias assessment in prognostic studies of patients with chronic pain using QUIPS and to elaborate on the use of this instrument. Methods: We performed a systematic review and a meta-analysis of prognostic factors for long-term outcomes after multidisciplinary rehabilitation in patients with chronic pain. Two researchers rated the risk of bias in 43 published papers in two rounds (15 and 28 papers, respectively). The interrater agreement and Cohen's quadratic weighted kappa coefficient (κ) and 95% confidence interval (95%CI) were calculated in all domains and separately for the first and second rounds. Results: The raters agreed in 61% of the domains (157 out of 258), with similar interrater agreement in the first (59%, 53/90) and second rounds (62%, 104/168). The overall weighted kappa coefficient (kappa for all domains and all papers) was weak: κ = 0.475 (95%CI = 0.358-0.601). A "minimal agreement" between the raters was found in the first round, κ = 0.323 (95%CI = 0.129-0.517), but increased to "weak agreement" in the second round, κ = 0.536 (95%CI = 0.390-0.682). Conclusion: Despite a relatively low interrater agreement, QUIPS proved to be a useful tool in assessing the risk of bias when performing a meta-analysis of prognostic studies in pain rehabilitation, since it demands of raters to discuss and investigate important aspects of study quality. Some

BACKGROUND Bleeding complications increase mortality in patients with acute coronary syndrome (ACS). Potential gender difference in bleeding regarding prevalence, location, severity and prognostic impact is still controversial and not well investigated. In regard to this aspect the relevance of triple antithrombotic therapy (TAT) is questioned. There is an ongoing debate on the clinical implications of TAT and furthermore assumed that bleeding complications, except impact on outcome, also are associated with great influence on health economy. The main focus of this thesis was to further investigate the incidence and impact of bleeding complications in patients treated for ACS, with special reference to gender disparities, TAT and health economics. The thesis will highlight the importance of improved bleeding prevention strategies for both men and women. METHOD Paper I, II and III Observational studies from the SWEDEHEART register. In paper I we investigated patients hospitalised with myocardial infarction (MI) during 2006–2008. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors. In paper II, all patients with MI, in the County of Östergötland, Sweden during 2010 were included and followed for one year. The patients' medical records were evaluated, in relation to short and long-term bleeding complications, bleeding location, withdrawal of platelet inhibiting drugs and nonfatal MI and death. Paper III included all patients discharged with (TAT) in the County of Östergötland 2009-2015. Information about bleeds and ischemic complications during one-year follow-up were retrieved from the medical records. Estimation of the health care costs associated with bleeding episodes were added to the evaluation. Paper IV Patients with MI, scheduled for coronary angiography were recruited. All patients received clopidogrel and aspirin. A subgroup of patients received GP IIb/IIIa-inhibitor. Outcomes were platelet aggregation asses

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population and is commonly recognized as the hepatic manifestation of the metabolic syndrome. The histological spectrum of NAFLD ranges from isolated steatosis to non-alcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. The gold standard for diagnosing NAFLD is liver biopsy. However, because of its invasive nature, several non-invasive methods have been developed and validated in evaluating fat and fibrosis in patients with NAFLD. Liver fat content can be assessed using various methods. The conventional histopathological method consists of a visual semiquantitative approach in which the pathologist uses a four-point scale: grade 0 corresponds to fat deposition in <5% of hepatocytes and grade 1−3 (which is needed for the diagnosis of NAFLD) corresponds to ≥5%. An alternate approach is to quantitatively assess steatosis using stereological point counting (SPC) – which rely on liver biopsy. However, in vivo proton magnetic resonance spectroscopy (1H-MRS) is a reliable noninvasive method that can be used to quantitatively assess total hepatic lipid content, or proton density fat fraction (PDFF). In Paper I we compared the conventional semiquantitative histological method (grade 0-3) with SPC and 1H-MRS. We found a strong positive correlation between 1H-MRS and SPC, whereas the correlations between 1H-MRS or SPC and histopathological grading were substantially weaker. Using the widely used cut-off value of PDFF ≥5%, all participants were found to have steatosis (specificity 100%, sensitivity 53%). Reducing the cut-off value to 3% maintained 100% specificity while increasing sensitivity to 79%. In Paper IV we evaluated quantitative steatosis, by SPC, in 106 biopsy-proven NAFLD patients during a 20-year follow-up. SPC was independently associated with an increased risk o

Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging. The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers. In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival. In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients. In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in s, Huvud- och halscancer (HH-cancer) innefattar tumörer belägna i huvud och halsområdet. Tobaksrökning ökar risken dramatiskt för olika sjukdomar. Knappt hälften av rökande patienter dör i de av rökning orsakade sjukdomarna. Cancer är orsaken till en tredjedel av de rökrelaterade dödsfallen av vilka HH-cancer är en. En andel av patienterna med HH-cancer dör på grund av att tumören varit för stor redan vid diagnos eller att tumören har spridit sig till övriga delar av kroppen. Men för många patienter är det mycket oklart vad som bestämmer behandlingsresultatet. Tumörerna är till synes lika och behandlingen standardiserad. Målet med denna doktorsavhandling var att undersöka billiga och lättillgängliga biologiska markörer som kan indikera risk för att drabbas av HH-cancer eller om dessa markörer kan förutspå behandlingsresultat och överlevnad hos de drabbade patienterna. Dessutom undersöktes hur cigarettrökning påverkade nivåerna av markörerna. I studie I, undersöktes om molekyler i blodet (biomarkörer), förknippade med immunförsvaret, kunde förutsäga överlevnaden hos HH-cancerpatienter. I jämförelse med friska individer sågs högre nivåer av molekylerna TNF-α och CRP hos patienterna och dessa förhöjningar var relaterade till förkortad överlevnad hos patienterna. I studie II, var målet att undersöka om variationer i gener, förknippade med immunförsvaret, celldelning, celldöd eller enzymer som reparerar skadat DNA, kunde påverka risk och prognos för HH-cancer. Resultatet visade framför allt att små ärftliga variationer i gener som reglerar immunförsvaret kunde påverkade risk för HH-cancer, risk för återfall i sjukdomen samt överlevnaden hos patienterna. I studie III, jämfördes inflammatoriska och immunförknippade biomarkörer som kunde påverkas av cigarettrökning mellan friska rökare och friska icke-rökare. Rökarna hade en högre inflammatorisk aktivitet med högre nivåer av totalt antal vita blodkroppar och tre av dess olika undergrupper (neutrofiler, monocyter och lymfocyter

Postoperative heart failure (PHF) remains the major cause of mortality after cardiac surgery. Unfortunately, generally accepted diagnostic criteria for PHF are lacking. This may explain why the evidence for the efficacy and safety of current treatment of PHF with inotropes is insufficient. In cardiology practice N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an established biomarker for heart failure. However, the association between NT-proBNP and PHF after cardiac surgery needs further clarification. Glutamate is a key intermediate in myocardial metabolism, which may improve myocardial tolerance to ischemia and facilitate post-ischemic recovery. Glutamate was associated with a reduced risk of developing severe PHF in high-risk patients undergoing coronary artery bypass surgery (CABG). The aim of this thesis was to study the role of NT-proBNP for prediction and assessment of PHF in cardiac surgery (Paper I-III) and the impact of intravenous glutamate infusion on postoperative NTproBNP after CABG (Paper IV). Paper I: We retrospectively studied the role of underlying heart disease for preoperative NT-proBNP in patients admitted for first time CABG (n=2226), aortic valve surgery (AVR) for aortic stenosis (AS) (n=406) and mitral valve surgery for mitral valve regurgitation (MR) (n=346) by adjusting for non-cardiac confounders (age, gender, obesity and renal function). The level of NT-proBNP in AS or MR was 1.67 (p<0.0001) and 1.41 times (p<0.0001) higher respectively than in coronary artery disease (CAD) after adjusting for confounders. Preoperative NT-proBNP was predictive of severe PHF in CAD and MR patients but less so in AS patients. Preoperative NT-proBNP emerged as an independent risk factor for severe PHF and postoperative mortality in CAD patients. Paper II-III: We prospectively studied the association between postoperative NT-proBNP and PHF in two cohorts, patients undergoing AVR for AS (n=203) and patients undergoing isolated CABG for acute cor

In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older. The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally. The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated). The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed, Supporter of this thesis not mentioned above are LiUCancer and NSC research grant; Linköping University Hospital for Neuro-research, Lion's Cancer Foundation, Cancer Foundation Norrland and Rotary Borgholm research grant.