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Abstract Background Although coordination of care and integrated care models aim to enhance patient satisfaction and perceived care quality, evidence regarding their practical implementation remains scarce. Understanding the nuances of collaboration across care providers to achieve effective coordination of care is imperative for seamless care integration. The aim of this study was to construct a grounded theory of how inter-organizational collaboration is performed to support coordination of care for patients with complex care needs. Methods A qualitative design with a constructivist grounded theory approach was applied. In total, 86 participants with diverse backgrounds were recruited across multiple care settings, including hospitals, ambulance services, primary care centers, municipal home healthcare and home care services. The grounded theory was developed iteratively, based on a combination of observations and interviews, and using constant comparative analysis. Results Coordination of care, a complex process that occurs across interconnected healthcare organizations, is manifested as “Negotiating care in organizational borderlands.” Care coordination evolves through a spectrum of inter-organizational collaboration, ranging from “Dividing care by disease-specific expertise” to “Establishing paths for collaboration” and ultimately “Co-constructing a comprehensive whole.” These categories highlight the challenges of coordinating care across both professional and organizational boundaries. In the multifaceted healthcare landscape, effective care coordination occurs when healthcare professionals actively bridge the divides, leveraging their collective expertise. Importantly, organizational boundaries may serve a purpose and should not be dissolved to facilitate effective care coordination. Conclusions The key to effective care coordination lies in robust inter-organizational collaboration. Even when patients receive integrated care, healthcare professionals may have fragmented roles. This research emphasizes the importance of clearly defined lines of accountability, reinforcing mutual responsibility and facilitating bridging of professional and organizational boundaries. Healthcare professionals and policymakers can use these insights to effectively utilize inter-organizational collaboration in supporting care coordination for patients with complex care needs.

Background: Autism spectrum disorder (ASD) is often accompanied by comorbidities such as epilepsy and behavioral problems. The interplay between epilepsy, behavior, and language suggests a potential role for antiepileptic drugs (AEDs) in managing ASD-related behavioral issues. Despite some preliminary studies indicating possible benefits, the evidence remains inconclusive. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of AEDs in managing behavioral issues in individuals with ASD. Methodology: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive search across multiple databases (PubMed, Ovid MEDLINE, Cochrane Library, Web of Science, and others) for double-blind, placebo-controlled randomized controlled trials (RCTs) published in English. Inclusion criteria focused on individuals with ASD exhibiting behavioral problems, with or without EEG abnormalities, treated with AEDs. Data extraction and quality assessment were performed by two independent reviewers. The primary outcome was focused on investigating the efficacy of AEDs in improving behavioral symptoms, predominantly irritability, and aggression. We also investigated the safety profiles of the AEDs. Results: Seven RCTs met the inclusion criteria, involving AEDs such as valproate, levetiracetam, and topiramate. Two RCTs were excluded due to incompatible outcome measures. Meta-analysis of the remaining five RCTs showed no significant difference in the reduction of aggression and irritability between AEDs and placebo, with high heterogeneity (I2 = 93%). Sensitivity analysis confirmed the nonsignificance and high heterogeneity (I2 = 87%). Adverse effects commonly reported included insomnia and weight gain. Conclusion: This meta-analysis found no significant benefit of AEDs in managing behavioral symptoms of ASD compared to placebo, consistent with previous findings. The high heterogeneity and methodological limitations highlight the need for more robust and larger-scale studies. Future research should consider the role of electroencephalography abnormalities and standardize outcome measures to better evaluate the potential of AEDs in this population or in a specific subgroup of ASD.

Abstract Highly pathogenic avian influenza viruses (HPAIV) of H5 clade 2.3.4.4b pose an ongoing threat worldwide. It remains unclear whether this panzootic situation would favor low virulent phenotypes expected by the ‘avirulence hypothesis’ of viral evolution. Assessing virulence in Pekin ducklings in an intramuscular infection model revealed that the two genotypes that dominated the epidemiological situation in Germany during the period 2021 and 2022 (EU-RL:CH and EU-RL:AB) were of high virulence. In contrast, rare genotypes were of intermediate virulence. The genetic constellation of these reassortants pointed to an important role of the viral polymerase complex (RdRP), particularly the PB1 genome segment, in shaping virulence in ducklings. Occulo-nasal infection of ducklings confirmed the phenotypes for two representative viruses and indicated a more efficient replication for the high virulence strain. These observations would be in line with the ‘virulence-transmission trade-off’ model for describing HPAIV epidemiology in wild birds in Germany.

Dette er en introduksjonsartikkel til et spesialnummer som diskuterer hvordan vi kan forstå migranters prekære arbeids- og livsforhold i den norske velferdsstaten. Vi argumenterer for at de etnografiske bidragene viser det vi kaller velferdsstaten nådeløse optimisme og at velferdsstaten bidrar til å produsere og opprettholde prekære arbeidsforhold, til tross for politikernes forsøk på det motsatte. Artikkelen avklarer begrepene «prekaritet», «prekarisering» og «prekariatet». Videre diskuterer den hvordan velferdsstaten og arbeidsmarkedets reguleringer bidrar til å skape prekære arbeidsforhold og livssituasjoner. Det norske arbeidsmarkedet har vært kjent som trygt og gjennomregulert. Økende globalisering, og demografiske endringer som økt migrasjon og en aldrende befolkning, påvirker hvordan dagens arbeid og arbeidsmarked organiseres på nye måter, også i Norge. Vi ser flere utrygge arbeidsplasser og økende prekære arbeidsforhold, hvor migranter er særlig utsatt. Spesialnummeret omhandler migranter med ulik juridisk status, og viser at prekære liv formes av migrasjonsbakgrunn, borgerskap, kjønn og alder samt av andre faktorer både innenfor og utenfor arbeidslivet. Vi hevder at dagens prekære arbeidsliv i Norge delvis skapes av politiske tiltak, slik som aktiveringspolitikken, integreringsregimet og velferdsstatlig grensekontroll og har vidtrekkende konsekvenser både for menneskers liv og for tilliten til velferdsstaten.

En norsk arbeidslivsmodell og omfattende velferdsordninger er med på å sikre et trygt arbeidsliv og støtte for mennesker som faller utenfor arbeidslivet. Likevel peker forskere på økende forekomst av prekære arbeidsforhold, og på at migranter er overrepresentert i slike jobber. Artikkelen bygger på feltarbeid blant migrantarbeidere i Norge, fortrinnsvis fra EU-land i Sentral- og Øst-Europa, samt på intervjuer og samtaler med representanter fra fagforeninger og sivilsamfunnsorganisasjoner. Til tross for medlemskap i et felleseuropeisk fritt marked, erfarer migrantene differensiert inkludering i norsk arbeidsliv og velferdssamfunn. Flere migranter opplever ulike former for utnyttelse – i offentlig diskurs kalt «arbeidslivskriminalitet». Artikkelen viser at under et velferdsregime hvor lønnet arbeid premieres og tjenester er opptjeningsrelatert, hindrer prekære arbeidskontrakter migranters tilgang til velferdstjenester, mens mangel på velferdstjenester gjør det vanskelig å bryte med utnyttende arbeidsforhold. Velferdstaten bidrar dermed til prekariseringen. Når velferdsstaten svikter, blir sivilsamfunnsorganisasjoner alternative sikkerhetsnett. Uformell sektor og plattformarbeid blir utvei for noen. Arbeidstakere som betaler skatt og fyller behovet for arbeidskraft, blir stående uten sosialt sikkerhetsnett og blir avhengige av humanitær bistand og selvorganiserte ressurser. Statens kamp mot såkalt «arbeidslivskriminalitet» rettes mot «useriøse» og «kriminelle» aktører, og tiltakene begrenses til arbeidsmarkedet. De sammensatte formene for prekaritet migranter opplever i og utenfor arbeidslivet blir oversett.

In September 2020, the US National Institutes of Health (NIH) allocated $12 million to support engagement with historically marginalized communities hardest hit by COVID-19. The award was designed to mobilize community-engagement in pandemic response, and to support partnerships as part of the NIH Community Engagement Alliance (CEAL) Against COVID-19 Disparities. All aspects of the award were fast-tracked, and NIH utilized a ‘more flexible’ funding mechanism (OTA) to facilitate swift distribution of funds. In this paper, we draw upon an analysis of findings from a 2021 survey conducted with 11 California CEAL sites representing urban and rural settings, private and public universities, and established and new community partners and qualitative analysis of 2020–2022 site-wide meeting minutes. We describe the challenges posed at the federal (e.g. NIH funding), university, and community–university partnership levels as well as opportunities and creative workarounds. Challenges include delays in subcontracts and payments to community partners that undermined trust and reproduced unequal and hierarchical power relationships. We build upon our findings and collective experience to propose a framework for decolonized fiscal relationships between universities and community partners which contains key recommendations for funders, universities, and community partners.

In the 1980s, my research career begun with microbial DNA diagnostics at Orion Pharmaceutica in Helsinki, Finland, where I was part of an innovative team that developed novel methods based on the polymerase chain reaction (PCR) and the biotin–avidin interaction. One of our key achievements during this time was the invention of the solid-phase minisequencing method for genotyping single nucleotide polymorphisms (SNPs). In the 1990s, I shifted focus to human genetics, investigating mutations of the ‘Finnish disease heritage’. During this period, I also developed quantitative methods using PCR and minisequencing of mitochondrial mutations and for forensic analyses. In the late 1990s and early 2000s, microarray-based SNP genotyping became a major topic for my research, first in Helsinki and later with my research group at Uppsala University in Sweden. By the mid-2000s, I began collaborating with leading clinicians on genetics of autoimmune disease, specifically systemic lupus erythematosus and later worked on the classification and clinical outcome of pediatric acute lymphoblastic leukemia, when large-scale genomics and epigenomics emerged. These collaborations, which focused on integrating genomics into clinical practice, lasted almost two decades until I retired from research in 2022. In parallel with my research activities, I led the SNP/DNA Technology Platform in the Wallenberg Consortium North program from 2001 to 2006. I continued as Director of the SNP&SEQ Technology Platform, which expanded rapidly during the 2010s, and became part of Science for Life Laboratory in 2013. Today (in 2024), the SNP&SEQ Technology Platform is one of the largest units of the Swedish National Genomics Infrastructure hosted by SciLifeLab. The present article provides a personal perspective on nearly four decades of research, highlighting projects and methods I found particularly exciting or important.

Abstract Background The transfer of innovations into healthcare is laden with challenges. Although healthcare professionals are expected to adopt and fulfil new policies, a more person-centered healthcare with conditions for preference-based patient participation is anticipated. Methods The aim of the study was to evaluate two implementation strategies for person-centered patient participation in kidney care, including dissemination of a clinical toolkit, and additional training and support of internal facilitators. Nine Swedish kidney care units joined the study (August 2019–September 2021), strategically organized into: a control group (three sites, no support); a standard dissemination group (three sites, with a tool for patient participation and guidance disseminated to the site managers); and a facilitated implementation group (three sites, with the tool and guidance disseminated as above, plus a six-month support program for designated internal facilitators). This process evaluation was comprised of repeat interviews with managers (n = 10), internal facilitators (n = 5), recordings, and notes from the interventions, and Alberta Context Tool survey data (n = 78). Hybrid analyses comprised mixed methods: descriptive and comparative statistics, and qualitative descriptive analysis. Results None of the control group sites addressed patient participation. While the standard dissemination sites’ managers received and appreciated the toolkit, they made no attempts to make further use of it. In the facilitated implementation group, five internal facilitators from three sites engaged in the support program. They welcomed the opportunity to learn about preference-based patient participation, and about implementation, including potentially enhanced opportunities for preference-based patient participation via the tool. Each site’s facilitators developed a separate strategy for the dissemination of the tool: the tool was used with a few patients in each site, and only some staff were involved. Although noting a general interest in improving patient participation, the internal facilitators described limited local support. Rather, they suggested a longer support program and more local backing and engagement. Conclusions Facilitating person-centered patient participation is complex, given the need to address attitudes, beliefs, and behaviors. This study indicates slow uptake and change, and more efficient strategies are needed to ensure the fundamentals of care remain accessible to all.

‘Turning the Tide’ (2020–present) is the most recent project in my lifelong involvement with seaweed. I write about my use of photography and drawing to capture the fleeting existence of seaweed strewn along the tideline. Spontaneous and free in their creation, my photographs explore the seaweed’s qualities of movement, texture, time and emotion; how it weaves into my own psychology. Seaweed has become a language which writes itself before and within me. ‘Turning the Tide’ redefines our understanding of our own place in the landscape and draws us to seek a wider and deeper connection to the tideline.

Abstract Background Genomic instability and evading apoptosis are two fundamental hallmarks of cancer and closely linked to DNA damage response (DDR). By analyzing expression quantitative trait loci (eQTL) upon cell stimulation (called exposure eQTL (e2QTL)) it is possible to identify context specific gene regulatory variants and connect them to oncological diseases based on genome-wide association studies (GWAS). Results We isolate CD8+ T cells from 461 healthy donors and stimulate them with high doses of 5 different carcinogens to identify regulatory mechanisms of DNA damage-induced apoptosis. Across all stimuli, we find 5,373 genes to be differentially expressed, with 85% to 99% of these genes being suppressed. While upregulated genes are specific to distinct stimuli, downregulated genes are shared across conditions but exhibit enrichment in biological processes depending on the DNA damage type. Analysis of eQTL reveals 654 regulated genes across conditions. Among them, 47 genes are significant e2QTL, representing a fraction of 4% to 5% per stimulus. To unveil disease relevant genetic variants, we compare eQTL and e2QTL with GWAS risk variants. We identify gene regulatory variants for KLF2, PIP4K2A, GPR160, RPS18, ARL17B and XBP1 that represent risk variants for oncological diseases. Conclusion Our study highlights the relevance of gene regulatory variants influencing DNA damage-induced apoptosis in cancer. The results provide new insights in cellular mechanisms and corresponding genes contributing to inter-individual effects in cancer development.

Abstract Multimodal brain network analysis enables a comprehensive understanding of neurological disorders by integrating information from multiple neuroimaging modalities. However, existing methods often struggle to effectively model the complex structures of multimodal brain networks. In this paper, we propose a novel tensor-based graph convolutional network (TGNet) framework that combines tensor decomposition with multi-layer GCNs to capture both the homogeneity and intricate graph structures of multimodal brain networks. We evaluate TGNet on four datasets—HIV, Bipolar Disorder (BP), and Parkinson’s Disease (PPMI), Alzheimer’s Disease (ADNI)—demonstrating that it significantly outperforms existing methods for disease classification tasks, particularly in scenarios with limited sample sizes. The robustness and effectiveness of TGNet highlight its potential for advancing multimodal brain network analysis. The code is available at https://github.com/rongzhou7/TGNet .

Abstract Background All children should have the possibility to be healthy during childhood, according to the Convention on the Rights of the Child. In Sweden, the Child Health Services (CHS) support all parents and children from birth until the age of six to promote children’s health and development. Some Swedish regions have introduced an extended home-visit programme, with CHS nurses and social workers visiting first-time parents together to provide parental support in collaboration. The programme aims to expand the task of promoting the child’s health and increase the possibilities of discovering risk factors in families earlier. The aim of the present study is to describe the professionals’ experiences of collaboration when introducing the extended home-visit programme to a broader population within the frame of a family centre. Methods The study used a reflexive thematic qualitative approach with focus group interviews. All staff at the family centre were invited to participate: CHS nurses, social workers, and managers who worked with the extended home-visit programme. Data were collected through focus group interviews with each profession separately and analysed through reflexive thematic analysis. Results One overarching theme emerged: A key to facilitating early support. Three connected themes – Ease for everyone on the family’s terms, From working alone to becoming a team, and A matter of supporting structures – illuminated the participants’ experiences. Their driving force was early detection of risk factors or needs in the family, to be able to provide support. The collaboration was enhanced by the different professional competencies complementing each other. That all were located at the family centre together was also important to facilitate collaboration. Conclusions The extended home-visits were appreciated and experienced as useful by all participants. That a family centre organization already existed was one of the facilitators, functioning as a meeting point to expand the collaboration. The managers’ support was essential, and it was experienced as positive that the organization invested resources to allow employees to participate in the development of the extended home-visit programmes. This way of working has the potential to add value for the children and families, and the CHS would benefit from using the extended home-visit programme further.

Abstract We retrospectively analyzed 129 treatment-naïve head and neck squamous cell carcinomas (HNSCCs) for the expression of programmed death ligand 1 (PD-L1), CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), tumor-infiltrating leukocytes (TILs), and tumor-associated macrophages (TAMs). We evaluated the relationships among these markers, human papilloma virus (HPV) status, and overall survival (OS). PD-L1 and CMTM6 (combined positive score (CPS) ≥ 1 and ≥ 5) were detected in ~ 70% of HNSCCs. HPV status had insignificant effects on marker expression. Most PD-L1-positive cases showed concomitant CMTM6 expression with comparable staining patterns. While PD-L1 and CMTM6 mRNA expression levels correlated with PD-L1 and CMTM6 protein status, no significant correlation was observed for PD-L1 and CMTM6 mRNA expression. Tumors expressing PD-L1 (p 1 were prognostically relevant. In addition to HPV status, PD-L1 and CD8+ T cells, CMTM6 was identified as an independent prognostic factor using a multivariate Cox regression analysis. PD-L1 and CMTM6 correlated with TILs and CD8+ cells but not with HPV. Our results identified CMTM6 as an important interaction partner in the crosstalk between TILs, CD8+ T cells, and PD-L1, which mediates anticancer efficacy. Assessments of CMTM6 may be helpful for prognostic prediction, and it may serve as a reliable biomarker for immunotherapy selection.

Abstract Background The prevalence of patients with prostate cancer is increasing, and the first year after treatment is a vulnerable period for patients as they experience symptoms and unmet needs. Although electronic patient-reported outcomes that focus on patient self-management have demonstrated benefits, evidence is sparse regarding patients with prostate cancer in primary care settings and the role of nurses as a supportive resource. The significant role of primary care in future cancer care is on the agenda. This study aims to test the feasibility of a complex intervention that includes electronic patient-reported outcomes and self-management advice in an app, combined with nurse-led support, in primary care settings during the first year after curative intended prostate cancer treatment. Methods The intervention lasted four weeks and was a single-arm study. Feasibility was assessed by examining the recruitment process, retention rate, adherence to the reporting of symptoms in the app, and acceptability of the intervention. Data was collected through (1) logged data from the app that included patient-reported outcomes and self-management advice, (2) field notes by the nurse, and (3) semi-structured interviews with patients. Descriptive statistics were applied to logged data. The interviews and the field notes were analysed using qualitative content analysis. Results The recruitment rate was 55%, yielding 11 patients with high retention as all completed the intervention. Adherence to reporting was 100%, and all functions in the app were used. Individual variation in how patients used the app was found, which was attributed to patients’ current needs. In total, 36 health dialogues with the nurse (virtual, face-to-face, telephone) were performed; all first dialogues lasted longer, while follow-ups were shorter. Patients described that the health dialogues covered relevant subjects and that the combination of using the app and health dialogues was tailored and provided supplementary support. No adverse events occurred; however, a few technical difficulties interfered with the intervention, and the patients gave valuable suggestions for improvement. Furthermore, patients suggested that the intervention should start immediately after treatment. Conclusion As the patients adhered to and accepted the intervention, it was considered feasible. Findings suggest intervention should start directly after treatment ends.

Abstract Background Programs for mental health promotion and prevention of nonsuicidal self-injury (NSSI) in schools have gained increased focus during the last decades, but less is known about adolescents’ experiences of such interventions. Methods A whole-school preventive intervention targeting mental health and NSSI was delivered to six secondary schools. Adolescents participated in the Youth Aware of Mental Health program combined with an NSSI-focused psychoeducation module. Caregivers and teachers were given online psychoeducation on NSSI, and school health care staff were given a workshop on self-injury. Eleven group interviews (n = 65 participants) were conducted with adolescents (ages 13–15 years, 65% females) exploring participant experiences. Interviews were analyzed using thematic analysis and interpreted in light of a biopsychosocial understanding of adolescence. Results The analysis generated two main themes. The first theme, Mental health in the context of adolescence, centered around adolescents’ conception of mental health, after having taken part in the intervention, framed in a context of coping with external stressors. The dilemma of autonomy versus help-seeking was also identified as part of the first main theme. The second theme, The who, when, what, and how of the intervention, described adolescents’ experiences of the intervention. This theme included increased awareness and knowledge of mental ill-health. The participants generally agreed that the topics included are important to adolescents and emphasized that the content needs to be relatable. Several factors that influence how a school-based program is received by adolescents were identified, such as who should be targeted and when. Adolescents also identified challenges and gave recommendations for future similar projects. Conclusions Adolescents generally perceived addressing mental health and NSSI in schools as important. Help-seeking initiatives need to be balanced against adolescents’ need for autonomy when planning mental health prevention and intervention.

Abstract Background Metabolic syndrome (MetS) increases the risk of cardiovascular disease morbidity and mortality. Physical activity (PA) reduces the likelihood of MetS, but it is a complex behavior and is accumulated in multiple domains. Purpose To cross-sectionally investigate the total and domain-specific relationships between PA and MetS in U.S. adults. Methods Data from 3,408 adults participating in the National Health and Nutrition Examination Survey (2013–2018) were analyzed. Blood pressure (BP), waist circumference (WC), fasting blood glucose (GLU), triglycerides (TRIG), and high-density lipoprotein (HDL) were measured. MetS and its risk factors were the primary and secondary outcomes, respectively. Weekly minutes of total PA and domain-specific PA (i.e., leisure-time (LTPA), transportation (TPA), occupational & household (OHPA)), were self-reported. For each exposure, participants were grouped into weekly PA: (1) 0 min, (2) 1–149 min, (3) 150–299 min, (4) 300–599 min, and (5) 600 + minutes. Logistic regression estimated the odds of having MetS, and its risk factors from PA. Results Total PA was associated with lower odds of most MetS risk factors. Compared to no LTPA, and independent of TPA and OHPA, engaging in 150–299 and 300–599 min/week of LTPA was associated with 30% (OR = 0.70 [95%CI: 0.50, 0.98]) and 43% (OR = 0.57 [95%CI: 0.35, 0.92]) lower odds of MetS, respectively. LTPA was also associated with lower odds of having high WC, GLU, TRIG, and low HDL (ORs = 0.52–0.68). Compared to no TPA, and independent of LTPA and OHPA, engaging in 300–599 min/week of TPA was associated with 54% lower odds of MetS (OR = 0.46 [95%CI: 0.25, 0.84]) and 40% lower odds of having a high WC (OR = 0.40 [95%CI: 0.21, 0.76]). Engaging in OHPA was not associated with MetS but was associated with greater odds of having a high WC (OR = 1.44 [95%CI: 1.03, 2.01]), and GLU (ORs = 1.52–1.83), independent of LTPA and TPA. Conclusion Total PA, seemingly driven by LTPA, was inversely associated with cardiometabolic health. TPA also showcases some protective associations, while OHPA appears to not confer cardiometabolic health benefits. Longitudinal data should confirm these associations using more robust PA measurement tools.

Abstract Food has been invented, consumed, modified, and evolved through the ages based on social conditions. This influence can be seen in Kerala, a South Indian state along the Arabian Sea, which has been part of the colonial expedition. The culinary heritage of Kerala is a unique blend of foreign influences from Arabs, Chinese, Portuguese, Dutch, and British who arrived on its shores. In this context, the aim of the study is to focus on the authenticity of Kerala’s traditional dish, meen curry, in relation to culinary nostalgia and familial identity. The research paper will provide a comprehensive analysis of meen curry and the ingredients used in Kerala-style restaurant, studio kitchen, toddy shop, and heirloom recipes to understand how the dish is prepared in various settings within and outside the state as an agent of culinary traditions and nostalgia. Semi-structured interviews were conducted with six participants to explore the gastronomic landscape of Bangalore and Kerala with respect to the authenticity of meen curry. The qualitative data from these interviews were analyzed using thematic analysis and categorized into three relevant themes. The findings of the study suggest that the authenticity of meen curry of Kerala is variable and subjective, and one single form of “authentic” meen curry that represents entire Kerala does not exist. The research will contribute to the current academic knowledge on how the authenticity of food is perceived by communities or individuals and suggests that this perspective may be applicable to other societies or cuisines for future research.

Abstract Background Ductal carcinoma in-situ (DCIS) is a pre-invasive form of invasive breast cancer (IBC). Due to improved breast cancer screening, it now accounts for ~ 25% of all breast cancers. While the treatment success rates are over 90%, this comes at the cost of considerable morbidity, considering that the majority of DCIS never become invasive and our understanding of the molecular changes occurring in DCIS that predispose to invasive disease is limited. The aim of this study is to characterize molecular changes that occur in DCIS, with the goal of improving DCIS risk stratification. Methods We identified and obtained a total of 197 breast tissue samples from 5 institutions (93 DCIS progressors, 93 DCIS non-progressors, and 11 adjacent normal breast tissues) that had at least 10-year follow-up. We isolated DNA and RNA from archival tissue blocks and characterized genome-wide mRNA expression, DNA methylation, DNA copy number variation, and RNA splicing variation. Results We obtained all four genomic data sets in 122 of the 197 samples. Our intrinsic expression subtype-stratified analyses identified multiple molecular differences both between DCIS subtypes and between DCIS and IBC. While there was heterogeneity in molecular signatures and outcomes within intrinsic subtypes, several gene sets that differed significantly between progressing and non-progressing DCIS were identified by Gene Set Enrichment Analysis. Conclusion DCIS is a molecularly highly heterogenous disease with variable outcomes, and the molecular events determining DCIS disease progression remain poorly defined. Our genome-wide multi-omic survey documents DCIS-associated alterations and reveals molecular heterogeneity within the intrinsic DCIS subtypes. Further studies investigating intrinsic subtype-stratified characteristics and molecular signatures are needed to determine if these may be exploitable for risk assessment and mitigation of DCIS progression. The highly significant associations of specific gene sets with IBC progression revealed by our Gene Set Enrichment Analysis may lend themselves to the development of a prognostic molecular score, to be validated on independent DCIS cohorts.

Abstract Background Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challenging due to heterogeneity of prior assessments. We examined the association between social vulnerability and breast cancer stage at diagnosis and mortality using a standardized measure of population risk for external stressors on health. Methods Using institutional cancer registry data, female patients aged 18 or older diagnosed with breast cancer between 2012 and 2019 were assigned a 2018 Social Vulnerability Index (SVI) rank based upon home address census tract. We used multinomial logistic regression and Cox proportional hazards model to examine the relationships between SVI and breast cancer stage at diagnosis and all-cause mortality. Covariates included age and, when assessing mortality, cancer stage, comorbidities, body mass index, insurance type, and treatment regimen. Results A total of 3,499 women with a median age of 59 (IQR 48–69) were included. 60% were White and 31% were Black. Median SVI was 0.36 (IQR 0.14–0.68) and median follow-up was 58 months (IQR 37.3–83.9). On adjusted analyses, each decile increase in SVI resulted in an 11% (OR 1.11, 95% CI 1.06–1.16, p

Background Hospitalizations and surgical procedures are unpleasant for both children and their parents. Therefore, postoperative pain assessments and management are less commonly performed in younger children than in adults. Purpose To evaluate the effect of nonpharmacological interventions on postoperative pain and anxiety in children. Methods In this randomized controlled trial, 160 children were randomly allocated to experimental (n=80) and control (n=80) groups. The children in the experimental group received age-appropriate distraction interventions for 3 postoperative days along with standard care. Children in the control group received standard care only. Each child was assessed for pain using EVENDOL pain scale, while their anxiety was measured using the modified Yale Preoperative Anxiety Scale. The Descriptive statistics (frequency, percentage, mean, and standard deviation) and repeated-measures analysis of variance were used to analyze the data. Results The children in the experimental group showed significantly decreased pain, anxiety, and physiological parameters (heart rate, respiratory rate, and oxygen saturation) compared to those in the control group. Significant intergroup differences were noted in the mean and standard deviation values of the pain, anxiety, and physiological parameters. Conclusion The distraction interventions provided by nurses reduced the pain and anxiety levels and improved the postoperative recovery among children.

The aim of the current study was to conduct a 12-year follow-up on the authors´ previously evaluated group of irradiated patients who underwent postmastectomy breast reconstruction with deep inferior epigastric perforator (DIEP) and latissimus dorsi (LD)-flaps with implant.The follow-up involved 67% of the patients from the original cohort (17 DIEP and 13 LD). Patient-reported outcome measures (PROMS) were measured using the BREAST-Q, SF-36, a satisfaction form, and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaires. Aesthetics were evaluated by a board of independent plastic surgeons.The average follow-up time was 12.6 years (DIEP) and 11.8 years (LD). Contralateral symmetry procedures were performed on 15 DIEP and 9 LD patients. Both groups underwent an average of 2.5 reconstructive procedures. The BREAST-Q and satisfaction questionnaires showed no group difference. SF-36 showed no group difference but had significantly higher values in both groups compared to the general population with regard to the physical role limitations (p=0.034 and p=0.004, respectively). The DASH scores showed minimal shoulder function impact in the LD group.Aesthetic evaluations revealed a discrepancy between the opinions of the patients and surgeons, with patients valuing the size (p=0.015) and overall aesthetic (p=0.012) of the reconstructed breast higher in the DIEP group. The weighted kappa analysis showed poor agreement between patients and surgeons. Over time, the patients´ preferences shifted from LD to DIEP flaps, possibly due to the more natural aging process associated with autologous reconstruction. This underscores the importance of long term follow-up studies.

Monoclonal antibodies (mAbs) hold significant potential as therapeutic agents and are invaluable tools in biomedical research. However, the lack of efficient high-throughput screening methods for single antibody-secreting cells (ASCs) has limited the diversity of available antibodies. Here, we introduce a novel, integrated workflow employing self-seeding microwells and an automated microscope-puncher system for the swift, high-throughput screening and isolation of single ASCs. The system allows for the individual screening and isolation of up to 6,400 cells within approximately one day, with the opportunity for parallelization and efficient upscaling. We successfully applied this workflow to both hybridomas and human patient-derived B cells, enabling subsequent clonal expansion or antibody sequence analysis through an optimized, single-cell nested reverse transcription-polymerase chain reaction (RT-PCR) procedure. By providing a time-efficient and more streamlined single ASC screening and isolation process, our workflow holds promise for driving forward progress in mAb development.

Abstract Background Due to demographic changes in the Western world governments emphasize the need for viable solutions, e.g. through decentralization of specialist health care services and better coordination within and between health care services. Both Norway and Canada have been through health care reforms and initiatives aiming to improve continuity and coordination of services. Organizational change to primary care in both countries encompasses both team-based service delivery involving allied health professionals, and new blended payment models. The objective of this study was to explore patient pathways in primary healthcare from various health personnel’s perspectives, and across various primary care organizations in Norway and Canada. Methods The study had a qualitative design, including interviews with physicians, nurses and managers (n = 19) in primary care, from a county in Norway and a region in Canada. Data were analyzed with a thematic approach, in line with recommendations from Braun & Clarke. Results Three themes were identified: 1) Structural challenges, 2) Towards a more specialized primary health care and 3) Dedication could improve continuity. Findings indicate that coordinating health care services was assumed difficult due to different health care levels, funding systems, managements, electronic record systems and organizations. Hospitals were assumed more task oriented, while primary health care services were considered more care oriented, and this challenged the coordination across organizations. Primary care services were perceived to be more and more specialized, also representing a threat for coordination and continuity. Health care personnel in both countries perceived that dedicated personnel for each patient could improve information flow and continuity across services. Conclusions Achieving continuity and coordination of health care services seems challenging. Integration strategies seem essential for reducing silo thinking and fragmentation of health care services.

Abstract Background Since June 2022, the legal framework has been created for German community pharmacies to offer their patients five reimbursed community pharmacy services that go beyond the current operating regulations. However, little is known about barriers that hinder their implementation. We therefore aimed to investigate the implementation of reimbursed community pharmacy services (i), barriers to the implementation (ii), solving strategies to overcome the barriers (iii), and future perspectives (iv). The objective of this study is to find out how the implementation of community pharmacy services can be facilitated for community pharmacies so that more services can be offered. Methods In July 2023, we created an online survey and sent it to pharmacists in community pharmacies, including those who offered reimbursed community pharmacy services and those who did not. Results Overall, 218 pharmacists from 218 different community pharmacies participated. (i) Of those, 176 (81%) already offered at least one reimbursed community pharmacy service. (ii) For hypertension service, 33% of the offering pharmacists reported barriers in “Communicating with patients,” and 41% reported “Too little patient demand.” For polymedication service, 53% of the offering pharmacists indicated “Barriers in communication with physicians,” and 44% mentioned “Fear of competing with physicians.” (iii) The most frequently reported solving strategies of pharmacists in offering pharmacies were taking advanced training (median of all five services 42%) and developing standardized procedures (median of all five services 34%). In contrast, pharmacists in non-offering pharmacies had not developed any solving strategies (median of all five services 40%). (iv) 64% of the pharmacists in non-offering pharmacies could imagine being able to offer reimbursed community pharmacy services in the future. Conclusions Many German pharmacies already offer reimbursed community pharmacy services. However, there are still barriers to widespread implementation. Therefore, customized support regarding the needs of the pharmacies should be provided since most pharmacists who do not yet offer these services today can imagine offering them in the future.

Abstract In this study we examined the effect of simultaneously elevated levels of parathyroid hormone (PTH) (≥ 65 ng/mL) and high levels of insulin-like growth factor-binding protein 1 (IGFBP-1) on the 10-year risk of all-cause mortality and hip fractures. Blood tests for levels of PTH and IGFBP-1 was collected at baseline in 338 community-dwelling women in Stockholm aged between 69 and 79 years. Data on hip fractures and all-cause mortality over the next 10 years were retrieved from healthcare registers. The participants were divided into four groups depending on their levels of PTH and IGFBP-1: (A) normal PTH and low IGFBP-1; (B) normal PTH and high IGFBP-1; (C) elevated PTH and low IGFBP-1; (D) elevated PTH and high IGFBP-1. Group D was used as reference. Cox proportional hazard regression (HR) model was used to compare age-adjusted association with hip fractures and all-cause mortality of the four groups. The group with elevated levels of PTH and high IGFBP-1 had a two to three times higher risk of all-cause mortality compared to the other groups but we found no association with hip fractures.

Abstract Beetles exhibit an extraordinary diversity of brilliant and colourful appearances and optical effects invisible to humans. Their underlying mechanisms have received some attention, but we know little about the ecological variables driving their evolution. Here we investigated environmental correlates of reflectivity and circular polarization in a group of optically diverse beetles (Scarabaeidae–Rutelinae). We quantified the optical properties of 261 specimens representing 46 species using spectrophotometry and calibrated photographs. Then, we examined associations between these properties and environmental variables such as temperature, humidity and vegetation cover, controlling for body size and phylogenetic relatedness. Our results showed larger beetles have higher visible reflectivity in drier environments. Unexpectedly, near-infrared (NIR) reflectivity was not correlated with ecological variables. However, we found a correlation between humidity and polarization (chiral nanostructures). We identified trade-offs between optical properties: beetles without polarization-associated nanostructures had higher NIR reflectivity. By contrast, visible reflectivity was negatively correlated with the accumulation of pigments such as melanin. Our study highlights the value of a macroecological approach for testing alternative hypotheses to explain the diversity of optical effects in beetles and to understand the link between structure and function.

Abstract Resting heart rate (RHR) has prognostic implications in heart failure with reduced ejection fraction, where ≤ 70 bpm is targeted. Whether a RHR > 70 bpm assessed within clinical practice goes along with elevated cardiovascular risk in implantable cardioverter-defibrillator (ICD) / cardiac resynchronization therapy-defibrillator (CRT-D) recipients remains incompletely understood. A total of 1589 patients (ICD n = 1172 / CRT-D n = 417, median age 65 years, 22.6% female) undergoing ICD/CRT-D implantation or revision in the prospective German DEVICE multicenter registry were analyzed. RHR was assessed via a 12-channel electrocardiogram at enrollment. 1-year outcomes (all-cause mortality, major cardio- and cerebrovascular events (MACCE), all-cause hospital admission) were compared between patients with a RHR ≤ 70 bpm and > 70 bpm. 733 patients (46.1%) showed a RHR > 70 bpm. Median RHR was 63 (interquartile range 59; 68) bpm (≤ 70 bpm group) and 80 (75; 89) bpm (> 70 bpm group). Heart failure with reduced ejection fraction was present in 76.3%, a prior myocardial infarction in 32.4% and non-ischemic heart disease in 44.9%. One-year all-cause mortality was similar between RHR groups (≤ 70 bpm 5.4% vs. > 70 bpm 5.4%, p = 0.96), and subgroup analysis regarding patient characteristics and comorbidities revealed only a significantly higher rate of patients with dual chamber ICD in the > 70 bpm group (0.8% vs. 9.2%, p = 0.003). MACCE (5.9% vs. 6.1%, p = 0.87) and defibrillator shock rates (9.9% vs. 9.8%, p = 1.0) were similar. Higher all-cause hospital admission rates were observed in patients with > 70 bpm RHR (23.1% vs. 29.0%, p = 0.027) driven by non-cardiovascular events (6.0% vs. 11.7%, p = 0.001). In conclusion, in ICD and CRT-D recipients a RHR at admission > 70 bpm may indicate patients at increased risk of all-cause hospital admission but not of other adverse cardiovascular events or death at 1-year follow-up.

Abstract We aimed to determine how a bout of resistance or aerobic exercise impacts physiological responses and performance during firefighting occupational tasks. Thirty-two non-firefighters completed two baseline assessments and three trials: resistance exercise (RE), aerobic exercise (AE), or a rested control (CON). Trials were followed by an occupational task assessment (OTA; four rounds of 10 deadlifts (38.6–61.4 kg) and 0.24-km 40lb-sandbag carry) in an environmental chamber (35 °C/50% humidity) while wearing standard municipal firefighter gear. Time to complete by condition was not statistically different (CON: 18.9 ± 4.4, AE: 20.0 ± 3.6, RE: 20.2 ± 5.0 min; p = 0.16). During the OTA average heart rate (CON: 149 ± 16, AE: 166 ± 12, RE: 160 ± 13 bpm; p

Abstract Background Today the prerequisites exist to initiate risk-stratified screening according to a woman’s individual risk of breast cancer as opposed to existing one-size-fits-all age-based programmes. This presupposes that the women accept having their personal risk score estimated and their screening intervals changed accordingly. Risk-stratified screening has not yet been implemented in any country, but in the future many European countries will very likely move towards more personalized screening. Methods This qualitative study among 46 women aged 50-69 years used an anthropological approach and interpretive description. Data was collected using semi-structured focus group interviews and telephone interviews. The interviews were analysed using systematic text condensation. Objective The aim of this study was to explore Danish women’s understanding of breast cancer risk and their attitudes towards the concept of risk-stratified breast cancer screening. Results The women highly valued the current screening program, seeing regular mammograms as crucial for early detection. The women had good knowledge of the causes of breast cancer, but they had not given much thought to their own risk. They found a personalized screening approach more reliable than age-based screening, understanding that low risk is not the same as no risk just as high risk is not equal to ever developing breast cancer. Despite concerns about increased anxiety arising from knowing one’s risk, they appreciated the possibility of more frequent screenings for high-risk individuals. Conclusion In general, the women showed acceptance of a new breast cancer screening concept estimating their personal risk score. Due to concerns about interval cancers and the prolonged screening intervals for women at low risk, offering more intensified screening for high-risk women may be less challenging than deescalating screening for low-risk women. Whether the expressed positive attitude and curious interest will translate into actual participation if implemented, remains to be investigated further in an ongoing Danish trial.

Abstract Background Primary transcripts are largely comprised of intronic sequences that are excised and discarded shortly after synthesis. In vertebrates, the shape of the intron size distribution is largely constant; however, most teleost fish have a diverged log-bimodal ‘teleost distribution’ (TD) that is seen only in teleosts. How the TD evolved and to what extent this was affected by adaptative or non-adaptive mechanisms is unknown. Results Here, we show that the TD has evolved independently at least six times and that its appearance is linked to the loss of the aKRAB domain from PRDM9. We determined intron size distributions and identified PRDM9 orthologues from annotated genomes in addition to scanning 1193 teleost assemblies for the aKRAB domain. We show that a diverged form of PRDM9 ( $$\beta$$ β ) is predominant in teleosts whereas the $$\alpha$$ α version is absent from most species. Only a subset of PRDM9- $$\alpha$$ α proteins contain aKRAB, and hence, it is present only in a small number of teleost lineages. Almost all lineages lacking aKRAB (but no species with) had TDs. Conclusions In mammals, PRDM9 defines the sites of meiotic recombination through a mechanism that increases structural variance and depends on aKRAB. The loss of aKRAB is likely to have shifted the locations of both recombination and structural variance hotspots. Our observations suggest that the TD evolved as a side-effect of these changes and link recombination to the evolution of intron size illustrating how genome architectures can evolve in the absence of selection.

Abstract In epithelia, apicobasal cell polarization is closely linked to cell-cell contact formation, both controlled by the conserved Crumbs (CRB) complex, which includes the transmembrane protein Crumbs (CRB3a) and adapter proteins PALS1, PATJ, and LIN7c. In MDCK II cells, a model for cell polarization, depletion of PALS1 - which binds to all CRB components - leads to defective cell polarization and improper distribution of tight junction proteins, resulting in severe epithelial barrier defects in 3D cyst models. This study investigated whether this phenotype is associated with transcriptional changes by analyzing wildtype (WT) and PALS1 knockout (KO) MDCK II cell lines grown under non-confluent conditions and in 3D cyst cultures. Our results indicate that the transition from non-confluent cells to 3D cysts involves numerous differentially expressed genes (DEGs) in both WT and KO cells. Importantly, the analyses revealed significant overlaps between WT and KO cells in their maturation processes, suggesting that most identified DEGs are linked to differentiation from non-confluent to polarized MDCK cells and likely not a result of PALS1 deficiency. Gene Ontology (GO) enrichment and over-representation analyses using REACTOME and KEGG databases confirmed these similarities. In contrast, the direct comparison of WT and KO cells at the two stages showed fewer DEGs and overlaps in associated biological processes and signaling pathways. DEGs associated with the 3D stage, in which the phenotype manifests, contain DEGs and pathways that were predominantly linked to cell cycle linked processes, centromere assembly, or DNA replication. Furthermore, the transcription of genes encoding key junction proteins, additional polarity proteins, and cell-substrate interaction proteins is less affected by the loss of PALS1, indicating that PALS1 influences the transcriptional profiles in epithelial cells as a modulating factor.

Abstract Background Healthy lifestyle habits (regular physical activity, a healthy diet, no smoking and non-hazardous alcohol consumption) alongside pharmacological treatment can lower the risk of cardiovascular diseases and improve symptoms and quality of life in patients with rheumatoid arthritis (RA). Therefore, healthcare professionals in rheumatology care are urged to discuss lifestyle habits with all patients. The aim of this study was to explore patients’ perceptions of lifestyle discussions in early rheumatology care. Methods Individual interviews were conducted with 20 patients with RA, 14 women and six men, aged 23 to 77 years, and with a mean disease duration of 2.4 years. All lifestyle discussions were performed during the first year with RA. A qualitative content analysis was performed. Results An overarching theme emerged, exploring how patients with RA perceived lifestyle discussions as facilitating self-management. Three categories illustrated this: (1) the usefulness of lifestyle discussions depended on the individual patient’s preferences and prioritization for lifestyle support; (2) the design of lifestyle discussions should be based on a person-centred approach, incorporating personalized lifestyle information and providing structured and recurrent support; (3) the outcomes of lifestyle discussions should contribute to enhanced knowledge and motivation for making healthy lifestyle changes. Conclusion Lifestyle discussions in early rheumatology care should, according to patients with RA, be based on a person-centred approach, be tailored to each patient’s preferences and needs, and have outcomes focusing on patient support for healthy lifestyle changes, all essential elements to facilitate self-management. The present findings can be used to guide the development and implementation of more person-centred lifestyle approaches targeted to facilitate lifestyle changes and benefit cardiovascular disease risk management in early rheumatology care.

Abstract Background Tissue stiffness, dictated by organisation of interstitial fibrillar collagens, increases breast cancer risk and contributes to cancer progression. Tamoxifen is a standard treatment for receptor-positive breast cancer and is also aproved for primary prevention. We investigated the effect of tamoxifen and its main metabolites on the breast tissue collagen organisation as a proxy for stiffness and explored the relationship between mammographic density (MD) and collagen organisation. Material and methods This sub-study of the double-blinded dose-determination trial, KARISMA, included 83 healthy women randomised to 6 months of 20, 10, 5, 2.5, and 1 mg of tamoxifen or placebo. Ultrasound-guided core-needle breast biopsies collected before and after treatment were evaluated for collagen organisation by polarised light microscopy. Results Tamoxifen reduced the amount of organised collagen and overall organisation, reflected by a shift from heavily crosslinked thick fibres to thinner, less crosslinked fibres. Collagen remodelling correlated with plasma concentrations of tamoxifen metabolites. MD change was not associated with changes in amount of organised collagen but was correlated with less crosslinking in premenopausal women. Conclusions In this study of healthy women, tamoxifen decreased the overall organisation of fibrillar collagens, and consequently, the breast tissue stiffness. These stromal alterations may play a role in the well-established preventive and therapeutic effects of tamoxifen. Trial registration ClinicalTrials.gov ID: NCT03346200. Registered November 1st, 2017. Retrospectively registered.

Regjeringens Demensplan 2025 danner grunnlaget for norsk politikk på demensfeltet. Det er et styringsdokument for demensomsorgens tjenester og en premissleverandør for forståelser av demens i samfunnet. Hensikten med artikkelen er å undersøke hvordan demens forstås i planen, og hvilke konsekvenser forståelsen får i praksis. Med Carol Bacchis «Hva er problemet?»-tilnærming som analyseverktøy finner vi at demens forstås som sykdom i hjernen, med den konsekvensen at demens blir til et individuelt sykdomsfenomen som helse- og omsorgsfeltet tar eierskapet til. Denne diskursen ekskluderer tenkemåter som bryter med sykdomslogikken, og som kan bidra konstruktivt til planens overordnede mål om et mer demensvennlig samfunn. Artikkelen konkluderer med at Demensplan 2025 heller enn å bygge opp om egen måloppnåelse svekker mulighetene for dette.

Background: The COVID-19 pandemic posed unprecedented challenges to higher education in Germany, necessitating a rapid transition to remote learning. This study evaluates the impact of the pandemic on academic functioning among German university students. Methods: An online survey was conducted with 207 students aged 18 to 35. Results: Significantly poorer academic functioning was evident during the pandemic, particularly in academic output and role satisfaction. Younger students (18 to 24 years) experienced a greater decrease in contact with teachers and lower academic output compared to older students (25 to 35 years). These findings suggest that younger students may struggle more with remote learning due to challenges in self-regulation and time management. Additionally, pandemic-induced disruptions blurred the boundaries between work and personal life, increasing stress and adversely affecting academic performance. No significant differences were found based on sex or living situation. Conclusion: Academic functioning was significantly poorer during the COVID-19 pandemic. This finding highlights the need for targeted support strategies to mitigate the negative effects of the pandemic on students’ academic performance and well-being. Further research is recommended to explore the long-term implications of the pandemic on academic outcomes and student well-being.

The Royal Brisbane and Women’s Hospital (RBWH) Swallowing and Nutrition Management Guidelines for Patients with Head and Neck Cancer were developed to enable evidence-based decision-making by the Head and Neck Multidisciplinary Team (H&N MDT) regarding enteral nutrition support options. The purpose of this study was to revalidate these guidelines in a cohort of patients receiving helical intensity-modulated radiotherapy (H-IMRT) compared to a historical cohort who received primarily 3D-conformal radiotherapy. Eligible patients attending the RBWH H&N MDT between 2013 and 2014 (n = 315) were assessed by the guidelines, with high-risk patients being recommended proactive gastrostomy tube placement. Data were collected on guideline adherence, gastrostomy tube insertions, the duration of enteral tube use and weight change. Sensitivity, specificity and positive predictive and negative predictive values were calculated and compared with the historical cohort. Overall guideline adherence was 84%, with 60% and 96% adherence to the high-risk and low-risk pathways, respectively. Seventy patients underwent proactive gastrostomy tube placement (n = 62 high-risk; n = 8 low-risk). Validation outcomes were sensitivity 73% (compared to 72%) and specificity 86% (compared to 96%). The guidelines yielded a high sensitivity and specificity, remaining valid in a cohort of patients treated with H-IMRT. Further studies are recommended to improve the sensitivity and understand the decrease in specificity in order to make ongoing guideline improvements.

Abstract Background Gonorrhea, induced by Neisseria gonorrhoeae infection, stands as a prevalent sexually transmitted inflammatory disease globally. Our earlier research illuminated that N. gonorrhoeae-infected macrophages provoke inflammation by activating the intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, a pivotal regulator in inflammatory diseases governing the maturation and secretion of interleukin (IL)-1β and IL-18. Nevertheless, effective therapies addressing N. gonorrhoeae-mediated NLRP3 inflammasome activation and ensuing inflammation are currently lacking. This study delves into the impact of the angiotensin II receptor antagonist Candesartan (CS) on N. gonorrhoeae-infected macrophages. Methods The protein expression levels were examined through ELISA and Western blotting. Intracellular H2O2 levels, mitochondrial reactive oxygen species, and mitochondrial membrane integrity were evaluated using targeted fluorescent probes and analyzed via flow cytometry. NF-κB transcriptional activity was assessed using NF-κB reporter cells. LC3-knockdown cells were created using CRISPR/Cas9 technology. Results CS effectively inhibits the NLRP3 inflammasome, as indicated by the suppression of caspase-1 activation, IL-1β secretion, NLRP3 release, and the release of apoptosis-associated speck-like protein containing a CARD (ASC) in N. gonorrhoeae-infected J774A.1 macrophages. Additionally, CS selectively impedes IL-6 secretion and iNOS expression in both N. gonorrhoeae-infected J774A.1 and RAW264.7 macrophages. Mechanistic insights uncover the inhibition of NF-κB by CS in N. gonorrhoeae-infected J774A.1 macrophages, while intracellular H2O2 generation, mitogen-activated protein kinases phosphorylation, and mitochondrial damage remain unaffected. Notably, our study highlights that CS-induced autophagy contributes partially to its inhibitory effect on the NLRP3 inflammasome. Conclusions These results underscore the potential of CS as an anti-inflammatory drug for the treatment of gonorrhea, addressing a critical unmet medical need in combating N. gonorrhoeae-induced inflammation.

Abstract Background This study aimed to explore whether cytotoxin-associated gene A (CagA) can inhibit cell cycle progression by activating nuclear factor of activated T cells (NFAT) in lymphoma B cells and contribute to Helicobacter pylori eradication (HPE) responsiveness (complete remission [CR] after HPE) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Materials and Methods We co-cultured three B-lymphoma cell lines (MA-1, OCI-Ly3, and OCI-Ly7) with HP strains (derived from HPE-responsive gastric MALT lymphoma) and evaluated the expression patterns of CagA, phosphorylated (p)-CagA (CagAP−Tyr), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser172), and NFATc1 using western blotting. Furthermore, we evaluated the association between nuclear NFATc1 expression in the tumor cells of 91 patients who received first-line HPE (59 patients with HPE responsiveness and 32 without HPE responsiveness) and HPE responsiveness and CagA expression in tumor cells. Results In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagAP−Tyr) and simultaneously dephosphorylated NFATc1, subsequently causing nuclear NFATc1 translocation and stimulating the expression of p-SHP-2/p-ERK/Bcl-xL. Activated NFATc1 causes G1 cell cycle retardation in both MA-1 and OCI-Ly3 cells by triggering p21 and p27 production. Nuclear NFATc1 localization was significantly associated with the presence of CagA in gastric MALT lymphomas (80% [41/51] vs. 33% [13/40]; p

Abstract Background The World Health Organization (WHO) encourages all member states to adopt and implement a package of essential evidence-based interventions called the Best Buys to reduce the burden of non-communicable diseases (NCDs). To date, little is known about the implementation of national policies and interventions for NCD control in the WHO member states in sub-Saharan Africa. Our study aimed to evaluate the implementation of national policies and interventions (WHO Best Buys) for non-communicable disease prevention and control in Ghana. Methods This was explanatory mixed methods research which started with a document review of Ghana’s WHO Best Buys scores from the 2015, 2017, 2018, 2020 and 2022 WHO NCD Progress Monitor Reports. Thereafter, we conducted 25 key informant interviews and one focus group discussion (11 participants) with key policymakers and stakeholders in the NCD landscape in Ghana to understand the implementation of the NCD policies and interventions, and the policy implementation gaps and challenges faced. Data from the NCD Progress reports were presented using mean scores whilst the qualitative data was analysed thematically. Results Ghana has shown some advancements in the implementation of the WHO Best Buys measures. Ghana’s implementation scores for 2015, 2017, 2020 and 2022 were 5.0, 9.0, 5.0 and 5.5 respectively, against the mean implementation scores of 7.6/19 for lower-middle-income countries and 9.5/19 for upper-middle-income countries. Efforts to decrease major risk factors such as excessive alcohol consumption and unhealthy diet have been progressing slowly. The most common challenges were related to a) the role of socio-cultural factors, b) stakeholder engagement, c) enforcement and implementation of public health policies, d) implementation guidelines, e) public awareness and education on NCDs, f) financing of NCD prevention and control, g) curative-centered health systems, and h) over-centralization of NCD care. Conclusion Ghana has made progress in adopting the WHO Best Buys targeting risk factors of NCDs. However, the country faces contextual barriers to effective implementation. With the retrogression of some measures over time despite making progress in some earlier years, further investigation is needed to identify facilitators for sustained implementation of the WHO Best Buys interventions.

Abstract Background Cytokines and growth factors (GF) have been implicated in the development of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD). We hypothesize that even small coordinated changes in inflammatory proteins or GFs may reveal changes in underlying regulating mechanisms that do not induce obvious changes in concentration of individual proteins. We therefore applied correlation network analysis of serum factors to determine early characteristics of these conditions. Methods Concentrations of 17 cytokines and five GFs were measured and analysed in blood samples from cord blood, on day one and during the following month in 72 extremely preterm infants. Spearman’s correlation networks distinguishing BPD and severe ROP patients from non-affected were created. Results Most cytokine concentrations correlated positively with each other and negatively with GFs. Very few individual cytokines differed between patients with and without ROP or BPD. However, networks of differently correlated serum factors were characteristic of the diseases and changed with time. In ROP networks, EPO, G-CSF and IL-8 (cord blood), BDNF and VEGF-A (first month) were prominent. In BPD networks, IL-1β, IGF-1 and IL-17 (day one) were noted. Conclusions Network analysis identifies protein signatures related to ROP or BPD in extremely preterm infants. The identified interactions between serum factors are not evident from the analysis of their individual levels, but may reveal underlying pathophysiological mechanisms in the development of these diseases.

Abstract Background Fluoropyrimidine (FP) chemotherapies are commonly prescribed for upper and lower gastrointestinal, breast and head and neck malignancies. Over 16,000 people with cancer require FP chemotherapies per annum in Australia. Between 10 and 40% patients experience grade 3–4 (≥ G3) toxicities that require hospital-based management ± intensive care admission. Approximately 1% of patients die secondary to FP toxicities. Prospective screening for DPYD gene variants (encoding the key enzyme for FP catabolism) can identify patients at risk of ≥ G3 toxicity and allow for dose adjustment prior to first FP exposure. Evidence supports this as a cost-effective method of improving patient safety and reducing healthcare burden internationally; however, no Australian data confirms its feasibility on a large scale. Method This investigator-led, single-arm study will determine large scale feasibility of prospective DPYD genotyping, confirming patient safety and cost-effectiveness within the Australian health care system. 5000 patients aged 18 years and older with solid organ cancers requiring FP chemotherapy will be consented and genotyped prior to commencing treatment, and early toxicity (within 60 days) post-FP exposure will be determined. Toxicity data for DPYD variant carriers who have dose adjustments will be compared to the wild-type cohort and historical cohorts of carriers who did not undergo genotyping prior to FP exposure, and prospective variant carriers who do not undergo dose-adjustment. Prevalence of the four standard DPYD gene variants will be confirmed in an Australian population. Additionally, health economic analysis, implementation research via semi-structured interviews of patients and clinicians, and feasibility of UGT1A1 genotyping will be conducted. Discussion This study will determine the prevalence of DPYD gene variant status in Australia and its impact on FP-induced toxicity among Australians with cancer. Feasibility and cost-effectiveness for Australian health care system will be estimated to support national roll-out of prospective DPYD genotyping prior to FP administration. Additionally, feasibility will be confirmed with the intention of including UGT1A1 in future pharmacogenomic panels to aid chemotherapy prescribing. Trial registration This trial was registered with the Australian and New Zealand Cancer Trials Registry on 13th Dec 2023, ACTRN12623001301651.

Abstract Background The long-term effectiveness of immunotherapies against Multiple Myeloma (MM) remains elusive, demonstrated by the inevitable relapse in patients. This underscores the urgent need for an in-depth analysis of the MM tumor-immune microenvironment (TME). Hereto, a representative immunocompetent MM mouse model can offer a valuable approach to study the dynamic changes within the MM-TME and to uncover potential resistance mechanisms hampering effective and durable therapeutic strategies in MM. Methods We generated a comprehensive single-cell RNA-sequencing atlas of the MM-TME in bone marrow and spleen encompassing different stages of disease, using the immunocompetent 5T33MM mouse model. Through comparative analysis, we correlated our murine dataset with the pathogenesis in MM patients by reanalyzing publicly available datasets of human bone marrow samples across various disease stages. Using flow cytometry, we validated the dynamic changes upon disease progression in the 5T33MM model. Furthermore, interesting target populations, as well as the immune-boosting anti-CD40 agonist (αCD40) therapy were tested ex vivo on murine and human primary samples and in vivo using the 5T33MM model. Results In this study, we identified the heterogenous and dynamic changes within the TME of murine and human MM. We found that the MM-TME was characterized by an increase in T cells, accompanied with an exhausted phenotype. Although neutrophils appeared to be rather innocuous at early disease stages, they acquired a pro-tumorigenic phenotype during MM progression. Moreover, conventional dendritic cells (cDCs) showed a less activated phenotype in MM, underscoring the potential of immune-boosting therapies such as αCD40 therapy. Importantly, we provided the first pre-clinical evaluation of αCD40 therapy and demonstrated successful induction of cDC- and T-cell activation, accompanied by a significant short-term anti-tumor response. Conclusions This resource provides a comprehensive and detailed immune atlas of the evolution in human and murine MM disease progression. Our findings can contribute to immune-based patient stratification and facilitate the development of novel and durable (immune) therapeutic strategies in MM.

Background: In Europe, arthroplasty surgeries are increasing while the level of physical activity is decreasing and overweight is rising. A transeuropean project promoting physical activity after total knee- or hip replacement was conducted. As a part of that project, this study has surveyed factors contributing to explain attitudes toward physical activity in patients in Norway after total knee- or hip replacement. Method: A survey consisting of background information on demographics, lifestyle, health, and health-service with questions on attitudes toward physical activity within the domains of Quality of life, Physical activity level, Function and Kinesiophobia was sent to 947 persons aged >18 years who had received total hip- or knee replacement 6-12 months earlier. MANOVA compared data between men and women and between hip - and knee operated. A regression analysis investigated which background variables that explained the attitudes toward physical activity. Results: The responses (n=714) were similar independent on men, women, or type of prosthesis. Most respondents had a positive attitude. For all domains, high former level of physical activity was the strongest positive factor, while old age, high body weight, and walking aids contributed to a less positive attitude. Participation in pre- and rehabilitation contributed positively to Physical activity level. Information from the health-service contributed positively to Quality of life and Physical activity level, but not to Function or Kinesiophobia. Implications and conclusion: For a positive attitude toward physical activity, focus should be directed to the importance of former physical activity engagement. Information from the health-service need to be individually adapted to make the patient feel safe with regard to being physically active, particularly for elderly and users of walking aids.

Abstract Background Cataract surgery requires a high level of dexterity and experience to avoid serious intra- and post-operative complications. Proper surgical training and evaluation during the learning phase are crucial to promote safety in the operating room (OR). This scoping review aims to report cataract surgery training efficacy for patient safety and trainee satisfaction in the OR when using virtual reality simulators (EyeSi [Haag-Streit, Heidelberg, Germany] or HelpMeSee [HelpMeSee foundation, Jersey city, New Jersey, United States]) or supervised surgical training on actual patients programs in residents. Methods An online article search in the PubMed database was performed to identify studies proposing OR performance assessment after virtual-reality simulation (EyeSi or HelpMeSee) or supervised surgical training on actual patients programs. Outcome assessment was primarily based on patient safety (i.e., intra- and post- operative complications, OR performance, operating time) and secondarily based on trainee satisfaction (i.e., subjective assessment). Results We reviewed 18 articles, involving 1515 participants. There were 13 using the EyeSi simulator, with 10 studies conducted in high-income countries (59%). One study used the HelpMeSee simulator and was conducted in India. The four remaining studies reported supervised surgical training on actual patients, mostly conducted in low- middle- income countries. Training programs greatly differed between studies and the level of certainty was considered low. Only four studies were randomized clinical trials. There were 17 studies (94%) proposing patient safety assessments, mainly through intraoperative complication reports (67%). Significant safety improvements were found in 80% of comparative virtual reality simulation studies. All three supervised surgery studies were observational and reported a high amount of cataract surgeries performed by trainees. However, intraoperative complication rates appeared to be higher than in virtual reality simulation studies. Trainee satisfaction was rarely assessed (17%) and did not correlate with training outcomes. Conclusions Patient safety assessment in the OR remains a major concern when evaluating the efficacy of a training program. Virtual reality simulation appears to lead to safer outcomes compared to that of supervised surgical training on actual patients alone, which encourages its use prior to performing real cases. However, actual training programs need to be more consistent, while maintaining a balance between financial, cultural, geographical, and accessibility factors.

Abstract Recent epidemiological studies have suggested a positive association between ultra-processed food consumption and breast cancer risk, although some studies also reported no association. Furthermore, the evidence regarding the associations between intake of food with lower degrees of processing and breast cancer risk is limited. Thus, we investigated the associations between dietary intake by degree of food processing and breast cancer risk, overall and by breast cancer subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intake of EPIC participants was assessed via questionnaires at baseline. More than 11,000 food ingredients were classified into four groups of food processing levels using the NOVA classification system: unprocessed/minimally processed (NOVA 1), culinary ingredients (NOVA 2), processed (NOVA 3) and ultra-processed (NOVA 4). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer per standard deviation increase in daily consumption (grams) of foods from each NOVA group. The current analysis included 14,933 breast cancer cases, diagnosed among the 318,686 EPIC female participants, (median follow-up of 14.9 years). No associations were found between breast cancer risk and the level of dietary intake from NOVA 1 [HR per 1 SD=0.99 (95% CI 0.97 – 1.01)], NOVA 2 [HR per 1 SD =1.01 (95% CI 0.98 – 1.03)] and NOVA 4 [HR per 1 SD =1.01 (95% CI 0.99 – 1.03)] foods. However, a positive association was found between NOVA 3 and breast cancer risk [HR per 1 SD =1.05 (95% CI 1.03 – 1.07)] which became non-significant after adjustment for alcohol intake [HR per 1 SD =1.01 (95% CI 0.98 – 1.05)] or when beer and wine were excluded from this group [HR per 1 SD =0.99 (95% CI 0.97 – 1.01)]. The associations did not differ by breast cancer subtype, menopausal status or body mass index. Findings from this large-scale prospective study suggest that the positive association between processed food intake and breast cancer risk was likely driven by alcoholic beverage consumption. Graphical Abstract

Background: The consortium project INTEGRATE-ADHD compared administrative data on the presence of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with the results of a parent survey and a comprehensive clinical assessment based on the S3 guideline of the Association of the Scientific Medical Societies in Germany (AWMF). Due to the COVID-19 pandemic, the clinical assessment was carried out online. Methods: The article describes how a guideline-based clinical assessment of ADHD can be implemented in an online setting. A specially developed diagnostic matrix is presented to illustrate the assessment procedures and the diagnostic decision-making process. The matrix is intended to help the diagnostician to gain an overview of the numerous individual findings that have been collected using different assessment perspectives and methods (e.g. diagnostic interviews, rating scales, performance tests) in order to make a well-founded and transparent diagnostic decision. Discussion: The consortium project INTEGRATE-ADHD has shown that an online assessment can be implemented in a guideline-compliant manner and allows a valid clinical decision. The diagnostic strategy is discussed with reference to international guidelines and recommendations for online diagnostics (e.g. aspects of feasibility, acceptability and safety of the assessment procedures). The challenges and opportunities of using online assessments in clinical practice are also described.

Background: This article examines discrepancies in the frequency of diagnoses of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in Germany using information on health care utilisation from both administrative and parent-reported survey data linked at person level. Methods: 5,461 parents of 0- to 17-year-olds insured with DAK-Gesundheit in 2020 and being registered with a confirmed administrative ADHD diagnosis (ICD-10 F90.0-9) in at least one quarter in 2020 (M1Q criterion) were surveyed online on their child’s ADHD diagnosis, utilisation of specialist care and therapeutic service providers. With regard to the presence of a parental report of the child’s documented ADHD diagnosis, administrative data and survey data were bi- and multivariately analysed. Results: The response rate was 21.5 %. ADHD diagnoses were given more frequently in the context of paediatric care, but in the multivariable model with the administrative data only the diagnosis made by mental health professionals (OR = 2.78), in the model with the survey data only utilisation of mental health professionals (OR = 2.99) positively predicted the parental diagnostic report. With regard to the utilisation of therapeutic service providers, only the utilisation of occupational therapy was associated with the parental report of the diagnosis in both data sources. Conclusions: Parental non-reporting of a child’s administrative ADHD diagnosis in survey studies can be in part be explained by utilisation characteristics.