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Abstract Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Abstract Objective The aim of this study is to evaluate treatment patterns and long‐term oncological outcomes of patients with locally advanced prostate cancer (LAPCa). Patients and methods This is a population‐based study including LAPC (cT3‐4, M0) patients from the Stockholm region (Sweden). A sub‐analysis was performed in men treated with primary cystoprostatectomy or total pelvic exenteration (TPE) for cT4 prostate cancer (PCa). Cox regression was used to identify predictors of overall mortality (OM) and cancer‐specific mortality (CSM). Biochemical progression‐free survival (BPFS) and 90 days complications were reported for the radical surgery subgroup. Results We included 2921 patients with cT3(N = 2713) or cT4(N = 208), M0 PCa diagnosed between 2003 and 2019. Out of these, 249(9%), 1497(51%) and 1175(40%) underwent radical prostatectomy, RT + ADT and androgen deprivation therapy (ADT), respectively. Survival rates were 76% (IQR: 68, 83), 47% (IQR: 44, 50) and 23% (IQR: 20, 27), respectively at 10 years. Irrespective of treatment modalities, cT4 patients had worse survival compared to cT3 patients (OM: HR1.44, IQR:1.17,1.77; PCSM: HR1.39, IQR:1.06,1.82). Twenty‐seven patients with cT4, N0‐1, M0 were treated with cystoprostatectomy or TPE. Twenty‐two patients (81.5%) received neoadjuvant ADT. The 5‐year BPFS, CSS and OS rates were 39.6%, 68.8% and 63.8%, respectively. Nine patients (33.3%) had Clavien‐Dindo grade III and 1 (3.7%) grade IV complication within 90 days after surgery. Conclusions Pelvic surgery with radical intent as part of a multidisciplinary management may be an effective alternative for selected patients with locally advanced PCa leading to local tumour control and an acceptable morbidity.

Abstract Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP–SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP–SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP–SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP–SNP interaction detection accuracy.

Abstract Background Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. Methods A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Results Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Conclusions Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

The increased interest in printed electronics necessitates the development of suitable sustainable substrates for them. In this study, the suitability of acetylated cellulose nanofiber (ACNF) films as substrates for printed electronics were examined through (I) the ink-substrates interaction, (II) print quality, and (III) electrical and (IV) mechanical properties of the printed pattern on the ACNF substrates. The results have been compared with cellulose nanofiber (CNF) and commercial reference material (CRM) substrates. The wetting of the silver nanoparticle (AgNP) ink on the ACNF substrate was found out to be excellent. The thickness of the printed pattern increased and the hole area fraction decreased with each consecutive layer of ink. The comparative investigations demonstrated that the electrical properties of the printed patterns were almost as good for 4 layers of ink on the ACNF substrate (1.6 Ω resistance) as the ones on the CRM substrate (1.2 Ω resistance). Additionally, the printed pattern on the ACNF substrate endured the adhesion and bending tests significantly better compared to the CRM substrate. Therefore, this study demonstrates that ACNF substrates could be a suitable candidate for printed electronics, which are more sustainable yet with similar functionalities in comparison with the conventional fossil based substrates.

In Swedish school health services, local initiatives have been taken to use physical activity on prescription (PAP) to encourage physically inactive children to become more active. Previous research shows that interprofessional collaboration plays a crucial role in promoting physical activity in children, as well as in promoting health in schools. However, there is a lack of knowledge about PAP for children in the school setting, including how medical and educational staff can work together to encourage children who have been recommended PAP. Therefore, this study aims to explore the perceived facilitators and barriers concerning interprofessional collaboration regarding physical activity on prescription in the school setting, as viewed from the professionals’ perspectives. Semi-structured interviews were conducted with 21 professionals who work with the method in school settings. The data were analyzed using Reflexive Thematic Analysis. The results reveal both barriers and facilitators for interprofessional collaboration on PAP in the school setting, as perceived by professionals. Organizational and structural obstacles within school institutions hinder collaboration, while a shared commitment to PAP, characterized by consensus-building, acts as a facilitating factor. PAP for children in a school setting is still an unexplored area and further research is required.

School nurses are in a key position to promote children's physical activity. They engage all children in health dialogues and use different approaches to inform children about physical activity and motivate them to change their physical activity level. In a school context, it is important to explore and problematize school nurses’ views of children's physical activity and the influence of these views on their professional practice in the school health service. Identifying and problematizing school nurses' views of physical activity would enable them to create improved guidelines and equivalent ways of working in the future. Therefore, this study aims to discursively explore Swedish school nurses' views on school children's physical activity and its promotion and elucidate them through a discursive framework based on sensitizing concepts. This study uses a qualitative research design with a constructivist grounded theory approach. Semi-structured interviews were conducted with 24 school nurses. The analysis resulted in a core category describing how school nurses use intertwined views to lead children from sedentarity to physical activity. Furthermore, the school nurses' practices were identified in three categories: fostering everyday movement as a tool for health, battling children's sedentarity under difficult conditions, and promoting everyday movement and compensating for unequal access. The results indicate that school nurses lack common and clear guidelines for their mission to promote physical activity to children, which may lead to inequality in access to physical activity for children and young people.

Abstract Background During the first year postpartum, about 25 per cent of Swedish women with severe perineal trauma (SPT), i.e., a third- or fourth-degree perineal laceration at childbirth, are unsatisfied with their healthcare contacts. Further, there is a lack of research on the more long-term experiences of healthcare encounters among women with persistent SPT-related health problems. This study explores how women with self-reported persistent SPT-related health problems experience their contact with healthcare services 18 months to five years after childbirth when the SPT occurred. Methods In this descriptive qualitative study, a purposive sample of twelve women with self-reported persistent health problems after SPT were individually interviewed from November 2020 – February 2022. The data was analysed using inductive qualitative content analysis. Results Our results showed a paradoxical situation for women with persistent health problems due to SPT. They struggled with their traumatised body, but healthcare professionals rejected their health problems as postpartum normalities. This paradox highlighted the women’s difficulties in accessing postpartum healthcare, rehabilitation, and sick leave, which left them with neglected healthcare needs, diminished emotional well-being, and loss of financial and social status. Our results indicated that these health problems did not diminish over time. Consequently, the women had to search relentlessly for a ‘key person’ in healthcare who acknowledged their persistent problems as legitimate to access needed care, rehabilitation, and sick leave, thus feeling empowered. Conclusions Our study revealed that women with persistent SPT-related health problems experienced complex health challenges. Additionally, their needs for medical care, rehabilitation, and sick leave were largely neglected. Thus, the study highlights an inequitable provision of SPT-related healthcare services in Sweden, including regional disparities in access to care. Hence, the authors suggest that Swedish national guidelines for SPT-related care need to be developed and implemented, applying a woman-centered approach, to ensure equitable, effective, and accessible healthcare.

Abstract Background Youth mental health is a major health concern in almost every country. Mental health accounts for about 13% of the global burden of disease in the 10-to-19-year age group. Still there are significant gaps between the mental health needs of young people and the quality and accessibility of available services. Collaboration between health and social service actors is a recognized way of reducing gaps in quality and access. Yet there is little scientific evidence on how these collaborations are applied, or on the challenges of cross-boundary collaboration in the youth mental health space. This study aims to explore how collaboration is understood and practiced by professionals working in the Swedish youth mental health system. Methods We conducted 42 interviews (November 2020 to March 2022) with health and social care professionals and managers in the youth mental health system in Sweden. Interviews explored participants’ experience and understanding of the purpose, realization, and challenges of collaboration. Data were analysed under an emergent study design using reflexive thematic analysis. Results The analysis produced three themes. The first shows that collaboration is considered as essential and important, and that it serves diverse purposes and holds multiple meanings in relation to professionals’ roles and responsibilities. The second addresses the different layers of collaboration, in relation to activities, relationships, and target levels, and the third captures the challenges and criticisms in collaborating across the youth mental health landscape, but also in growing possibilities for future development. Conclusion We conclude that collaboration serves multiple purposes and takes many shapes in the Swedish youth mental health system. Despite the many challenges, participants saw potential in further building collaboration. Interestingly our participants also raised concerns about too much collaboration. There was scepticism about collaboration directing attention away from young people to the professionals, thereby risking the trust and confidentiality of their young clients. Collaboration is not a panacea and will not compensate for an under-resourced youth mental health system.

Purpose The suicidal process contains both observable and non-observable phases, and patients have described the process as characterized by loneliness and darkness. Ambulance clinicians encounter patients in all phases of the suicidal process but little is known on what meaning this encounter has to the patients. The aim of this study was to elucidate meanings of encountering ambulance clinicians while being in a suicidal process. Methods Data were collected through fifteen individual interviews with eight participants who had lived experiences of encountering ambulance clinicians. Inductive design using phenomenological hermeneutical approach was used. Findings Patients are impacted by the clinicians, both in how they find their value in the situation, but also in expected trajectory. Three themes; ‘Being impacted by representatives of society’, ‘Being unsure of one´s own value’ and ‘Regaining hope in moments of togetherness’ generated the main theme ´Navigating oneself through the eyes of the other´. Conclusion The way ambulance clinicians communicate impacts how patients navigate themselves in the ambivalence about living or dying, and the encounter either consolidate a feeling of being a burden, or instil hope of an endurable life. Through conversation, clinicians could support the patients in taking the first steps in the journey of recovery.

Purpose The aim of this study was to explore how health care providers at youth clinics (YCs) in Sweden engage with, focus on, and navigate across the mental health youth space, while upholding the core bedrock principle of “youth-centeredness”. Methods Qualitative interviews were conducted with 21 health care professionals working in three YCs located in three different regions of Sweden. Data were analysed using reflexive thematic analysis informed by the work of Braun and Clarke. Results The three themes were: 1) “youth mission—at the core of the YCs” work and challenged by a stronger involvement in mental ill health’; 2) “YCs” unique and complementary role in the youth mental health system: a holistic perspective, team work, and a focus on normalization’, and 3) “Caught between a rock and a hard place: to treat at a care level that is not optimal for the young users” needs or to refer within an unreliable system’. Conclusion This study reflects the individuality and key features of YCs, their widening roles within the mental health sphere, and the challenges faced in maintaining and expanding the characteristic “youth-centred” approach while expanding their work with mental health.

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Abstract The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium‐induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200‐fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo‐oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.

Abstract Objectives This study aimed to retrospectively assess cardiac autonomic activity in children with LQTS, considering genotype, symptoms, sex, age, and beta‐blocker therapy (BB) and compare it to healthy controls. Methods Heart rate variability (HRV), using power spectrum analysis, was analyzed in 575 Holter recordings from 116 children with LQTS and in 69 healthy children. The data were categorized into four age‐groups and four heart rate (HR) ranges. Results In LQT1 and LQT2, increasing HR corresponded to significantly lower low (LF) and high frequency (HF) compared to controls. Total power (PTOT) was lower in all LQT1 age‐groups compared to controls at HR 120–140 bpm (1–15 years: p

Objectives: Computed tomography pulmonary angiography (CTPA) is the gold standard diagnostic method for patients with suspected pulmonary embolism (PE), but it has its drawbacks, including exposure to ionizing radiation and iodinated contrast agent. The present study aims to evaluate the diagnostic performance of our in-house developed non-contrast MRI protocol for PE diagnosis in reference to CTPA. Methods: 107 patients were included, all of whom underwent MRI immediately before or within 36 hours after CTPA. Additional cases examined only with MRI and a negative result were added to reach a PE prevalence of approximately 20%. The protocol was a non-contrast 2D steady-state free precession (SSFP) sequence under free-breathing, without respiratory or cardiac gating, and repeated five times to capture the vessels at different breathing/cardiac phases. The MRIs were blinded and read by two radiologists and the results were compared to CTPA. Results: Of the 243 patients included, 47 were positive for PE. Readers 1 and 2 demonstrated 89% and 87% sensitivity, 100% specificity, 98% accuracy and Cohen’s kappa of 0.88 on patient level. In the per embolus comparison, readers 1 and 2 detected, 60 and 59/61 (98, 97%) proximal, 101 and 94/113 (89, 83%) segmental, and 5 and 2/32 (16, 6%) subsegmental emboli, resulting in 81 and 75% sensitivity respectively. Conclusion: The repeated 2D SSFP can reliably be used for the diagnosis of acute PE at the proximal and segmental artery levels.

The objective was to reflect on the experience of working collaboratively across education programmes, departments, and faculties from the perspective of university teachers at a higher education institution. Nine teachers from five programmes working together to develop a new curriculum for interprofessional education (IPE) participated in a focus group discussion. Data were analysed using thematic analysis. Findings suggest that teacher experiences can be understood in terms of teamwork processes valued from both professional and IPE experiential variations within the group. Since findings illustrate pedagogical collaboration across department and faculty boundaries, they can inspire teachers who are planning a similar process.

The presence of Global Navigation Satellite System (GNSS) interference poses a significant risk to both GNSS and the infrastructures that depend on them. This article describes how an existing GNSS infrastructure, the Swedish Continuously Operating Reference Stations network SWEPOS with more than 500 stations, can be leveraged to control the quality of GNSS signals and to be able to detect interferences in GNSS and adjacent frequency bands. This study introduces a SWEPOS-based automatic system that effectively detects GNSS interference by examining the signal-to-noise ratio (SNR) of Global Positioning System, Globalnaya Navigatsionnaya Sputnikovaya Sistema, Galileo, and BeiDou frequency bands. By comparing the SNR of tracked satellites against historical data, the system detects radio frequency interference (RFI) by statistically characterizing the SNR of simultaneously tracked satellites. Furthermore, based on the SNR characteristics across satellites, the system distinguishes between RFI and non-RFI sources. The effectiveness of the detection system is demonstrated through both simulated signal interference waves and real-world interference events.

Background: Cerebral blood flow (CBF) is believed to be relatively constant within an upper and lower blood pressure limit. Different methods are available to monitor CBF autoregulation during surgery. This study aims to critically analyze the application of the cerebral oxygenation index (COx), one of the commonly used techniques, using a reference to data from a series of clinical registrations. Method: CBF was monitored using near-infrared spectroscopy, while cerebral blood pressure was estimated by recordings obtained from either the radial or femoral artery in 10 patients undergoing cardiopulmonary bypass. The association between CBF and blood pressure was calculated as a moving continuous correlation coefficient. A COx index > 0.4 was regarded as a sign of abnormal cerebral autoregulation (CA). Recordings were examined to discuss reliability measures and clinical feasibility of the measurements, followed by interpretation of individual results, identification of possible pitfalls, and suggestions of alternative methods. Results and Conclusion: Monitoring of CA during cardiopulmonary bypass is intriguing and complex. A series of challenges and limitations should be considered before introducing this method into clinical practice.

Objective: We aimed to compare perioperative and oncologic outcomes for patients undergoing robotic-assisted radical cystectomy (RARC) with intracorporeal ileal conduit (IC) and neobladder (NB) urinary diversion. Methods: Patients undergoing RARC with intracorporeal urinary diversion between January 2017 and January 2022 at the Icahn School of Medicine at Mount Sinai, New York, NY, USA were indexed. Baseline demographics, clinical characteristics, perioperative, and oncologic outcomes were analyzed. Survival was estimated with Kaplan-Meier plots. Results: Of 261 patients (206 [78.9%] male), 190 (72.8%) received IC while 71 (27.2%) received NB diversion. Median age was greater in the IC group (71 [interquartile range, IQR 65–78] years vs. 64 [IQR 59–67] years, p

Abstract Background The World Health Organization claims that rehabilitation is important to meet the needs of persons with dementia. Rehabilitation programmes, however, are not routinely available. Person-centred, multidimensional, and interdisciplinary rehabilitation can increase the opportunities for older adults with dementia and their informal primary caregivers to continue to live an active life and participate in society. To our knowledge, staff team experiences of such rehabilitation programmes, involving older adults with dementia and their informal caregivers has not been previously explored. Methods The aim of this qualitative focus group study was to explore the experiences of a comprehensive staff team providing person-centred multidimensional, interdisciplinary rehabilitation to community-dwelling older adults with dementia, including education and support for informal primary caregivers. The 13 staff team members comprised 10 professions who, during a 16-week intervention period, provided individualised interventions while involving the rehabilitation participants. After the rehabilitation period the staff team members were divided in two focus groups who met on three occasions each (in total six focus groups) and discussed their experiences. The Grounded Theory method was used for data collection and analysis. Results The analysis resulted in four categories: Achieving involvement in rehabilitation is challenging, Considering various realities by acting as a link, Offering time and continuity create added value, and Creating a holistic view through knowledge exchange, and the core category: Refining a co-creative process towards making a difference. The core category resembles the collaboration that the staff had within their teams, which included participants with dementia and caregivers, and with the goal that the intervention should make a difference for the participants. This was conducted with flexibility in a collaborative and creative process. Conclusions The staff team perceived that by working in comprehensive teams they could provide individualised rehabilitation in creative collaboration with the participants through interaction, knowledge exchange, time and continuity, coordination and flexibility, and a holistic view. Challenges to overcome were the involvement of the person with dementia in goal setting and the mediating role of the staff team members. The staff pointed out that by refinement they could achieve well-functioning, competence-enhancing and timesaving teamwork.

We present a checklist of annelids from recent United Kingdom Seabed Resources (UKSR) expeditions (Abyssal Baseline - ABYSSLINE project) to the eastern abyssal Pacific Clarion-Clipperton Zone (CCZ) polymetallic nodule fields, based on DNA species delimitation, including imagery of voucher specimens, Darwin Core (DwC) data and links to vouchered specimen material and new GenBank sequence records. This paper includes genetic and imagery data for 129 species of annelids from 339 records and is restricted to material that is, in general, in too poor a condition to describe formally at this time, but likely contains many species new to science. We make these data available both to aid future taxonomic studies in the CCZ that will be able to link back to these genetic data and specimens and to better underpin ongoing ecological studies of potential deep-sea mining impacts using the principles of FAIR (Findable, Accessible, Interoperable, Reusuable) data and specimens that will be available for all.We include genetic, imagery and all associated metadata in Darwin Core format for 129 species of annelids from the Clarion-Clipperton Zone, eastern abyssal Pacific, with 339 records.

Abstract Background Temporomandibular disorders (TMD) are common and therefore managed by dentists on a daily basis. However, patients with TMD consistently go undetected and therefore untreated in dentistry. The reasons for these shortcomings have not been fully explored, specifically with regard to patients’ perspectives. Therefore, this study aimed to explore patients’ experiences of TMD and related treatment, with special focus on the experiences of having TMD, factors related to seeking care, and perspectives on received treatment. Methods Purposive sampling was used to recruit adult patients at the Public Dental Health services (PDHS) in the Region of Västerbotten, Sweden, during 2019. Individual semi-structured interviews were conducted and analysed using Qualitative Content Analysis. Sixteen patients were interviewed (ten women and six men, 20–65 years). The interviews probed the patients’ perspectives of having TMD, seeking care, and receiving treatment. All participants were also examined according to the Diagnostic Criteria for TMD (DC/TMD) and qualified for at least one DC/TMD diagnosis. Results The data analysis led to the main theme Seeking care when the situation becomes untenable, but dental care fails to meet all needs. The patients expressed worry and social discomfort because of the symptoms but still strived to have an as normal daily life as possible. However, severe symptoms and associated consequences compelled them to seek professional help. Experiences of distrust together with challenges to access the PDHS were identified and related to the patients’ unfulfilled expectations. Conclusions Patients’ reported experiences indicate that receiving timely and appropriate care is more of an unfulfilled expectation than the current state of management of patients with TMD in dentistry.

The DNA taxonomy of six species of the annelid family Lumbrineridae collected from the Clarion-Clipperton Zone (CCZ) in the Central Pacific, an area of potential mining interest for polymetallic nodules, is presented. Lumbrinerids are an ecologically important and understudied annelid family within the deep sea, with many species still undescribed. This study aims to document the taxonomy and biodiversity of the CCZ using specimens collected from the UK-1, OMS, and NORI-D exploration contract areas and Areas of Particular Environmental Interest. Species were identified through a combination of morphological and molecular phylogenetic analysis. We present informal species descriptions associated with voucher specimens, accessible through the Natural History Museum (London) collections, to improve future taxonomic and biodiversity studies of this region. Five taxa in this study had no morphological or genetic matches within the literature and therefore are possibly new to science, but their suboptimal morphological preservation prevented the formalisation of new species. The most abundant taxon Lumbrinerides cf. laubieri (NHM_0020) was compared with the holotype of Lumbrinerides laubieri Miura, 1980 from the deep Northeast Atlantic. Currently no reliable morphological characters separating the Pacific and Atlantic specimens have been found and molecular data from the Atlantic specimens was not available.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Extensive genome-wide sequencing efforts have unveiled the intricate regulatory potential of long non-protein coding RNAs (lncRNAs) within the domain of haematological malignancies. Notably, lncRNAs have been found to directly modulate chromatin architecture, thereby impacting gene expression and disease progression by interacting with DNA, RNA, and proteins in a tissue- or condition-specific manner. Furthermore, recent studies have highlighted the intricate epigenetic control of lncRNAs in cancer. Consequently, this provides a rationale to explore the possibility of therapeutically targeting lncRNAs themselves or the epigenetic mechanisms that govern their activity. Within the scope of this review, we will assess the current state of knowledge regarding the epigenetic regulation of lncRNAs and how, in turn, lncRNAs contribute to chromatin remodelling in the context of multiple myeloma.

Background Physical activity is a useful means to improve symptoms and memory performance to some extent in individuals with stress-induced exhaustion disorder. Individuals in this group commonly do not need to reach the recommended levels of physical activity. Developing methods to support physical activity as a lasting behaviour is important. Objective The aim of the study was to explore the processes involved when using physical activity prescription as part of rehabilitation in a group context for individuals with stress-induced exhaustion disorder. Method A total of 27 individuals with stress-induced exhaustion disorder participated in six focus groups. The informants underwent a multimodal intervention including prescription of physical activity. The physical activity prescription had a cognitive behaviour approach and included information about physical activity, home assignments and goal setting. The data was analysed with grounded theory method using constant comparison. Results The analysis of the data was developed into the core category ‘trying to integrate physical activity into daily life in a sustainable way’, and three categories: ‘acceptance of being good enough’, ‘learning physical activity by doing’ and ‘advocation for physical activity in rehabilitation’. The informants identified that during the physical activity prescription sessions they learned what physical activity was, what was ‘good enough’ in terms of dose and intensity of physical activity, and how to listen to the body’s signals. These insights, in combination with performing physical activity during home assignments and reflecting with peers, helped them incorporate physical activity in a new and sustainable way. A need for more customised physical activity with the ability to adjust to individual circumstances was requested. Conclusion Prescription of physical activity in a group context may be a useful method of managing and adjusting physical activity in a sustainable way for individuals with stress-induced exhaustion disorder. However, identifying people who need more tailored support is important.

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

In the deep ocean, whale falls (deceased whales that sink to the seafloor) act as a boost of productivity in this otherwise generally food-limited setting, nourishing organisms from sharks to microbes during the various stages of their decomposition. Annelid worms are habitual colonizers of whale falls, with new species regularly reported from these settings and their systematics helping to resolve biogeographic patterns among deep-sea organic fall environments. During a 2017 expedition of the Australian research vessel RV Investigator to sample bathyal to abyssal communities off Australia’s east coast, a natural whale fall was opportunistically trawled at ~1000 m depth. In this study, we provide detailed taxonomic descriptions of the annelids associated with this whale-fall community, using both morphological and molecular techniques. From this material we describe nine new species from five families (Dorvilleidae: Ophryotrocha dahlgreni sp. nov. Ophryotrocha hanneloreae sp. nov., Ophryotrocha ravarae sp. nov.; Hesionidae: Vrijenhoekia timoharai sp. nov.; Nereididae: Neanthes adriangloveri sp. nov., Neanthes visicete sp. nov.; Orbiniidae: Orbiniella jamesi sp. nov.), including two belonging to the bone-eating genus Osedax (Siboglinidae: Osedax waadjum sp. nov., Osedax byronbayensis sp. nov.) that are the first to be described from Australian waters. We further provide systematic accounts for 10 taxa within the Ampharetidae, Amphinomidae, Microphthalmidae, Nereididae, Orbiniidae, Phyllodocidae, Protodrilidae, Sphaerodoridae and Phascolosomatidae. Our investigations uncover unique occurrences and for the first time enable the evaluation of biogeographic links between Australian whale falls and others in the western Pacific as well as worldwide.

Abstract Background Dynamic spirometry is an important investigation to differentiate between impaired and normal lung function. This study aimed to evaluate the results of lung function testing in a cohort of subjects from Northern Sweden without any known heart or pulmonary disease. Our focus was to compare with two reference materials that have showed differences in the age-dependency of lung function in Swedish subjects. Methods The study population consisted of 285 healthy adults (148 males, 52%) between 20–90 years of age. The subjects had been randomly selected from the population register for inclusion in a study investigating cardiac function in heart-healthy subjects, but were also assessed with dynamic spirometry. At least seven percent reported smoking. Sixteen subjects presented with pulmonary functional impairments and were excluded from the current study. The sex-specific age-dependency in lung volumes was estimated using the LMS model, where non-linear equations were derived for the mean value (M), the location (L) or skewness, and the scatter (S) or coefficient of variation. This model of the observed lung function data was compared with reference values given by the original LMS model published by the Global Lung Initiative (GLI), and with the model from the recent Obstructive Lung Disease In Norrbotten (OLIN) study, where higher reference values were presented for Swedish subjects than those given by the GLI model. Results No differences were found in the age-dependency of pulmonary function between the LMS model developed in the study and the OLIN model. Although the study group included smokers, the original GLI reference values suggested significantly lower normal values of FEV1 (forced expiratory volume) and FVC (forced vital capacity), and consequently fewer subjects below the lower limit of normality, than both the rederived LMS and OLIN models. Conclusions Our results are in line with previous reports and support that the original GLI reference values underestimate pulmonary function in the adult Swedish population. This underestimation could be reduced by updating the coefficients in the underlying LMS model based on a larger cohort of Swedish citizens than was available in this study.