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Histopathological investigation of metastasis in core needle axillary lymph node (ALN) biopsies is crucial for the prognosis and treatment planning of breast cancer patients. Biopsies are typically sliced and evaluated as two-dimensional (2D) images. Biopsy sampling errors and the limited view provided by 2D histology are leading factors contributing to false-negative results in the preoperative detection of metastatic lymph nodes and underestimation of metastatic foci.In this proof-of-concept study, we aim to explore the technical feasibility and the potential capacities of tridimensional (3D) X-ray micro-computed tomography imaging to expedite error detection, enhancement of histopathological accuracy, and precise measurement of metastatic lesion on ALN core needle biopsies of two breast cancer patients. Our self-developed micro-CT protocol uses eosin for the first time, a common histological dye, to enhance 3D architecture of ALNs. Performed analysis on the images of the ALN biopsies involves cancer tissue segmentation, swift biopsy evaluation, and measurement of the metastatic longest diameter and deposit volume.The eosin micro-CT protocol shows potential for an improved tumor deposit estimates, offering additional clinical value compared to standard 2D histology, however, further studies for validating this method are needed., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March-August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3-6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318., (© 2024. The Author(s).)

Developing microphysiological cell culture platforms with a three-dimensional (3D) microenvironment has been a significant advancement from traditional monolayer cultures. Still, most of the current microphysiological platforms are limited in closed designs, i.e. are not accessible after 3D cell culture loading. Here, we report an open-top microfluidic chip which enables the generation of two sequentially loaded 3D cell cultures without physical barriers restricting the nurture, gas exchange and cellular communication. As a proof-of-concept, we demonstrated the formation of two 3D vasculatures, one in the upper and the other in the lower compartment, under three distinct flow conditions: asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side. We used computational modelling to characterize initial flow pressures in cell culture compartments. We showed prominent vessel formation and branched vasculatures in upper and lower cell culture compartments with interconnecting, lumenized vessels with in vivo-relevant diameter in all flow conditions. With advanced image processing, we quantified and compared the overall vascular network volume and the total length formed in asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side flow conditions. Our results indicate that the developed chip can house two distinct 3D cell cultures with merging vessels between compartments and by providing asymmetric side-to-center or symmetric center-to-side flow vascular morphogenesis is enhanced in terms of overall network length. The developed open-top microfluidic chip may find various applications in generation of tissue-specific 3D-3D co-cultures for studying cellular interactions in vascularized tissues and organs., (© 2024. The Author(s).)

While hundreds of cancer-associated long noncoding RNAs (lncRNAs) have been discovered, their functional role in cancer cells is still largely a mystery. An increasing number of lncRNAs are recognized to function in the cytoplasm, e.g., as modulators of translation. Here, we investigated the detailed molecular identity and functional role of EPCART, a lncRNA we previously discovered to be a potential oncogene in prostate cancer (PCa). First, we interrogated the transcript structure of EPCART and then confirmed EPCART to be a non-peptide-coding lncRNA using in silico methods. Pathway analysis of differentially expressed protein-coding genes in EPCART knockout cells implied that EPCART modulates the translational machinery of PCa cells. EPCART was also largely located in the cytoplasm and at the sites of translation. With quantitative proteome analysis on EPCART knockout cells we discovered PDCD4, an inhibitor of protein translation, to be increased by EPCART reduction. Further studies indicated that the inhibitory effect of EPCART silencing on translation was mediated by reduced activation of AKT and inhibition of the mTORC1 pathway. Together, our findings identify EPCART as a translation-associated lncRNA that functions via modulation of the PI3K/AKT/mTORC1 pathway in PCa cells. Furthermore, we provide evidence for the prognostic potential of PDCD4 in PCa tumors in connection with EPCART., (© 2024. The Author(s).)

Background: In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available., Methods: Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies., Results: All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1., Conclusions: Long-term darolutamide treatment was well tolerated; no new safety signals observed. In patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide., (© 2023. The Author(s).)

We investigated the association of prediagnostic use of menopausal hormone therapy (MHT) with breast cancer survival among women with type 2 diabetes (T2D). The study cohort was identified from a Finnish nationwide diabetes database, and consisted of women with T2D, who were diagnosed with breast cancer between 2000 and 2011 (n = 3189). The patients were classified according to their previous MHT use: systemic MHT, local MHT, and no history of any MHT. The cumulative mortality from breast cancer, cardiovascular diseases, and other causes in three MHT groups was described by the Aalen-Johansen estimator. The cause-specific mortality rates were analyzed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of MHT. The breast cancer mortality appeared to be lower among systemic MHT users (HR 0.49, 95% Cl 0.36-0.67) compared with non-users of MHT. The mortality from cardiovascular diseases and from other causes of death was found to be lower among systemic MHT users, (HR 0.49, 95% Cl 0.32-0.74), and (HR 0.51, 95% Cl 0.35-0.76), respectively. In conclusion, prediagnostic systemic MHT use is associated with reduced breast cancer, cardiovascular, and other causes of mortality in women with T2D., (© 2024. The Author(s).)

A previous study suggested that fetal inheritance of chromosomally integrated human herpesvirus 6 (ici-HHV6) is associated with the hypertensive pregnancy disorder preeclampsia (PE). We aimed to study this question utilizing cord plasma samples (n = 1276) of the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 from a pregnancy with PE and 737 without. We studied these samples and 30 placentas from PE pregnancies by a multiplex qPCR for the DNAs of all nine human herpesviruses. To assess the population prevalence of iciHHV-6, we studied whole-genome sequencing data from blood-derived DNA of 3421 biobank subjects. Any herpes viral DNA was detected in only two (0.37%) PE and one (0.14%) control sample (OR 2.74, 95% CI 0.25-30.4). One PE sample contained iciHHV-6B and another HHV-7 DNA. The control's DNA was of iciHHV-6B; the fetus having growth restriction and preterm birth without PE diagnosis. Placentas showed no herpesviruses. In the biobank data, 3 of 3421 subjects (0.08%) had low level HHV-6B but no iciHHV-6. While iciHHV-6 proved extremely rare, both fetuses with iciHHV-6B were growth-restricted, preterm, and from a pregnancy with maternal hypertension. Our findings suggest that human herpesviruses are not a significant cause of PE, whereas iciHHV-6 may pose some fetal risk., (© 2024. The Author(s).)

Epicardial adipose tissue (EAT) is the cardiac visceral fat depot proposed to play a role in the etiology of various cardiovascular disease outcomes. Little is known about EAT determinants in a general population. We examined cardiometabolic, dietary, lifestyle and socioeconomic determinants of echocardiograpghically measured EAT in early adulthood. Data on cardiometabolic, dietary, lifestyle and socioeconomic factors were collected from participants of the Cardiovascular Risk in Young Finns Study (YFS; N = 1667; age 34-49 years). EAT thickness was measured from parasternal long axis echocardiograms. Multivariable regression analysis was used to study potential EAT determinants. Possible effect modification of sex was addressed. Mean EAT thickness was 4.07 mm (95% CI 4.00-4.17). Multivariable analysis [β indicating percentage of change in EAT(mm) per one unit increase in determinant variable] indicated female sex (β = 11.0, P < 0.0001), type 2 diabetes (β = 14.0, P = 0.02), waist circumference (cm) (β = 0.38, P < 0.0001), systolic blood pressure (mmHg) (β = 0.18, P = 0.02) and red meat intake (g/day) (β = 0.02, P = 0.05) as EAT determinants. Sex-specific analysis revealed age (year) (β = 0.59, P = 0.01), alcohol intake (drinks/day) (β = 4.69, P = 0.006), heavy drinking (yes/no) (β = 30.4, P < 0.0001) as EAT determinants in women and fruit intake (g/day) (β = -1.0, P = 0.04) in men. In the YFS cohort, waist circumference, systolic blood pressure and red meat intake were directly associated with EAT among all participants. In women, age, alcohol intake, heavy drinking and type 2 diabetes associated directly with EAT, while an inverse association was observed between fruit intake and EAT in men., (© 2024. The Author(s).)

Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility., (© 2024. The Author(s).)

Road traffic injuries cause considerable financial strain on health care systems worldwide. We retrospectively analyzed injury-related costs of 252 severely injured (New Injury Severity Score, NISS ≥ 16) patients treated at Tampere University Hospital (TAUH) between 2013 and 2017, with 2-year follow-up. The costs were divided into direct treatment, indirect costs, and other costs. We analyzed various injury- and patient-related factors with costs. The total costs during the 2-year study period were 20 million euros. Median cost was 41,202 euros (Q1 23,409 euros, Q3 97,726 euros), ranging from 2,753 euros to 549,787 euros. The majority of costs (69.1%) were direct treatment costs, followed by indirect costs (28.4%). Other costs were small (5.4%). Treatment costs increased with the severity of the injury or when the injury affected the lower extremities or the face. Indirect costs were higher in working age patients and in patients with a higher level of education. The relative proportions of direct and indirect costs were constant regardless of the amount of the total costs. The largest share of costs was caused by a relatively small proportion of high-cost patients during the 1st year after injury. Combined, this makes planning of resource use challenging and calls for further studies to further identify factors for highest costs., (© 2024. The Author(s).)

We evaluated whether previous inguinal hernia repair may affect the choice of prostate carcinoma treatment in a population-based cohort. It has been suggested that previous laparoscopic inguinal hernia repair (LIHR) could limit the subsequent possibility of performing a prostatectomy. Several small studies have suggested otherwise. The study cohort included all new prostate cancer cases in Finland 1998-2015 identified through the Finnish cancer registry. Data on the treatment of prostate cancer and surgical inguinal hernia repairs in 1998-2016 was obtained from the HILMO hospital discharge registry. After linkage, the study cohort included 7206 men. Of these, 5500 had no history of inguinal hernia, 1463 had an open hernia repair, and 193 had a minimally invasive repair (LIHR). Compared to men with no history of hernia repair, those with previous hernia repairs were more likely to undergo prostatectomy over radiation therapy as the primary treatment for prostate cancer HR 1.34 (CI 95% 1.19-1.52). The association did not depend on the method of hernia repair, HR 1.58 (CI 95% 1.15-2.18), in men with previous LIHR. The increased likelihood of choosing prostatectomy over radiation therapy concerns all type prostatectomies. Previous hernia repair is not a limiting factor when choosing treatment for prostate cancer., (© 2024. The Author(s).)

Wearable long-term monitoring applications are becoming more and more popular in both the consumer and the medical market. In wearable ECG monitoring, the data quality depends on the properties of the electrodes and on how they interface with the skin. Dry electrodes do not require any action from the user. They usually do not irritate the skin, and they provide sufficiently high-quality data for ECG monitoring purposes during low-intensity user activity. We investigated prospective motion artifact-resistant dry electrode materials for wearable ECG monitoring. The tested materials were (1) porous: conductive polymer, conductive silver fabric; and (2) solid: stainless steel, silver, and platinum. ECG was acquired from test subjects in a 10-min continuous settling test and in a 48-h intermittent long-term test. In the settling test, the electrodes were stationary, whereas both stationary and controlled motion artifact tests were included in the long-term test. The signal-to-noise ratio (SNR) was used as the figure of merit to quantify the results. Skin-electrode interface impedance was measured to quantify its effect on the ECG, as well as to leverage the dry electrode ECG amplifier design. The SNR of all electrode types increased during the settling test. In the long-term test, the SNR was generally elevated further. The introduction of electrode movement reduced the SNR markedly. Solid electrodes had a higher SNR and lower skin-electrode impedance than porous electrodes. In the stationary testing, stainless steel showed the highest SNR, followed by platinum, silver, conductive polymer, and conductive fabric. In the movement testing, the order was platinum, stainless steel, silver, conductive polymer, and conductive fabric., (© 2024. The Author(s).)

Background: Outliers can influence regression model parameters and change the direction of the estimated effect, over-estimating or under-estimating the strength of the association between a response variable and an exposure of interest. Identifying visit-level outliers from longitudinal data with continuous time-dependent covariates is important when the distribution of such variable is highly skewed., Objectives: The primary objective was to identify potential outliers at follow-up visits using interquartile range (IQR) statistic and assess their influence on estimated Cox regression parameters., Methods: Study was motivated by a large TEDDY dietary longitudinal and time-to-event data with a continuous time-varying vitamin B 12 intake as the exposure of interest and development of Islet Autoimmunity (IA) as the response variable. An IQR algorithm was applied to the TEDDY dataset to detect potential outliers at each visit. To assess the impact of detected outliers, data were analyzed using the extended time-dependent Cox model with robust sandwich estimator. Partial residual diagnostic plots were examined for highly influential outliers., Results: Extreme vitamin B 12 observations that were cases of IA had a stronger influence on the Cox regression model than non-cases. Identified outliers changed the direction of hazard ratios, standard errors, or the strength of association with the risk of developing IA., Conclusion: At the exploratory data analysis stage, the IQR algorithm can be used as a data quality control tool to identify potential outliers at the visit level, which can be further investigated., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism 1-7 . This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases 8-11 . Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases., (© 2024. The Author(s).)

Ultra-low-dose computed tomography (ULD-CT) may combine the high sensitivity of conventional computed tomography (CT) in detecting sarcoma pulmonary metastasis, with a radiation dose in the same magnitude as chest X-ray (CXR). Fifty patients with non-metastatic high-grade soft tissue sarcoma treated with curative intention were recruited. Their follow-up involved both CXR and ULD-CT to evaluate their different sensitivity. Suspected findings were confirmed by conventional CT if necessary. Patients with isolated pulmonary metastases were treated with surgery or stereotactic body radiation therapy (SBRT) with curative intent if possible. The median effective dose from a single ULD-CT study was 0.27 mSv (range 0.12 to 0.89 mSv). Nine patients were diagnosed with asymptomatic lung metastases during the follow-up. Only three of them were visible in CXR and all nine in ULD-CT. CXR had therefore only a 33% sensitivity compared to ULD-CT. Four patients were operated, and one had SBRT to all pulmonary lesions. Eight of them, however, died of the disease. Two patients developed symptomatic metastatic recurrence involving extrapulmonary sites+/-the lungs between two imaging rounds. ULD-CT has higher sensitivity for the detection of sarcoma pulmonary metastasis than CXR, with a radiation dose considerably lower than conventional CT.Clinical trial registration: NCT05813808. 04-14-2023., (© 2024. The Author(s).)

Evidence on the intergenerational continuity of loneliness and on potential mechanisms that connect loneliness across successive generations is limited. We examined the association between loneliness of (G0) parents (859 mothers and 570 fathers, mean age 74 years) and their children (G1) (433 sons and 558 daughters, mean age 47 years) producing 991 parent-offspring pairs and tested whether these associations were mediated through subjective socioeconomic position, temperament characteristics, cognitive performance, and depressive symptoms. Mean loneliness across parents had an independent effect on their adult children's experienced loneliness (OR = 1.72, 95% CI 1.23-2.42). We also found a robust effect of mothers' (OR = 1.64, 95% CI 1.17-2.29), but not of fathers' loneliness (OR = 1.47, 95% CI 0.96-2.25) on offspring's experienced loneliness in adulthood. The associations were partly mediated by offspring depressive (41-54%) and anxiety (29-31%) symptoms. The current findings emphasize the high interdependence of loneliness within families mediated partly by offspring's mental health problems., (© 2024. The Author(s).)

Background: Allopurinol is gout medication that inhibits uric acid formation. Its possible anti-carcinogenic properties have been under research in past years. Studies based on Taiwanese registries showed that long term allopurinol use might reduce prostate cancer (PCa) incidence. However, our studies based on Finnish registries did not support those findings. In this study, we evaluate whether allopurinol use is associated with prostate cancer-specific survival (CSS) or overall survival (OS) in a Finnish population-based cohort., Methods: The study cohort was originally enrolled for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). We included all newly diagnosed PCa cases during 1996-2015, 9252 men in total. Information on allopurinol purchases was from the national prescription registry of the Social Insurance Institution of Finland. Information about deaths, treatments, and use of other medications was obtained from registries, and tumor stage and PSA at diagnosis from medical records. Follow-up started at diagnosis, and we analysed separately two endpoints: PCa-specific death and overall death. We used an extended Cox regression with adjustment for age at diagnosis, Charlson comorbidity index, FinRSPC trial arm, use of other drugs and EAU PCa risk group., Results: During a median follow-up of 9.86 years, 2942 deaths occurred, including 883 from PCa. There was no difference in CSS between allopurinol user and non-users, but allopurinol users had lower OS (multivariable-adjusted hazard ratio 1.77; 95% CI: 1.57-2.00). However, this decrease in OS was mitigated along with increasing intensity of allopurinol use., Conclusions: We found no marked difference in CSS by allopurinol use. Allopurinol users had lower OS but there were no significant differences by duration or intensity of allopurinol use. Allopurinol use may not have anticancer effects against prostate cancer; instead, it may be a surrogate for metabolic problems causing shorter OS among men with PCa., (© 2022. The Author(s).)

When studying emergency department (ED) visits, electronic health record systems of hospitals provide a good basis for retrospective studies. However, many intoxication patients presenting to the ED, may not be identified retrospectively if only a single search method is applied. In this study, a new four-way combined patient search method was used to retrospectively identify intoxication patients presenting to the ED. The search included reason for admission to the ED, laboratory results related to intoxication diagnostics, ICD-10 codes, and a novel free word search (FWS) of patient records. After the automated search, the researcher read the medical records of potential substance abuse patients to form comprehensive profiles and remove irrelevant cases. The addition of a free word search identified 36% more substance abuse patients than the combination of the other three methods mentioned above. Patients identified by the FWS search alone were generally admitted to the ED for trauma or mental health problems and were often found to be heavily under the influence of alcohol and/or drugs. The main intoxicants were ethanol and benzodiazepines. The free word search was highly complementary to traditional patient search methods, highlighting the importance of the combined patient search method in retrospective data collection., (© 2024. The Author(s).)

Heart failure (HF) is a major burden worldwide, and new therapies are urgently needed. Gene therapy is a promising new approach to treat myocardial diseases. However, current cardiac gene delivery methods for producing global myocardial effects have been inefficient. The aim of this study was to develop an endovascular, reproducible, and clinically applicable gene transfer method for global left ventricular (LV) transduction. Domestic pigs (n = 52) were used for the experiments. Global LV myocardium coverage was achieved by three retrograde injections into the three main LV vein branches. The distribution outcome was significantly improved by simultaneous transient occlusions of the corresponding coronary arteries and the main anastomotic veins of the retroinjected veins. The achieved cardiac distribution was visualized first by administering Indian Ink solution. Secondly, AdLacZ (2 × 10 12 vp) and AAV2-GFP (2 × 10 13 vg) gene transfers were performed to study gene transduction efficacy of the method. By retrograde injections with simultaneous coronary arterial occlusions, both adenovirus (Ad) and adeno-associated virus (AAV) vectors were shown to deliver an efficient transduction of the LV. We conclude that retrograde injections into the three main LV veins is a potential new approach for a global LV gene transfer., (© 2024. The Author(s).)

In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and in 1273-3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90-290], P = 6.7 × 10 -5 ) and a low risk for heterozygous women (OR = 1.39 [1.18-1.64], P = 7.8 × 10 -5 ). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene., (© 2023. The Author(s).)

The analysis of mammograms using artificial intelligence (AI) has shown great potential for assisting breast cancer screening. We use saliency maps to study the role of breast lesions in the decision-making process of AI systems for breast cancer detection in screening mammograms. We retrospectively collected mammograms from 191 women with screen-detected breast cancer and 191 healthy controls matched by age and mammographic system. Two radiologists manually segmented the breast lesions in the mammograms from CC and MLO views. We estimated the detection performance of four deep learning-based AI systems using the area under the ROC curve (AUC) with a 95% confidence interval (CI). We used automatic thresholding on saliency maps from the AI systems to identify the areas of interest on the mammograms. Finally, we measured the overlap between these areas of interest and the segmented breast lesions using Dice's similarity coefficient (DSC). The detection performance of the AI systems ranged from low to moderate (AUCs from 0.525 to 0.694). The overlap between the areas of interest and the breast lesions was low for all the studied methods (median DSC from 4.2% to 38.0%). The AI system with the highest cancer detection performance (AUC = 0.694, CI 0.662-0.726) showed the lowest overlap (DSC = 4.2%) with breast lesions. The areas of interest found by saliency analysis of the AI systems showed poor overlap with breast lesions. These results suggest that AI systems with the highest performance do not solely rely on localized breast lesions for their decision-making in cancer detection; rather, they incorporate information from large image regions. This work contributes to the understanding of the role of breast lesions in cancer detection using AI., (© 2023. The Author(s).)

A cerebrospinal fluid (CSF) sample containing no red blood cells (RBC), colloquially known as a champagne tap, is an ideal outcome of a lumbar puncture (LP). In this pseudoprospective study of 2573 patients aged from 0 days to 95 years, we examined in four different age categories (neonates and infants, children and adolescents, adults, and older adults) whether a champagne tap in the patient's first LP procedure and a shorter time than 1 week between the two successive procedures are independently associated with fewer blood-contaminated CSF samples (traumatic LP) in the following procedure. One out of five CSF samples from the patient's first LP procedures were RBC-free on average, varying from about 9% in neonates and infants to about 36% in children and adolescents. The mean incidence of champagne taps was 19.5%. According to binary logistic regression, a champagne tap in the previous LP procedure significantly determined whether the following procedure was not blood-contaminated. The odds of traumatic LP were halved or even reduced tenfold after a champagne tap. Less than a week between the two successive procedures, in turn, multiplied the odds of traumatic LP in the latter even more than tenfold. A champagne tap was not significantly associated with traumatic LP in the following procedure among pediatric patients. If the patient's condition or therapy plan permits and the blood contamination can compromise the reliability of the CSF-based analysis and consequent diagnosis, postponing the LP procedure by several days is advisable to improve the odds of receiving a high-quality CSF sample., (© 2023. The Author(s).)

To compare the effect of statin use in relation to castration-resistant prostate cancer (CRPC) treatment, we assessed the risk of ADT-treated PCa-patients to initiate CRPC treatment by statin use and the outcomes of CRPC treatment by statin use. Our study cohort consisted of 1169 men who participated in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) and initiated androgen deprivation therapy (ADT) during the follow-up (1996-2017). Statin use was associated with slightly decreased risk of initiating CRPC treatment (HR 0.68; 95% CI 0.47-0.97) with a 5.7 years' median follow-up until CRPC for non-users and 7.5 years for statin users. The risk of discontinuation of first or second line CRPC treatment due to inefficacy was not modified by statin use and the results remained similar in subgroup analysis assessing separately patients treated with taxans or androgen receptor signaling inhibitors. We observed an inverse association between statin use and the risk of initiation of the CRPC treatment. No beneficial risk modification by statin use during CRPC treatment was observed. These results suggest that statins might be beneficial during hormone-sensitive phase but not in the later phases of prostate cancer treatment., (© 2023. The Author(s).)

In survivors of severe coronavirus disease 2019 (COVID-19) incomplete mental and physical recovery may considerably impact daily activities and health-related quality of life (HRQoL). HRQoL can be evaluated with the RAND-36 questionnaire, a multidimensional instrument that assesses physical and mental aspects of health in eight dimensions. The objective was to investigate HRQoL in intensive care patients previously treated for COVID-19 at three Nordic university hospitals, in a prospective multi-center cohort study. HRQoL was measured using RAND-36, 3-9 months after discharge from intensive care units (ICU). One hospital performed a second follow-up 12 months after discharge. A score under the lower limit of the 95% confidence interval in the reference cohorts was considered as significantly reduced HRQoL. We screened 542 and included 252 patients. There was more than twice as many male (174) as female (78) patients and the median age was 61 (interquartile range, IQR 52-69) years. Hypertension was the most common comorbidity observed in 132 (52%) patients and 121 (48%) patients were mechanically ventilated for a median of 8 (IQR 4-14) days. In RAND-36 physical functioning, physical role functioning, general health (p < 0.001 for all) and social functioning (p < 0.05) were below reference, whereas bodily pain, emotional role functioning and mental health were not. In a time-to-event analysis female sex was associated with a decreased chance of reaching the reference HRQoL in the physical function, bodily pain and mental health dimensions. Higher body mass index was found in the physical functioning dimension and hypertension in the physical functioning, vitality and social functioning dimensions. Similar results were seen for diabetes mellitus in general health, vitality and mental health dimensions, as well as pulmonary illness in the physical role functioning dimension and psychiatric diagnosis in the social functioning dimension. Mechanical ventilation was associated with a decreased likelihood of achieving reference HRQoL in the bodily pain and physical functioning dimensions. Patients treated in an ICU because of COVID-19 had lower HRQoL 3-9 months after ICU discharge than 95% of the general population. Physical dimensions were more severely affected than mental dimensions. Female sex and several comorbidities were associated with a slower rate of recovery.Study registration: clinicaltrials.gov: NCT04316884 registered on the 13th of March 2020, NCT04474249 registered on the 29th of June 2020 and NCT04864938 registered on the 4th of April 2021., (© 2023. Springer Nature Limited.)

Traumatic muscle injury represents a collection of skeletal muscle pathologies caused by trauma to the muscle tissue and is defined as damage to the muscle tissue that can result in a functional deficit. Traumatic muscle injury can affect people across the lifespan and can result from high stresses and strains to skeletal muscle tissue, often due to muscle activation while the muscle is lengthening, resulting in indirect and non-contact muscle injuries (strains or ruptures), or from external impact, resulting in direct muscle injuries (contusion or laceration). At a microscopic level, muscle fibres can repair focal damage but must be completely regenerated after full myofibre necrosis. The diagnosis of muscle injury is based on patient history and physical examination. Imaging may be indicated to eliminate differential diagnoses. The management of muscle injury has changed within the past 5 years from initial rest, immobilization and (over)protection to early activation and progressive loading using an active approach. One challenge of muscle injury management is that numerous medical treatment options, such as medications and injections, are often used or proposed to try to accelerate muscle recovery despite very limited efficacy evidence. Another challenge is the prevention of muscle injury owing to the multifactorial and complex nature of this injury., (© 2023. Springer Nature Limited.)

Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children., (© 2023. Springer Nature Limited.)

Preoperative radiological identification of mandibular canals is essential for maxillofacial surgery. This study demonstrates the reproducibility of a deep learning system (DLS) by evaluating its localisation performance on 165 heterogeneous cone beam computed tomography (CBCT) scans from 72 patients in comparison to an experienced radiologist's annotations. We evaluated the performance of the DLS using the symmetric mean curve distance (SMCD), the average symmetric surface distance (ASSD), and the Dice similarity coefficient (DSC). The reproducibility of the SMCD was assessed using the within-subject coefficient of repeatability (RC). Three other experts rated the diagnostic validity twice using a 0-4 Likert scale. The reproducibility of the Likert scoring was assessed using the repeatability measure (RM). The RC of SMCD was 0.969 mm, the median (interquartile range) SMCD and ASSD were 0.643 (0.186) mm and 0.351 (0.135) mm, respectively, and the mean (standard deviation) DSC was 0.548 (0.138). The DLS performance was most affected by postoperative changes. The RM of the Likert scoring was 0.923 for the radiologist and 0.877 for the DLS. The mean (standard deviation) Likert score was 3.94 (0.27) for the radiologist and 3.84 (0.65) for the DLS. The DLS demonstrated proficient qualitative and quantitative reproducibility, temporal generalisability, and clinical validity., (© 2023. Springer Nature Limited.)

Ceramides contribute to the development of type 2 diabetes but it is uncertain whether they predict gestational diabetes (GDM). In this multicentre case-control study including 1040 women with GDM and 958 non-diabetic controls, early pregnancy (mean 10.7 gestational weeks) concentrations of four ceramides-Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)-were determined by a validated mass-spectrometric method from biobanked serum samples. Traditional lipids including total cholesterol, LDL, HDL and triglycerides were measured. Logistic and linear regression and the LASSO logistic regression were used to analyse lipids and clinical risk factors in the prediction of GDM. The concentrations of four targeted ceramides and total cholesterol, LDL and triglycerides were higher and HDL was lower among women with subsequent GDM than among controls. After adjustments, Cer(d18:1/24:0), triglycerides and LDL were independent predictors of GDM, women in their highest quartile had 1.44-fold (95% CI 1.07-1.95), 2.17-fold (95% CI 1.57-3.00) and 1.63-fold (95% CI 1.19-2.24) odds for GDM when compared to their lowest quartiles, respectively. In the LASSO regression modelling ceramides did not appear to markedly improve the predictive performance for GDM alongside with clinical risk factors and triglycerides. However, their adverse alterations highlight the extent of metabolic disturbances involved in GDM., (© 2023. Springer Nature Limited.)

Wnt pathway dysregulation through genetic and non-genetic alterations occurs in multiple cancers, including ovarian cancer (OC). The aberrant expression of the non-canonical Wnt signaling receptor ROR1 is thought to contribute to OC progression and drug resistance. However, the key molecular events mediated by ROR1 that are involved in OC tumorigenesis are not fully understood. Here, we show that ROR1 expression is enhanced by neoadjuvant chemotherapy, and Wnt5a binding to ROR1 can induce oncogenic signaling via AKT/ERK/STAT3 activation in OC cells. Proteomics analysis of isogenic ROR1-knockdown OC cells identified STAT3 as a downstream effector of ROR1 signaling. Transcriptomics analysis of clinical samples (n = 125) revealed that ROR1 and STAT3 are expressed at higher levels in stromal cells than in epithelial cancer cells of OC tumors, and these findings were corroborated by multiplex immunohistochemistry (mIHC) analysis of an independent OC cohort (n = 11). Our results show that ROR1 and its downstream STAT3 are co-expressed in epithelial as well as stromal cells of OC tumors, including cancer-associated fibroblasts or CAFs. Our data provides the framework to expand the clinical utility of ROR1 as a therapeutic target to overcome OC progression., (© 2023. The Author(s).)

In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy., (© 2023. The Author(s).)

Low birth weight predisposes to the development of hypertension in middle- and high-income countries. We examined the relation of early life length-for-age score (Z-score) on cardiovascular function in young adults in Malawi, a low-income country. Capture of supine, seated, and standing brachial pulse waveforms (Mobil-O-Graph) were performed in 223 females and 152 males (mean age 21 years), and analyzed according to the length-for-age Z-score tertiles during the first month of life. Plasma LDL cholesterol in young adulthood was slightly lower in the lowest versus highest tertile. Otherwise, blood hemoglobin and plasma chemistry were similar in all tertiles. Irrespective of posture, blood pressure, forward and backward wave amplitudes, and pulse wave velocity were corresponding in all tertiles. In the three postures, the lowest tertile presented with 4.5% lower systemic vascular resistance than the highest tertile (p = 0.005), and 4.4% and 5.5% higher cardiac output than the middle and highest tertiles, respectively (p < 0.01). Left cardiac work was 6.8% and 6.9% higher in the lowest tertile than in the middle and highest tertiles, respectively (p < 0.01). To conclude, in a low-income environment, low length-for-age Z-score after birth predicted hyperdynamic circulation at 21 years of age without changes in blood pressure and metabolic variables., (© 2023. The Author(s).)

A plethora of classification models for the detection of glaucoma from fundus images have been proposed in recent years. Often trained with data from a single glaucoma clinic, they report impressive performance on internal test sets, but tend to struggle in generalizing to external sets. This performance drop can be attributed to data shifts in glaucoma prevalence, fundus camera, and the definition of glaucoma ground truth. In this study, we confirm that a previously described regression network for glaucoma referral (G-RISK) obtains excellent results in a variety of challenging settings. Thirteen different data sources of labeled fundus images were utilized. The data sources include two large population cohorts (Australian Blue Mountains Eye Study, BMES and German Gutenberg Health Study, GHS) and 11 publicly available datasets (AIROGS, ORIGA, REFUGE1, LAG, ODIR, REFUGE2, GAMMA, RIM-ONEr3, RIM-ONE DL, ACRIMA, PAPILA). To minimize data shifts in input data, a standardized image processing strategy was developed to obtain 30° disc-centered images from the original data. A total of 149,455 images were included for model testing. Area under the receiver operating characteristic curve (AUC) for BMES and GHS population cohorts were at 0.976 [95% CI: 0.967-0.986] and 0.984 [95% CI: 0.980-0.991] on participant level, respectively. At a fixed specificity of 95%, sensitivities were at 87.3% and 90.3%, respectively, surpassing the minimum criteria of 85% sensitivity recommended by Prevent Blindness America. AUC values on the eleven publicly available data sets ranged from 0.854 to 0.988. These results confirm the excellent generalizability of a glaucoma risk regression model trained with homogeneous data from a single tertiary referral center. Further validation using prospective cohort studies is warranted., (© 2023. The Author(s).)

Distinct gut microbiome ecology may be implicated in the prevention of aging-related diseases as it influences systemic immune function and resistance to infections. Yet, the viral component of the microbiome throughout different stages in life remains unexplored. Here we present a characterization of the centenarian gut virome using previously published metagenomes from 195 individuals from Japan and Sardinia. Compared with gut viromes of younger adults (>18 yr) and older individuals (>60 yr), centenarians had a more diverse virome including previously undescribed viral genera, such as viruses associated with Clostridia. A population shift towards higher lytic activity was also observed. Finally, we investigated phage-encoded auxiliary functions that influence bacterial physiology, which revealed an enrichment of genes supporting key steps in sulfate metabolic pathways. Phage and bacterial members of the centenarian microbiome displayed an increased potential for converting methionine to homocysteine, sulfate to sulfide and taurine to sulfide. A greater metabolic output of microbial hydrogen sulfide in centenarians may in turn support mucosal integrity and resistance to pathobionts., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

With over 17 million annual deaths, cardiovascular diseases (CVDs) dominate the cause of death statistics. CVDs can deteriorate the quality of life drastically and even cause sudden death, all the while inducing massive healthcare costs. This work studied state-of-the-art deep learning techniques to predict increased risk of death in CVD patients, building on the electronic health records (EHR) of over 23,000 cardiac patients. Taking into account the usefulness of the prediction for chronic disease patients, a prediction period of six months was selected. Two major transformer models that rely on learning bidirectional dependencies in sequential data, BERT and XLNet, were trained and compared. To our knowledge, the presented work is the first to apply XLNet on EHR data to predict mortality. The patient histories were formulated as time series consisting of varying types of clinical events, thus enabling the model to learn increasingly complex temporal dependencies. BERT and XLNet achieved an average area under the receiver operating characteristic curve (AUC) of 75.5% and 76.0%, respectively. XLNet surpassed BERT in recall by 9.8%, suggesting that it captures more positive cases than BERT, which is the main focus of recent research on EHRs and transformers., (© 2023. The Author(s).)

Background: Antibiotics have been associated with several individual autoimmune diseases (ADs). This study aims to discover whether pre-diagnostic antibiotics are associated with the onset of ADs in general., Methods: From a cohort of 11,407 children, 242 developed ADs (type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis (JIA), or inflammatory bowel diseases) by a median age of 16 years. Antibiotic purchases from birth until the date of diagnosis (or respective date in the matched controls n = 708) were traced from national registers., Results: Total number of antibiotic purchases was not related to the onset of ADs when studied as a group. Of specific diagnoses, JIA was associated with the total number of antibiotics throughout the childhood and with broad-spectrum antibiotics before the age of 3 years. Intriguingly, recent and frequent antibiotic use (within 2 years before diagnosis and ≥3 purchases) was associated with the onset of ADs (OR 1.72, 95% CI 1.08-2.74). Regardless of frequent use in childhood (40% of all antibiotics), penicillin group antibiotics were not related to any ADs., Conclusions: Use of antibiotics was relatively safe regarding the overall development of ADs. However, broad-spectrum antibiotics should be used considerately as they may associate with an increased likelihood of JIA., Impact: Increasing numbers of antibiotic purchases before the age of 3 years or throughout childhood were not associated with the development of pediatric autoimmune diseases. Broad-spectrum antibiotics were related to the development of autoimmune diseases, especially juvenile idiopathic arthritis in children, while penicillin group antibiotics were not. The use of broad-spectrum antibiotics in children should be cautious as they may carry along a risk for autoimmune disease development., (© 2022. The Author(s).)

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30-45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research., (© 2023. The Author(s).)

Children have special rights for protection compared to adults in our society. However, more than 1/4 of children globally have no documentation of their date of birth. Hence, there is a pressing need to develop biological methods for chronological age prediction, robust to differences in genetics, psychosocial events and physical living conditions. At present, DNA methylation is the most promising biological biomarker applied for age assessment. The human genome contains around 28 million DNA methylation sites, many of which change with age. Several epigenetic clocks accurately predict chronological age using methylation levels at age associated GpG-sites. However, variation in DNA methylation increases with age, and there is no epigenetic clock specifically designed for adolescents and young adults. Here we present a novel age Predictor for Adolescents and Young Adults (PAYA), using 267 CpG methylation sites to assess the chronological age of adolescents and young adults. We compared different preprocessing approaches and investigated the effect on prediction performance of the epigenetic clock. We evaluated performance using an independent validation data set consisting of 18-year-old individuals, where we obtained a median absolute deviation of just below 0.7 years. This tool may be helpful in age assessment of adolescents and young adults. However, there is a need to investigate the robustness of the age predictor across geographical and disease populations as well as environmental effects., (© 2023. The Author(s).)

Management of the operative treatment of fractures is challenged by daily variation in patient flow. For upper limb fractures there has recently been an increasing tendency to temporarily discharge the patient to wait for a daytime operation to be performed during the next few days. The objective of this study was to study the safety of controlled delay in surgery. Upper limb fractures (N = 1 944) treated in a level 2 trauma center from 2010 to 2016 were identified and included in this retrospective cohort study with 5-year follow-up. Delay in surgery, inpatient time, readmissions, ED revisits and mortality were analyzed. Depending on the nature of the injury, controlled delay to surgery was implemented. Urgency of surgery was coded as green (2 days to 2 weeks) yellow (8-48 h) or red (less than 8 h). Harms and benefits to the groups were compared. Controlled delay of surgery (median delay of 5 days 7 h) was applied in 1 074 out of 1 944 fractures. The number of revisits to the emergency department (11.1% vs. 17.9-24.1%, p < 0.001) or hospital readmissions for any reason (0.99 per 100 person years in the delayed group vs. 3.74 and 4.35 in the non-delayed groups, p < 0.001) was no higher in patients with delayed (green) compared to those with non-delayed (yellow and red) operations. Inpatient time was significantly lower in the delayed group than other groups (IRR 2.31-3.36, (p < 0.001)). The standardized mortality ratio was 0.83 (CI 0.57-1.22) in the delayed group vs. 1.49 (CI 1.17-1.90) and 1.61 (CI 1.16-2.23) in the non-delayed groups. Controlled delay in upper limb trauma surgery did not lead to increased readmissions or mortality and was associated with reduced inpatient time., (© 2023. The Author(s).)

Metabolic dysfunction, partly driven by altered liver function, predisposes to coronary artery disease (CAD), but the role of liver in vulnerable atherosclerotic plaque development remains unclear. Here we produced hepatocyte-like cells (HLCs) from 27 induced pluripotent stem cell (iPSC) lines derived from 15 study subjects with stable CAD (n = 5), acute CAD (n = 5) or healthy controls (n = 5). We performed a miRNA microarray screening throughout the differentiation, as well as compared iPSC-HLCs miRNA profiles of the patient groups to identify miRNAs involved in the development of CAD. MicroRNA profile changed during differentiation and started to resemble that of the primary human hepatocytes. In the microarray, 35 and 87 miRNAs were statistically significantly deregulated in the acute and stable CAD patients, respectively, compared to controls. Down-regulation of miR-149-5p, -92a-3p and -221-3p, and up-regulation of miR-122-5p was verified in the stable CAD patients when compared to other groups. The predicted targets of deregulated miRNAs were enriched in pathways connected to insulin signalling, inflammation and lipid metabolism. The iPSC-HLCs derived from stable CAD patients with extensive lesions had a distinct genetic miRNA profile possibly linked to metabolic dysfunction, potentially explaining the susceptibility to developing CAD. The iPSC-HLCs from acute CAD patients with only the acute rupture in otherwise healthy coronaries did not present a distinct miRNA profile, suggesting that hepatic miRNAs do not explain susceptibility to plaque rupture., (© 2023. The Author(s).)

BK (BKPyV) and JC (JCPyV) polyomavirus infections are commonly subclinical and known infrequently to cause serious clinical diseases. Longitudinal follow-up studies regarding JCPyV and BKPyV serological outcomes are scanty. We analyzed JCPyV and BKPyV IgG-antibodies in 327 pregnant women and their 132 spouses, enrolled in the longitudinal Finnish Family HPV cohort at Turku University Hospital, Finland. Blood samples taken at baseline, and at 12-, 24-, and 36-month follow-up visits were analyzed for capsid protein VP1-antibodies using multiplex serology. Seroprevalence was constant for both BKPyV and JCPyV across the follow-up, varying between 95-99% and 59-68%, respectively, in women and between 96-97% and 66-72%, respectively, in their spouses. Seroconversion to BKPyV and JCPyV was detected in 15% and 18% of the women and in 13% and 19% of the men, respectively. Waning of BKPyV and JCPyV antibodies was infrequent, present in only 5% of the women (both viruses) and in 1.5% of the male spouses (only BKPyV). The number of lifetime sexual partners (p = 0.038) was lower among JCPyV seropositive men. To conclude, seropositivity to BKPyV and JCPyV is common among marital couples in Finland, with only slight differences between genders. In men, the sexual behavior might be associated with JCPyV seroprevalence., (© 2023. The Author(s).)

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored 1,2 . FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10 -11 ) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants., (© 2023. The Author(s).)

While sunlight may influence cognitive function through several pathways, associations of residential sunlight exposure with cognitive function are not well known. We evaluated associations of long-term residential sunlight exposure with cognitive function among a representative cohort of 1838 Finnish adults residing in Finland who underwent comprehensive cognitive assessment in midlife. We linked daily recordings of global solar radiation to study participants using residential information and calculated the average daily residential exposure to sunlight for four exposure time intervals: 2 months, 1 year, 2 years and 5 years prior to the date of the cognition assessment. Associations of the residential sunlight exposure with cognitive function were assessed using linear regression analyses adjusting for season, sex, age, and individual- and neighborhood-level socioeconomic characteristics. Greater average residential sunlight exposure over 2 and 5 years prior to the cognitive function assessment was associated with better global cognitive function (b = 0.13, 95% CI = 0.01, 0.25; b = 0.17, 95% CI = 0.05, 0.29, per 1 MJ/m 2 difference in sunlight exposure), while no associations with global cognitive function were observed at shorter exposure time intervals. In domain-specific analyses, greater residential exposure to sunlight over 1, 2 and 5 years prior to the cognitive function assessment was associated with better performance on new learning and visual memory (b = 0.10, 95% CI = 0.00, 0.20; b = 0.16, 95% CI = 0.04, 0.28; b = 0.19, 95% CI = 0.08, 0.31) and sustained attention (b = 0.15, 95% CI = 0.05, 0.25; b = 0.18, 95% CI = 0.06, 0.30; b = 0.17, 95% CI = 0.05, 0.29), but worse performance on reaction time (b =  - 0.12, 95% CI =  - 0.22, - 0.02; b = -0.15, 95% CI =  - 0.28, - 0.02; b =  - 0.18, 95% CI =  - 0.30, - 0.05). Residential sunlight exposure was not associated with executive function. These findings suggest long-term residential sunlight exposure may be an environmental factor influencing cognitive function among a cognitively healthy cohort residing in Northern Europe. Further studies in populations residing in different geographical locations are needed., (© 2022. The Author(s).)

Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54-0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68-0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days., (© 2022. The Author(s).)

Deep learning approach has been demonstrated to automatically segment the bilateral mandibular canals from CBCT scans, yet systematic studies of its clinical and technical validation are scarce. To validate the mandibular canal localization accuracy of a deep learning system (DLS) we trained it with 982 CBCT scans and evaluated using 150 scans of five scanners from clinical workflow patients of European and Southeast Asian Institutes, annotated by four radiologists. The interobserver variability was compared to the variability between the DLS and the radiologists. In addition, the generalisation of DLS to CBCT scans from scanners not used in the training data was examined to evaluate its out-of-distribution performance. The DLS had a statistically significant difference (p < 0.001) with lower variability to the radiologists with 0.74 mm than the interobserver variability of 0.77 mm and generalised to new devices with 0.63 mm, 0.67 mm and 0.87 mm (p < 0.001). For the radiologists' consensus segmentation, used as a gold standard, the DLS showed a symmetric mean curve distance of 0.39 mm, which was statistically significantly different (p < 0.001) compared to those of the individual radiologists with values of 0.62 mm, 0.55 mm, 0.47 mm, and 0.42 mm. These results show promise towards integration of DLS into clinical workflow to reduce time-consuming and labour-intensive manual tasks in implantology., (© 2022. The Author(s).)

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)