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The timing of dental development in ethnic Finns and Somalis, who were born and living in Finland, was compared, with efforts to minimize environmental bias. The developmental status of seven lower left permanent teeth were staged according to Demirjian et al., using panoramic radiographs from 2,100 Finnish and 808 Somali females and males, aged 2 to 23 years. For each tooth, a continuation-ratio model was constructed to analyze the allocated stages as a function of sex and ethnic origin. Several statistically significant differences in mean age of certain tooth developmental stage transitions were revealed. While Somalis generally displayed stage transitions at younger age, none of the seven teeth consistently showed earlier stage transitions in Somalis compared to Finns. Within each tooth, the lowest (or highest) mean age of stage transition varied without any discernible pattern between the two ethnic groups. Overall, the observed differences in mean age of stage transition between the groups was minimal, suggesting a low impact on clinical and forensic age assessment practice. In conclusion, the studied ethnic Finn and Somali groups with equal nutritional and /or environmental conditions exhibit similar timing in the development of all lower left permanent teeth., (© 2024. The Author(s).)

Pangenomes reduce reference bias by representing genetic diversity better than a single reference sequence. Yet when comparing a sample to a pangenome, variants in the pangenome that are not part of the sample can be misleading, for example, causing false read mappings. These irrelevant variants are generally rarer in terms of allele frequency, and have previously been dealt with by filtering rare variants. However, this blunt heuristic both fails to remove some irrelevant variants and removes many relevant variants. We propose a new approach that imputes a personalized pangenome subgraph by sampling local haplotypes according to k-mer counts in the reads. We implement the approach in the vg toolkit ( https://github.com/vgteam/vg ) for the Giraffe short-read aligner and compare its accuracy to state-of-the-art methods using human pangenome graphs from the Human Pangenome Reference Consortium. This reduces small variant genotyping errors by four times relative to the Genome Analysis Toolkit and makes short-read structural variant genotyping of known variants competitive with long-read variant discovery methods., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aligning DNA sequences retrieved from fossils or other paleontological artifacts, referred to as ancient DNA, is particularly challenging due to the short sequence length and chemical damage which creates a specific pattern of substitution (C→T and G→A) in addition to the heightened divergence between the sample and the reference genome thus exacerbating reference bias. This bias can be mitigated by aligning to pangenome graphs to incorporate documented organismic variation, but this approach still suffers from substitution patterns due to chemical damage. We introduce a novel methodology introducing the RYmer index, a variant of the commonly-used minimizer index which represents purines (A,G) and pyrimidines (C,T) as R and Y respectively. This creates an indexing scheme robust to the aforementioned chemical damage. We implemented SAFARI, an ancient DNA damage-aware version of the pangenome aligner vg giraffe which uses RYmers to rescue alignments containing deaminated seeds. We show that our approach produces more correct alignments from ancient DNA sequences than current approaches while maintaining a tolerable rate of spurious alignments. In addition, we demonstrate that our algorithm improves the estimate of the rate of ancient DNA damage, especially for highly damaged samples. Crucially, we show that this improved alignment can directly translate into better insights gained from the data by showcasing its integration with a number of extant pangenome tools.

Background: Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumor-infiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis., Methods: CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells., Results: Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICS low subgroup., Conclusion: Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy., Competing Interests: TS reports a consultation fee from Amgen Finland, and being a co-owner and CEO of Healthfund Finland Ltd, and the Clinical Advisory Board of LS Cancer Diag Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wirta, Szeto, Koppatz, Nordin, Mäkisalo, Arola, Sirén, Ahtiainen, Böhm, Mecklin, Sallinen and Seppälä.)

Background: The aim of this study was to assess the incidence of bacterobilia at the time of a pancreaticoduodenectomy (PD) and the association of resistant bacteria in bile to surgical site infections (SSI)., Methods: This was a retrospective cohort study including patients undergoing PD in a single center between May 2016 and October 2020. Data of preoperative biliary drainage (PBD), intraoperative biliary cultures (IBC) and postoperative complications were analysed to assess the risk factors for resistant bacteria in IBC and SSIs., Results: Of 361 patients included, 254 (70%) had undergone PBD. Second-generation cephalosporin resistant bacteria were found in IBC of 183 (64%) of all the patients. PBD was the only risk factor for second-generation cephalosporin resistance. The risk for second-generation cephalosporin resistance was more than 20-fold in patients with PBD [n = 170/254 (67%) (OR 22.58 (95% CI, 9.61-53.01), p < 0.001)] compared to patients who did not have PBD (n = 13/107 (12%)). Also, if the time between PBD and surgery was 2 months or more the second-generation cephalosporin resistance in IBC increased the risk for SSIs (OR 4.14 (95% CI, 1.18-14.51), p = 0.027)., Conclusion: The second-generation cephalosporin resistance in IBC is common in patients who have undergone PBD. Broad-spectrum antibiotics in prophylaxis may be beneficial for these patients., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Indication-specific optimum field-of-views (FOVs) have been assessed for CBCT scans of impacted maxillary canines and mandibular third molars, as 40∅ × 35 mm and 35∅ × 35 mm, respectively. The objective was to investigate possible changes in absorbed organs and effective doses, for these two imaging indications, performing CBCT examinations with optimum FOV sizes instead of commonly used FOVs. Additionally, radiation exposure-induced cancer risk was calculated for both imaging indications with optimum FOVs., Methods: An adult female head phantom (ATOM 702-D, CIRS, Norfolk, VA, USA) was scanned using Planmeca Viso G7 CBCT-device (Planmeca, Helsinki, Finland). Scanning factors, different FOV sizes, dose-area product (DAP) values and anatomical FOV locations were used for Monte Carlo PCXMC-simulation and ImpactMC software. In the PCXMC- simulation, 10-year-old child and 30-year-old adult phantoms were used to estimating effective and absorbed organ doses., Results: The effective dose varied from 58 µSv to 284 µSv for impacted maxillary canines, and from 38 µSv to 122 µSv for mandibular third molars, the lowest dose value for each corresponding to optimum FOV. Effective dose reduction between the optimum FOV and the smallest common FOV of 50∅ × 50 mm, maintaining other scanning factors constant, was 33% for impacted maxillary canines, and 45% for mandibular third molars. At all examinations, the highest absorbed organ doses were in salivary glands or in oral mucosa., Conclusions: Optimum FOVs, 40∅ × 35 mm for impacted maxillary canine and 35∅ × 35 mm for mandibular third molar, could decrease effective doses received by young patients, and improve radiation safety in these common CBCT imaging procedures.

Pangenomes, by including genetic diversity, should reduce reference bias by better representing new samples compared to them. Yet when comparing a new sample to a pangenome, variants in the pangenome that are not part of the sample can be misleading, for example, causing false read mappings. These irrelevant variants are generally rarer in terms of allele frequency, and have previously been dealt with using allele frequency filters. However, this is a blunt heuristic that both fails to remove some irrelevant variants and removes many relevant variants. We propose a new approach, inspired by local ancestry inference methods, that imputes a personalized pangenome subgraph based on sampling local haplotypes according to k -mer counts in the reads. Our approach is tailored for the Giraffe short read aligner, as the indexes it needs for read mapping can be built quickly. We compare the accuracy of our approach to state-of-the-art methods using graphs from the Human Pangenome Reference Consortium. The resulting personalized pangenome pipelines provide faster pangenome read mapping than comparable pipelines that use a linear reference, reduce small variant genotyping errors by 4x relative to the Genome Analysis Toolkit (GATK) best-practice pipeline, and for the first time make short-read structural variant genotyping competitive with long-read discovery methods.

Objectives: The aim was to analyse the costs and duration of orthodontic-surgical treatment with mandibular advancement in the public health care sector in Finland., Materials: The study was conducted as a retrospective registry study in a public district hospital on all nonsyndromic patients that were ethnic Finns and treated with full fixed appliances and mandibular advancement surgery in 2016-2020., Results: The mean treatment duration of the included 45 patients was 28.1 months, including 18.9 months pre and 9.2 months postoperative orthodontics. The median number of visits was 27, including 17 visits before and 9 visits after surgery. The mean total treatment time was 14.5 h. The mean total direct costs per course of treatment were 7574 € to the municipality and 947 € to the patient. The costs positively correlated with the duration of the treatment (rho = 0.71, P = .000), but were not associated to gender or age of patient. The mean surgery time was 78 minutes, and significantly less with an experienced surgeon (P = .002). It was calculated that the mean minimum treatment costs would be 45% of the present total, achievable with a patient with optimum dental arches at the start of treatment., Limitations: The major limitation of the study is the relatively small number of study subjects., Conclusion: A 55% share of the costs is influenced by case- and operator-dependent factors. This indicates that the complexity and performance of the orthodontic phases of treatment are important determinants in the cost structure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Orthodontic Society.)

Viral diversity has been discovered across scales from host individuals to populations. However, the drivers of viral community assembly are still largely unknown. Within-host viral communities are formed through co-infections, where the interval between the arrival times of viruses may vary. Priority effects describe the timing and order in which species arrive in an environment, and how early colonizers impact subsequent community assembly. To study the effect of the first-arriving virus on subsequent infection patterns of five focal viruses, we set up a field experiment using naïve Plantago lanceolata plants as sentinels during a seasonal virus epidemic. Using joint species distribution modelling, we find both positive and negative effects of early season viral infection on late season viral colonization patterns. The direction of the effect depends on both the host genotype and which virus colonized the host early in the season. It is well established that co-occurring viruses may change the virulence and transmission of viral infections. However, our results show that priority effects may also play an important, previously unquantified role in viral community assembly. The assessment of these temporal dynamics within a community ecological framework will improve our ability to understand and predict viral diversity in natural systems.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals 1 . These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample., (© 2023. The Author(s).)

Pangenomics is emerging as a powerful computational paradigm in bioinformatics. This field uses population-level genome reference structures, typically consisting of a sequence graph, to mitigate reference bias and facilitate analyses that were challenging with previous reference-based methods. In this work, we extend these methods into transcriptomics to analyze sequencing data using the pantranscriptome: a population-level transcriptomic reference. Our toolchain, which consists of additions to the VG toolkit and a standalone tool, RPVG, can construct spliced pangenome graphs, map RNA sequencing data to these graphs, and perform haplotype-aware expression quantification of transcripts in a pantranscriptome. We show that this workflow improves accuracy over state-of-the-art RNA sequencing mapping methods, and that it can efficiently quantify haplotype-specific transcript expression without needing to characterize the haplotypes of a sample beforehand., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: The aim of the study was to compare the effects of a 30 µg/day versus 10 µg/day vitamin D supplementation, given during the two first years of life, on oral health at the age of six to 7 years., Methods: In 2013-2016, we conducted a randomized, double-blinded, clinical trial from age 2 weeks to 2 years of daily vitamin D3 supplementation (10 vs. 30 µg), including 975 healthy infants. For the present follow-up study at age 6-7 years, a sample of 123 children underwent oral examination by investigators blinded to the intervention group. Tooth enamel defect and caries findings, oral rinse active matrix metalloproteinase-8 levels, and tooth eruption were recorded. The intervention groups were compared with χ2 and Mann-Whitney U tests. Associations of the oral health outcomes were evaluated with correlation analysis and logistic regression., Results: Of the children (median age 7.4 years, 51% boys), 56% belonged to the 30 µg intervention group. Developmental defect of enamel (DDE) was found in 39% of the children in the 10 µg intervention group and in 53% of the 30 µg group (p = 0.104). In total, 94% of children were vitamin D sufficient (25[OH]D ≥50 nmol/L) and 88% had caries-free teeth. No associations were found between vitamin D intervention group in infancy and oral health or the presence of DDE., Conclusion: Daily supplementation with 10 µg vitamin D3 in the Northern Hemisphere seems adequate in healthy children younger than 2 years in ensuring good oral health at early school age., (© 2022 S. Karger AG, Basel.)

Motivation: Pangenome graphs representing aligned genome assemblies are being shared in the text-based Graphical Fragment Assembly format. As the number of assemblies grows, there is a need for a file format that can store the highly repetitive data space efficiently., Results: We propose the GBZ file format based on data structures used in the Giraffe short-read aligner. The format provides good compression, and the files can be efficiently loaded into in-memory data structures. We provide compression and decompression tools and libraries for using GBZ graphs, and we show that they can be efficiently used on a variety of systems., Availability and Implementation: C++ and Rust implementations are available at https://github.com/jltsiren/gbwtgraph and https://github.com/jltsiren/gbwt-rs, respectively., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Highly utilized risk scores for clinically relevant postoperative pancreatic fistula (CR-POPF) have guided clinical decision-making in pancreatoduodenectomy. However, none has been successfully developed for distal pancreatectomy. This study aimed to develop and validate a new fistula risk score for distal pancreatectomy., Methods: Patients undergoing distal pancreatectomy at Helsinki University Hospital, Finland from 2013 to 2021, and at Karolinska University Hospital, Sweden, from 2010 to 2020, were included retrospectively. The outcome was CR-POPF, according to the 2016 International Study Group of Pancreatic Surgery definition. Preoperative clinical demographics and radiological parameters such as pancreatic thickness and duct diameter were measured. A logistic regression model was developed, internally validated with bootstrapping, and the performance assessed in an external validation cohort., Results: Of 668 patients from Helsinki (266) and Stockholm (402), 173 (25.9 per cent) developed CR-POPF. The final model consisted of three variables assessed before surgery: transection site (neck versus body/tail), pancreatic thickness at transection site, and diabetes. The model had an area under the receiver operating characteristic curve (AUROC) of 0.904 (95 per cent c.i. 0.855 to 0.949) after internal validation, and 0.798 (0.748 to 0.848) after external validation. The calibration slope and intercept on external validation were 0.719 and 0.192 respectively. Four risk groups were defined in the validation cohort for clinical applicability: low (below 5 per cent), moderate (at least 5 but below 30 per cent), high (at least 30 but below 75 per cent), and extreme (75 per cent or more). The incidences in these groups were 8.7 per cent (11 of 126), 22.0 per cent (36 of 164), 63 per cent (57 of 91), and 81 per cent (17 of 21) respectively., Conclusion: The DISPAIR score after distal pancreatectomy may guide decision-making and allow a risk-adjusted outcome comparison for CR-POPF., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Recent studies have suggested postoperative acute pancreatitis (POAP) as a serious complication after pancreaticoduodenectomy (PD) and have speculated on its possible role in the pathogenesis of postoperative pancreatic fistula (POPF). This study aimed to assess the impact of POAP on post-PD outcomes and fistula risk score (FRS) performance in predicting POAP., Methods: All PDs at Helsinki University Hospital between 2013 and 2020 were analysed. POAP was defined as a plasma amylase activity greater than the normal upper limit on postoperative day (POD) 1 and stratified as clinically relevant (CR)-POAP once C-reactive protein (CRP) reached or exceeded 180 mg/l, and non-CR-POAP once CRP was less than 180 mg/l on POD 2. The Comprehensive Complication Index (CCI) was used to assess total postoperative morbidity. Different FRSs were assessed using receiver operating characteristic curves., Results: Of the 508 patients included, POAP occurred in 202 (39.8 per cent) patients, of whom 91 (17.9 per cent) had CR-POAP. The incidence of CR-POPF was 12.6 per cent (64 patients). Patients with non-CR-POAP had a similar morbidity to patients with no POAP (median CCI score 24.2 versus 22.6; P = 0.142), while CCI score was significantly higher (37.2) in patients with CR-POAP (P < 0.001). CR-POAP was associated with increased rates of CR-POPF, delayed gastric emptying, haemorrhage, and bile leak, while non-CR-POAP was associated only with CR-POPF. Ninety-day mortality was 1.6 per cent, 0.9 per cent, and 3.3 per cent in patients with no-POAP, non-CR-POAP, and CR-POAP, respectively. Updated alternative FRS showed the best performance in predicting CR-POAP (area under the curve 0.834)., Conclusion: CR-POAP was associated with a higher CCI score, suggesting CR-POAP as a distinct entity from non-CR-POAP. FRSs can be used to assess the risk of CR-POAP., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Computational pangenomics is an emerging research field that is changing the way computer scientists are facing challenges in biological sequence analysis. In past decades, contributions from combinatorics, stringology, graph theory and data structures were essential in the development of a plethora of software tools for the analysis of the human genome. These tools allowed computational biologists to approach ambitious projects at population scale, such as the 1000 Genomes Project. A major contribution of the 1000 Genomes Project is the characterization of a broad spectrum of genetic variations in the human genome, including the discovery of novel variations in the South Asian, African and European populations-thus enhancing the catalogue of variability within the reference genome. Currently, the need to take into account the high variability in population genomes as well as the specificity of an individual genome in a personalized approach to medicine is rapidly pushing the abandonment of the traditional paradigm of using a single reference genome. A graph-based representation of multiple genomes, or a graph pangenome , is replacing the linear reference genome. This means completely rethinking well-established procedures to analyze, store, and access information from genome representations. Properly addressing these challenges is crucial to face the computational tasks of ambitious healthcare projects aiming to characterize human diversity by sequencing 1M individuals (Stark et al. 2019). This tutorial aims to introduce readers to the most recent advances in the theory of data structures for the representation of graph pangenomes. We discuss efficient representations of haplotypes and the variability of genotypes in graph pangenomes, and highlight applications in solving computational problems in human and microbial (viral) pangenomes.