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Objective Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. Design Retrospective cohort study. Methods Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980–2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel–Haenszel method. Overall survival was analysed with Kaplan–Meier and Cox regression analyses. Results The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02–4.22)), intestinal obstruction (18.65 (2.09–166.86)), and possibly breast (4.46 (1.29–15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). Conclusions The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.

Importance Both hydrocortisone and pasireotide have been shown in randomized clinical trials to be effective in reducing postoperative complications of pancreatic surgery, but to date no randomized clinical trial has evaluated the effectiveness of pasireotide compared with hydrocortisone. Objective To assess the noninferiority of hydrocortisone compared with pasireotide in reducing complications after partial pancreatectomy. Design, Setting, and Participants A noninferiority, parallel-group, individually randomized clinical trial was conducted at a single academic center between May 19, 2016, and December 17, 2018. Outcome collectors and analyzers were blinded. A total of 281 patients undergoing partial pancreatectomy were assessed for inclusion. Patients younger than 18 years, those allergic to hydrocortisone or pasireotide, patients undergoing pancreaticoduodenectomy with hard pancreas or dilated pancreatic duct, and patients not eventually undergoing partial pancreatectomy were excluded. Modified intention-to-treat analysis was used in determination of the results. Interventions Treatment included pasireotide, 900 μg, subcutaneously twice a day for 7 days or hydrocortisone, 100 mg, intravenously 3 times a day for 3 days. Main Outcomes and Measures The primary outcome was the Comprehensive Complication Index (CCI) score within 30 days. The noninferiority limit was set to 9 CCI points. Results Of the 281 patients (mean [SD] age, 63.8 years) assessed for eligibility, 168 patients (mean [SD] age, 63.6 years) were randomized and 126 were included in the modified intention-to-treat analyses. Sixty-three patients received pasireotide (35 men [56%]; median [interquartile range] age, 64 [56-70] years) and 63 patients received hydrocortisone (25 men [40%]; median [interquartile range] age, 67 [56-73] years). The mean (SD) CCI score was 23.94 (17.06) in the pasireotide group and 30.11 (20.47) in the hydrocortisone group (mean difference, –6.16; 2-sided 90% CI, –11.73 to –0.60), indicating that hydrocortisone was not noninferior. Postoperative pancreatic fistula was detected in 34 patients (54%) in the pasireotide group and 39 patients (62%) in the hydrocortisone group (odds ratio, 1.39; 95% CI, 0.68-2.82;P = .37). One patient in the pasireotide group and 2 patients in the hydrocortisone group died within 30 days. In subgroup analyses of patients undergoing distal pancreatectomy, the CCI score was a mean of 10.3 points lower (mean [SD], 16.03 [11.94] vs 26.28 [21.76]; 2-sided 95% CI, −19.34 to −2.12;P = .03) and postoperative pancreatic fistula rate was lower (37% vs 67%;P = .02) in the pasireotide group compared with the hydrocortisone group. Conclusions and Relevance In this study, hydrocortisone was not noninferior compared with pasireotide in patients undergoing partial pancreatectomy. Pasireotide may be more effective than hydrocortisone in patients undergoing distal pancreatectomy. Trial Registration ClinicalTrials.gov identifier:NCT02775227; EudraCT identifier:2016-000212-16

Objective: Insulinomas are rare pancreatic neoplasms, which can usually be cured by surgery. As the diagnostic delay is often long and the prolonged hyperinsulinemia may have long‐term effects on health and the quality of life, we studied the long‐term health‐related quality of life (HRQoL) in insulinoma patients. Design, patients and measurements: The HRQoL of adults diagnosed with an insulinoma in Finland in 1980‐2010 was studied with the 15D instrument, and the results were compared to those of an age‐ and gender‐matched sample of the general population. The minimum clinically important difference in the total 15D score has been defined as ±0.015. The clinical characteristics, details of insulinoma diagnosis and treatment, and the current health status of the subjects were examined to specify the possible determinants of long‐term HRQoL. Results: Thirty‐eight insulinoma patients participated in the HRQoL survey (response rate 75%). All had undergone surgery with a curative aim, a median of 13 (min 7, max 34) years before the survey. The insulinoma patients had a clinically importantly and statistically significantly better mean 15D score compared with the controls (0.930 ± 0.072 vs 0.903 ± 0.039, P = .046) and were significantly better off regarding mobility, usual activities and eating. Among the insulinoma patients, younger age at the time of survey, higher level of education and smaller number of chronic diseases were associated with better overall HRQoL. Conclusions: In the long term, the overall HRQoL of insulinoma patients is slightly better than that of the general population.

Purpose This study compared the utility of different statistical methods in differentiating sexual crimes committed by the same person from sexual crimes committed by different persons. Methods Logistic regression, iterative classification tree (ICT), and Bayesian analysis were applied to a dataset of 3,364 solved, unsolved, serial, and apparent one-off sexual assaults committed in five countries. Receiver Operating Characteristic analysis was used to compare the statistical approaches. Results All approaches achieved statistically significant levels of discrimination accuracy. Two out of three Bayesian methods achieved a statistically higher level of accuracy (Areas Under the Curve [AUC] = 0.89 [Bayesian coding method 1]; AUC = 0.91 [Bayesian coding method 3]) than ICT analysis (AUC = 0.88), logistic regression (AUC = 0.87), and Bayesian coding method 2 (AUC = 0.86). Conclusions The ability to capture/utilize between-offender differences in behavioral consistency appear to be of benefit when linking sexual offenses. Statistical approaches that utilize individual offender behaviors when generating crime linkage predictions may be preferable to approaches that rely on a single summary score of behavioral similarity. Crime linkage decision-support tools should incorporate a range of statistical methods and future research must compare these methods in terms of accuracy, usability, and suitability for practice.

Background While 3D laparoscopy increases surgical performance under laboratory conditions, it is unclear whether it improves outcomes in real clinical scenarios. The aim of this trial was to determine whether the 3D laparoscopy can enhance surgical efficacy in laparoscopic cholecystectomy (LCC). Method This prospective randomized controlled study was conducted between February 2015 and April 2017 in a day case unit of an academic teaching hospital. Patients scheduled for elective LCC were assessed for eligibility. The exclusion criteria were: (1) planned secondary operation in addition to LCC, (2) predicted to be high-risk for conversion, and (3) surgeons with less than five previous 3D laparoscopic procedures. Patients were operated on by 12 residents and 3 attendings. The primary endpoint was operation time. All surgeons were tested for stereoaquity (Randot® stereotest). The study was registered in ClinicalTrials.gov (NCT02357589). Results A total of 210 patients were randomized; 105 to 3D laparoscopy and 104 to 2D laparoscopy. Median operation time as similar in the 3D and 2D laparoscopy groups (49 min vs. 48 min, p = 0.703). Operation times were similar in subgroup analyses for surgeon’s sex (male vs. female), surgeon’s status (resident vs. attending), surgeon’s stereovision (stereopsis 10 vs. less than 10), surgeon’s experience (performed 200 LCCs or below versus over 200 LCCs), or patient’s BMI (≤ 25 vs. 25–30 vs. > 30). No differences in intra- or postoperative complications were noted between the 3D and 2D groups. Conclusion 3D laparoscopy did not show any advantages over 2D laparoscopy in LCC.

Many pathogens possess the capacity for sex through outcrossing, despite being able to reproduce also asexually and/or via selfing. Given that sex is assumed to come at a cost, these mixed reproductive strategies typical of pathogens have remained puzzling. While the ecological and evolutionary benefits of outcrossing are theoretically well-supported, support for such benefits in pathogen populations are still scarce. Here, we analyze the epidemiology and genetic structure of natural populations of an obligate fungal pathogen, Podosphaera plantaginis. We find that the opportunities for outcrossing vary spatially. Populations supporting high levels of coinfection –a prerequisite of sex – result in hotspots of novel genetic diversity. Pathogen populations supporting coinfection also have a higher probability of surviving winter. Jointly our results show that outcrossing has direct epidemiological consequences as well as a major impact on pathogen population genetic diversity, thereby providing evidence of ecological and evolutionary benefits of outcrossing in pathogens., eLife digest The existence of sex – broadly defined as the coming together of genes from different individuals – is one of the big evolutionary puzzles. Reproduction allows an organism to pass on its genes to future generations. However, while asexual and self-fertilizing individuals transmit all of their genes to their offspring, individuals that reproduce through sex transmit only half of their genome. This is considered the cost of sex. Many pathogens reproduce through sex, despite often also being able to reproduce asexually or by self-fertilization. Typically a pre-requisite of sex in pathogens is for at least two different strains to infect the same host. Aside from this limitation, little is known about when, where and why pathogens have sex. It has been tricky to study due to the microscopic size of pathogens and the difficulties of identifying different sexes. Moreover, sexual reproduction may be triggered by environmental cues that are difficult to mimic under controlled experimental conditions. Are there any benefits associated with pathogen sex? To find out, Laine et al. analyzed data collected over the course of four years from thousands of populations of a powdery mildew fungus that infected plants across the Åland islands. This revealed that the opportunities for pathogen sex vary in different locations. Areas where multiple strains of the fungus commonly infect the same plants result in hotspots of new genetic diversity. These mixed populations are also more likely to survive winter. This demonstrates the potential for pathogen sexual reproduction to provide an ecological benefit. Identifying areas and populations where pathogens have sex can help to identify when and where new strains are most likely to emerge. In the future, studies that use similar methods to Laine et al. could help to predict where infections and diseases are highly likely to arise.

Both theory and experimental evolution studies predict migration to influence the outcome of antagonistic coevolution between hosts and their parasites, with higher migration rates leading to increased diversity and evolutionary potential. Migration rates are expected to vary in spatially structured natural pathosystems, yet how spatial structure generates variation in coevolutionary trajectories across populations occupying the same landscape has not been tested. Here, we studied the effect of spatial connectivity on host evolutionary potential in a natural pathosystem characterized by a stable Plantago lanceolata host network and a highly dynamic Podosphaera plantaginis parasite metapopulation. We designed a large inoculation experiment to test resistance of five isolated and five well-connected host populations against sympatric and allopatric pathogen strains, over 4 years. Contrary to our expectations, we did not find consistently higher resistance against sympatric pathogen strains in the well-connectedpopulations. Instead, host local adaptation varied considerably among populations and through time with greater fluctuations observed in the well-connected populations. Jointly, our results suggest that in populations where pathogens have successfully established, they have the upper hand in the coevolutionary arms race, but hosts may be better able to respond to pathogen-imposed selection in the well-connected than in the isolated populations. Hence, the ongoing and extensive fragmentation of natural habitats may increase vulnerability to diseases.

1. Individual-based models (IBMs) allow realistic and flexible modelling of ecological systems, but their parameterization with empirical data is statistically and computationally challenging. Approximate Bayesian computation (ABC) has been proposed as an efficient approach for inference with IBMs, but its applicability to data on natural populations has not been yet fully explored. 2. We construct an IBM for the metapopulation dynamics of a species inhabiting a fragmented patch network, and develop an ABC method for parameterization of the model. We consider several scenarios of data availability from count data to combination of mark-recapture and genetic data. We analyse both simulated and real data on white-starred robin (Pogonocichla stellata), a passerine bird living in montane forest environment in Kenya, and assess how the amount and type of data affect the estimates of model parameters and indicators of population state. 3. The indicators of the population state could be reliably estimated using the ABC method, but full parameterization was not achieved due to strong posterior correlations between model parameters. While the combination of the data types did not provide more accurate estimates for most of the indicators of population state or model parameters than the most informative data type (ringing data or genetic data) alone, the combined data allowed robust simultaneous estimation of all unknown quantities. 4. Our results show that ABC methods provide a powerful and flexible technique forparameterizing complex IBMs with multiple data sources, and assessing the dynamics of the population in a robust manner.

Objective. Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods. Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980–2010. Results. Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p=0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p<0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions. The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

Phylogeny can provide information about the processes that have shaped extant diversity. Here, we complement existing comparative phylogenetic methods by developing a model that couples diversity-dependent diversification rate and range dynamics. Unlike many models, we used Approximate Bayesian Computation to fit the model to the data. We validated the inference by estimating known parameter values from simulated data, and found that within-region speciation and extinction rates cannot be simultaneously estimated most likely due to correlations among parameter values. Since the model can estimate a diversification rate, we applied the model to a monophyletic lineage of 74 species of dung beetles (Canthonini: Nanos and Apotolamprus) endemic to Madagascar. The estimated diversification rate is clearly higher in northern than in eastern or western Madagascar. The current species richness is highest in North where complex topography and a mixture of biomes likely favour ecological diversification. The approach we have developed here is a step towards examining weaknesses and strengths of phylogenetic comparative methods in an explicit spatial context. Further development and testing of the model is needed before its routine application to empirical data.

Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction.

We consider the diffusion approximation of the multivariate Wright-Fisher process with mutation. Analytically tractable formulas for the first-and second-order moments of the allele frequency distribution are derived, and the moments are subsequently used to better understand key population genetics parameters and modeling frameworks. In particular we investigate the behavior of the expected homozygosity (the probability that two randomly sampled genes are identical) in the transient and stationary phases, and how appropriate the Dirichlet distribution is for modeling the allele frequency distribution at different evolutionary time scales. We find that the Dirichlet distribution is adequate for the pure drift model (no mutations allowed), but the distribution is not sufficiently flexible for more general mutation models. We suggest a new hierarchical Beta distribution for the allele frequencies in the Wright-Fisher process with a mutation model on the nucleotide level that distinguishes between transitions and transversions. (C) 2015 Elsevier Inc. All rights reserved.