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Objectives: Colorectal cancer is the third most common cancer worldwide, with an obvious need for more accurate prognostics. Previous studies identified C-reactive protein (CRP) as a prognostic serum biomarker for colorectal cancer, whereas the biomarkers tumor-associated trypsin inhibitor (TATI) and tumor-associated trypsin-2 (TAT-2) are less well-known prognostic factors. Therefore, in this study, we aimed to compare the prognostic role of these biomarkers. Materials and Methods: Our cohort consisted of 219 women and 274 men who underwent colorectal cancer surgery at Helsinki University Central Hospital from 1998 through 2005. Serum and plasma samples were collected before surgery, aliquoted, stored at −80°C, and then analyzed using high-sensitivity methods with commercially available time-resolved immunofluorometric assay kits. Results: In univariate analysis, CRP (HR 1.67; 95% confidence interval [CI]: 1.25–2.23; p = 0.001), TATI (HR 1.87; 95% CI: 1.13–3.08; p = 0.014), and TAT-2 (HR 1.52; 95% CI: 1.13–2.06; p = 0.006) were significant prognostic biomarkers across the entire cohort. In subgroup analyses, TATI and TAT-2 represented significant negative prognostic factors among patients older than 66, while patients with left-sided disease, a high serum TAT-2, or a high plasma CRP experienced worse prognosis. None of the biomarkers emerged as important in the disease stage subgroup analysis nor did they serve as independent factors in the multivariate analysis. Conclusions: TATI and TAT-2 as well as CRP significantly, but not independently, served as prognostic factors in our cohort of colorectal cancer patients. Further research is needed to fully understand their clinical role in colorectal cancer.

Background The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer. Patients and methods A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made. Results Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61–76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11–3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28–3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09–3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15–3.18, P = 0.021) analyses. Conclusion This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.

Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p p p p p p p p p p p p p Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation. Graphical abstract

Purpose High-maternal caffeine intake during pregnancy may be harmful for perinatal outcomes and future child health, but the level of fetal cumulative exposure has been difficult to measure thus far. Here, we present maternal dietary caffeine intake during the last trimester and its correlation to caffeine content in newborn hair after birth. Methods Maternal third trimester diets and dietary caffeine intake were prospectively collected in Kuopio Birth Cohort (KuBiCo) using a 160-item food frequency questionnaire (n = 2840). Newborn hair was collected within 48 h after birth and analyzed by high-resolution mass spectrometry (HRMS) for caffeine (n = 316). Correlation between dietary caffeine intake and neonatal hair caffeine content was evaluated from 203 mother–child pairs. Results Mean dietary caffeine intake was 167 mg/days (95% CI 162–172 mg/days), of which coffee comprised 81%. Caffeine in the maternal diet and caffeine content in newborn hair correlated significantly (r = 0.50; p Conclusion Caffeine exposure, estimated from newborn hair samples, reflects maternal third trimester dietary caffeine intake and introduces a new method to assess fetal cumulative caffeine exposure. Further studies to evaluate the effects of caffeine exposure on both perinatal and postnatal outcomes are warranted, since over 40% of pregnant women consume caffeine more than the current suggested recommendations (European Food Safety Association, EFSA recommendations).

Background Colon cancer (CC) is one of the most commonly diagnosed malignancies worldwide. Several biomarkers have been suggested for improved prognostic evaluation, but few have been implemented in clinical practice. There is a need for biomarkers that predict the tumor behavior in CC and allow stratification of patients that would benefit from adjuvant therapy. We recently identified and functionally characterized a previously unknown protein that we called ASTROPRINCIN (APCN) due to its abundance in astrocytes. APCN, also annotated as FAM171A1, is found in trophoblasts of early placenta. We demonstrated that high expression levels of APCN in cancer cells induced motility and ability of invasive growth in semisolid medium. Methods We screened by immunohistochemistry a tissue microarray material from the tumors of 429 CC patients with clinical follow-up in a test series and 255 CC patients in a validation series. Results We showed that low or absent APCN expression correlates with a favorable prognosis while high APCN expression was a sign of an adverse outcome. Cox uni- and multivariable analysis revealed that elevated tumor expression of APCN constitutes a robust marker of poor prognosis independent of stage, grade, patient’s age, or gender. Conclusion Our findings demonstrate that APCN is a novel independent prognostic marker in CC and could potentially select patients for more intense postoperative adjuvant treatment and follow-up.

ObjectiveThe aim of this study was to evaluate the effects of a single family room architecture in a neonatal intensive care unit (SFR-NICU) on parents’ presence, parent–infant skin-to-skin contact (SSC) and the quality of family centered care.Study designTwo cohorts of parents of preterm infants were compared: those in the unit before and after the move to SFR-NICU. The parents used daily diaries to report their presence and SSC, and they responded to daily text message questions about the quality of family centered care.ResultsParents spent more time in the SFR-NICU, but no significant change was found in SSC. Parents rated the quality of family centered care highly in both unit architectures, without a change in rating after the move.ConclusionThe SFR-NICU increased parents’ presence but not SSC. The change in architecture did not affect parents’ evaluations of the quality of family centered care, which was already highly rated before the move.

Background The physiological benefit of parent-infant skin-to-skin contact (SSC) is uncertain for preterm infants with ventilatory support. We aimed to investigate whether SSC stabilizes the respiration compared to incubator care in mechanically ventilated preterm infants. Methods The prospective observational study was performed in Turku University Hospital, Finland. Preterm infants were eligible if they were born before 36 weeks gestation and received respiratory support with either invasive or non-invasive neurally adjusted ventilatory assist (NAVA). SSC was applied as soon as possible after birth. Respiratory variables were collected from the ventilator log data, and SSC episodes were compared with matched control periods during incubator care. Results A total of 167 episodes of SSC were recorded from 17 preterm infants: 138 episodes during invasive NAVA and 29 episodes during non-invasive NAVA. During invasive NAVA, peak electrical activity of the diaphragm (Edi), minimum Edi, respiratory rate, time on backup ventilation, peak inspiratory pressure, and mean airway pressure were significantly lower in SSC than in incubator care. During non-invasive NAVA, peak Edi, minimum Edi, time on backup ventilation, and peak inspiratory pressure were significantly lower in SSC than in incubator care. Conclusions SSC stabilized and improved the respiratory physiology in mechanically ventilated preterm infants. Impact Skin-to-skin contact reduced work of breathing compared to incubator care in mechanically ventilated preterm infants. Skin-to-skin contact reduced the need for backup ventilation during neurally adjusted ventilatory assist in preterm infants. Skin-to-skin contact among ventilated preterm infants was not only safe but also stabilized and improved their respiratory physiology.

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting., Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.

Background Alarm fatigue is hypothesized to be caused by vast amount of patient monitor alarms. Objectives were to study the frequency and types of patient monitor alarms, to evaluate alarm fatigue, and to find unit specific alarm threshold values in a university hospital emergency department. Methods We retrospectively gathered alarm data from 9 September to 6 October 2019, in Jorvi Hospital Emergency department, Finland. The department treats surgical, internal and general medicine patients aged 16 and older. The number of patients is on average 4600 to 5000 per month. Eight out of 46 monitors were used for data gathering and the monitored modalities included electrocardiography, respiratory rate, blood pressure, and pulse oximetry. Results Total number of alarms in the study monitors was 28 176. Number of acknowledged alarms (ie acknowledgement indicator pressed in the monitor) was 695 (2.5%). The most common alarm types were: Respiratory rate high, 9077 (32.2%), pulse oximetry low, 4572 (16.2%) and pulse oximetry probe off, 4036 (14.3%). Number of alarms with duration under 10 s was 14 936 (53%). Number of individual alarm sounds was 105 000, 469 per monitor per day. Of respiratory rate high alarms, 2846 (31.4%) had initial value below 30 breaths min(-1). Of pulse oximetry low alarms, 2421 (53.0%) had initial value above 88%. Conclusions Alarm sound load, from individual alarm sounds, was nearly continuous in an emergency department observation room equipped with nine monitors. Intervention by the staff to the alarms was infrequent. More than half of the alarms were momentary.

Background and aims We assessed the possibility to rule out negative urine cultures by counting with UriSed 3 PRO (77 Elektronika, Hungary) at Helsinki and Uusimaa Hospital District. Materials and methods Bacteria counting of the UriSed 3 PRO automated microscope was verified with reference phase contrast microscopy against growth in culture. After acceptance into routine, results of bacteria and leukocyte counting from 56 426 specimens with eight UriSed 3 PRO instruments were compared against results from parallel samples cultured on chromogenic agar. Laboratory data including preanalytical details were accessed through the regional database of the Helsinki and Uusimaa Hospital District. Results A combined sensitivity of 87–92% and a negative predictive value of 90–96% with a specificity of 54–50% was reached, depending on criteria. Preanalytical data (incubation time in bladder) combined with the way of urine collection would improve these figures if reliable. Conclusions Complex patient populations, regional logistics and data interfases, and economics related to increased costs of additional particle counts against costs of screening cultures of all samples, did not support adaptation of a screening process of urine cultures. This conclusion was made locally, and may not be valid elsewhere.

Background and aims Ten UriSed 3 PRO automated microscopes (77 Elektronika, Hungary) were verified for nine HUSLAB laboratories with 160 000 annual urine samples. Materials and methods Particle counting of the primary UriSed 3 PRO instrument (77 Elektronika, Hungary) was verified against reference visual microscopy with 463 urine specimens, and against urine culture on chromogenic agar plates with parallel 396 specimens. Nine secondary instruments were compared pairwise with the primary instrument. Results Relative imprecisions compared to Poisson distribution, R(CV), were estimated to be 1.0 for white blood cell (WBC) and 1.5 for red blood cell (RBC) counts, respectively. Spearman’s correlations against visual microscopy were rS = 0.94 for WBC, rS = 0.87 for RBC, and rS = 0.82 for squamous epithelial cell (SEC) counts. Agreement with visual microscopy (Cohen’s weighted kappa) was 0.94 for WBC, 0.89 for RBC, 0.88 for SEC, 0.59 for combined casts, and 0.49 for non-squamous epithelial cells (NEC). Bacteria were detected with a sensitivity of 90 % and specificity of 39 against culture at 107 CFB/L (104 CFU/mL. Created flagging limits allowed automated reporting for 70-75 % of patient results. Conclusions UriSed 3 PRO instruments were adopted into routine use after acceptance of the verification.

Aims The use of computed tomography pulmonary angiography (CTPA) in the detection of pulmonary embolism (PE) has considerably increased due developing technology and better availability of imaging. The underuse of pre-test probability scores and overuse of CTPA has been previously reported. We sought to investigate the indications for CTPA at a University Hospital emergency clinic and seek for factors eliciting the potential overuse of CTPA. Methods and results Altogether 1001 patients were retrospectively collected and analysed from the medical records using a structured case report form. PE was diagnosed in 222/1001 (22.2%) of patients. Patients with PE had more often prior PE/deep vein thrombosis, bleeding/thrombotic diathesis and less often asthma, chronic obstructive pulmonary disease, coronary artery disease, or decompensated heart failure. Patients were divided into three groups based on Wells PE risk-stratification score and two groups based on the revised Geneva score. A total of 9/382 (2.4%), 166/527 (31.5%), and 47/92 (52.2%) patients had PE in the CTPA in the low, intermediate, and high pre-test likelihood groups according to Wells score, and 200/955 (20.9%) and 22/46 (47.8%) patients had PE in the CTPA in the low-intermediate and the high pre-test likelihood groups according to the revised Geneva score, respectively. D-dimer was only measured from 568/909 (62.5%) and 597/955 (62.5%) patients who were either in the low or the intermediate-risk group according to Wells score and the revised Geneva score. Noteworthy, 105/1001 (10.5%) and 107/1001 (10.7%) of the CTPAs were inappropriately ordered according to the Wells score and the revised Geneva score. Altogether 168/1001 (16.8%) could theoretically be avoided. Conclusions This study highlights scant utilization of guideline-recommended risk-stratification tools in CTPA use at the emergency department.

Motivation A major challenge in analyzing cancer patient transcriptomes is that the tumors are inherently heterogeneous and evolving. We analyzed 214 bulk RNA samples of a longitudinal, prospective ovarian cancer cohort and found that the sample composition changes systematically due to chemotherapy and between the anatomical sites, preventing direct comparison of treatment-naive and treated samples. Results To overcome this, we developed PRISM, a latent statistical framework to simultaneously extract the sample composition and cell-type-specific whole-transcriptome profiles adapted to each individual sample. Our results indicate that the PRISM-derived composition-free transcriptomic profiles and signatures derived from them predict the patient response better than the composite raw bulk data. We validated our findings in independent ovarian cancer and melanoma cohorts, and verified that PRISM accurately estimates the composition and cell-type-specific expression through whole-genome sequencing and RNA in situ hybridization experiments. Availabilityand implementation https://bitbucket.org/anthakki/prism. Supplementary information Supplementary data are available at Bioinformatics online.

Aim: To evaluate the validity of the Language Environment Analysis (LENA) system's automatic measures in two neonatal intensive care units supporting parent-infant closeness, and in two Finno-Ugric languages: Finnish and Estonian. Methods: The sound environment of 70 very preterm infants was recorded for 16 h in the neonatal intensive care units with the LENA system roughly at the gestational age of 32 (+2) weeks. Of these, the recordings of 14 infants (20%, two 5-min samples with a high percentage of speech, totally 140 min) were analysed in detail and in two different ways. Parental closeness diaries were used to document the presence of the parents. Agreements between LENA system and human coder estimates were analysed. Results: Findings showed a high variation in agreements. The highest agreements were found in female and adult word counts (r = 0.91 and 0.95). The agreements for child vocalisation count, conversational turns and silence were modest or low (r = −0.03 to 0.64). Conclusion: Our study provides novel information on the validity of the LENA system in the neonatal intensive care unit. Findings show that the LENA system provides valid information on adult words, but LENA estimates for child vocalisations were less valid at this early age. publishedVersion

Recent studies have acknowledged the many benefits of including fossils in phylogenetic inference (e.g., reducing long-branch attraction). However, unstable taxa are known to be problematic, as they can reduce either the resolution of the strict consensus or branch support. In this study, we evaluate whether unstable taxa that reduce consensus resolution affect support values, and the extent of such impact, under equal and extended implied weighting. Two sets of analyses were conducted across 30 morphological datasets to evaluate complementary aspects. The first focused on the analytical conditions incrementing the terminal instability, while the second assessed whether pruning wildcards improves support. Changes in support were compared with the “number of nodes collapsed by unstable terminals,” their “distance to the root,” the “proportion of missing data in a dataset,” and the “proportion of sampled characters.” Our results indicate that the proportion of missing entries distributed among closely related taxa (for a given character) might be as detrimental for stability as those distributed among characters (for a given terminal). Unstable terminals that (1) collapse few nodes or (2) are closely located to the root node have more influence on the estimated support values. Weighting characters according to their extra steps while assuming that missing entries contribute to their homoplasy reduced the instability of wildcards. Our results suggest that increasing character sampling and using extended implied weighting decreases the impact of wildcard terminals. This study provides insights for designing future research dealing with unstable terminals, a typical problem of paleontological data.

Background Fine motor and coordination problems are frequently reported among adolescents born preterm. We aimed to assess performance in hand coordination tasks and to compare concurrent brain activation between adolescents born very preterm and at term at 13 years. Methods A total of 34 right-handed adolescents born very preterm (gestational age less than 32 weeks/birth weight ≤1500 grams) and 37 controls born at term during 2003 to 2006 in Turku University Hospital, Finland, were recruited. At 13 years, finger opposition and diadochokinesis were assessed, and brain functional magnetic resonance imaging data were acquired while the adolescents performed unimanual hand coordination tasks in response to visual cue. Results Adolescents born very preterm performed similar to controls in hand coordination tasks. The very preterm group evoked greater brain activation than the controls in the right precentral gyrus and in the right postcentral gyrus during left-hand finger opposition and in the right postcentral gyrus during left-hand diadochokinesis. Within the very preterm group, lower gestational age was associated with reduced activation in the left superior parietal lobule during right-hand diadochokinesis. Regarding left-hand tasks, lower gestational age was associated with stronger activation in the right cerebellar lobule V and left cerebellar lobule VI during finger opposition and stronger activation in the right superior parietal lobule during diadochokinesis. Conclusions Very preterm birth affected hand coordination-related brain activation. Most of the effects were found for nondominant hand. Clinical performance during the hand coordination tasks was similar in adolescents born very preterm and controls.

A series of substituted sulfonanilide analogs were prepared and evaluated as novel potent inhibitors of SH2 domaincontaining inositol polyphosphate 5′-phosphatase 2 (SHIP2). SHIP2 has been shown to be a new attractive target for the treatment of insulin resistance in type 2 diabetes mellitus (T2D), which can lead to life-threatening diabetic kidney disease (DKD). Amongst the synthesized compounds, the two most promising candidates, 10 and 11, inhibited SHIP2 significantly. Additionally, these compounds induced Akt activation in a dose-dependent manner, increased the presence of glucose transporter 4 at the plasma membrane, and enhanced glucose uptake in cultured myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.

Background: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP. Methods: Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at −80°C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival. Results: High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41–0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45–0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33–0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08–2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35–0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04–4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37–0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28–1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables. Conclusions: High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.

OBJECTIVE To examine the impact of alcohol consumption on the treatment profile, mortality and causes of death in intensive care unit (ICU)-admitted patients with liver cirrhosis and other liver disease. METHODS Data on liver disease and ICU treatment of patients with previously diagnosed liver disease between 2015 and 2017 were retrospectively collected from medical records at Oulu University Hospital, Finland. The median follow-up was 367 days. The causes of death were obtained from Statistics Finland. RESULTS From 250 patients, high-risk alcohol consumption was present in 74.7% (71 of 95) cirrhotic patients and 43.2% (67 of 155) patients in the other liver disease group. Gastrointestinal causes were the most common admission causes. Despite the higher SOFA scores in the alcoholic liver cirrhosis patients compared with the non-alcoholic cirrhosis, there were no differences in the need for organ support, length of ICU stay or outcome between the groups or the subgroups. There were no differences in 1-year mortality between the cirrhosis groups (alcoholic cirrhosis 43.7% versus non-alcoholic cirrhosis 45.8%, p = 1.0) or between the other liver disease groups (patients with alcohol consumption 37.3% versus patients without alcohol consumption 36.4%, p = 1.0). The patients with high-risk alcohol consumption died more often due to liver disease, whereas the patients without high-risk alcohol consumption died often due to malignancies. CONCLUSIONS We report no significant impact of alcohol consumption on the ICU treatment profile or mortality of patients with cirrhosis or other liver disease. The high mortality underlines the importance of preventive measures after ICU admission.

Motivation Single-cell proteomics technologies, such as mass cytometry, have enabled characterization of cell-to-cell variation and cell populations at a single-cell resolution. These large amounts of data, require dedicated, interactive tools for translating the data into knowledge. Results We present a comprehensive, interactive method called Cyto to streamline analysis of large-scale cytometry data. Cyto is a workflow-based open-source solution that automates the use of state-of-the-art single-cell analysis methods with interactive visualization. We show the utility of Cyto by applying it to mass cytometry data from peripheral blood and high-grade serous ovarian cancer (HGSOC) samples. Our results show that Cyto is able to reliably capture the immune cell sub-populations from peripheral blood and cellular compositions of unique immune- and cancer cell subpopulations in HGSOC tumor and ascites samples. Availabilityand implementation The method is available as a Docker container at https://hub.docker.com/r/anduril/cyto and the user guide and source code are available at https://bitbucket.org/anduril-dev/cyto. Supplementary information Supplementary data are available at Bioinformatics online.

Catechol-O-methyltransferase (COMT) methylates both endogenous and exogenous catechol compounds to inactive and safe metabolites. We first optimised conditions for a convenient and sensitive continuous fluorescence-based 6-O-methylation assay of esculetin, which we used for investigating the COMT activity in human, mouse, rat, dog, rabbit, and sheep liver cytosols and microsomes and in ten different rat tissues. Furthermore, we compared the inhibition potencies and mechanisms of two clinically used COMT inhibitors, entacapone and tolcapone, in these species. In most tissues, the COMT activity was at least three times higher in cytosol than in microsomes. In the rat, the highest COMT activity was found in the liver, followed by kidney, ileum, thymus, spleen, lung, pancreas, heart, brain, and finally, skeletal muscle. Entacapone and tolcapone were characterised as highly potent mixed type tight-binding inhibitors. The competitive inhibition type dominated over the uncompetitive inhibition with entacapone, whereas uncompetitive inhibition dominated with tolcapone. Rats, dogs, pigs, and sheep are high COMT activity species, in contrast to humans, mice, and rabbits; COMT activity is highest in the liver. Both entacapone and tolcapone are potent COMT inhibitors, but their inhibition mechanisms differ.

Background Heavy alcohol use has been associated with altered circulating metabolome. We investigated whether changes in the circulating metabolome precede incident diagnoses of alcohol-related diseases. Methods This is a prospective population-based cohort study where the participants were 42-60-year-old males at baseline (years 1984-1989). Subjects who received a diagnosis for an alcohol-related disease during the follow-up were defined as cases (n = 92, mean follow-up of 13.6 years before diagnosis). Diagnoses were obtained through linkage with national health registries. We used two control groups: controls who self-reported similar levels of alcohol use as compared to cases at baseline (alcohol-controls, n = 92), and controls who self-reported only light drinking at baseline (control-controls, n = 90). A non-targeted metabolomics analysis of baseline serum samples was performed. Results There were significant differences between the study groups in the baseline serum levels of 64 metabolites: in amino acids (e.g. glutamine [FDR corrected q-value = 0.0012]), glycerophospholipids (e.g. lysophosphatidylcholine 16:1 [q = 0.0008]), steroids (e.g. cortisone [q = 0.00001]), and fatty acids (e.g. palmitoleic acid [q = 0.0031]). The main finding was that after controlling for baseline levels of self-reported alcohol use and the biomarker of alcohol use, gamma-glutamyl transferase, and when compared to both alcohol-control and control-control group, the alcohol-case group had lower serum levels of asparagine (Cohen's d = -0.48 [95% CI -0.78 to -0.19] and d = -0.49 [-0.78 to -0.19], respectively) and serotonin (d = -0.45 [-0.74 to -0.15], and d = -0.46 [-0.75 to -0.16], respectively), with no difference between the two control groups (asparagine d = 0.00 [-0.29 to 0.29], and serotonin d = -0.01 [-0.30 to 0.29]). Conclusions Changes in the circulating metabolome, especially lower serum levels of asparagine and serotonin, are associated with later diagnoses of alcohol-related diseases, even after adjustment for the baseline level of alcohol use.

Background Preterm and sick infants benefit from parent-infant closeness and family-centered care (FCC) in neonatal intensive care units (NICUs). Prospective and feasible tools are needed to measure these care practices to facilitate their implementation. Aims To describe the development process of three prospective data collection tools that measure parent-infant closeness and the quality of FCC. Methods Data collection tools were developed in an iterative process consisting of three development cycles. Feedback was gathered from parents, staff, and researchers. The first stages of development focused on the content validity, appropriate scaling, and optimization of the response rate of these tools. Results The study included parents of 490 infants and the nurses working at bedside in 15 NICUs in six countries. The Parent-Infant Closeness Diary was developed to measure the daily duration of parental presence, holding, and skin-to-skin contact. The optimal duration for daily diaries was 14 consecutive days to maintain a good response rate. Parents provided reliable documentation of parent-infant closeness. Digital FCC tools covering the nine aspects of FCC for parents and nurses were developed to measure the quality of FCC. Participants provided answers on a 7-point Likert scale. Parents' response rates remained >50% for approximately 1 month, and the nurses' mean response rate was 55% (39%-87%) for the 3-month study period. Linking evidence to action These new tools provide prospective daily information to aid the implementation of parent-infant closeness and the quality of FCC in NICU in different countries. They can be used to study and evaluate the implementation of these clinical practices NICUs in an international context.

Sagittaria is a genus of ca. 40 species in the aquatic plant family Alismataceae with a nearly global distribution, and a center of diversity in the New World. Two thirds of the known species are native to the Americas, while only a few species are distributed in Africa, Asia and Europe. A previous biogeographic analysis of the genus suggested an African origin for the genus with subsequent dispersal to North America and then to East Asia. Here we expanded the taxon sampling with a focus on the New World taxa and applied species delimitation and biogeographic analyses to revise the knowledge of the phylogeny and evolution of the genus. We obtained largely similar topologies from the chloroplast DNA and nuclear DNA (ITS) data sets. The 74 accessions sampled for our analyses were delimited into 29 species and several cryptic taxa were revealed in widely distributed species. Biogeographic analysis supported basal diversification in South America and subsequent colonization to North America and Asia.

Objectively defined early-onset hypertension, based on repeated blood pressure measurements, is associated with greater odds of organ damage and cardiovascular mortality than late-onset hypertension. In this study we examined the association between two factors that are easily available in primary care, self-reported hypertension onset age and electrocardiographic left ventricular hypertrophy (ECG-LVH), in a nationwide population sample of 2864 Finns aged ≥50 years. We observed that, in contrast to prior findings, the odds of ECG-LVH were similar between self-reported hypertension onset age groups, and thus self-reported early-onset hypertension does not seem to associate with ECG-LVH more strongly than simple presence of hypertension.

Background Isolated greater tuberosity fractures account for up to a fifth of all proximal humeral fractures. There have been several retrospective cohort studies and case series reporting outcomes after treatment of this pathology. This study aims to report on the clinical outcomes of surgically treated isolated greater tuberosity fractures, as well as diagnostic workup and complications associated with fracture fixation. Methods A systematic review was performed under PRISMA guidelines to identify studies that reported the results or clinical outcomes of isolated greater tuberosity fracture. The searches were performed using MEDLINE through PubMed, the Elsevier Embase database, and the Cochrane Database of Systematic Reviews. Results Sixteen studies met inclusion criteria comprising 345 patients and 345 shoulders. The mean age was 52.9 years and mean follow-up was 3.4 months. The mean postoperative American Shoulder and Elbow Surgeon Score, the most frequently utilized patient reported outcome measure across studies, was 90.1% of ideal maximum. All studies used standard shoulder radiographs in their initial workup and most commonly referred to a minimum of 5 mm displacement as an indication for surgery. Fifty five percent of patients were treated using open fixation and 35.9 with arthroscopic fixation. Ninety three percent of patients were able to return to work. A total of fifty-two (15.1%) complications were reported in the included studies. Conclusions The current literature describes overall satisfactory functional outcomes and minimal occupational morbidity following either open or arthroscopic fixation of isolated greater tuberosity fractures despite a notable rate of complications. Level of Evidence IV, systematic review.

Oxidovanadium complexes with organic ligands are well known to have cytotoxic or differentiating capabilities against a range of cancer cell types. Their limited use in clinical testing though has resulted largely from uncertainties about the long-term toxicities of such complexes, due in part to the speciation to vanadate ions in the circulation. We hypothesised that more highly stable complexes, delivered using liposomes, may provide improved opportunities for oxidovanadium applications against cancer. In this study we sourced specifically hydrophobic forms of oxidovanadium complexes with the explicit aim of demonstrating liposomal encapsulation, bioavailability in cultured neuroblastoma cells, and effective cytotoxic or differentiating activity. Our data show that four ethanol-solubilised complexes with amine bisphenol, aminoalcohol bisphenol or salan ligands are equally or more effective than a previously used complex bis(maltolato)oxovanadium(V) in neuroblastoma cell lines. Moreover, we show that one of these complexes can be stably incorporated into cationic liposomes where it retains very good bioavailability, apparently low speciation and enhanced efficacy compared to ethanol delivery. This study provides the first proof-of-concept that stable, hydrophobic oxidovanadium complexes retain excellent cellular activity when delivered effectively to cancer cells with nanotechnology. This offers the improved prospect of applying oxidovanadium-based drugs in vivo with increased stability and reduced off-target toxicity.

Background Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden. Methods We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries. Results We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children Conclusions Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines.

Most organisms have finite life spans. The maximum life span of mammals, for example, is at most some years, decades, or centuries. Why not thousands of years or more? Can we explain and predict maximum life spans theoretically, based on other traits of organisms and associated ecological constraints? Existing theory provides reasons for the prevalence of ageing, but making explicit quantitative predictions of life spans is difficult. Here, I show that there are important unappreciated differences between two backbones of the theory of senescence: Peter Medawar's verbal model, and William Hamilton's subsequent mathematical model. I construct a mathematical model corresponding more closely to Medawar's verbal description, incorporating mutations of large effect and finite population size. In this model, the drift barrier provides a standard by which the limits of natural selection on age-specific mutations can be measured. The resulting model reveals an approximate quantitative explanation for typical maximum life spans. Although maximum life span is expected to increase with population size, it does so extremely slowly, so that even the largest populations imaginable have limited ability to maintain long life spans. Extreme life spans that are observed in some organisms are explicable when indefinite growth or clonal reproduction is included in the model.

Summary Multiple protocols have been published for generation of iMGLs from hESCs/iPSCs. To date, there are no guides to assist researchers to determine the most appropriate methodology for microglial studies. To establish a framework to facilitate future microglial studies, we first performed a comparative transcriptional analysis between iMGLs derived using three published datasets, which allowed us to establish the baseline protocol that is most representative of bona fide human microglia. Secondly, using CRISPR to tag the classic microglial marker CX3CR1 with nanoluciferase and tdTomato, we generated and functionally validated a reporter ESC line. Finally, using this cell line, we demonstrated that co-culture of iMGL precursors with human glia and neurons enhanced transcriptional resemblance of iMGLs to ex vivo microglia. Together, our comprehensive molecular analysis and reporter cell line are a useful resource for neurobiologists seeking to use iMGLs for disease modeling and drug screening studies., Highlights • Integrated molecular characterization reveals differences in four iMGL protocols • A dual tdTomato and nanoluciferase reporter tool was generated to track iMGLs via CX3CR1 • Kinetics of surface marker expression during iMGL differentiation • Co-culture with glia/neurons restores ex vivo microglial transcription factors, In this article, Jose Polo and colleagues molecularly compare existing microglia differentiation methods from stem cells, generate a new dual fluorescent and enzymatic reporter tool to study microglia, and show that human glia/neuron co-culture pushes the regulatory landscape of in vitro microglia-like cells to more closely resemble bona fide microglia.

Background While previous studies have evaluated the effect of some patient characteristics (e.g. gender, American Society of Anesthesiologists (ASA) class and comorbidity) on outcome in orthopedic and hand day surgery, more detailed information on anesthesia related factors has previously been lacking. Our goal was to investigate the perioperative factors that affect overstay, readmission and contact after day surgery in order to find certain patient profiles more prone to problemed outcomes after day surgery. Methods We examined orthopedic and hand day surgery at an orthopedic day surgery unit of Helsinki University Hospital. Patient data of all adult orthopedic and hand day surgery patients (n = 542) over a 3-month period (January 1 – March 31, 2015) operated on at the unit were collected retrospectively using the hospital’s surgery database. These data comprised anesthesia and patient records with a follow-up period of 30 days post-operation. Patients under the age of 16 and patients not eligible for day surgery were excluded. Patient records were searched for an outcome of overstay, readmission or contact with the emergency room or policlinic. Pearson chi-square test, Fischer’s exact test and multivariable logistic regression were used to analyze the effect of various perioperative factors on postoperative outcome. Results Various patient and anesthesia related factors were examined for their significance in the outcomes of overstay, readmission or contact. Female gender (p = 0.043), total amount of fentanyl (p = 0.00), use of remifentanil (p = 0.036), other pain medication during procedure (p = 0.005) and administration of antiemetic medication (p = 0.048) emerged as statistically significant on outcome after day surgery. Conclusions Overstay and readmission in orthopedic and hand day surgery were clearly connected with female patients undergoing general anesthesia and needing larger amounts of intraoperative opioids. By favoring local and regional anesthesia, side effects of general anesthesia, as well as recovery time, will decrease.

OBJECTIVES The optimal temperature management of hypothermic circulatory arrest is still controversial. Moderate hypothermia preserves cerebral autoregulation and shortens cardiopulmonary bypass (CPB) duration. However, moderate hypothermia alone has inferior organ protection to deep hypothermia, so adjuncts that increase the ischaemic tolerance are needed. Thus, we hypothesized that a combination of remote ischaemic preconditioning (RIPC) and moderate hypothermia would be superior to deep hypothermia alone. METHODS Sixteen pigs were randomized to either RIPC or control groups (8 + 8). The RIPC group underwent 4 cycles of transient hind limb ischaemia. The RIPC group underwent cooling with CPB to 24°C, and the control group underwent cooling with CPB to 18°C, followed by a 30-min arrest period and subsequent rewarming to 36°C. Measurements of cerebral metabolism were made from sagittal sinus blood samples and common carotid artery blood flow. The permissible periods of hypothermic circulatory arrest were calculated based on these measurements. Neurological recovery was evaluated daily during a 7-day follow-up, and the brain was harvested for histopathological analysis. RESULTS Six pigs in the RIPC group reached normal neurological function, but none in the control group reached normal neurological function (P = 0.007). The composite neurological score of all postoperative days was higher in the RIPC group than in the control group [55 (52–58) vs 45 (39–51), P = 0.026]. At 24°C, the estimated permissible periods of hypothermic circulatory arrest were 21 (17–25) min in the RIPC group and 11 (9–13) min in the control group (P = 0.007). CONCLUSIONS RIPC combined with moderate hypothermia provides superior cerebral protection.

Aims Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are inflammatory cardiomyopathies sharing histopathological and clinical features. Their differentiation is difficult and susceptible of confusion and apparent mistakes. The possibility that they represent different phenotypes of a single disease has been debated. Methods and results We made a retrospective audit of 73 cases of GCM diagnosed in Finland since the late 1980s. All available histological material was reanalyzed as were other examinations pertinent to the distinction between GCM and CS. Finding granulomas in or outside the heart was considered diagnostic of CS and exclusive of GCM. Altogether 45 of the 73 cases of GCM (62%) were reclassified as CS. In all except one case, this was based on finding sarcoid granulomas that either had been originally missed (n = 29) or misinterpreted (n = 11) or were found in additional posttransplant myocardial specimens (n = 3) or samples of extracardiac tissue (n = 1) accrued over the disease course. Supporting the reclassification, patients relocated to the CS group had less heart failure at presentation (prevalence 20% vs. 46%, P = 0.017) and better 1 year transplant-free survival (82% vs. 45%, P = 0.011) than patients considered to represent true GCM. Conclusions Recognizing granulomas in or outside the heart remains a challenge for the pathologist. Given that CS and GCM are considered distinct diseases and granulomas exclusive of GCM, many cases of GCM, if thoroughly scrutinized, may need reclassification as CS. However, whether CS and GCM are truly different entities or parts of a one-disease continuum has not yet been conclusively settled.

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

PURPOSE The purpose of the co-development project was to create a tool that enhances children's active participation and agency in rehabilitation and in everyday life. MATERIALS AND METHODS Action research was the methodological approach. Participants in the different phases of the process (2015-2017) were children with disabilities, parents and rehabilitation professionals. The co-development process included: (1) designing the tool's first version, (2) piloting the tool, (3) evaluating the tool by collecting feedback and reflection, (4) generating the tool's final version. RESULTS Through the co-development process, an accommodating and digital tool called the CMAP Book-a description of the child's meaningful activities and participation-was developed. The CMAP Book is used with an electronic app enabling the identification and description of what is meaningful in daily life from the child's perspective with videos, photos, pictures, recording and writing. The tool enables the child, family and professionals to prepare and build collaboration in rehabilitation with flexibility according to child and family needs. CONCLUSIONS Use of the CMAP Book promotes the active involvement of the child and parents in designing the rehabilitation process in daily life in partnership with professionals. The stakeholder involvement in the co-development facilitated meaningful results and a concrete tool for rehabilitation.IMPLICATIONS FOR REHABILITATIONThe CMAP book is a new tool that enhances the child's active participation and agency in the rehabilitation process based on meaningful activities in everyday life expressed by the child.Identifying and utilising meaningful issues in the child's daily life through collaboration increases the child's commitment and motivation, and thus may enhance the benefits and effects of rehabilitation. Through co-development, the child and his/her family can be active and equal partners not only in development projects but also in the rehabilitation process.In the future, child-specific practices and policies should be developed to promote participatory co-research between families and clinicians linked to the daily lives of families with children.

We investigated how the phylogenetic structure of Amazonian plant communities varies along an edaphic gradient within the non‐inundated forests. Forty localities were sampled on three terrain types representing two kinds of soil: clayey soils of a high base cation concentration derived from the Solimões formation, and loamy soils with lower base cation concentration derived from the Içá formation and alluvial terraces. Phylogenetic community metrics were calculated for each locality for ferns and palms both with ferns as one group and for each of three fern clades with a crown group age comparable to that of palms. Palm and fern communities showed significant and contrasting phylogenetic signals along the soil gradient. Fern species richness increased but standard effect size of mean pairwise distance (SES.MPD) and variation of pairwise distances (VPD) decreased with increasing soil base cation concentration. In contrast, palm communities were more species rich on less cation‐rich soils and their SES.MPD increased with soil base cation concentration. Species turnover between the communities reflected the soil gradient slightly better when based on species occurrences than when phylogenetic distances between the species were considered. Each of the three fern subclades behaved differently from each other and from the entire fern clade. The fern clade whose phylogenetic patterns were most similar to those of palms also resembled palms in being most species‐rich on cation‐poor soils. The phylogenetic structuring of local plant communities varies along a soil base cation concentration gradient within non‐inundated Amazonian rain forests. Lineages can show either similar or different phylogenetic community structure patterns and evolutionary trajectories, and we suggest this to be linked to their environmental adaptations. Consequently, geological heterogeneity can be expected to translate into a potentially highly diverse set of evolutionarily distinct community assembly pathways in Amazonia and elsewhere., We investigated the phylogenetic structure of Amazonian fern and palm communities on edaphically distinct sites. We show that phylogenetic community structure varies along a soil base cation concentration gradient within non‐inundated Amazonian rain forests. Our results suggest that geological heterogeneity can translate into a potentially highly diverse set of evolutionarily distinct community assembly pathways in Amazonia.

Soybean dwarf virus (SbDV, genus Luteovirus) is a single-stranded positive-sense RNA virus able to infect several legume species. SbDV was first reported in Japan where it was associated with significant yield losses in soybean (Tamada, 1969). Since then the virus has been detected worldwide. In Europe, the virus has only been reported from Germany (Abraham et al. 2007; Gaafar et al. 2020). In July 2018, several white clover plants (Trifolium repens L.) with leaf discoloration were observed in different locations in Oulu region in northern Finland. Individual plants were collected and analysed for the presence of viruses using small-RNA (sRNA) sequencing (Kreuze et. al. 2009) and reverse transcription-PCR (RT-PCR). Total RNA was extracted using EZNA micro RNA kit (Omega Bio-Tek, GA, USA). For sRNA analysis, sequencing libraries were constructed using the TruSeq small RNA library prep kit (Illumina, CA, USA) and sequenced on Illumina MiSeq platform. On average, 1.3 million single-end reads were obtained per sample, of which 27% were 18-25 nt long and used for the subsequent analysis. Contig assembly and virus identification with VirusDetect software (Zheng et al. 2017) detected SbDV in five out of six white clover samples analysed. Depending on the sample, 26-39 contigs (with lengths up to 301-469 nt) aligned to complete genome of a SbDV isolate previously described from white clover in USA (accession no. JN674402). The cumulative alignment coverage ranged from 35.5 % to 65.3 % with nucleotide identities between 94.4 % and 97.3 %. Additionally, two samples seemed to contain an unidentified closterovirus and one contained White clover cryptic virus 2. No additional viruses were detected from two of the samples.To confirm the presence of SbDV, the samples were tested by RT-PCR using primers MDF, MYF and MUR in multiplex (Schneider et al. 2011) together with SuperScript III One-Step RT-PCR System with the Platinum Taq DNA polymerase kit (Thermo Fisher Scientific, USA), essentially as instructed by the manufacturer. RT-PCR product of approximately 400 bp was produced from each of the five samples previously tested SbDV positive by sRNA analysis. No products were produced from the sample that was SbDV negative in sRNA analysis. Direct sequencing of two of the PCR products produced 347 and 361 bp sequences (GenBank: MZ355392 and MW929169) that were 95.7 % and 95.2 % identical, respectively, to a SbDV isolate (accession no. AB038148) that causes yellowing on soybean and is transmitted by Acyrthosiphon pisum (Terauchi et al. 2003). To our knowledge this is the first report of SbDV in Finland. SbDV is transmitted only by aphids (neither mechanical nor seed transmission occurs). In siRNA analysis all the isolates from Finland formed contigs that aligned almost perfectly (100 % coverage with ≥ 99 % nucleotide identity) to the coat protein (accession no. EF466131) of an SbDV isolate transmittable from white clover to faba bean by A. pisum (Abraham et al. 2007), an aphid common in Finland. Although significant yield losses by SbDV have only been reported on soybean (Tamada, 1969), the virus also causes symptoms in other legume crops, such as growth reduction on pea (Tian et al. 2017) and faba bean (Abraham et al. 2007), both of which are cultivated in Finland. References: Abraham et al. 2007. Plant Dis. 91: 1059. Gaafar et al. 2020. Front microbiol. 11: 583242. Kreuze et al. 2009. Virology 388:1. Schneider et al. 2011. Virology 412: 46. Tamada. 1969. Ann Phytopathol Soc Jpn. 35: 282. Terauchi et al. 2003. Phytopathology 93: 1560. Tian et al. 2017. Viruses 9: 155. Zheng et al. 2017. Virology 500: 130.

Adaptive radiations have proven important for understanding the mechanisms and processes underlying biological diversity. The convergence of form and function, as well as admixture and adaptive introgression, are common in adaptive radiations. However, distinguishing between these two scenarios remains a challenge for evo-lutionary research. The Midas cichlid species complex (Amphilophus spp.) is a prime example of adaptive radiation, with phenotypic diversification occurring at various stages of genetic differentiation. One species, A. labiatus, has large fleshy lips, is as-sociated with rocky lake substrates, and occurs patchily within Lakes Nicaragua and Managua. By contrast, the similar, but thin- lipped, congener, A. citrinellus, is more com-mon and widespread. We investigated the evolutionary history of the large- lipped form, specifically regarding whether the trait has evolved independently in both lakes from ancestral thin- lipped populations, or via dispersal and/or admixture events. We collected samples from distinct locations in both lakes, and assessed differences in morphology and ecology. Using RAD-seq, we genotyped thousands of SNPs to measure population structure and divergence, demographic history, and admixture. We found significant between-species differences in ecology and morphology, local intraspecific differences in body shape and trophic traits, but only limited intraspe-cific variation in lip shape. Despite clear ecological differences, our genomic approach uncovered pervasive admixture between the species and low genomic differentiation, with species within lakes being genetically more similar than species between lakes. Taken together, our results suggest a single origin of large-lips, followed by pervasive admixture and adaptive introgression, with morphology being driven by local ecologi-cal opportunities, despite ongoing gene-flow., Funding was also provided by a Monash University travel grant (to WS) and from the SYNTHESYS Project (http://www.synthesys.info/) financed by the European Community Research Infrastructure Action under the FP7 "Capacities" Program (to TKL and MB).

Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP−/−) mouse podocytes. Oxidative stress was also increased in CD2AP−/− mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP−/− or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP−/− podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT- and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP.

Background: Organ protection for transplantation is perfusion with ice-cold preservation solutions, although saline is also used in animal experiments and living donor transplantations. However, ice-cold perfusion can contribute to initial graft injury. Our aim was to test if cytoskeletal damage of parenchymal cells is caused by saline itself or by the ice-cold solution. Methods: F344 rat kidneys were flushed with cold (4 &deg, C) saline, ischemic and sham kidneys were not perfused. In a separate set, F344 kidneys were flushed with saline or preservation solution at 4 or 15 &deg, C. Ischemia time was 30 min. Results: Renal injury was significantly more severe following cold ischemia (CI) than after ischemia-reperfusion without flushing (ischemia/reperfusion (I/R)). Functional and morphologic damage was accompanied by severe loss of ezrin from glomerular and tubular epithelial cells after CI. Moreover, saline caused serious injury independently from its temperature, while the perfusion solution was more beneficial, especially at 4 &deg, C. Conclusions: Flushing the kidney with ice-cold saline can cause more severe injury than ischemia-reperfusion at body temperature even during a short (30 min) ischemia. Saline perfusion can prolong recovery from ischemia in kidney transplantation, which can be prevented by using preservation solutions.

Motivation Non-parametric dimensionality reduction techniques, such as t-distributed stochastic neighbor embedding (t-SNE), are the most frequently used methods in the exploratory analysis of single-cell datasets. Current implementations scale poorly to massive datasets and often require downsampling or interpolative approximations, which can leave less-frequent populations undiscovered and much information unexploited. Results We implemented a fast t-SNE package, qSNE, which uses a quasi-Newton optimizer, allowing quadratic convergence rate and automatic perplexity (level of detail) optimizer. Our results show that these improvements make qSNE significantly faster than regular t-SNE packages and enables full analysis of large datasets, such as mass cytometry data, without downsampling. Availability and implementation Source code and documentation are openly available at https://bitbucket.org/anthakki/qsne/. Supplementary information Supplementary data are available at Bioinformatics online.

Background The objective of this study was to examine how nonverbal skills at age five years relate to visual perception and brain activation during visual perception tasks at age 12 years in very preterm subjects without visual or other neurodevelopmental impairments or major brain pathologies. Methods At age five years, 36 prematurely born (birth weight ≤1500 g or gestational age less than 32 weeks) and 31 term-born control children were assessed with the nonverbal subtests of the Wechsler Preschool and Primary Scale of Intelligence-Revised and the NEPSY-Second Edition. At age 12 years the same children were re-assessed with tasks from the Motor-Free Visual Perception Test, Third Edition, during functional magnetic resonance imaging. Results Test performance at age five years was significantly poorer in the very preterm group than the control subjects, but at age 12 years performance was similar in both groups. In the very preterm group, better nonverbal skills at age five years were significantly associated with stronger neural activation during the visual perception task at age 12 years. No associations between nonverbal skills at age five years and brain activation at age 12 years appeared in the control group. Conclusions The associations between better nonverbal skills and stronger neural activation during visual perception task only observed in the very preterm group may reflect delayed development of the visual perception network and/or prematurity-related neural plasticity. The developmental follow-up of very preterm children should include psychological assessment of nonverbal skills at least until age five years.

Background: Epidemiologic evidence suggests that diets rich in whole grains are associated with a reduced risk of developing chronic diseases and all-cause mortality. However, the molecular mechanisms behind these beneficial metabolic effects are poorly understood. Objective: Our aim was to investigate novel trimethylated (betainized) compounds from mice and humans, and their association with whole grain-rich diets and insulin resistance and insulin secretion. Design: Fasting plasma samples were obtained in a mouse (C57BL/6J male) feeding trial and a controlled dietary intervention. The mouse trial involved feeding the mice a rye and wheat bran-enriched feed which was compared with a high-fat diet. In the human trial, participants recruited from Kuopio, Finland (n = 69) and Naples, Italy (n = 54) with characteristics of the metabolic syndrome were randomly assigned to either a whole grain-enriched diet or a control diet for 12 wk. Plasma concentrations of betainized compounds were analyzed with the use of liquid chromatography-tandem mass spectrometry. Insulin resistance and insulin secretion were assessed in an oral-glucose-tolerance test and a meal-glucose-tolerance test. Results: The betaines that were increased in mouse plasma after bran-enriched feeding were identified de novo via chemical synthesis and liquid chromatography-tandem mass spectrometry, and confirmed to be associated with an increased intake of whole-grain products in humans. In particular, the concentrations of pipecolic acid betaine were increased at the end of the whole-grain intervention in both the Kuopio cohort (P

Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wahala, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119

Motivation Fusion genes are both useful cancer biomarkers and important drug targets. Finding relevant fusion genes is challenging due to genomic instability resulting in a high number of passenger events. To reveal and prioritize relevant gene fusion events we have developed FUsionN Gene Identification toolset (FUNGI) that uses an ensemble of fusion detection algorithms with prioritization and visualization modules. Results We applied FUNGI to an ovarian cancer dataset of 107 tumor samples from 36 patients. Ten out of 11 detected and prioritized fusion genes were validated. Many of detected fusion genes affect the PI3K-AKT pathway with potential role in treatment resistance. Availabilityand implementation FUNGI and its documentation are available at https://bitbucket.org/alejandra_cervera/fungi as standalone or from Anduril at https://www.anduril.org. Supplementary information Supplementary data are available at Bioinformatics online.

AimThe purpose of the study was to determine aerosol exposure generated by coughing in operation room environments to create a quantitative limit value for high-risk aerosol-generating medical procedures.BackgroundCoughing is known to produce a significant amount of aerosols and is thus commonly used as a best reference for high-risk aerosol-generation. Accordingly, procedures during which aerosol generation exceeds the amount of aerosol generated in instances of coughing are seen as high-risk aerosol generating procedures. However, no reliable quantitative values are available for high-risk aerosol-generation.MethodsCoughing was measured from 37 healthy volunteers in the operating room environment. Aerosol particles generated during coughing within the size range of 0.3–10 µm were measured with Optical Particle Sizer from 40cm, 70cm, and 100cm distances. The distances reflected potential exposure distances where personnel are during surgeries.ResultsA total of 306 coughs were measured. Average aerosol concentration during coughing was 1.580 ± 13.774 particles/cm3 (range 0.000 – 195.528).DiscussionThe aerosol concentration measured in this study can be used as a limit for high-risk aerosol generation in the operating room environment when assessing the aerosol generating procedures and the risk of operating room staff’s exposure for aerosol particles.

The filmy fern genus Trichomanes mainly comprises Neotropical species and a few taxa in Africa and the western Indian Ocean. The aim of this study is to infer the phylogenetic placement of all five Afro-Malagasy taxa in the genus and to investigate their history via an expanded and dated phylogenetic analysis including 39 species representing over half the diversity of the genus. The results support the monophyly of Trichomanes including all the sampled species attributed to the genus, but also suggest the inclusion of the species Abrodictyum cellulosum, revealing a morphological diversity of the genus greater than what was traditionally recognized, and highlighting the importance of the campanulate sorus as a generic diagnostic character. To accommodate those new phylogenetic results and morphological investigations, we describe a new subgenus Afrotrichomanes grouping the Afro-Malagasy taxa (except T. crenatum). The dated history of the genus among the trichomanoids suggests at least two origins for the Palaeotropical species. A recent Cainozoic colonization from the Neotropics towards Africa gave rise to the West African taxon T. crenatum, and a possible Mesozoic vicariance event gave rise to subgenus Afrotrichomanes. The low species diversity of the genus in the Afro-Malagasy region is discussed.

During neurally adjusted ventilatory assist (NAVA) both the timing and degree of ventilatory assist are controlled by the patient's respiratory center (1) resulting in improved synchrony and lower peak inspiratory pressures and lower oxygen requirements compared with conventional ventilation in low birth weight infants (2,3). However, there are no randomized controlled trials yet available evaluating the effects of NAVA ventilation on the neurodevelopmental outcomes, nor are there studies reporting the use of NAVA ventilation as a standard neonatal intensive care unit practice in extremely preterm infants.