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The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Tadpole pupil is a rare phenomenon characterized by a brief and irregular deformation of the pupil caused by segmental contraction of the iris dilator muscle. It is most prevalent in adult women and is, in these cases, often associated with migraine., Case Presentation: We present a unique case of a 16-year-old girl who presented with recurrent episodes of tadpole pupil and vestibular migraine. This association has not been previously demonstrated in pediatric patients. During a thorough clinical examination, a thyroid carcinoma was found which due to its localization was not causative of the tadpole pupil and was considered an incidental finding., Conclusions: The association between migraine and tadpole pupil in this patient, which has not previously been described in pediatric patients, adds to the demographics of tadpole pupil. A possible pathophysiological link between the two conditions is discussed but further research is needed to understand the pathophysiology underpinning it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Scheid, Gammelgaard Henneberg and Hansen.)

With ongoing global warming, increasing water deficits promote physiological stress on forest ecosystems with negative impacts on tree growth, vitality, and survival. How individual tree species will react to increased drought stress is therefore a key research question to address for carbon accounting and the development of climate change mitigation strategies. Recent tree-ring studies have shown that trees at higher latitudes will benefit from warmer temperatures, yet this is likely highly species-dependent and less well-known for more temperate tree species. Using a unique pan-European tree-ring network of 26,430 European beech (Fagus sylvatica L.) trees from 2118 sites, we applied a linear mixed-effects modeling framework to (i) explain variation in climate-dependent growth and (ii) project growth for the near future (2021-2050) across the entire distribution of beech. We modeled the spatial pattern of radial growth responses to annually varying climate as a function of mean climate conditions (mean annual temperature, mean annual climatic water balance, and continentality). Over the calibration period (1952-2011), the model yielded high regional explanatory power (R 2  = 0.38-0.72). Considering a moderate climate change scenario (CMIP6 SSP2-4.5), beech growth is projected to decrease in the future across most of its distribution range. In particular, projected growth decreases by 12%-18% (interquartile range) in northwestern Central Europe and by 11%-21% in the Mediterranean region. In contrast, climate-driven growth increases are limited to around 13% of the current occurrence, where the historical mean annual temperature was below ~6°C. More specifically, the model predicts a 3%-24% growth increase in the high-elevation clusters of the Alps and Carpathian Arc. Notably, we find little potential for future growth increases (-10 to +2%) at the poleward leading edge in southern Scandinavia. Because in this region beech growth is found to be primarily water-limited, a northward shift in its distributional range will be constrained by water availability., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

The future performance of the widely abundant European beech (Fagus sylvatica L.) across its ecological amplitude is uncertain. Although beech is considered drought-sensitive and thus negatively affected by drought events, scientific evidence indicating increasing drought vulnerability under climate change on a cross-regional scale remains elusive. While evaluating changes in climate sensitivity of secondary growth offers a promising avenue, studies from productive, closed-canopy forests suffer from knowledge gaps, especially regarding the natural variability of climate sensitivity and how it relates to radial growth as an indicator of tree vitality. Since beech is sensitive to drought, we in this study use a drought index as a climate variable to account for the combined effects of temperature and water availability and explore how the drought sensitivity of secondary growth varies temporally in dependence on growth variability, growth trends, and climatic water availability across the species' ecological amplitude. Our results show that drought sensitivity is highly variable and non-stationary, though consistently higher at dry sites compared to moist sites. Increasing drought sensitivity can largely be explained by increasing climatic aridity, especially as it is exacerbated by climate change and trees' rank progression within forest communities, as (co-)dominant trees are more sensitive to extra-canopy climatic conditions than trees embedded in understories. However, during the driest periods of the 20th century, growth showed clear signs of being decoupled from climate. This may indicate fundamental changes in system behavior and be early-warning signals of decreasing drought tolerance. The multiple significant interaction terms in our model elucidate the complexity of European beech's drought sensitivity, which needs to be taken into consideration when assessing this species' response to climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD)., Methods: We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable., Results: We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1 kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n = 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p = 0.004) and mortality (hazard ratio 3.22, p = 0.01)., Conclusion: LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring., Impact and Implications: Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Early detection of liver fibrosis is believed to promote lifestyle changes. We evaluated self-reported changes in alcohol intake, diet, exercise, and weight after participating in a screening study for liver fibrosis., Methods: We conducted a prospective screening study of individuals at risk of alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD). We provided lifestyle advice to all participants and evaluated lifestyle changes by questionnaires after 1 week and 6 months, with re-examination of a subgroup after 2 years., Results: A total of 1850 at risk of ALD and 2946 at risk of MASLD were included, of whom 383 (8%) were screening positive (transient elastography ≥8 kPa). A total of 84% replied to the 6-month questionnaire. In ALD participants, excessive drinking decreased from 46% to 32% after 6 months. Only 15% reported increased drinking, without differences between screening positive and negative individuals (P = .698). In high-risk drinkers, a positive screening test predicted abstinence or decreased alcohol use after 6 months (odds ratio, 2.45; 95% confidence interval, 1.32-4.57; P = .005). After 2 years, excessive drinking decreased from 52% to 41% in a subgroup of 752 individuals and a positive screening test predicted abstinence or decreased alcohol use after 2 years (odds ratio, 1.84; 95% confidence interval, 1.09-3.11, P = .023). MASLD participants showed similar improvements: 35% improved their diet, 22% exercised more, and 13% reported a weight loss ≥5% after 6 months., Conclusions: Screening for liver fibrosis is associated with sustained improvements in alcohol consumption, diet, weight, and exercise in at-risk ALD and MASLD. The changes are most pronounced in screening positive participants but not limited to this group., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Steatotic liver disease is a new overarching term that includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related steatotic liver disease (MetALD), and alcohol-related liver disease (ALD). We aimed to validate the prognostic importance of MASLD, MetALD, and ALD as steatotic liver disease subclasses., Methods: Between April 18, 2013, and Sept 17, 2018, we prospectively recruited patients aged 18-75 years with current or previous excessive alcohol intake (>24 g/day for women and >36 g/day for men) for at least a year and no previous hepatic decompensation from the Department of Gastroenterology and Hepatology at Odense University Hospital (Odense, Denmark). Participants were followed up until Sept 15, 2022. Here, we characterise these patients according to steatotic liver disease subclasses. We classified patients as having MASLD, MetALD, or ALD in accordance with the nomenclature definitions, on the basis of metabolic comorbidity and self-reported average alcohol intake in the 3 months leading up to inclusion. Histological scoring was done by a pathologist who was masked to the clinical data. We compared prognoses between classes using Cox regression analyses on hepatic decompensation and overall mortality as the two outcome measures. Patients not meeting the criteria for steatotic liver disease were classified as no steatotic liver disease and served as a reference group., Findings: We enrolled 446 patients with a history of excessive alcohol intake were included in this analysis (334 [75%] were male and 112 [25%] were female; median age 56 years [SD 10]). Cirrhosis was present in 58 (13%), and 435 (98%) had at least one cardiometabolic risk factor. 321 (72%) met steatotic liver disease criteria and 125 (28%) did not have steatotic liver disease, meaning no evident liver steatosis and no significant fibrosis (≥F2). Of the 321 patients with steatotic liver disease, six (2%) were identified as having ALD due to the absence of cardiometabolic risk factors. The remaining 315 (98%) patients presented with at least one cardiometabolic risk factor. Of these patients, 153 (49%) had MASLD, 76 (24%) had MetALD, and 86 (27%) had ALD. During follow-up, 67 (15%) of 446 patients decompensated and 97 (22%) died (median follow-up 70 months [IQR 53-94]). Patients with steatotic liver disease had a significantly higher risk of hepatic decompensation and overall mortality than those without steatotic liver disease, independent of age, sex, and liver stiffness. The risk of decompensation increased in a stepwise manner from MASLD (hazard ratio 4·73 [95% CI 1·03-21·6]), through MetALD (7·69 [1·66-35·6]), to ALD (10·2 [2·24-46·4]). Similarly, overall mortality increased from MASLD (HR 2·30 [95% CI 1·08-4·90]), through MetALD (2·94 [1·31-6·58]), to ALD (3·57 [1·64-7·80]), independent of age, sex, and liver stiffness., Interpretation: Steatotic liver disease and its subclasses portend distinct prognoses. There is a need to specify how historical alcohol intake should be integrated into the nomenclature and risk stratification of steatotic liver disease., Funding: EU Horizon 2020 Research and Innovation Program., Competing Interests: Declaration of interests JKH has received speaking fees from Norgine. CW received an EASL bursary to attend the International Liver Congress (ILC) 2023. KPL received an EASL bursary to attend ILC 2023, has received consulting fees from Novo Nordisk and speaking fees and support for travel from Siemens, and owns stock in Evido. EAT has received consulting fees from Novo Nordisk, Boehringer, Pfizer, and Siemens, and speaking fees from Echosens, NovoNordisk, and Dr Falk. MT has received grants from the Novo Nordisk Foundation, consulting fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, speaking fees from Siemens Healthcare, Norgine, Echosens, Tillotts Pharma, Takeda, and Madrigal; and is vice chair on the board of non-governmental organisation Alcohol & Society and co-founder and board member for Evido. MER, in the past 24 months, has done scientific consulting for Boehringer Ingelheim, Intercept Pharmaceuticals, Madrigal, NGM Biopharmaceuticals, Novo Nordisk, GlaxoSmithKline, Sonic Incytes, Histoindex, Takeda, and CytoDyn, and has received support for travel to symposia from GlaxoSmithKline and Novo Nordisk. AK has received grants from EU Horizon 2020, the Novo Nordisk Foundation, Innovationfund Denmark, the Danish National Research Foundation, Region of Southern Denmark, and AstraZeneca; receives royalties from Gyldendal as a co-author on a textbook of internal medicine; served as speaker for Novo Nordisk, Norgine, Siemens, and Nordic Bioscience; and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics, Boehringer Ingelheim, and Novo Nordisk, all outside the submitted work. AK has also received research support from Norgine, Siemens, Nordic Bioscience, AstraZeneca, and Echosens, does consulting for Takeda, Resalis Therapeutics, Zealand Pharma, and AlphaSights, and is a board member and co-founder Evido. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background & Aims: Infections are frequent in patients with cirrhosis and worsen prognosis. We evaluated the incidence of infections and their impact on decompensation and death in patients with early alcohol-related liver disease (ALD) during long-term follow-up., Methods: We performed a prospective cohort study of patients in secondary care with a history of excess alcohol intake, no prior decompensation, and with liver biopsies along with clinical investigations conducted at baseline. During follow-up, we reviewed the patients' electronic healthcare records for cases of infections, hospitalizations, transient elastography measurements, decompensations, all-cause mortality, and alcohol intake., Results: We included 461 patients with a mean age of 56±10 years (76% males; fibrosis stage F0-1/F2/F3-4 = 259/107/93 [56%/23%/20%]). During a median follow-up of 4.5 years (IQR 2.9-6.3), 134 patients (29%) developed a total of 312 infections, most frequently pneumonia (106/312, 34%) and urinary tract infections (57/312, 18%). Excessive alcohol intake during follow-up, smoking ≥30 pack years, MELD score and elevated liver stiffness during follow-up were independent predictors of infections. Patients who developed at least one infection had a significantly increased risk of subsequent decompensation (hazard ratio 4.98, 95% CI 2.47-10.03) and death (hazard ratio 8.24, 95% CI 4.65-14.59). Infections increased the risk of decompensation and death independently of baseline fibrosis stage, age, gender, and MELD score., Conclusions: Almost one-third of patients with early ALD develop an infection, which worsens their prognosis by increasing the risk of decompensation and death. The risk of infections increases with liver disease severity and ongoing harmful use of alcohol., Impact and Implications: This study reveals that infections significantly worsen the prognosis of patients with early alcohol-related liver disease (ALD), increasing the likelihood of decompensation and death by up to eight times. These findings, pertinent to healthcare providers, researchers, and policymakers, emphasize the importance of early prevention and management of infections in patients with ALD, even those in early stages who may be asymptomatic. It was observed that nearly one-third of patients with early-stage ALD developed infections over 4.5 years, with risk factors including alcohol overuse, smoking, and higher MELD scores. The research underscores the critical need to incorporate these insights into clinical practice and public health policies to improve patient outcomes and mitigate the impact of infections in patients with ALD., Competing Interests: MT: Speaker’s fee for Echosens, Siemens Healthcare, Norgine, Madrigal, Takeda, and Tillotts Pharma. Advisory fee from GE Healthcare, Boehringer Ingelheim, GSK and AstraZeneca. Co-founder and board member for Evido. Board member for Alcohol & Society (non-governmental organisation). AK has received grants from EU Horizon 2020, Novo Nordisk Foundation, Innovationfund Denmark, Danish National Research Foundation, Region of Southern Denmark, and AstraZeneca, receives royalties from Gyldendal as a co-author on a textbook of internal medicine, served as speaker for Novo Nordisk, Norgine, Siemens and Nordic Bioscience, and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics, Boehringer Ingelheim and Novo Nordisk. Research support; Norgine, Siemens, Nordic Bioscience, AstraZeneca, Echosens. Consulting Takeda, Resalis Therapeutics, Zealand Pharma, AlphaSights. Board member and co-founder of Evido. JKH: Speaker’s fee from Norgine. MK: Speaker’s fee from Siemens Healthcare. SJ, SL, DNR, MI, KL, CDH, KT, NT, PA, USJ, SD, HBJ, and TH have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)

Background: Planting tested forest reproductive material is crucial to ensure the increased resilience of intensively managed productive stands for timber and wood product markets under climate change scenarios. Single-step Genomic Best Linear Unbiased Prediction (ssGBLUP) analysis is a cost-effective option for using genomic tools to enhance the accuracy of predicted breeding values and genetic parameter estimation in forest tree species. Here, we tested the efficiency of ssGBLUP in a tropical multipurpose tree species, Cordia africana, by partial population genotyping. A total of 8070 trees from three breeding seedling orchards (BSOs) were phenotyped for height. We genotyped 6.1% of the phenotyped individuals with 4373 single nucleotide polymorphisms. The results of ssGBLUP were compared with pedigree-based best linear unbiased prediction (ABLUP) and genomic best linear unbiased prediction (GBLUP), based on genetic parameters, theoretical accuracy of breeding values, selection candidate ranking, genetic gain, and predictive accuracy and prediction bias., Results: Genotyping a subset of the study population provided insights into the level of relatedness in BSOs, allowing better genetic management. Due to the inbreeding detected within the genotyped provenances, we estimated genetic parameters both with and without accounting for inbreeding. The ssGBLUP model showed improved performance in terms of additive genetic variance and theoretical breeding value accuracy. Similarly, ssGBLUP showed improved predictive accuracy and lower bias than the pedigree-based relationship matrix (ABLUP)., Conclusions: This study of C. africana, a species in decline due to deforestation and selective logging, revealed inbreeding depression. The provenance exhibiting the highest level of inbreeding had the poorest overall performance. The use of different relationship matrices and accounting for inbreeding did not substantially affect the ranking of candidate individuals. This is the first study of this approach in a tropical multipurpose tree species, and the analysed BSOs represent the primary effort to breed C. africana., (© 2023. The Author(s).)

Background: Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease., Aim: To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls., Methods: Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention., Results: Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis., Conclusion: Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment., Clinical Trial Number: NCT03018990., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone., Methods: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method., Discussion: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis., Trial Registration: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial., (© 2023. The Author(s).)

In-field data were collected in Costa Rica between 2018-2021 on newly planted grafted and non-grafted coffee plants grown under artificial shade nets and across an elevation gradient (1050, 1250 and 1450 m.a.s.l). The coffee plants consisted of Coffea arabica F1 hybrid plants ('H3 i.e. Caturra cv. X Ethiopian 531'), which were derived from a somatic embryogenesis clonal propagation process, an American C. arabica pure line ('Villa Sarchi') and C. canephora 'Nemaya' (the latter two both being produced by seed). Data from eight different coffee types (including these three genotypes) and different grafting combinations (including reverse and auto-grafting) were collected. Data concerned plant traits such as grafting compatibility (plant collar diameters above and below graft union), agronomic characteristics (aerial and root traits), leaf ecophysiology (leaf gas-exchange and chlorophyll fluorescence), yield and quality attributes (bean size, peaberry percentage, WB100 and SCA note). Climate data were also included for comparison on the farm plots along the elevation gradient. Linear mixed models were used to test for effects of elevation (test sites), coffee types (grafted or non-grafted combinations) and interaction between coffee types and elevations. Least square mean estimates were calculated for significant fixed effects and Tukey tests applied for pairwise tests. A tangential hyperbola curve was used to analyse leaf gas-exchange data. These datasets and R scripts can be re-used as a guide for future analyses concerning coffee agronomy or eco-physiological interactions for other plant species. Other potential re-uses could be meta-analyses aimed at comparing coffee yield, quality, or other agronomic traits across different environmental conditions (such as under shade of an agroforestry system or across different elevation sites)., (© 2023 Published by Elsevier Inc.)

Background & Aims: There is a need for accurate biomarkers of fibrosis for population screening of alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We compared the performance of the enhanced liver fibrosis (ELF) test to the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), using transient elastography as the reference standard., Methods: We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8 kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively., Results: We included 3,378 participants (1,973 general population, 953 at risk of ALD, 452 at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in the general population, 12%/14% who were at-risk of ALD/NAFLD, respectively). Most participants with TE <8 kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho = 0.207). ELF was associated with significantly fewer false positives (11%) than FIB-4 and NFS (35% and 45%), while retaining a low rate of false negatives (<8%). A screening strategy of FIB-4 followed by ELF in indeterminate cases resulted in false positives in 8%, false negatives in 4% and the correct classification in 88% of cases. We performed a liver biopsy in 155/242 (64%) patients who screened positive, of whom 54 (35%) had advanced fibrosis (≥F3). ELF diagnosed advanced fibrosis with significantly better diagnostic accuracy than FIB-4 and NFS: AUROC 0.85 (95% CI 0.79-0.92) vs. 0.73 (0.64-0.81) and 0.66 (0.57-0.76), respectively., Conclusion: The ELF test alone or combined with FIB-4 for liver fibrosis screening in the general population and at-risk groups reduces the number of futile referrals compared to FIB-4 and NFS, without overlooking true cases., Impact and Implications: We need referral pathways that are efficient at detecting advanced fibrosis from alcohol-related and non-alcoholic fatty liver disease in the population, but without causing futile referrals or excessive use of resources. This study indicates that a sequential test strategy of FIB-4 followed by the ELF test in indeterminate cases leads to few patients referred for confirmatory liver stiffness measurement, while retaining a high rate of detected cases, and at low direct costs. This two-step referral pathway could be used by primary care for mass, targeted, or opportunistic screening for liver fibrosis in the population., Clinical Trial Number: Clinicaltrials.gov number NCT03308916., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pott's puffy tumor (PPT) is a rare and potentially deadly complication of frontal sinusitis consisting of subperiosteal abscess and osteomyelitis of the frontal bone., Case Presentation: We report the case of a 9-year-old boy who presented with fever and soft tissue swelling of the forehead. Magnetic resonance imaging (MRI) depicted an abscess in the subcutaneous tissue frontally and an epidural empyema, while a cranial computed tomography (CT) scan revealed bone erosion as a sign of osteomyelitis. The patient was treated accordingly., Conclusions: This rare condition is essential to keep in mind as it needs a multidisciplinary approach and relevant imaging to start proper treatment and thus decrease the risk of intracranial complications., (© 2023. The Author(s).)

Background: Alcohol is the leading cause of liver-related mortality worldwide. The gut-liver axis is considered a key driver in alcohol-related liver disease. Rifaximin-α improves gut-barrier function and reduces systemic inflammation in patients with cirrhosis. We aimed to compare the efficacy and safety of rifaximin-α with placebo in patients with alcohol-related liver disease., Methods: GALA-RIF was an investigator-initiated, randomised, double-blind, placebo-controlled, single-centre, phase 2 trial done at Odense University Hospital in Denmark. Eligible participants were adults (aged 18-75 years) who had current or previous alcohol overuse (at least 1 year with ≥24 g of alcohol per day for women and ≥36 g of alcohol per day for men), biopsy-proven alcohol-related liver disease, and no previous hepatic decompensation. Patients were randomly allocated (1:1) through a web-based randomisation system to receive oral rifaximin-α (550 mg) twice daily or matched placebo for 18 months. Randomisation was done in blocks of four and stratified according to fibrosis stage and alcohol abstinence. Participants, sponsor, investigators, and nurses involved in the study were masked to the randomisation outcome. The primary endpoint was a histological decrease from baseline to 18-month treatment of at least one fibrosis stage, according to the Kleiner fibrosis score. We also assessed the number of patients with progression by at least one fibrosis stage from baseline to 18 months. Primary analyses were done in the per-protocol and modified intention-to-treat populations; safety was assessed in the full intention-to-treat population. The per-protocol population was defined as all randomly assigned patients who did not present serious protocol violations, who ingested at least 75% of the treatment, and who were not withdrawn from the study due to non-adherence (interruption of treatment for 4 weeks or more). Participants receiving at least one dose of the intervention were included in the modified intention-to-treat analyses. This completed trial is registered with EudraCT, number 2014-001856-51., Findings: Between March 23, 2015, and Nov 10, 2021, we screened 1886 consecutive patients with a history of excessive alcohol consumption and no previous hepatic decompensation, of whom 136 were randomly assigned to either rifaximin-α (n=68) or placebo (n=68). All patients were White (100%), 114 (84%) were men, and 22 (16%) were women. 133 (98%) patients received at least one dose of the intervention and were included in the modified intention-to-treat analysis; 108 (79%) completed the trial per protocol. In the per-protocol analysis, 14 (26%) of 54 patients in the rifaximin-α group and 15 (28%) of 54 patients in the placebo group had a decrease in fibrosis stage after 18 months (odds ratio 1·10 [95% CI 0·45-2·68]; p=0·83). In the modified intention-to-treat analysis, 15 (22%) of 67 patients in the rifaximin-α group and 15 (23%) of 66 patients in the placebo group had a decrease in fibrosis stage at 18 months (1·05 [0·45-2·44]; p=0·91). In the per-protocol analysis, increase in fibrosis stage occurred in 13 (24%) patients in the rifaximin-α group and 23 (43%) patients in the placebo group (0·42 [0·18-0·98]; p=0·044). In the modified intention-to-treat analysis, increase in fibrosis stage occurred in 13 (19%) patients in the rifaximin-α group and 23 (35%) patients in the placebo group (0·45 [0·20-1·02]; p=0·055). The number of patients with adverse events (48 [71%] of 68 patients in the rifaximin-α group; 53 [78%] of 68 in the placebo group) and serious adverse events (14 [21%] in the rifaximin-α group; 12 [18%] in the placebo group) was similar between the groups. No serious adverse events were deemed related to treatment. Three patients died during the trial, but none of the deaths were considered treatment related., Interpretation: In patients with alcohol-related liver disease, rifaximin-α might reduce progression of liver fibrosis. These findings warrant confirmation in a multicentre phase 3 trial., Funding: The EU Horizon 2020 Research and Innovation Program and The Novo Nordisk Foundation., Competing Interests: Declaration of interests JKH has received speaking fees from Norgine. KPL has received speaking fees and support for travels from Siemens. MKj has received speaking fees from Siemens. MKa owns stock in Nordic Bioscience. MA has received speaking or consulting fees from Roche, Lundbeck Pharma, and SNIPR Biome. JT has received speaking or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Alexion, Falk, Grifols, Genfit, and CSL Behring and participated in advisory boards for Versantis, Alexion, Sobi, Gore, Grifols, Genfit, and CSL Behring. MT has received speaking fees from Siemens Healthcare, Norgine, Echosens, and Tillotts Pharma; consulting fees from GE Healthcare; and participated in advisory boards for ID Liver and Alcohol & Society. AK has served as speaker for Norgine, Siemens, and Nordic Bioscience and participated in advisory boards for Norgine and Siemens, all outside the submitted work. AK receives royalties from Gyldendal and has received equipment, drugs, or other services from Norgine, Siemens, and Echosense. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated., Objective: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet., Design: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078)., Setting: Odense University Hospital in Denmark from November 2016 until June 2020., Participants: 165 participants with T2DM., Intervention: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins., Measurements: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD., Results: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A 1c (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up., Limitation: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons., Conclusion: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention., Primary Funding Source: Novo Nordisk Foundation.

Background: The best choice of orthosis in the treatment of acute Achilles tendon rupture is still under debate., Objective: To investigate if choice of orthosis in the first 3 weeks of treatment affected patient reported outcome (Achilles tendon Total Rupture Score (ATRS)), tendon elongation (Achilles Tendon Resting Angle (ATRA) and Heel Rise Height (HRH)) and re-rupture., Methods: Registry study in the Danish Achilles tendon Database. Patients treated with cast and patients treated with walker in the first 3 weeks of treatment were compared using a linear mixed-effects model adjusted for potential confounders., Results: 1304 patients were included in the study. No clinically relevant difference was found: Adjusted mean difference (using walker the whole period as reference)(95% CI) ATRS after 1 year = 0.1(-3.0; 4.1), ATRS after 6 months = 2.0(-4.5; 5.8), ATRS after 2 years = 3.0(-0.7; 7.0), HRH difference = 0.6(-6.6; 8.2), ATRA difference = 0.03°(-1.5; 1.6), re-rupture(odds ratio) = 0.812(0.4; 1.61)., Conclusion: Patients treated with cast the first 3 weeks after acute Achilles tendon rupture did not have better treatment outcome than patients treated with walker., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Objective: This article describes the methodology used for the Pediatric Craniofacial Collaborative Group (PCCG) Consensus Conference., Design: This is a novel Consensus Conference of national experts in Pediatric Craniofacial Surgery and Anesthesia, who will follow standards set by the Institute of Medicine and using the Research and Development/University of California, Los Angeles appropriateness method, modeled after the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Topics related to pediatric craniofacial anesthesia for open cranial vault surgery were divided into twelve subgroups with a systematic review of the literature., Setting: A group of 20 content experts met virtually between 2019 and 2020 and will collaborate in their selected topics related to perioperative management for pediatric open cranial vault surgery for craniosynostosis. These groups will also identify where future research is needed., Conclusions: Experts in pediatric craniofacial surgery and anesthesiology are developing recommendations on behalf of the Pediatric Craniofacial Collaborative Group for perioperative management of patients undergoing open cranial vault surgery for craniosynostosis and identifying future research priorities., (© 2020 John Wiley & Sons Ltd.)

Background and Aims: Sugammadex is a novel agent for reversal of steroidal neuromuscular blocking agents (NMBAs) with potential advantages over acetylcholinesterase inhibitors. In preclinical trials, there have been rare instances of bradycardia with progression to cardiac arrest. To better define this issue, its incidence and mitigating factors, we prospectively evaluated the incidence of bradycardia after sugammadex administration in adults., Material and Methods: Patients ≥ 18 years of age who received sugammadex were included in this prospective, open label trial. After administration, heart rate (HR) was continuously monitored. HR was recorded every minute for 15 minutes and then every five minutes for the next 15 minutes or until patient was transferred out of the operating room. Bradycardia was defined as HR less than 60 beats/minute (bpm) or decrease in HR by ≥ 10 beats per minute (bpm) if the baseline HR was <70 bpm., Results: The study cohort included 200 patients. Bradycardia was observed in 13 cases (7%; 95% confidence interval: 4, 11), occurring a median of 4 minutes after sugammadex administration (IQR: 4, 9, range: 2-25). Among patients developing bradycardia, two (15%) had cardiac comorbid conditions. One patient received treatment for bradycardia with ephedrine. No clinically significant blood pressure changes were noted. On bivariate analysis, patients receiving a higher initial sugammadex dose were more likely to develop bradycardia. On multivariable logistic regression, initial sugammadex dose was not associated with the risk of bradycardia., Conclusion: The incidence of bradycardia after administration of sugammadex in our study was low and not associated with significant hemodynamic changes., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Anaesthesiology Clinical Pharmacology.)

Background: Acute postinfectious cerebellar ataxia is the most common cause of acute ataxia in childhood. One previous case study has suggested that cerebellar cognitive affective syndrome may be comorbid with acute postinfectious cerebellar ataxia, but this was not confirmed by formal assessments., Methods: Children aged three to 15 years with a confirmed diagnosis of acute postinfectious cerebellar ataxia were invited to participate. Three patients were included and assessed by a pediatrician, neuropsychologist, and logopedist at the subacute stage (less than 14 days post-onset) and after six months and one year of follow-up., Results: All three children complied with the diagnostic criteria of cerebellar cognitive affective syndrome. The cognitive and affective symptoms persisted longer than the motor symptoms. Child A (girl, aged three years and eight months) was most severely affected with slow progression of motor cerebellar symptom; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up. Child B (boy, aged four years and four months) had more subtle motor cerebellar symptoms that swiftly remitted within the first week; the cerebellar cognitive affective symptoms were also more subtle. Child C (boy, aged seven years and eleven months) was considerably affected by motor cerebellar symptoms but showed marked improvement within the first month; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up., Conclusion: Cognitive affective cerebellar syndrome may be an overlooked complication of acute postinfectious cerebellar ataxia. The severity of cerebellar cognitive affective symptoms seemed to correspond to the severity of the cerebellar motor symptoms, but the improvement was remarkably slower., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Sugammadex is a novel agent to reverse steroidal neuromuscular blocking agents (NMBA) with potential clinical advantages over acetylcholinesterase inhibitors such as neostigmine. However, rare instances of bradycardia were reported during its initial clinical trials. To better define this issue, its incidence and mitigating factors, we prospectively evaluated heart rate changes after sugammadex administration in pediatric-aged patients., Methods: Patients less than 18 years of age who were to receive sugammadex were included. After sugammadex administration, heart rate (HR) was recorded every minute for 15 min and then every 5 min for the next 15 min or until the patient was transferred from the operating room. Bradycardia was defined as HR below the 5th percentile for age., Results: The study cohort included 221 children. Bradycardia was noted in 18 cases (8%; 95% confidence interval 5%, 13%), occurring at a median of 2 min (IQR: 1, 6) after sugammadex administration. Among patients developing bradycardia, 7 of 18 (38%) had comorbid cardiac conditions (congenital heart disease). No patient required treatment for bradycardia and no clinically significant blood pressure (BP) changes were noted. On bivariate analysis, initial sugammadex dose was not associated with bradycardia onset. In multivariable analysis, cardiac comorbid conditions and male gender were associated with an increased incidence of bradycardia., Conclusions: The incidence of bradycardia following the administration of sugammadex is low, is not associated with BP changes or other clinically significant effects, and did not require treatment. A higher incidence of bradycardia was noted in patients with cardiac comorbid conditions.

The management of pain and sedation during burn dressing change is challenging. Previous reviews and studies have identified wide variability in such practices in hospitalized burn patients. This survey-based study aimed to determine the most commonly utilized sedation and analgesia practices in adult burn patients treated in the outpatient setting. The goal was to identify opportunities for improvement and to assist burn centers in optimizing sedation procedures. A 23-question survey was sent to members of the American Burn Association. Nonpharmacological interventions including music, television, games, and virtual reality were used by 68% of survey respondents. Eighty-one percent reported premedicating with oral opioids, 32% with intravenous opioids, and 45% with anxiolytics. Fifty-nine percentage of respondents indicated that the initial medication regimen for outpatient dressing changes consisted of the patient's existing oral pain medications. Forty-three percent indicated that there were no additional options if this regimen provided inadequate analgesia. Fifty-six percentage of respondents felt that pain during dressing change was adequately controlled 75% to 100% of the time, and 32% felt it was adequately controlled 50% to 75% of the time. Nitrous oxide was used by 8%. Anesthesia providers and an acute pain service are available in a minority of cases (13.7% and 28%, respectively) and are rarely consulted. Procedural burn pain remains significantly undertreated in the outpatient setting and the approach to treatment is variable among burn centers in the United States. Such variation likely represents an opportunity for identifying and implementing optimal practices and developing guidelines for burn pain management in the outpatient setting., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clinicians nominate the distribution of leg pain as being important in diagnosing nerve root involvement. This study aimed to identify: (i) common unisegmental radicular pain patterns and whether they were dermatomal, and (ii) whether these radicular pain patterns assisted clinician discrimination of the nerve root level involved., Methods: A cross-sectional diagnostic accuracy study of adult patients with radicular leg pain at a hospital in Denmark. All patients had positive neurological signs (average 2.8 signs - hypoalgesia, diminished reflexes, muscle weakness, positive Straight Leg Raise test).Part 1 (pain patterns) was a secondary analysis of baseline pain pattern data collected during a clinical trial. The pain charts of 93 patients with an MRI and clinically confirmed single-level disc herniation with nerve root compression were digitised and layered to form a composite picture of the radicular patterns for the L5 and S1 nerve roots, which were then compared to published dermatomes.In Part 2 (clinical utility) we prospectively measured the discriminative ability of the identified pain patterns. The accuracy was calculated of three groups of six clinicians at classifying the nerve root affected in a randomized sequence of 53 patients, when not shown, briefly shown or continuously shown the composite pain patterns. In each group were two chiropractors, two medical doctors and two physiotherapists., Results: There was a wide overlap in pain patterns from compromised L5 and S1 nerve roots but some distinguishing features. These pain patterns had approximately 50 to 80% overlap with published dermatomes. Clinicians were unable to determine with any accuracy above chance whether an individual pain drawing was from a person with a compromised L5 or S1 nerve root, and use of the composite pain drawings did not improve that accuracy., Conclusions: While pain distribution may be an indication of radiculopathy, pain patterns from L5 or S1 nerve root compression only approximated those of sensory dermatomes, and level-specific knowledge about radicular pain patterns did not assist clinicians' diagnostic accuracy of the nerve root impinged. These results indicate that, on their own, pain patterns provide very limited additional diagnostic information about which individual nerve root is affected., Competing Interests: Competing interestsThe authors have no competing interests to declare., (© The Author(s). 2019.)

Sedation practices for pediatric burn patients during dressing changes vary between institutions and providers. To better understand the current trends in pediatric sedation practice, a survey was conducted among the members of the American Burn Association (ABA). Questions asked about nonoperating room sedation and analgesia practices for burn patients (ages 0-17) having dressing changes in the intensive care unit, inpatient unit, and outpatient clinics. ABA members providing sedation for pediatric patients undergoing burn dressing changes are diverse. Physician respondents included surgeons, critical care intensivists, and anesthesiologists. Others included physician assistants, nurse anesthetists, nurse practitioners, and sedation credentialed nurses. Opioids for pain control were prescribed by 100% of respondents, but use of adjuvant nonopioid analgesics was utilized <50% of the time. Benzodiazepines and ketamine were prescribed more than twice as often as other sedatives. Many noted that up to 50% of children did not have adequately controlled anxiety and pain with initial sedation plans, and escalation of care was needed to complete dressing changes. Self-reported adverse events were infrequent. In outpatient settings, benzodiazepines, ketamine, oral opioids, and topical lidocaine were used frequently, as were nonpharmacologic methods of distraction and comfort. Sedation in pediatric burn patients is challenging. Responses highlighted areas for improvement regarding pain control during dressing changes and increasing use of multimodal analgesia. Commonly used medications including opioids, benzodiazepine, and ketamine are well established in the treatment of burn patients, as are nonpharmacologic methods. A collaborative effort among institutions is needed to formulate practice guidelines for sedation during burn dressing changes., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The natural distribution, habitat, growth and evolutionary history of tree species are strongly dependent on ecological and genetic processes in ecosystems subject to fluctuating climatic conditions, but there have been few experimental comparisons of sensitivity between species. We compared the responses of two broadleaved tree species ( Fagus sylvatica and Quercus petraea ) and two conifer tree species ( Pinus sylvestris and Picea abies ) to climatic transfers by fitting models containing the same climatic variables. We used published data from European provenance test networks to model the responses of individual populations nested within species. A mixed model approach was applied to develop a response function for tree height over climatic transfer distance, taking into account the climatic conditions at both the seed source and the test location. The two broadleaved species had flat climatic response curves, indicating high levels of plasticity in populations, facilitating adaptation to a broader range of environments, and conferring a high potential for resilience in the face of climatic change. By contrast, the two conifer species had response curves with more pronounced slopes, indicating a lower resilience to climate change. This finding may reflect stronger genetic clines in P. sylvestris and P. abies, which constrain their climate responses to narrower climatic ranges. The response functions had maxima that deviated from the expected maximum productivity in the climate of provenance towards cooler/moister climate conditions, which we interpreted as an adaptation lag. Unilateral, linear regression analyses following transfer to warmer and drier sites confirmed a decline in productivity, predictive of the likely impact of ongoing climate change on forest populations. The responses to mimicked climate change evaluated here are of considerable interest for forestry and ecology, supporting projections of expected performance based on "real-time" field data., Competing Interests: The authors declare there are no competing interests.

The genus Quercus comprises important species in forestry not only for their productive value but also for their ability to withstand drought. Hence an evaluation of inter- and intraspecific variation in drought tolerance is important for selecting the best adapted species and provenances for future afforestation. The presence of long vessels makes it difficult to assess xylem vulnerability to embolism in oak. Thanks to the development of an in situ flow centrifuge equipped with a large rotor, we quantified (i) the between species variability of embolism resistance in four native and two exotic species of oaks in Europe and (ii) the within species variability in Quercus petraea . Embolism resistance varied significantly among species, with the pressure inducing 50% loss of hydraulic conductivity ( P 50 ) ranging between - 7.0 and -4.2 MPa. Species native to the Mediterranean region were more resistant than pan-European species. In contrast, intraspecific variability in embolism resistance in Q. petraea was low within provenances and null among provenances. A positive correlation between P 50 and vessel diameter among the six oak species indicates that the more embolism resistant species had narrower xylem vessels. However, this tradeoff between hydraulic efficiency and safety was not observed between Q. petraea provenances.

We assessed the level of geographic differentiation of Tilia cordata in Denmark based on tests of 91 trees selected from 12 isolated populations. We used quantitative analysis of spring phenology and population genetic analysis based on SSR markers to infer the likely historical genetic processes within and among populations. High genetic variation within and among populations was observed in spring phenology, which correlated with spring temperatures at the origin of the tested T. cordata trees. The population genetic analysis revealed significant differentiation among the populations, but with no clear sign of isolation by distance. We infer the findings as indications of ongoing fine scale selection in favor of local growth conditions made possible by limited gene flow among the small and fragmented populations. This hypothesis fits well with reports of limited fruiting in the investigated Danish T. cordata populations, while the species is known for its ability to propagate vegetatively by root suckers. Our results suggest that both divergent selection and genetic drift may have played important roles in forming the genetic patterns of T. cordata at its northern distribution limit. However, we also speculate that epigenetic mechanism arising from the original population environment could have created similar patterns in regulating the spring phenology.

Springtails are important members of the soil fauna and play a key role in plant litter decomposition, for example through stimulation of the microbial activity. However, their interaction with soil microorganisms remains poorly understood and it is unclear which microorganisms are associated to the springtail (endo) microbiota. Therefore, we assessed the structure of the microbiota of the springtail Orchesella cincta (L.) using 16S rRNA gene amplicon sequencing. Individuals were sampled across sites in the field and the microbiota and in particular the endomicrobiota were investigated. The microbiota was dominated by the families of Rickettsiaceae, Enterobacteriaceae and Comamonadaceae and at the genus level the most abundant genera included Rickettsia, Chryseobacterium, Pseudomonas, and Stenotrophomonas. Microbial communities were distinct for the interior of the springtails for measures of community diversity and exhibited structure according to collection sites. Functional analysis of the springtail bacterial community suggests that abundant members of the microbiota may be associated with metabolism including decomposition processes. Together these results add to the understanding of the microbiota of springtails and interaction with soil microorganisms including their putative functional roles.

The ability of perennial species to adapt their phenology to present and future temperature conditions is important for their ability to retain high fitness compared to other competing plant species, pests, and pathogens. Many transplanting studies with forest tree species have previously reported substantial genetic differentiation among populations within their native range. However, the question of "how local is local" is still highly debated in conservation biology because studies on genetic patterns of variation within and among populations at the local scale are limited and scattered. In this study, we compare the level of genetic differentiation among populations of six different perennial plant species based on their variation in spring flushing. We assess the level of additive genetic variation present within the local population. For all six species, we find significant differentiation among populations from sites with mean annual temperature ranging between 7.4°C and 8.4°C. The observed variation can only be partly explained by the climate at the site of origin. Most clear relationship between early flushing and higher average spring temperature is observed for the three wind-pollinated species in the study, while the relations are much less clear for the three insect-pollinated species. This supports that pollination system can influence the balance between genetic drift and natural selection and thereby influence the level of local adaptation in long-lived species. On the positive side, we find that the native populations of woody plant species have maintained high levels of additive genetic variation in spring phenology, although this also differs substantially among the six studied species.

How temperate forests will respond to climate change is uncertain; projections range from severe decline to increased growth. We conducted field tests of sessile oak (Quercus petraea), a widespread keystone European forest tree species, including more than 150 000 trees sourced from 116 geographically diverse populations. The tests were planted on 23 field sites in six European countries, in order to expose them to a wide range of climates, including sites reflecting future warmer and drier climates. By assessing tree height and survival, our objectives were twofold: (i) to identify the source of differential population responses to climate (genetic differentiation due to past divergent climatic selection vs. plastic responses to ongoing climate change) and (ii) to explore which climatic variables (temperature or precipitation) trigger the population responses. Tree growth and survival were modeled for contemporary climate and then projected using data from four regional climate models for years 2071-2100, using two greenhouse gas concentration trajectory scenarios each. Overall, results indicated a moderate response of tree height and survival to climate variation, with changes in dryness (either annual or during the growing season) explaining the major part of the response. While, on average, populations exhibited local adaptation, there was significant clinal population differentiation for height growth with winter temperature at the site of origin. The most moderate climate model (HIRHAM5-EC; rcp4.5) predicted minor decreases in height and survival, while the most extreme model (CCLM4-GEM2-ES; rcp8.5) predicted large decreases in survival and growth for southern and southeastern edge populations (Hungary and Turkey). Other nonmarginal populations with continental climates were predicted to be severely and negatively affected (Bercé, France), while populations at the contemporary northern limit (colder and humid maritime regions; Denmark and Norway) will probably not show large changes in growth and survival in response to climate change., (© 2017 John Wiley & Sons Ltd.)

Background: Craniosynostosis surgery is associated with large volume blood loss and the need for blood transfusion. Recently, the use of tranexamic acid (TXA) has been demonstrated to be helpful in reducing perioperative blood loss in many pediatric procedures. This study used a low-dose pharmacokinetic TXA dosing protocol and assessed its ability to limit perioperative blood loss for craniosynostosis repairs., Methods: A retrospective chart review was conducted of pediatric craniosynostosis surgeries performed at our institution between September 2011 and December 2014. Outcome measures included comparisons of perioperative blood loss and transfusion rates in patients who had surgery with or without TXA., Results: Twenty-five patients met inclusion criteria. Nine patients had craniosynostosis surgery without TXA (no-TXA group) and 16 patients received TXA (TXA group). The TXA group had significantly higher postoperative hemoglobin levels than the no-TXA group (P = 0.009). This finding was supported by significantly higher postoperative estimated red cell volume in the TXA group (P = 0.017). Postoperative 24-hour drain output was significantly lower in the TXA group (P = 0.042). The volume of packed red blood cells transfused perioperatively was not significantly different between groups., Conclusions: Patients who received TXA during craniosynostosis surgery at our institution had higher postoperative hemoglobin levels and lower 24-hour drain output. However, TXA was not associated with lower perioperative blood transfusion rates.

Tadpole pupil is a rarely encountered phenomenon caused by episodic, segmental iris dilator muscle spasm of short duration (2-15 minutes), occurring in clusters without a known precipitating factor. It has most commonly been described in women aged 28 to 48 years. A few hypotheses on pathogenesis have been discussed but none has been proved. Here, we present an adolescent girl with bilateral tadpole pupil that appeared during physical exercise. This is the first pediatric case of tadpole pupil, not caused by preceding surgery, to be published. Based on (1) this case in which tadpole pupil developed when the norepinephrine level rose during exercise, (2) the high ratio of patients with tadpole pupil who concurrently have or later develop Horner syndrome, in which denervation hypersensitivity is well described, (3) a previous report of a patient with both tadpole pupil and Horner syndrome who had denervation hypersensitivity on pharmacological testing, (4) a 29-year-old man with unilateral tadpole pupil induced by exercise, and (5) a 19-year-old man with bilateral tadpole pupil and possible autonomic neuropathy, we suggest denervation hypersensitivity as a probable pathogenic mechanism causing tadpole pupil. In addition, a suggestion for investigations to be performed in future pediatric cases is provided., Competing Interests: Conflict of Interest: None of the authors has any conflict of interest. Financial Disclosure None of the authors has any financial interest to disclose. Funding Source No funding has been provided., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices., Methods: Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes., Results: One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable., Conclusions: The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement.

Background: The cerebellar cognitive affective syndrome (CCAS), is characterised by disturbances in executive functions, visuospatial difficulties, personality changes, and linguistic difficulties. It is well described in other diseases of the cerebellum such as tumour resection and cerebellar stroke but has not previously been described in detail in paediatric cases of acute post-infectious ataxia (APCA)., Methods: Case study. A 12-year-old boy was admitted with severe ataxia, dysmetria, dysdiadokinesia, and dysarthria. He was diagnosed with acute post-infectious cerebellar ataxia (APCA). Besides motor symptoms, the patient showed signs of disturbances in executive functions, visiospatial difficulties, personality changes, and linguistic difficulties. These symptoms correspond to CCAS., Conclusion: CCAS may be an overlooked complication to APCA. In addition, APCA is considered a transient, monophasic disease and studying CCAS in this disease may give insight into subtle cases of CCAS and thus provide new knowledge about CCAS., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Decentralized biomass processing facilities, known as biomass depots, may be necessary to achieve feedstock cost, quantity, and quality required to grow the future U.S. bioeconomy. In this paper, we assess three distinct depot configurations for technical difference and economic performance. The depot designs were chosen to compare and contrast a suite of capabilities that a depot could perform ranging from conventional pelleting to sophisticated pretreatment technologies. Our economic analyses indicate that depot processing costs are likely to range from ∼US$30 to US$63 per dry metric tonne (Mg), depending upon the specific technology implemented and the energy consumption for processing equipment such as grinders and dryers. We conclude that the benefits of integrating depots into the overall biomass feedstock supply chain will outweigh depot processing costs and that incorporation of this technology should be aggressively pursued., (Copyright © 2015. Published by Elsevier Ltd.)

Purpose: Postoperative positive end-expiratory pressure (PEEP) selection in patients who are mechanically ventilated after cardiac operations often seems random. The aim of this investigation was to compare the 2 most common postoperative initial PEEP settings at our institution, 8 and 5 cm H2O, on postoperative initial tracheal intubation time (primary outcome); cardiovascular intensive care unit (CVICU); hospital length of stay (LOS); occurrence of pneumonia; and hospital mortality (secondary outcomes)., Materials and Methods: The electronic medical records of patients who were mechanically ventilated after isolated coronary artery bypass grafting (CABG) or combined CABG and valve operations were reviewed. Propensity score matching was used to compare patients with an initial postoperative PEEP setting of 8 cm H2O (n = 4722 [25.9%]) with those who had PEEP of 5 cm H2O (n = 13 535 [74.1%]) on the primary and secondary outcomes listed earlier., Results: There was no difference in initial postoperative intubation time between the PEEP of 8 cm H2O and the PEEP of 5 cm H2O patient groups (mean 11.9 vs 12.0 hours [median 8.2 vs 8.8 hours], P = .89). The groups did not differ on the occurrence of pneumonia (0.43% vs 0.60%, P = .25) nor on hospital mortality (0.47% vs 0.43%, P = .76). Aspiration pneumonia occurrence approached a significant difference (0.06% vs 0.21%, P value = .052), as did CVICU LOS (mean: 47.9 vs 49.8 hours [median: 28.5 vs 28.4 hours], P = .057), but were not statistically different. There was a slight but likely clinically unimportant difference in hospital LOS (7.7 vs 7.4 days, PEEP = 8 vs 5, P < .001)., Conclusion: Patients being mechanically ventilated after cardiac operations with an initial postoperative PEEP setting of 8 versus 5 cm H2O differed significantly only on hospital LOS but the difference was likely clinically unimportant. Thus, use of 8 cm H2O PEEP in these patients without a clinical indication, although likely not harmful, does not seem beneficial., (© The Author(s) 2014.)

Purpose: Dental treatment of patients with Tourette syndrome (TS) may present special challenges to the dentist. The aim was to systematically review the literature regarding perioperative procedures including sedation and general anaesthesia (GA) of patients with TS., Materials and Methods: Literature searches were performed in PubMed and Embase to identify papers concerning TS in combination with dental treatment, sedation, and/or GA in order to study outcomes regarding co-morbidity, perioperative complications, and drug interactions., Results: The literature search identified six publications (case reports or series) which addressed the topic. No unexpected adverse effects or drug interactions in relation to sedation or GA in TS patients and no perioperative complications were reported., Conclusions: The literature on TS is scarce and the evidence level is low. Therefore, guidelines regarding the dental treatment of patients with TS cannot be formulated at the present time., (© 2014 Special Care Dentistry Association and Wiley Periodicals, Inc.)

Background Context: Blood loss in patients with adolescent idiopathic scoliosis (AIS) who are undergoing posterior spinal instrumentation and fusion (PSIF) varies greatly. The reason for this wide range is not clear. There are reports of unexpected massive hemorrhage during these surgeries. Many studies reflect authors' preferences for describing blood loss in terms of levels fused, weight, or percent blood volume., Purpose: We sought to define excessive blood loss clinically, determine its incidence in our study population, and identify associated variables. Results are intended to inform perioperative preparation for these cases. Results may be used to inform prospective study designs., Study Design: This was a retrospective uncontrolled case series., Patient Sample: A total of 311 consecutive AIS PSIF cases during the years 2005-2010 performed at Children's Hospital Colorado were studied., Outcome Measures: We measured estimated blood loss (EBL) and its association with multiple patient, surgical, and anesthetic variables., Methods: Thirty-one variables potentially related to blood loss were collected retrospectively from electronic medical records for analysis. When no cases of clearly excessive blood loss were identified on the basis of visual examination of EBL distribution, we chose to use the top 10% of blood loss cases as an arbitrary determinant of excessive blood loss. Three cut-off strategies captured the top 10% of EBL cases with little variation in who was selected: 1) >1,700 mL of EBL, 2) >50% EBL/estimated blood volume, and 3) >150 mL/level fused EBL. Variables were compared with the χ(2) test, Fisher exact, or t-tests, when appropriate. A generalized linear mixed logistic model was used to determine the probability of excessive blood loss based on the number of levels fused., Results: The average EBL was 89.17 mL/level fused (range, 45-133 mL). EBL fit a progressively wider distribution as surgical complexity (number of levels fused) increased. Number of levels fused (p<.0001), operative time (p=.0139), number of screws (p<.0001), and maximal preoperative Cobb angle (p=.0491) were significantly associated with excessive blood loss. The variable that was most strongly associated with excessive blood loss was the number of levels fused, with ≥12 levels having a probability of >10% of excessive hemorrhage., Conclusion: Excessive blood loss may be an arbitrary number until future research suggests otherwise. We show that the probability of exceeding one of our arbitrary definitions is approximately 10% when 12 or more levels are fused. If a 10% incidence of excessive blood loss is determined to be clinically relevant, teams might wish to pursue hematologic consultation and maximal blood conservation strategy when 12 or more levels are planned for fusion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To describe the use of antibiotics for urinary tract infection (UTI) before and after surgery for urinary incontinence (UI); and for those with use of antibiotics before surgery, to estimate the risk of treatment for a postoperative UTI, relative to those without use of antibiotics before surgery., Design: A historical population-based cohort study., Setting: Denmark., Participants: Women (age ≥18 years) with a primary surgical procedure for UI from the county of Funen and the Region of Southern Denmark from 1996 throughout 2010. Data on redeemed prescriptions of antibiotics ±365 days from the date of surgery were extracted from a prescription database., Main Outcome Measures: Use of antibiotics for UTI in relation to UI surgery, and the risk of being a postoperative user of antibiotics for UTI among preoperative users., Results: A total of 2151 women had a primary surgical procedure for UI; of these 496 (23.1%) were preoperative users of antibiotics for UTI. Among preoperative users, 129 (26%) and 215 (43.3%) also redeemed prescriptions of antibiotics for UTI within 0-60 and 61-365 days after surgery, respectively. Among preoperative non-users, 182 (11.0%) and 235 (14.2%) redeemed prescriptions within 0-60 and 61-365 days after surgery, respectively. Presurgery exposure to antibiotics for UTI was a strong risk factor for postoperative treatment for UTI, both within 0-60 days (adjusted OR, aOR=2.6 (95% CI 2.0 to 3.5)) and within 61-365 days (aOR=4.5 (95% CI 3.5 to 5.7))., Conclusions: 1 in 4 women undergoing surgery for UI was treated for UTI before surgery, and half of them had a continuing tendency to UTIs after surgery. Use of antibiotics for UTI before surgery was a strong risk factor for antibiotic use after surgery. In women not using antibiotics for UTI before surgery only a minor proportion initiated use after surgery.

Objective: To describe the use of symptom-relieving drugs (antimuscarinic drugs or duloxetine) before and after surgery for urinary incontinence (UI); and for those with use of antimuscarinic drugs or duloxetine before surgery, to estimate the risk of being a postoperative user, relative to those without use before surgery., Design: A historical population-based cohort study., Setting: Denmark., Participants: Women ≥18 years with a first-time surgical procedure for UI from the county of Funen, Denmark between 1 January 1996 and 31 December 2006, extended to the Region of Southern Denmark from 1 January 2007 to the end of 2010. For these women, data on redeemed prescriptions ±365 days of date of surgery were extracted., Main Outcome Measures: Effect of preoperative use of antimuscarinic drugs or duloxetine on the risk of being a postoperative user of these drugs., Results: Of 2151 women with a first-time surgical procedure for UI, 358 (16.6%) were preoperative users of antimuscarinic drugs or duloxetine and 1793 were not (83.4%). A total of 110 (30.7%) of the preoperative users also redeemed prescriptions for these drugs within 0-60 days after surgery, and 152 (42.5%) of the preoperative users redeemed prescriptions for these drugs within 61-365 days after surgery. Among preoperative non-users, 25 (1.4%) and 145 (8.1%) redeemed prescriptions within 0-60 and 61-365 days after surgery, respectively. Presurgery exposure to antimuscarinic drugs or duloxetine was a strong risk factor of postoperative drug use, both within 0-60 days (adjusted OR=33.0, 95% CI 20.0 to 54.7) and 61-365 days (OR=7.2, 95% CI 5.4 to 9.6)., Conclusions: A substantial number of women will continue to be prescribed symptom-relieving drugs after surgery for UI within a year of follow-up. Only a minority of preoperative non-users initiated usage of symptom-relieving drugs after surgery. Compared with other factors included in the regression model, preoperative use of antimuscarinic drugs or duloxetine was the strongest risk factor for postoperative use.

Introduction and Hypothesis: The aim of this study was to evaluate the impact of urogynecological surgery on quality of life based on patient reported outcome measures (PROMs)., Methods: Data were retrieved from the Danish Urogynaecological Database. Inclusion criteria were Danish women undergoing surgery for urinary incontinence (UI) or pelvic organ prolapse (POP) from 2006 to 2011. Using frequency of symptoms and a visual analogue scale (VAS) both pre- and postoperatively, their severity of symptoms and quality of life were measured by questionnaires., Results: During the study period, 20,629 urogynecological procedures were performed. The questionnaires on severity of symptoms and the VAS had been completed both pre- and postoperatively for approximately one third of women undergoing surgery. For UI surgery, 83% had improved symptoms, 13% were unchanged, and 4% had worse symptoms postoperatively. For POP surgery, 80, 17, and 3% were improved, unchanged, and worsened, respectively. The postoperative bother of symptoms and interference in everyday life evaluated by VAS were significantly reduced for both UI [preoperative median VAS score 9, postoperative median score 1 (p < 0.001)] and POP [8 preoperatively and 0 postoperatively (p < 0.001)]., Conclusions: Based on PROMs, surgery for UI and POP is effective in alleviating symptoms associated with UI or POP, and it can improve quality of life in symptomatic women. Pre- and postoperative questionnaires are useful tools in assessing symptomatic outcome measures after surgery.

Introduction and Hypothesis: The Danish Urogynaecological Database (DugaBase) is a nationwide clinical database established in 2006 to monitor, ensure and improve the quality of urogynaecological surgery. We aimed to describe its establishment and completeness and to validate selected variables. This is the first study based on data from the DugaBase., Methods: The database completeness was calculated as a comparison between urogynaecological procedures reported to the Danish National Patient Registry and to the DugaBase. Validity was assessed for selected variables from a random sample of 200 women in the DugaBase from 1 January 2009 to 31 October 2010, using medical records as a reference., Results: A total of 16,509 urogynaecological procedures were registered in the DugaBase by 31 December 2010. The database completeness has increased by calendar time, from 38.2 % in 2007 to 93.2 % in 2010 for public hospitals. All medical records were retrievable for the validation study. The overall percent agreement was at least 90 % for the following variables: surgical procedure code, hospital department, date of surgery, use of antibiotic prophylaxis, prior gynaecological surgery, height, weight, parity and smoking., Conclusions: The database completeness of the DugaBase has improved over time, now with a nearly complete registration from all public hospitals in Denmark. The overall percent agreement between selected variables and medical records is high. We conclude that due to the high degree of database completeness and data of high validity the DugaBase offers a unique possibility for continuing quality assessment of urogynaecological surgery in Denmark and future research.

Application of ferric chloride (FeCl(3)) to exposed blood vessels is widely used to initiate thrombosis in laboratory mice. Because the mechanisms by which FeCl(3) induces endothelial injury and subsequent thrombus formation are little understood, we used scanning electron and brightfield intravital microscopy to visualize endothelial damage and thrombus formation occurring in situ. Contrary to generally accepted belief, FeCl(3) does not result in appreciable subendothelial exposure within the time frame of thrombosis. Furthermore, the first cells to adhere to FeCl(3)-treated endothelial surfaces are red blood cells (RBCs) rather than platelets. Energy dispersive x-ray spectroscopy demonstrated that ferric ions predominantly localize to endothelial-associated RBCs and RBC-derived structures rather than to the endothelium. With continuing time points, RBC-derived structures rapidly recruit platelets, resulting in large complexes that subsequently enlarge and coalesce, quickly covering the endothelial surface. Further studies demonstrated that neither von Willebrand factor nor platelet glycoprotein Ib-α receptor (GPIb-α) is required for RBCs to adhere to the endothelium, and that deficiency of GPIb-α greatly abrogated the recruitment of platelets to the endothelial-associated RBC material. These findings illuminate the mechanisms of FeCl(3)-mediated thrombosis and reveal a previously unrecognized ability of RBCs to participate in thrombosis by mediating platelet adhesion to the intact endothelial surface.

Idiopathic intracranial hypertension is often believed to be an illness exclusively occurring in obese women in their twenties and thirties. This case describes a four-year-old boy presenting with headache, vomiting photophobia and double vision for six days. He did not have a fever; and all exams and tests, including a magnetic resonance imaging of the brain showed normal values. During the eye examination, he was found to have bilateral papilloedema and when undergoing lumbar puncture an elevated pressure of 230 mm H(2)O was discovered. The patient was diagnosed with idiopathic intracranial hypertension and treated with azetazolamide. Within few days, his symptoms disappeared.