Sources of particulate-matter air pollution and its oxidative potential in Europe.

Particulate matter is a component of ambient air pollution that has been linked to millions of annual premature deaths globally1-3. Assessments of the chronic and acute effects of particulate matter on human health tend to be based on mass concentration, with particle size and composition also thought to play a part4. Oxidative potential has been suggested to be one of the many possible drivers of the acute health effects of particulate matter, but the link remains uncertain5-8. Studies investigating the particulate-matter components that manifest an oxidative activity have yielded conflicting results7. In consequence, there is still much to be learned about the sources of particulate matter that may control the oxidative potential concentration7. Here we use field observations and air-quality modelling to quantify the major primary and secondary sources of particulate matter and of oxidative potential in Europe. We find that secondary inorganic components, crustal material and secondary biogenic organic aerosols control the mass concentration of particulate matter. By contrast, oxidative potential concentration is associated mostly with anthropogenic sources, in particular with fine-mode secondary organic aerosols largely from residential biomass burning and coarse-mode metals from vehicular non-exhaust emissions. Our results suggest that mitigation strategies aimed at reducing the mass concentrations of particulate matter alone may not reduce the oxidative potential concentration. If the oxidative potential can be linked to major health impacts, it may be more effective to control specific sources of particulate matter rather than overall particulate mass.

Global spatial risk assessment of sharks under the footprint of fisheries.

Effective ocean management and the conservation of highly migratory species depend on resolving the overlap between animal movements and distributions, and fishing effort. However, this information is lacking at a global scale. Here we show, using a big-data approach that combines satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space-use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively), and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of fishing effort in marine areas beyond national jurisdictions (the high seas). Our results demonstrate an urgent need for conservation and management measures at high-seas hotspots of shark space use, and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real-time, dynamic management.

Translational and Posttranslational Dynamics in a Model Peptidergic System.

The cell bodies of hypothalamic magnocellular neurones are densely packed in the hypothalamic supraoptic nucleus, whereas their axons project to the anatomically discrete posterior pituitary gland. We have taken advantage of this unique anatomical structure to establish proteome and phosphoproteome dynamics in neuronal cell bodies and axonal terminals in response to physiological stimulation. We have found that proteome and phosphoproteome responses to neuronal stimulation are very different between somatic and axonal neuronal compartments, indicating the need of each cell domain to differentially adapt. In particular, changes in the phosphoproteome in the cell body are involved in the reorganization of the cytoskeleton and in axonal terminals the regulation of synaptic and secretory processes. We have identified that prohormone precursors including vasopressin and oxytocin are phosphorylated in axonal terminals and are hyperphosphorylated following stimulation. By multiomic integration of transcriptome and proteomic data, we identify changes to proteins present in afferent inputs to this nucleus.

Real-Time Identification of Aerosol-Phase Carboxylic Acid Production Using Extractive Electrospray Ionization Mass Spectrometry.

Comprehensive identification of aerosol sources and their constituent organic compounds requires aerosol-phase molecular-level characterization with a high time resolution. While real-time chemical characterization of aerosols is becoming increasingly common, information about functionalization and structure is typically obtained from offline methods. This study presents a method for determining the presence of carboxylic acid functional groups in real time using extractive electrospray ionization mass spectrometry based on measurements of [M - H + 2Na]+ adducts. The method is validated and characterized using standard compounds. A proof-of-concept application to α-pinene secondary organic aerosol (SOA) shows the ability to identify carboxylic acids even in complex mixtures. The real-time capability of the method allows for the observation of the production of carboxylic acids, likely formed in the particle phase on short time scales (<120 min). Our research explains previous findings of carboxylic acids being a significant component of SOA and a quick decrease in peroxide functionalization following SOA formation. We show that the formation of these acids is commensurate with the increase of dimers in the particle phase. Our results imply that SOA is in constant evolution through condensed-phase processes, which lower the volatility of the aerosol components and increase the available condensed mass for SOA growth and, therefore, aerosol mass loading in the atmosphere. Further work could aim to quantify the effect of particle-phase acid formation on the aerosol volatility distributions.

Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase kinase 3 (MKK3) inhibitors.

The dual-specificity protein kinase MKK3 has been implicated in tumor cell proliferation and survival, yet its precise role in cancer remains inconclusive. A critical step in elucidating the kinase's involvement in disease biology is the identification of potent, cell-permeable kinase inhibitors. Presently, MKK3 lacks a dedicated tool compound for these purposes, along with validated methods for the facile screening, identification, and optimization of inhibitors. In this study, we have developed a TR-FRET-based enzymatic assay for the detection of MKK3 activity in vitro and a BRET-based assay to assess ligand binding to this enzyme within intact human cells. These assays were instrumental in identifying hit compounds against MKK3 that share a common chemical scaffold, sourced from a library of bioactive kinase inhibitors. Initial hits were subsequently expanded through the synthesis of novel analogs. The resulting structure-activity relationship (SAR) was rationalized using molecular dynamics simulations against a homology model of MKK3. We expect our findings to expedite the development of novel, potent, selective, and bioactive inhibitors, thus facilitating investigations into MKK3's role in various cancers.

3D Models as a Source for Neuroanatomy Education: A Stepwise White Matter Dissection Using 3D Images and Photogrammetry Scans.

White matter dissection (WMD) involves isolating bundles of myelinated axons in the brain and serves to gain insights into brain function and neural mechanisms underlying neurological disorders. While effective, cadaveric brain dissections pose certain challenges mainly due to availability of resources. Technological advancements, such as photogrammetry, have the potential to overcome these limitations by creating detailed three-dimensional (3D) models for immersive learning experiences in neuroanatomy. This study aimed to provide a detailed step-by-step WMD captured using two-dimensional (2D) images and 3D models (via photogrammetry) to serve as a comprehensive guide for studying white matter tracts of the brain. One formalin-fixed brain specimen was utilized to perform the WMD. The brain was divided in a sagittal plane and both cerebral hemispheres were stored in a freezer at -20 °C for 10 days, then thawed under running water at room temperature. Micro-instruments under an operating microscope were used to perform a systematic lateral-to-medial and medial-to-lateral dissection, while 2D images were captured and 3D models were created through photogrammetry during each stage of the dissection. Dissection was performed with comprehensive examination of the location, main landmarks, connections, and functions of the white matter tracts of the brain. Furthermore, high-quality 3D models of the dissections were created and housed on SketchFab®, allowing for accessible and free of charge viewing for educational and research purposes. Our comprehensive dissection and 3D models have the potential to increase understanding of the intricate white matter anatomy and could provide an accessible platform for the teaching of neuroanatomy.

Bachmann-Bupp syndrome and treatment.

Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.

Effect of prolonged feeding of broodstock diet with increased inclusion of essential n-3 fatty acids on maturing and spawning performance in 3-year-old Atlantic salmon (Salmo salar).

Atlantic salmon (Salmo salar) broodstock recruits are normally fed a specialized diet with a higher content of essential nutrients for a limited time period prior to fasting and transfer to freshwater. Typically, this period lasts for about six months, but may vary among producers. Reduced use of marine ingredients in commercial salmon diets during the last decades has affected the content of essential nutrients, such as n-3 long chained polyunsaturated fatty acids (LC-PUFA), minerals and vitamins. Furthermore, to minimize the risk of losses and implement new breeding achievements faster, breeding companies have shortened the production cycle of broodstock from 4 to 3 years, which may affect the number of fish that are large enough to mature. In the present study, we have extended the broodstock feeding period from 6 to 15 months prior to the freshwater transfer giving a higher content of n-3 LC-PUFA (higher inclusion of marine oils) from February to December (Phase 1), and thereafter a diet with a higher energy content to ensure growth towards the spring and maturation (Phase 2). Four sea cages with approximately 80.000 salmon postsmolt, two sea cages with males and two with females, were given a control diet and an experimental diet. Samples were taken in Phase 1 at start (1.7 kg), mid (3.4 kg) and end Phase 1/start of Phase 2 (8.3 kg), and end of Phase 2 (13.4 kg). The fish were thereafter fasted, and selected fish transferred to landbased freshwater tanks where light and temperature were used to manipulate the spawning time of the fish in two groups (early or late). Due to disease in the facility, measures of egg quality and hatching were only obtained from the early group. During the trial and spawning period, biometrical measurements were recorded, and samples of liver, gonad, fillet and red blood cells (RBC) were collected for fatty acid composition and blood plasma for analysis of lipid and health-related parameters. Samples were also collected for gonadal transcriptomic analysis by microarray and qPCR (end Phase 2) and plasma steroids (end Phase 2, mid maturation and spawning). Males fed the test diet had a larger body size compared to the control group at the end of Phase 2, while no differences were observed between dietary groups for the females. Total mortality in the trial was lower in the test group compared to the control, losses were caused mainly by sea lice treatments, loser fish or cardiomyopathy syndrome (CMS). The dietary LC-PUFA levels in the test diet were reflected in the tissues particularly during Phase 1, but only different in the fillet samples and eggs at the end of Phase 2 and at spawning. Plasma sex steroids content increased at mid maturation and showed lower levels of androgens and estrogens in females fed the test diet compared to the control. At the end of Phase 2, transcriptional analysis showed upregulation of steroidogenic enzymes, although not reflected in changes in plasma steroids in Phase 2, indicating changes to come during maturation. The differences in LC-PUFA content in tissues and plasma steroids did not appear to affect fecundity, sperm quality, egg survival or hatching rate, but the test group had larger eggs compared to the control in the early spawner-group. Prolonged feeding of n-3 LC-PUFA to pre-puberty Atlantic salmon broodstock appears to be important for higher survival in challenging sea cage environments and has an effect on sex steroid production that, together with high energy diet during early maturation, cause the test group to produce larger eggs.

Refractive outcomes of immediately sequential bilateral cataract surgery in eyes with long and short axial lengths.

PURPOSE: To report the refractive outcomes of long (≥25.00 mm) and short (≤22.00 mm) axial length (AL) eyes undergoing immediately sequential bilateral cataract surgery (ISBCS). METHODS: In this retrospective cohort study, patients who underwent ISBCS were identified and eyes of patients with bilateral long and short ALs were included. Pre- and postoperative biometry, autorefraction, and ocular comorbidities or complications were recorded. The primary outcome was the mean refractive prediction error. RESULTS: Thirty-seven patients (74 eyes) with long ALs and 18 patients (36 eyes) with short ALs were included. The means ± standard deviations of the ALs were 26.40 ± 1.38 mm and 21.44 ± 0.46 mm in the long and short AL groups, respectively. In long AL eyes, the mean absolute error from the biometry-predicted refraction was - 0.16 ± 0.46 D, corresponding to 74% of eyes achieving a refraction within ±0.50 D of the predicted value. In short AL eyes, the mean absolute error was - 0.63 ± 0.73 D, corresponding to 44% of eyes achieving a refraction within ±0.50 D of the predicted value. Eight (44.4%) patients with short AL eyes had a myopic deviation greater than ±0.50 D from the predicted result in both eyes. CONCLUSIONS: Compared to patients with long AL eyes, ISBCS in patients with short ALs had a wider variance in refractive outcome and a lower rate of achieving a postoperative refraction within ±0.50 D of the predicted target.

Alteration of DNA supercoiling serves as a trigger of short-term cold shock repressed genes of E. coli.

Cold shock adaptability is a key survival skill of gut bacteria of warm-blooded animals. Escherichia coli cold shock responses are controlled by a complex multi-gene, timely-ordered transcriptional program. We investigated its underlying mechanisms. Having identified short-term, cold shock repressed genes, we show that their responsiveness is unrelated to their transcription factors or global regulators, while their single-cell protein numbers' variability increases after cold shock. We hypothesized that some cold shock repressed genes could be triggered by high propensity for transcription locking due to changes in DNA supercoiling (likely due to DNA relaxation caused by an overall reduction in negative supercoiling). Concomitantly, we found that nearly half of cold shock repressed genes are also highly responsive to gyrase inhibition (albeit most genes responsive to gyrase inhibition are not cold shock responsive). Further, their response strengths to cold shock and gyrase inhibition correlate. Meanwhile, under cold shock, nucleoid density increases, and gyrases and nucleoid become more colocalized. Moreover, the cellular energy decreases, which may hinder positive supercoils resolution. Overall, we conclude that sensitivity to diminished negative supercoiling is a core feature of E. coli's short-term, cold shock transcriptional program, and could be used to regulate the temperature sensitivity of synthetic circuits.

Data-driven modeling of equatorial atmospheric waves: The role of moisture and nonlinearity on global-scale instabilities and propagation speeds.

The equatorial region of the Earth's atmosphere serves as both a significant locus for phenomena, including the Madden-Julian Oscillation (MJO), and a source of formidable complexity. This complexity arises from the intricate interplay between nonlinearity and thermodynamic processes, particularly those involving moisture. In this study, we employ a normal mode decomposition of atmospheric reanalysis ERA-5 datasets to investigate the influence of nonlinearity and moisture on amplitude growth, propagation speed, and mode coupling associated with equatorially trapped waves. We focus our analysis on global-scale baroclinic Kelvin and Rossby waves, recognized as crucial components contributing to the variability of the MJO. We examine the dependence of wave amplitudes on the background moisture field in the equatorial region, as measured by total column water vapor. Our analysis demonstrates the crucial role of moisture in exciting these waves. We further investigate the dependence of the propagation speed of the waves on their amplitudes and the background moisture field. Our analysis reveals a robust correlation between the phase speed of the normal modes and their corresponding amplitude, whereas a weaker correlation is found between the eigenmodes' phase speed and the moisture field. Hence, our findings suggest that moisture plays a role in exciting the global-scale Rossby-Kelvin structure of the MJO. In this context, the propagation speed of the eigenmodes is mainly influenced by their amplitudes, underscoring the significant role of nonlinearity in wave propagation.

Interspecific interaction network of mites associated with mango trees.

Direct and indirect ecological interactions, environmental factors, and the phenology of host plants can shape the way mites interact. These relationships interfere with species occurrence and consequently alter the structure and stability of the intraplant community. As predatory mites act as regulators of herbivorous mites, we hypothesized that these mites may occupy a central position in a network of interactions among mite species associated with mango trees, and the occurrence of these species is mediated by environmental variables and the phenological stage of the host plant. We evaluated the global structure of the interaction network of mites associated with individual Mangifera indica plants and analyzed the interspecific relationships of the species using an undirected Bayesian network approach. Additionally, we observed a correlation between mite population density and plant phenological stage. Environmental variables, such as average monthly temperature, monthly precipitation, and average monthly relative humidity at different sampling date were used in the correlation analysis. The modularity at the mite-plant network level showed a low specialization index H2 = 0.073 (generalist) and high robustness (R = 0.93). Network analysis revealed that Amblyseius largoensis, Bdella ueckermanni, Parapronematus acaciae, and Tuckerella ornata occupied central positions in the assembly of mites occurring on mango trees. Environmental variables, average monthly temperature, and monthly precipitation were correlated with the occurrence of Brachytydeus formosa, Cisaberoptus kenyae, Oligonychus punicae, T. ornata, and Vilaia pamithus. We also observed a correlation between the plant phenological stage and population densities of Neoseiulus houstoni, O. punicae, P. acaciae, and V. pamithus.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Do sex, age, and comorbidities modify the association of socioeconomic status and opioid use after total hip arthroplasty?: a population-based study from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: We aimed to examine the association between socioeconomic status (SES) markers and opioid use after primary total hip arthroplasty (THA) due to osteoarthritis, and whether sex, age, or comorbidities modify any association. METHODS: Using Danish databases, we included 80,038 patients undergoing primary THA (2001-2018). We calculated prevalences and prevalence ratios (PRs with 95% confidence intervals [CIs]) of immediate post-THA opioid use (≥ 1 prescription within 1 month) and continued opioid use (≥ 1 prescription in 1-12 months) among immediate opioid users. Exposures were individual-based education, cohabitation, and wealth. RESULTS: The prevalence of immediate opioid use was ~45% in preoperative non-users and ~60% in preoperative users (≥ 1 opioid 0-6 months before THA). Among non-users, the prevalences and PRs of continued opioid use were: 28% for low vs. 21% for high education (PR 1.28, CI 1.20-1.37), 27% for living alone vs. 23% for cohabiting (PR 1.09, CI 1.04-1.15), and 30% for low vs. 20% for high wealth (PR 1.43, CI 1.35-1.51). Among users, prevalences were 67% for low vs. 55% for high education (1.22, CI 1.17-1.27), 68% for living alone vs. 60% for cohabiting (PR 1.10, CI 1.07-1.12), and 73% for low wealth vs. 54% for high wealth (PR 1.32, CI 1.28-1.36). Based on testing for interaction, sex, age, and comorbidity did not statistically significant modify the associations. Nevertheless, associations were stronger in younger patients for all SES markers (mainly for non-users). CONCLUSION: Markers of low SES were associated with a higher prevalence of continued post-THA opioid use. Age modified the magnitude of the associations, but it was not statistically significant.

Multimorbidity measured with Charlson Comorbidity Index is not associated with clinically relevant risk of revision after primary total hip arthroplasty: a population-based cohort study on 98,647 patients from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: Evidence for guiding healthcare professionals on the risks of total hip arthroplasty (THA) in multimorbid patients is sparse. We aimed to examine the association between multimorbidity and the risk of revision due to any cause and specific causes after primary THA due to osteoarthritis. PATIENTS AND METHODS: We identified 98,647 THA patients and subsequent revisions in the Danish Hip Arthroplasty Register from 1995 to 2018. Multimorbidity was measured with the Charlson Comorbidity Index (CCI). Using the CCI (low, medium, high), we calculated the cumulative incidence function (CIF) of first revision up to 10 years after THA. Adjusted cause-specific hazard ratios (aHRs) were estimated using Cox regressions. All estimates are presented with 95% confidence intervals (CI). RESULTS: Overall, the prevalence of patients with low, medium, and high CCI was 70%, 24%, and 6%. The CIF of any revision within 10 years was 6.5% (CI 6.2-6.7) in low and 6.5% (CI 5.8-7.3) in high CCI, with an aHR of 1.4 (CI 1.2-1.6) for patients with high compared with low CCI. The corresponding aHRs for cause-specific revision were 1.3 (CI 1.0-1.6) for aseptic loosening within 10 years, 1.2 (CI 0.9-1.6) for infection, and 1.7 (CI 1.3-2.2) for dislocation, both within 2 years. CONCLUSION: Multimorbidity is associated with a minor but not clinically relevant increased risk of revision up to 10 years after primary THA.

Neuromuscular Blocking Agent Use in Critical Care Transport Not Associated With Intubation.

OBJECTIVE: Variable indications exist for neuromuscular blocking agents (NMBAs) in the critical care transport setting beyond facilitation of intubation. METHODS: This retrospective cohort study included adult patients (≥ 18 years) who underwent critical care transport from July 1, 2020, to May 2, 2023, and received NMBAs during transport that was not associated with intubation. The primary outcome was the indication for NMBA administration. Secondary outcomes included the characterization of NMBA use, mean Richmond Agitation Sedation Scale score before NMBA administration, sedation strategy used, and continuation of NMBAs within 48 hours of hospital admission. RESULTS: One hundred twenty-six patients met the inclusion criteria. The most common indication for NMBA administration was ventilator dyssynchrony (n = 71, 56.4%). The majority of patients received rocuronium during transport (n = 113, 89.7%). The mean pre-NMBA Richmond Agitation Sedation Scale score was -3.7 ± 2.4. The most common sedation strategy was a combination of continuous infusion and bolus sedatives (76.2%). One hundred (79.4%) patients had sedation changes in response to NMBA administration. Seventy-two (57.1%) received NMBAs during the first 48 hours of their intensive care unit admission. CONCLUSION: NMBAs were frequently administered for ventilator dyssynchrony and continuation of prior therapy. Optimization opportunities exist to ensure adequate deep sedation and reassessment of NMBA indication.

Sensitivity Constraints of Extractive Electrospray for a Model System and Secondary Organic Aerosol.

The quantification of an aerosol chemical composition is complicated by the uncertainty in the sensitivity of each species detected. Soft-ionization response factors can vary widely from molecule to molecule. Here, we have employed a method to separate molecules by their volatility through systematic evaporation with a thermal denuder (TD). The fraction remaining after evaporation is compared between an extractive electrospray ionization time-of-flight mass spectrometer (EESI-TOF) and a scanning mobility particle sizer (SMPS), which provides a comparison between a quantified mass loss by the SMPS and the signal loss in the EESI-TOF. The sensitivity of the EESI-TOF is determined for both a simplified complex mixture (PEG-300) and also for a complex mixture of α-pinene secondary organic aerosol (SOA). For PEG-300, separation is possible on a molecule-by-molecule level with the TD and provides insights into the molecule-dependent sensitivity of the EESI-TOF, showing a higher sensitivity toward the most volatile molecule. For α-pinene SOA, sensitivity determination for specific classes is possible because of the number of molecular formula observed by the EESI-TOF. These classes are separated by their volatility and are broken down into monomers (O3-5,6-7,8+), dimers (O4-7,8+), and higher order oligomers (e.g., trimers and tetramers). Here, we show that the EESI-TOF initially measures 60.1% monomers, 32.7% dimers, and 7.2% trimers and tetramers in α-pinene SOA, but after sensitivity correction, the distribution of SOA is 37.4% monomers, 56.1% dimers, and 6.4% trimers and tetramers. These results provide a path forward for the quantification of aerosol components with the EESI-TOF in other applications and potentially for atmospheric measurements.

The phylogeny and global biogeography of Primulaceae based on high-throughput DNA sequence data.

The angiosperm family Primulaceae is morphologically diverse and distributed nearly worldwide. However, phylogenetic uncertainty has obstructed the identification of major morphological and biogeographic transitions within the clade. We used target capture sequencing with the Angiosperms353 probes, taxon-sampling encompassing nearly all genera of the family, tree-based sequence curation, and multiple phylogenetic approaches to investigate the major clades of Primulaceae and their relationship to other Ericales. We generated dated phylogenetic trees and conducted broad-scale biogeographic analyses as well as stochastic character mapping of growth habit. We show that Ardisia, a pantropical genus and the largest in the family, is not monophyletic, with at least 19 smaller genera nested within it. Neotropical members of Ardisia and several smaller genera form a clade, an ancestor of which arrived in the Neotropics and began diversifying about 20 Ma. This Neotropical clade is most closely related to Elingamita and Tapeinosperma, which are most diverse on islands of the Pacific. Both Androsace and Primula are non-monophyletic by the inclusion of smaller genera. Ancestral state reconstructions revealed that there have either been parallel transitions to an herbaceous habit in Primuloideae, Samolus, and at least three lineages of Myrsinoideae, or a common ancestor of nearly all Primulaceae was herbaceous. Our results provide a robust estimate of phylogenetic relationships across Primulaceae and show that a revised classification of Myrsinoideae and several other clades within the family is necessary to render all genera monophyletic.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Assessment of Bone Microarchitecture in Patients with Systemic Mastocytosis and its Association with Clinical and Biochemical Parameters of the Disease.

Patients with systemic mastocytosis (SM) are at high risk of bone deterioration. However, the evaluation of bone microarchitecture in this disease remains unclear. We aimed to assess bone microarchitecture in patients with SM. This was a cross-sectional study of 21 adult patients with SM conducted in a quaternary referral hospital in Sao Paulo, Brazil. A healthy, age-, weight-, and sex-matched cohort of 63 participants was used to provide reference values for bone microarchitecture, assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). Total volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness at the radius were significantly lower in the control group compared with the SM group (all P < 0.001). Patients with aggressive SM had significantly lower trabecular number (Tb.N) (P = 0.035) and estimated failure load (F.load) (P = 0.032) at the tibia compared with those with indolent SM. Handgrip strength was significantly higher in patients who had more Tb.N at the radius (ρ, 0.46; P = 0.036) and tibia (ρ, 0.49; P = 0.002), and lower who had more trabecular separation at the radius (ρ, -0.46; P = 0.035) and tibia (ρ, -0.52; P = 0.016). Strong and positive associations between F.load (ρ, 0.75; P < 0.001) and stiffness (ρ, 0.70; P < 0.001) at the radius, and between F.load at the tibia (ρ, 0.45; P = 0.038) were observed with handgrip strength. In this cross-sectional study, aggressive SM was more susceptible to bone deterioration compared with indolent SM. In addition, the findings demonstrated that handgrip strength was associated with bone microarchitecture and bone strength.