A quantitative test of the "Ecomorphotype Hypothesis" for fossil true seals (Family Phocidae).

The fossil record of true seals (Family Phocidae) is mostly made up of isolated bones, some of which are type specimens. Previous studies have sought to increase referral of non-overlapping and unrelated fossils to these taxa using the 'Ecomorphotype Hypothesis', which stipulates that certain differences in morphology between taxa represent adaptations to differing ecology. On this basis, bulk fossil material could be lumped to a specific ecomorphotype, and then referred to species in that ecomorphotype, even if they are different bones. This qualitative and subjective method has been used often to expand the taxonomy of fossil phocids, but has never been quantitatively tested. We test the proposed ecomorphotypes using morphometric analysis of fossil and extant northern true seal limb bones, specifically principal components analysis and discriminant function analysis. A large amount of morphological overlap between ecomorphotypes, and poor discrimination between them, suggests that the 'Ecomorphotype Hypothesis' is not a valid approach. Further, the analysis failed to assign fossils to ecomorphotypes designated in previous studies, with some fossils from the same taxa being designated as different ecomorphotypes. The failure of this approach suggests that all fossils referred using this method should be considered to have unknown taxonomic status. In light of this, and previous findings that phocid limb bones have limited utility as type specimens, we revise the status of named fossil phocid species. We conclude that the majority of named fossil phocid taxa should be considered nomina dubia.

Site-Selective Activation and Stereospecific Functionalization of Bis(boronic esters) Derived from 2-Alkenes: Construction of Propionates and Other 1,2-Difunctional Motifs.

Non-directed regioselective activation of diboronic esters, followed by functionalization, is reported. A bulky activator is shown to selectively activate the less hindered boronic ester enabling it to undergo stereospecific cross-coupling to a variety of electrophiles. This steric-based regioselectivity provides a simple and efficient method to prepare highly functionalized, enantiomerically enriched products starting from simple alkenes.

Bird's-Eye View of the Activity Distribution on a Catalyst Surface via a Machine Learning-Driven Adequate Sampling Algorithm.

Rational design of catalysts relies on a deep understanding of the active centers. The structure and activity distribution of active centers on a surface are two of the central issues in catalysis and important targets of theoretical and experimental investigations. Herein, we report a machine learning-driven adequate sampling (MLAS) framework for obtaining a statistical understanding of the chemical environment near catalyst sites. Combined strategies were implemented to achieve highly efficient sampling, including the decomposition of degrees of freedom, stratified sampling, Gaussian process regression, and well-designed constraint optimization. The MLAS framework was applied to the rate-determining step in NH3 synthesis, namely the N2 activation process. We calculated the produced population function, PA, which provides a comprehensive and intuitive understanding of active centers. The MLAS framework can be broadly applied to other more complicated catalyst materials and reaction networks.

Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

Acute exercise-induced release of innate immune proteins via small extracellular vesicles changes with aerobic fitness and age.

AIM: Physical exercise triggers the secretion of small extracellular vesicles (sEVs) into the circulation in humans, enabling signalling crosstalk between tissues. Exercise-derived EVs and their cargo have been proposed to mediate adaptations to exercise; however, our understanding of how exercise-derived EV protein cargo is modulated by factors such as aerobic fitness and age of an individual is currently unknown. Here, we examined the circulating sEV proteome following aerobic exercise in healthy males of different ages and aerobic fitness to understand exercise-induced EV response during the aging process. METHODS: Twenty-eight healthy men completed a bout of 20-min cycling exercise at 70% estimated VO2peak . Small EVs were isolated from blood samples collected before and immediately after exercise, and then quantified using particle analysis and Western blotting. Small EV proteome was examined using quantitative proteomic analysis. RESULTS: We identified a significant increase in 13 proteins in small plasma EVs following moderate-to-vigorous intensity exercise. We observed distinct changes in sEV proteome after exercise in young, mature, unfit, and fit individuals, highlighting the impact of aerobic fitness and age on sEV protein secretion. Functional enrichment and pathway analysis identified that the majority of the significantly altered sEV proteins are associated with the innate immune system, including proteins known to be damage-associated molecular patterns (DAMPs). CONCLUSION: Together, our findings suggest that exercise-evoked acute stress can positively challenge the innate immune system through the release of signalling molecules such as DAMPs in sEVs, proposing a novel EV-based mechanism for moderate-to-vigorous intensity exercise in immune surveillance pathways.

Diagnostics, treatment and outcomes of cardiac sarcoidosis in a Norwegian cohort.

BACKGROUND: Evidence-based guidelines for cardiac sarcoidosis (CS) regarding use of second- and third-line agents, treatment duration, surveillance and prognostic factors are lacking. OBJECTIVE: To analyze the clinical presentation, diagnostics, treatment, monitoring and clinical outcomes in a Norwegian cohort. METHODS: Using discharge diagnoses between 2017 through 2020 from a large tertiary center, we identified 52 patients with CS. We performed a systematic chart review following a pre-specified checklist. The primary outcome of major cardiovascular events (MACE) was defined as a composite of cardiovascular hospitalization, defibrillator therapy, cardiac transplantation, or death. RESULTS: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed pathological tracer uptake in 35/36 (97%) of immunosuppression-naïve patients. Immunosuppressive treatment was administered to 49/52 patients (94%) for a median of 43 (IQR 34) months; 69% were treated with second-line (methotrexate, azathioprine, mycophenolate mofetil) and 25% with third-line (rituximab, infliximab) agents, respectively. Rituximab reduced inflammation as assessed by interval FDG-PET imaging and was overall well tolerated. Median duration to first MACE was 6 (IQR 10) months and 17/23 patients (74%) experienced a MACE within 12 months from CS diagnosis. No mortality was recorded and 20% achieved full remission. Age below the median of 53 years at time of diagnosis was associated with an increased risk of a MACE. CONCLUSION: Long-term immunosuppression including a liberal use of non-steroidal agents, appeared essential in treating CS. Although the burden of cardiovascular events was substantial, the survival was excellent in this contemporary cohort. Prospective randomized studies are urgently needed to define the best therapy for these patients.

The utility of cemented femoral stems in modern THA: a 10-year comparative analysis of the Charnley and Exeter stems.

BACKGROUND: Total hip replacement (THR) is one of the most common surgical procedures performed worldwide. The controversy surrounding the relative merits of a cemented composite beam or cemented taper-slip stem in total hip replacement continues. Our aims primarily were to assess the 10-year outcomes of cemented stems using Charnley and Exeter prostheses with regional registry data and secondarily to assess the main predictors of revision. METHODS: We prospectively collected registry data for procedures performed between January 2005 and June 2008. Only cemented Charnley and Exeter stems were included. Patients were prospectively reviewed at 6 months, 2, 5 and 10 years. The primary outcome measure was a 10-year all-cause revision. Secondary outcomes included 're-revision', 'mortality' and functional 'Western Ontario and McMaster Universities Osteoarthritis Index' (WOMAC) scores. RESULTS: We recorded a total of 1351 cases in the cohort, 395 Exeter and 956 Charnley stems. The overall all-cause revision rate at 10 years was 1.6%. The revision rate for Charnley stem was 1.4% and 2.3% revision rate for all Exeter stems with no significant difference noted between the two cohorts (p = 0.24). The overall time to revision was 38.3 months. WOMAC scores at 10 years were found to be insignificantly higher for Charnley stems (mean 23.8, σ = 20.11) compared to Exeter stems (mean 19.78, σ = 20.72) (p = 0.1). CONCLUSION: There is no significant difference between cemented Charnley and Exeter stems; they both perform well above the international average. The decline in the use of cemented THA is not fully supported by this regional registry data.

JETWING technique: Combination therapy of JETSTREAMⓇ and aggressive wire recanalization in calcified atheroma and dilatation technique for eccentric heavy calcified plaques using WINGMAN for insertion of protection wire.

Although endovascular treatment (EVT) has developed and still progressing, calcified lesions remain a big challenge to operators in obtaining good results. Whenever, the eccentric and calcified plaques or nodules are present, balloon dilatation may be difficult and vascular complications may frequently occur. We present a 73-year-old woman, with severe, eccentric, calcified lesion in the right superficial femoral artery (SFA). First, we performed the aggressive wire recanalization in calcified atheroma and dilatation (ARCADIA) technique for the eccentric plaques. Then, we used a WingmanⓇ crossing catheter (ReFlow Medical, Inc.) to penetrate and pass through the calcifications and eventually exchanged to a ParachuteⓇ (Good Care, Inc.) filter wire. Finally, we performed rotational atherectomy using the JETSTREAMⓇ (Boston Scientific) rotational atherectomy device for debulking to obtain good lesion expansion and was able to avoid potential complications. Performing ARCADIA technique then using a Wingman catheter for inserting a filter wire before JETSTREAMⓇ atherectomy is safe and effective for heavily calcified, eccentric lesions. Further studies will be needed to validate the safety and efficacy of this approach.

Survey of current UK alpaca husbandry practices: Vaccination, treatment and supplementation.

BACKGROUND: The popularity of alpacas in the UK is increasing, with the British Alpaca Society (BAS) estimating that there are currently 45,000 registered alpacas and a further 15,000 unregistered alpacas. This research set about to investigate what husbandry procedures are currently undertaken on alpacas in the UK. METHODS: An online survey of 47 questions was created using Jisc and was available for 4.5 months. RESULTS: All 116 holdings implemented shearing and foot trimming (100.0%), and most vaccinated against clostridial disease (95.7%) and supplemented with vitamin D (91.4%). There was no obvious pattern in vitamin D dosing. A significant positive association was found between the size of the holding and whether injectable or oral vitamin D was used (p = 0.034), with smaller holdings preferring oral vitamin D products. LIMITATIONS: The survey was distributed online, including via the BAS e-Newsletter. The percentage of BAS-registered alpacas was not clarified, so it is unknown if the data are skewed by this. CONCLUSION: Although owners are ensuring that routine interventions are implemented, variation in responses implies there is no current standard protocol. This highlights that these differences may be due to logistical choices, training or varied advice, which may be due to the lack of published literature.

Spatial patterns of hyperparasitism along a latitudinal gradient of forest genus diversity: insights from the spruce budworm-parasitoids community.

High-order mobile predators are generally thought to increase ecosystem stability and resilience to natural perturbations. In many insect food-webs, higher trophic positions are occupied by parasitoids, which are themselves hosts for hyperparasitoids that can reduce primary parasitoids' efficiency in controlling insect pests. Hyperparasitoids can thus provide ecosystem disservices by facilitating pest outbreaks, or ecosystem services by stabilizing food web fluctuations over longer time periods. To better understand how hyperparasitism affects multitrophic forest systems, we examined for the first time spatial variations in hyperparasitism associated with the spruce budworm. We examined 2 common primary parasitoids of the spruce budworm during outbreaks (Apanteles fumiferanae and Glypta fumiferanae), and estimated their true and pseudohyperparasitism rates in 2014-2015 from 28 locations across a latitudinal gradient (over 450 km) of forest genus diversity. Hyperparasitoid cryptic diversity was also quantified using DNA-barcoding. We found that A. fumiferanae and G. fumiferanae share at least 2 of 5 common hyperparasitoid species, confirming the connected nature of the spruce budworm-parasitoid food web. Moreover, hyperparasitism is modulated by spatial context as we observed a positive correlation between forest genus diversity and hyperparasitism for A. fumiferanae, but not for G. fumiferanae. Further monitoring hyperparasitism holds significant potential to provide new insights into how forest composition affects multitrophic interactions and spatio-temporal outbreak dynamics.

Bacterial Brain Abscesses Expand Despite Effective Antibiotic Treatment: A Process Powered by Osmosis Due to Neutrophil Cell Death.

BACKGROUND AND OBJECTIVES: A bacterial brain abscess is an emergency and should be drained of pus within 24 hours of diagnosis, as recently recommended. In this cross-sectional study, we investigated whether delaying pus drainage entails brain abscess expansion and what the underlying mechanism might be. METHODS: Repeated brain MRI of 47 patients who did not undergo immediate pus drainage, pus osmolarity measurements, immunocytochemistry, proteomics, and 18F-fluorodeoxyglucose positron emission tomography. RESULTS: Time from first to last MRI before neurosurgery was 1 to 14 days. Abscesses expanded in all but 2 patients: The median average increase was 23% per day (range 0%-176%). Abscesses expanded during antibiotic therapy and even if the pus did not contain viable bacteria. In a separate patient cohort, we found that brain abscess pus tended to be hyperosmolar (median value 360 mOsm; range 266-497; n = 14; normal cerebrospinal fluid osmolarity is ∼290 mOsm). Hyperosmolarity would draw water into the abscess cavity, causing abscess expansion in a ballooning manner through increased pressure in the abscess cavity. A mechanism likely underlying pus hyperosmolarity was the recruitment of neutrophils to the abscess cavity with ensuing neutrophil cell death and decomposition of neutrophil proteins and other macromolecules to osmolytes: Pus analysis showed the presence of neutrophil proteins (protein-arginine deiminases, citrullinated histone, myeloperoxidase, elastase, cathelicidin). Previous studies have shown very high levels of osmolytes (ammonia, amino acids) in brain abscess pus. 18F-fluorodeoxyglucose positron emission tomography showed focal neocortical hypometabolism 1 to 8 years after brain abscess, indicating long-lasting damage to brain tissue. CONCLUSION: Brain abscesses expand despite effective antibiotic treatment. Furthermore, brain abscesses cause lasting damage to surrounding brain tissue. These findings support drainage of brain abscesses within 24 hours of diagnosis.

Asthma and COPD as co-morbidities in patients hospitalised with Covid-19 disease: a global systematic review and meta-analysis.

BACKGROUND: Factors predisposing to increased mortality with COVID-19 infection have been identified as male sex, hypertension, obesity, and increasing age. Early studies looking at airway diseases gave some contradictory results. The purpose of our study was to determine global variation in studies in patients hospitalized with COVID-19 in the prevalence of COPD and asthma; and to determine whether the presence of asthma or COPD affected mortality in the same hospital population. METHODS: A systematic review and meta-analysis of the published literature of COPD and asthma as co-morbidities in patients hospitalized with COVID-19 was performed, looking firstly at the prevalence of these diseases in patients hospitalized with COVID-19, and secondly at the relative risk of death from any cause for patients with asthma or COPD. RESULTS: Prevalence of both airway diseases varied markedly by region, making meaningful pooled global estimates of prevalence invalid and not of clinical utility. For individual studies, the interquartile range for asthma prevalence was 4.21 to 12.39%, and for COPD, 3.82 to 11.85%. The relative risk of death with COPD for patients hospitalized with COVID-19 was 1.863 (95% CI 1.640-2.115), while the risk with asthma was 0.918 (95% CI 0.767 to 1.098) with no evidence of increased mortality. CONCLUSIONS: For asthma and COPD, prevalence in patients hospitalized with COVID-19 varies markedly by region. We found no evidence that asthma predisposed to increased mortality in COVID-19 disease. For COPD, there was clear evidence of an association with increased mortality. TRIAL REGISTRATION: The trial was registered with PROSPERO: registration number CRD42021289886.

Vulval superficial myofibroblastoma with lymphocytic and eosinophilic infiltrate.

We present the case of a vulval superficial myofibroblastoma with a lymphocytic and eosinophilic rim in a woman in her late 20s. The tumour presented in pregnancy as a cystic lesion with pain and increasing size. While the histopathology of superficial myofibroblastomas has been well defined in the literature, to our knowledge, there has been no documentation of the presence of an inflammatory infiltrate of lymphocytes and eosinophils surrounding and within the tumour. This may potentially act as a diagnostic or prognostic reference.

Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines.

Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.

First-in-human clinical trial of allogeneic, platelet-derived extracellular vesicles as a potential therapeutic for delayed wound healing.

The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand-based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP-isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF-ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first-in-human, double-blind, placebo-controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP-purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing.

Dendrillic Acids A and B: Nitrogenous, Rearranged Spongian Nor-Diterpenes from a Dendrilla sp. Marine Sponge.

Two nitrogenous rearranged spongian nor-diterpenoids, dendrillic acids A and B, were isolated from a marine sponge Dendrilla sp. (order: Dendroceratida; family: Darwinellidae). The structures of the metabolites were elucidated on the basis of spectroscopic analysis as well as density functional theory prediction of NMR chemical shifts and application of the DP4+ algorithm. The absolute configuration of the metabolites was established via comparison of experimental and time-dependent density functional theory predicted electronic circular dichroism data. An unusual epimerization reaction was observed leading to the interconversion of the metabolites upon storage in dimethyl sulfoxide solution, which is proposed to proceed via an anionic pathway as probed via isotopic incorporation experiments. Evaluation against a panel of micro-organisms and cell lines revealed that the compounds were devoid of any significant biological activity against all organisms tested, with the exception of mild antiprotozoal activity displayed by dendrillic acid B (2) against Giardia duodenalis.

Synthesis, Characterization, and Bioactivity of the Lichen Pigments Pulvinamide, Rhizocarpic Acid, and Epanorin and Congeners.

The lichen natural products pulvinamide, rhizocarpic acid, and epanorin have been synthesized and characterized spectroscopically and by X-ray crystallography. The syntheses, by ring-opening of pulvinic acid dilactone (PAD), may well be biomimetic, given the well-known occurrence of PAD in lichen. The enantiomers, ent-rhizocarpic acid and ent-epanorin, and corresponding carboxylic acids, norrhizocarpic acid and norepanorin, were similarly prepared. All compounds were assessed for growth inhibitory activity against selected bacteria, fungi, a protist, a mammalian tumor cell line, and normal cells. Rhizocarpic acid is weakly antibacterial (Bacillus subtilis MIC = 50 µg/mL) and possesses modest but selective antitumor activity (NS-1 murine myeloma MIC = 3.1 µg/mL) with >10-fold potency relative to its enantiomer (MIC = 50 µg/mL).

Of clockwork and catastrophes: advances in spatiotemporal dynamics of forest Lepidoptera.

We applied a systematic global literature survey from the last 2.5 years on spatiotemporal population dynamics - broadly defined - of Lepidopteran forest pests. Articles were summarized according to domain-specific (planetary ecology - remote sensing, evolutionary ecology - genetics and genomics, and theoretical ecology - modeling) contributions to contemporary investigation of the above theme. 'Model systems' dominating our literature survey were native Choristoneura fumiferana and invasive Lymantria dispar. These systems represent opposing ends of a more general equilibrium-disequilibrium gradient, with implications for less-studied taxa. The dynamics of Lepidopteran systems defy simple modeling approaches. Technologies and insights emerging from 'slower' science domains are informing more complex theory, including predictions of spread, impacts, or both posed by more recent invasions and the disrupting effects of climate change.

Atypical presentation of Lemierre syndrome in a young healthy man with acute jaundice.

This report presents a case of Lemierre syndrome caused by Fusobacterium necrophorum in a healthy young adult who presented atypically with shortness of breath and jaundice but no clinical or diagnostic evidence of thrombophlebitis. Due to this unusual presentation with jaundice, diagnosis was challenging and delayed. However, the patient was successfully initiated on a prolonged course of intravenous antibiotics; he required a period in the intensive care unit and was discharged without significant complications. This report aims to raise awareness of the diagnosis and treatment of this rare condition and to highlight both common and unusual presentations of the syndrome.