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1.
Am Surg ; : 31348241275718, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39162622

ABSTRACT

BACKGROUND: Normal coagulation TEG values on admission negatively correlate with overall risk of multiple organ failure, but less is known about association between coagulation and late-resolving multiple organ failure (LRMOF) risk. Here, the relationship between TEG parameters and development of LRMOF was investigated. METHODS: We conducted a retrospective assessment of patients at high postinjury multiple organ failure risk at our center. The primary outcome was LRMOF. RESULTS: Analysis included 742 patients. Demographics were 76% male, mean age of 41, mean ISS of 23, 34% hypercoagulability, and 16% developed LRMOF. Patients with normal admission TEG developed LRMOF at significantly lower unadjusted rates than patients with coagulation disturbances (9 vs 16%-19%, P = 0.029); however, multivariable logistic regression demonstrated that neither coagulation profile nor individual admission TEG parameters showed association with LRMOF. CONCLUSIONS: In this series, we found no significant relationship between coagulation status and LRMOF development.

2.
Radiology ; 312(2): e232972, 2024 08.
Article in English | MEDLINE | ID: mdl-39189899

ABSTRACT

Background Field-cycling imaging (FCI) is a new technology developed at the University of Aberdeen that measures change in T1 relaxation time constant of tissues over a range of low magnetic field strengths (0.2-200 mT) by rapidly switching between different fields during the pulse sequence. This provides new sources of contrast, including some invisible to clinical MRI scanners, and may be a useful alternative imaging modality for stroke. Purpose To test whether a prototype whole-body FCI scanner can be used to identify infarct regions in patients with subacute ischemic stroke. Materials and Methods This prospective study screened consecutive adult patients admitted to a single center stroke unit from February 2018 to March 2020 and April to December 2021. Included participants with confirmed ischemic stroke underwent FCI 1-6 days after ictus. FCI scans were obtained at four to six evolution fields between 0.2 mT and 0.2 T, with five evolution times from 5 to 546 msec. T1 maps were generated. The Wilcoxon signed-rank test was used to compare infarct region and contralateral unaffected brain, and Spearman rank correlation was used to examine associations between infarct to contralateral tissue contrast ratio and field strengths. Two independent readers blinded to clinical images rated the FCI scans. Results Nine participants (mean age, 62 years ± 16 [SD]; all male) successfully completed FCI. FCI scans below 0.2 T exhibited hyperintense T1 regions corresponding to the infarct region identified at baseline imaging, visually confirmed with 86% interrater agreement (Cohen κ = 0.69). Infarct to contralateral tissue contrast ratio increased as magnetic field decreased between 0.2 mT and 0.2 T (r[24] = -0.68; P < .001). T1 dispersion slopes differed between infarct and unaffected tissues (median, 0.23 [IQR, 0.18-0.37] vs 0.35 [IQR, 0.27-0.43]; P = .03). Conclusion Whole-brain FCI can be used to identify subacute ischemic stroke by T1 relaxation mechanisms at field strengths as low as 0.2 mT. Research Registry no. 1813 Published under a CC BY 4.0 license. Supplemental material is available for this article.


Subject(s)
Ischemic Stroke , Magnetic Resonance Imaging , Humans , Male , Ischemic Stroke/diagnostic imaging , Prospective Studies , Female , Magnetic Resonance Imaging/methods , Middle Aged , Aged , Brain/diagnostic imaging
3.
Disabil Health J ; : 101680, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39152070

ABSTRACT

BACKGROUND: Peer mentors have a role in facilitating the participation, health and well-being of people who have had a traumatic injury. Few studies have explored the involvement of peer mentors in an early intervention vocational rehabilitation (EIVR) service following trauma. OBJECTIVE: This study aimed to explore the experience of implementing peer support within the context of an EIVR service from the perspectives of the peer mentors themselves, the vocational therapists supervising them, and the patients that received peer mentoring. METHODS: Semi-structured interviews were conducted with twenty participants from three groups: peer mentors (n = 4); vocational therapists (n = 3); and patients who received the EIVR intervention (n = 24). Data were thematically analysed. RESULTS: Three themes were identified: The value of peer input in an EIVR service, The facilitators impacting the value of peer involvement as part of the EIVR service, The challenges impacting peer input as part of an EIVR service. CONCLUSIONS: The inclusion of peer mentors early after major traumatic injury was a unique and valuable addition to the EIVR service. Offering peer support early on in rehabilitation enabled patients to gain a sense of hope for their future, and the expectation that returning to work was a realistic option. The careful selection of peer mentors, and ensuring they receive adequate preparation and ongoing supervision are vital to support their well-being during the intervention. Aiming to match peer mentors with similar injuries and work backgrounds to patients is an important contributor to the likely ongoing engagement of the mentee with the mentor.

4.
R Soc Open Sci ; 11(7): 240154, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39170929

ABSTRACT

Eukaryotes have evolved to dominate the biosphere today, accounting for most documented living species and the vast majority of the Earth's biomass. Consequently, understanding how these biologically complex organisms initially diversified in the Proterozoic Eon over 539 million years ago is a foundational question in evolutionary biology. Over the last 70 years, palaeontologists have sought to document the rise of eukaryotes with fossil evidence. However, the delicate and microscopic nature of their sub-cellular features affords early eukaryotes diminished preservation potential. Chemical biomarker signatures of eukaryotes and the genetics of living eukaryotes have emerged as complementary tools for reconstructing eukaryote ancestry. In this review, we argue that exceptionally preserved Proterozoic microfossils are critical to interpreting these complementary tools, providing crucial calibrations to molecular clocks and testing hypotheses of palaeoecology. We highlight recent research on their preservation and biomolecular composition that offers new ways to enhance their utility.

5.
J Physiol ; 602(14): 3489-3504, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39008710

ABSTRACT

Cerebral palsy (CP) describes some upper motoneuron disorders due to non-progressive disturbances occurring in the developing brain that cause progressive changes to muscle. While longer sarcomeres increase muscle stiffness in patients with CP compared to typically developing (TD) patients, changes in extracellular matrix (ECM) architecture can increase stiffness. Our goal was to investigate how changes in muscle and ECM architecture impact muscle stiffness, gait and joint function in CP. Gracilis and adductor longus biopsies were collected from children with CP undergoing tendon lengthening surgery for hamstring and hip adduction contractures, respectively. Gracilis biopsies were collected from TD patients undergoing anterior cruciate ligament reconstruction surgery with hamstring autograft. Muscle mechanical testing, two-photon imaging and hydroxyproline assay were performed on biopsies. Corresponding data were compared to radiographic hip displacement in CP adductors (CPA), gait kinematics in CP hamstrings (CPH), and joint range of motion in CPA and CPH. We found at matched sarcomere lengths muscle stiffness and collagen architecture were similar between TD and CP hamstrings. However, CPH stiffness (R2 = 0.1973), collagen content (R2 = 0.5099) and cross-linking (R2 = 0.3233) were correlated to decreased knee range of motion. Additionally, we observed collagen fibres within the muscle ECM increase alignment during muscular stretching. These data demonstrate that while ECM architecture is similar between TD and CP hamstrings, collagen fibres biomechanics are sensitive to muscle strain and may be altered at longer in vivo sarcomere lengths in CP muscle. Future studies could evaluate the impact of ECM architecture on TD and CP muscle stiffness across in vivo operating ranges. KEY POINTS: At matched sarcomere lengths, gracilis muscle mechanics and collagen architecture are similar in TD patients and patients with CP. In both TD and CP muscles, collagen fibres dynamically increase their alignment during muscle stretching. Aspects of muscle mechanics and collagen architecture are predictive of in vivo knee joint motion and radiographic hip displacement in patients with CP. Longer sarcomere lengths in CP muscle in vivo may alter collagen architecture and biomechanics to drive deficits in joint mobility and gait function.


Subject(s)
Cerebral Palsy , Collagen , Humans , Cerebral Palsy/physiopathology , Cerebral Palsy/pathology , Child , Male , Female , Collagen/metabolism , Biomechanical Phenomena , Adolescent , Gracilis Muscle , Range of Motion, Articular , Muscle, Skeletal/physiology , Muscle, Skeletal/physiopathology , Gait/physiology , Hamstring Muscles/physiology , Hamstring Muscles/physiopathology , Extracellular Matrix/physiology
6.
NPJ Syst Biol Appl ; 10(1): 34, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38565568

ABSTRACT

Minimal Cut Sets (MCSs) identify sets of reactions which, when removed from a metabolic network, disable certain cellular functions. The traditional search for MCSs within genome-scale metabolic models (GSMMs) targets cellular growth, identifies reaction sets resulting in a lethal phenotype if disrupted, and retrieves a list of corresponding gene, mRNA, or enzyme targets. Using the dual link between MCSs and Elementary Flux Modes (EFMs), our logic programming-based tool aspefm was able to compute MCSs of any size from GSMMs in acceptable run times. The tool demonstrated better performance when computing large-sized MCSs than the mixed-integer linear programming methods. We applied the new MCSs methodology to a medically-relevant consortium model of two cross-feeding bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. aspefm constraints were used to bias the computation of MCSs toward exchanged metabolites that could complement lethal phenotypes in individual species. We found that interspecies metabolite exchanges could play an essential role in rescuing single-species growth, for instance inosine could complement lethal reaction knock-outs in the purine synthesis, glycolysis, and pentose phosphate pathways of both bacteria. Finally, MCSs were used to derive a list of promising enzyme targets for consortium-level therapeutic applications that cannot be circumvented via interspecies metabolite exchange.


Subject(s)
Algorithms , Wound Infection , Humans , Models, Biological , Metabolic Networks and Pathways/genetics , Genome
7.
Anaesthesia ; 79(7): 748-758, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38508699

ABSTRACT

Post-intensive care syndrome describes the physical, cognitive and emotional symptoms which persist following critical illness. At present there is limited understanding of the pathological mechanisms contributing to the development of post-intensive care syndrome. The aim of this systematic review was to synthesise current evidence exploring the association between inflammation and features of post-intensive care syndrome in survivors of critical illness. Relevant databases were systematically searched for studies of human participants exposed to critical illness. We sought studies that reported results for biomarkers with an identified role in the pathophysiology of inflammation obtained at any time-point in the patient journey and an outcome measure of any feature of post-intensive care syndrome at any point following hospital discharge. We included 32 studies, with 23 in the primary analysis and nine in a brain injury subgroup analysis. In the primary analysis, 47 different biomarkers were sampled and 44 different outcome measures were employed. Of the biomarkers which were sampled in five or more studies, interleukin-8, C-reactive protein and interleukin-10 most frequently showed associations with post-intensive care syndrome outcomes in 71%, 62% and 60% of studies, respectively. There was variability in terms of which biomarkers were sampled, time-points of sampling and outcome measures reported. Overall, there was mixed evidence of a potential association between an inflammatory process and long-term patient outcomes following critical illness. Further high-quality research is required to develop a longitudinal inflammatory profile of survivors of critical illness over the recovery period and evaluate the association with outcomes.


Subject(s)
Biomarkers , Critical Care , Critical Illness , Inflammation , Humans , Inflammation/blood , Biomarkers/blood
8.
Proc Biol Sci ; 291(2019): 20232606, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38503334

ABSTRACT

The brain is thought to be among the first human organs to decompose after death. The discovery of brains preserved in the archaeological record is therefore regarded as unusual. Although mechanisms such as dehydration, freezing, saponification, and tanning are known to allow for the preservation of the brain on short time scales in association with other soft tissues (≲4000 years), discoveries of older brains, especially in the absence of other soft tissues, are rare. Here, we collated an archive of more than 4400 human brains preserved in the archaeological record across approximately 12 000 years, more than 1300 of which constitute the only soft tissue preserved amongst otherwise skeletonized remains. We found that brains of this type persist on time scales exceeding those preserved by other means, which suggests an unknown mechanism may be responsible for preservation particular to the central nervous system. The untapped archive of preserved ancient brains represents an opportunity for bioarchaeological studies of human evolution, health and disease.


Subject(s)
Brain , Central Nervous System , Humans , Head
9.
Environ Res ; 241: 117476, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-37879388

ABSTRACT

Chinook salmon (Oncorhynchus tshawytscha) along the west coast of North America have experienced significant declines in abundance and body size over recent decades due to several anthropogenic stressors. Understanding the reasons underlying the relatively high levels of persistent organic pollutants (POPs) in Chinook stocks is an important need, as it informs recovery planning for this foundation species, as well for the Chinook-dependent Resident killer whales (Orcinus orca, RKW) of British Columbia (Canada) and Washington State (USA). We evaluated the influence of stock-related differences in feeding ecology, using stable isotopes, and marine rearing ground on the concentrations and patterns of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Chinook salmon. A principal components analysis (PCA) revealed a clear divergence of PCB and PBDE congener patterns between Chinook with a nearshore rearing distribution ('shelf resident') versus a more offshore distribution. Shelf resident Chinook had 12-fold higher PCB concentrations and 46-fold higher PBDE concentrations relative to offshore stocks. Shelf resident Chinook had PCB and PBDE profiles that were heavier and dominated by more bioaccumulative congeners, respectively. The higher δ13C and δ15N in shelf resident Chinook compared to the offshore rearing stocks, and their different marine distributions explain the large divergence in contaminant levels and profiles, with shelf resident stocks being heavily influenced by land-based sources of industrial contamination. Results provide compelling new insight into the drivers of contaminant accumulation in Chinook salmon, raise important questions about the consequences for their health, and explain a major pathway to the heavily POP-contaminated Resident killer whales that consume them.


Subject(s)
Polychlorinated Biphenyls , Whale, Killer , Animals , Polychlorinated Biphenyls/analysis , Salmon/metabolism , Halogenated Diphenyl Ethers/analysis , Pacific Ocean , Whale, Killer/metabolism , British Columbia
10.
Res Microbiol ; 175(1-2): 104115, 2024.
Article in English | MEDLINE | ID: mdl-37572823

ABSTRACT

Halotolerant, acidophilic, bioleaching microorganisms are crucial to biomining operations that utilize saline water. Compatible solutes play an important role in the adaptation of these microorganisms to saline environments. Acidithiobacillus ferrooxidans ATCC 23270, an iron- and sulfur-oxidizing acidophilic bacterium, synthesizes trehalose as its native compatible solute but is still sensitive to salinity. Recently, halotolerant bioleaching bacteria were found to use ectoine as their key compatible solute. Previously, bioleaching bacteria were recalcitrant to genetic manipulation; however, recent advancements in genetic tools and techniques allow successful genetic modification of A. ferrooxidans ATCC 23270. Therefore, this study aimed to test, in silico, the effect of native and synthetic compatible solute biosynthesis by A. ferrooxidans ATCC 23270 on its growth and metabolism. Metabolic network flux modelling was used to provide a computational framework for the prediction of metabolic fluxes during production of native and synthetic compatible solutes by A. ferrooxidans ATCC 23270, in silico. Complete pathways for trehalose biosynthesis by the bacterium are proposed and captured in the updated metabolic model including a newly discovered UDP-dependent trehalose synthesis pathway. Finally, the effect of nitrogen sources on compatible solute production was simulated and showed that using nitrogen gas as the sole nitrogen source enables the ectoine-producing 'engineered' microbe to oxidize up to 20% more ferrous iron in comparison to the native microbe that only produces trehalose. Therefore, the predictive outcomes of the model have the potential to guide the design and optimization of a halotolerant strain of A. ferrooxidans ATCC 23270 for saline bioleaching operations.


Subject(s)
Acidithiobacillus , Trehalose , Trehalose/metabolism , Acidithiobacillus/genetics , Acidithiobacillus/metabolism , Bacteria/metabolism , Iron/metabolism , Nitrogen/metabolism
11.
Pharmacogenomics ; 24(16): 845-857, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37929326

ABSTRACT

Background: CYP2C19 is important in the metabolism of clopidogrel and several antidepressants. This study aimed to characterize the distribution of CYP2C19 star alleles (haplotypes) across diverse African populations compared with global populations. Methods: CYP2C19 star alleles and diplotypes were called from high coverage genomes using the StellarPGx pipeline. Results: CYP2C19*1 (51%), *2 (17%) and *17 (22%) were the most common star alleles across African populations in this study. It was observed that 3% of African participants had potentially novel CYP2C19 haplotypes. Conclusion: This study supports the necessity for CYP2C19 pharmacogenetic testing in African and global clinical settings, as well as the importance of comprehensive star allele characterization in the African context.


Subject(s)
Pharmacogenetics , Platelet Aggregation Inhibitors , Humans , Genotype , Cytochrome P-450 CYP2C19/genetics , Haplotypes/genetics , Clopidogrel/therapeutic use , Alleles
12.
Cell Rep ; 42(11): 113435, 2023 11 28.
Article in English | MEDLINE | ID: mdl-37952158

ABSTRACT

The dorsal striatum is organized into functional territories defined by corticostriatal inputs onto both direct and indirect spiny projection neurons (SPNs), the major cell types within the striatum. In addition to circuit connectivity, striatal domains are likely defined by the spatially determined transcriptomes of SPNs themselves. To identify cell-type-specific spatiomolecular signatures of direct and indirect SPNs within dorsomedial, dorsolateral, and ventrolateral dorsal striatum, we used RNA profiling in situ hybridization with probes to >98% of protein coding genes. We demonstrate that the molecular identity of SPNs is mediated by hundreds of differentially expressed genes across territories of the striatum, revealing extraordinary heterogeneity in the expression of genes that mediate synaptic function in both direct and indirect SPNs. This deep insight into the complex spatiomolecular organization of the striatum provides a foundation for understanding both normal striatal function and for dissecting region-specific dysfunction in disorders of the striatum.


Subject(s)
Corpus Striatum , Interneurons , Mice , Animals , Mice, Transgenic , Corpus Striatum/metabolism , Neostriatum , Neurites
13.
Am J Physiol Cell Physiol ; 325(4): C1017-C1030, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37661921

ABSTRACT

The muscle extracellular matrix (ECM) forms a complex network of collagens, proteoglycans, and other proteins that produce a favorable environment for muscle regeneration, protect the sarcolemma from contraction-induced damage, and provide a pathway for the lateral transmission of contractile force. In each of these functions, the structure and organization of the muscle ECM play an important role. Many aspects of collagen architecture, including collagen alignment, cross linking, and packing density affect the regenerative capacity, passive mechanical properties, and contractile force transmission pathways of skeletal muscle. The balance between fortifying the muscle ECM and maintaining ECM turnover and compliance is highly dependent on the integrated organization, or architecture, of the muscle matrix, especially related to collagen. While muscle ECM remodeling patterns in response to exercise and disease are similar, in that collagen synthesis can increase in both cases, one outcome leads to a stronger muscle and the other leads to fibrosis. In this review, we provide a comprehensive analysis of the architectural features of each layer of muscle ECM: epimysium, perimysium, and endomysium. Further, we detail the importance of muscle ECM architecture to biomechanical function in the context of exercise or fibrosis, including disease, injury, and aging. We describe how collagen architecture is linked to active and passive muscle biomechanics and which architectural features are acutely dynamic and adapt over time. Future studies should investigate the significance of collagen architecture in muscle stiffness, ECM turnover, and lateral force transmission in the context of health and fibrosis.


Subject(s)
Extracellular Matrix , Muscle, Skeletal , Humans , Muscle, Skeletal/metabolism , Extracellular Matrix/metabolism , Collagen/metabolism , Proteoglycans/metabolism , Fibrosis
14.
Article in English | MEDLINE | ID: mdl-37661216

ABSTRACT

Autism spectrum disorder (ASD) is a disabling neurodevelopmental condition with complex etiology. Emerging evidence has pointed to maternal atopy as a possible risk factor. It is hypothesized that maternal atopic disease during pregnancy can lead to increased levels of inflammatory cytokines in fetal circulation via placental transfer or increased production. These cytokines can then pass through the immature blood-brain barrier, causing aberrant neurodevelopment via mechanisms including premature microglial activation. The objective of this study is to systematically review observational studies that investigate whether a maternal history of atopic disease (asthma, allergy, or eczema/atopic dermatitis) is associated with a diagnosis of ASD in offspring. A search was conducted in Ovid MEDLINE, PsycINFO, and Embase databases for relevant articles up to November 2021; this was later updated in January 2022. Observational studies published in peer-reviewed journals were included. Data were synthesized and qualitatively analyzed according to the specific atopic condition. Quality assessment was done using the Newcastle-Ottawa Scale. Nine articles were identified, with all including asthma as an exposure, alongside four each for allergy and eczema. Findings were inconsistent regarding the association between a maternal diagnosis of either asthma, allergy, or eczema, and ASD in offspring, with variations in methodology contributing to the inconclusiveness. More consistent associations were demonstrated regarding maternal asthma that was treated or diagnosed during pregnancy. Evidence suggests that symptomatic maternal asthma during pregnancy could be associated with ASD in offspring, underscoring the importance of effective management of atopic conditions during pregnancy. Further research is needed, particularly longitudinal studies that use gold-standard assessment tools and correlate clinical outcomes with laboratory and treatment data.PROSPERO Registration Number and Date: CRD42018116656, 26.11.2018.

15.
Animal ; 17 Suppl 1: 100828, 2023 May.
Article in English | MEDLINE | ID: mdl-37567652

ABSTRACT

The goal of in vitro gametogenesis is to reproduce the events of sperm and oocyte development in the laboratory. Significant advances have been made in the mouse in the last decade, but evolutionary divergence from the murine developmental program has prevented the replication of these advances in large mammals. In recent years, intensive work has been done in humans, non-human primates and livestock to elucidate species-specific differences that regulate germ cell development, due to the number of potential applications. One of the most promising applications is the use of in vitro gametes to optimize the spread of elite genetics in cattle. In this context, embryonic stem cells have been posed as excellent candidates for germ cell platforms. Here, we present the most relevant advances in in vitro gametogenesis of interest to livestock science, including new types of pluripotent stem cells with potential for germline derivation, characterization of the signaling environment in the gonadal niche, and experimental systems used to reproduce different stages of germ cell development in the laboratory.


Subject(s)
Livestock , Pluripotent Stem Cells , Male , Cattle , Animals , Mice , Semen , Germ Cells/metabolism , Embryonic Stem Cells/physiology , Pluripotent Stem Cells/metabolism , Cell Differentiation , Mammals
16.
Nat Commun ; 14(1): 4826, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37563143

ABSTRACT

The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.


Subject(s)
Chromatin , Trophoblasts , Pregnancy , Female , Humans , Trophoblasts/metabolism , Chromatin/genetics , Chromatin/metabolism , Placentation/genetics , Cell Differentiation/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Lineage/genetics , Placenta/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism
17.
Surg Oncol ; 49: 101965, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37348195

ABSTRACT

AIMS: Minor hepatectomy, which is increasingly carried out laparoscopically (LLR), is a cornerstone of curative treatment for hepatocellular carcinoma (HCC). The majority of relevant publications however originate from regions with endemic viral hepatitis. Although the incidence of HCC in the UK is increasing, little is known about outcomes following LLR. METHODS: Consecutive patients undergoing minor (involving ≤2 segments) LLR or open resection (OLR) at our institute between 2014 and 2021 were compared. Selection from a plethora of factors potentially impacting on overall (OS) and disease free survival (DFS) was optimised with Lasso regression. To enable analysis of patients having repeat resection, multivariate frailty modelling was utilised to calculate hazard ratios (HR). RESULTS: The analysis of 111 liver resections included 55 LLR and 56 OLR. LLR was associated with a shorter hospital stay (5 ± 2 vs. 7 ± 2 days; p < 0.001) and a lower comprehensive complication index (4.43 vs. 9.96; p = 0.006). Mean OS (52.3 ± 2.3 vs. 49.9 ± 3.0 months) and DFS (33.9 ± 3.4 vs. 36.5 ± 3.6 months; p = 0.59) were comparable between LLR and OLR, respectively (median not reached). Presence of mixed cholangiocarcinoma/HCC, satellite lesions and AFP level predicted OS and DFS. In addition tumour size was predictive of DFS. CONCLUSIONS: In the studied population minor LLR was associated with shorter hospital stay and fewer complications while offering non-inferior long-term outcomes. A number of predictors for disease free survival have been elucidated that may aid in identifying patients with a high risk of disease recurrence and need for further treatment.


Subject(s)
Carcinoma, Hepatocellular , Laparoscopy , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Hepatectomy , Liver Neoplasms/pathology , Retrospective Studies , Laparoscopy/adverse effects , Postoperative Complications/etiology , United Kingdom/epidemiology , Length of Stay
18.
Bioorg Med Chem Lett ; 92: 129387, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37369333

ABSTRACT

Metallo-ß-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since ß-lactam antibiotics, which are inactivated by MBLs, constitute ∼65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against prominent representatives of the MBL family. Several compounds are potent inhibitors of each MBL tested, making them promising candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL family, with Ki values in the low µM range. Furthermore, this compound also appears to display synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents a promising starting point to develop new drugs to inhibit a major mechanism of antibiotic resistance.


Subject(s)
beta-Lactamase Inhibitors , beta-Lactamases , beta-Lactamase Inhibitors/pharmacology , Anti-Bacterial Agents/pharmacology , Meropenem , Drug Resistance, Multiple, Bacterial
19.
Trends Ecol Evol ; 38(11): 1060-1071, 2023 11.
Article in English | MEDLINE | ID: mdl-37385847

ABSTRACT

Estimates for animal antiquity exhibit a significant disconnect between those from molecular clocks, which indicate crown animals evolved ∼800 million years ago (Ma), and those from the fossil record, which extends only ∼574 Ma. Taphonomy is often held culpable: early animals were too small/soft/fragile to fossilise, or the circumstances that preserve them were uncommon in the early Neoproterozoic. We assess this idea by comparing Neoproterozoic fossilisation processes with those of the Cambrian and its abundant animal fossils. Cambrian Burgess Shale-type (BST) preservation captures animals in mudstones showing a narrow range of mineralogies; yet, fossiliferous Neoproterozoic mudstones rarely share the same mineralogy. Animal fossils are absent where BST preservation occurs in deposits ≥789 Ma, suggesting a soft maximum constraint on animal antiquity.


Subject(s)
Biological Evolution , Fossils , Animals , CLOCK Proteins
20.
West J Emerg Med ; 24(3): 552-565, 2023 May 02.
Article in English | MEDLINE | ID: mdl-37278791

ABSTRACT

INTRODUCTION: The epidemic of gun violence in the United States (US) is exacerbated by frequent mass shootings. In 2021, there were 698 mass shootings in the US, resulting in 705 deaths and 2,830 injuries. This is a companion paper to a publication in JAMA Network Open, in which the nonfatal outcomes of victims of mass shootings have been only partially described. METHODS: We gathered clinical and logistic information from 31 hospitals in the US about 403 survivors of 13 mass shootings, each event involving greater than 10 injuries, from 2012-19. Local champions in emergency medicine and trauma surgery provided clinical data from electronic health records within 24 hours of a mass shooting. We organized descriptive statistics of individual-level diagnoses recorded in medical records using International Classification of Diseases codes, according to the Barell Injury Diagnosis Matrix (BIDM), a standardized tool that classifies 12 types of injuries within 36 body regions. RESULTS: Of the 403 patients who were evaluated at a hospital, 364 sustained physical injuries-252 by gunshot wound (GSW) and 112 by non-ballistic trauma-and 39 were uninjured. Fifty patients had 75 psychiatric diagnoses. Nearly 10% of victims came to the hospital for symptoms triggered by, but not directly related to, the shooting, or for exacerbations of underlying conditions. There were 362 gunshot wounds recorded in the Barell Matrix (1.44 per patient). The Emergency Severity Index (ESI) distribution was skewed toward higher acuity than typical for an emergency department (ED), with 15.1% ESI 1 and 17.6% ESI 2 patients. Semi-automatic firearms were used in 100% of these civilian public mass shootings, with 50 total weapons for 13 shootings (Route 91 Harvest Festival, Las Vegas. 24). Assailant motivations were reported to be associated with hate crimes in 23.1%. CONCLUSION: Survivors of mass shootings have substantial morbidity and characteristic injury distribution, but 37% of victims had no GSW. Law enforcement, emergency medical systems, and hospital and ED disaster planners can use this information for injury mitigation and public policy planning. The BIDM is useful to organize data regarding gun violence injuries. We call for additional research funding to prevent and mitigate interpersonal firearm injuries, and for the National Violent Death Reporting System to expand tracking of injuries, their sequelae, complications, and societal costs.


Subject(s)
Firearms , Mass Casualty Incidents , Mental Disorders , Wounds, Gunshot , Humans , United States/epidemiology , Wounds, Gunshot/epidemiology , Public Health , Homicide
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