Distinct clinical endpoints of Staphylococcus aureus bacteraemia complicate assessment of outcome.

BACKGROUND: We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to SAB. METHODS: We conducted a retrospective observational study of adults with SAB between 20/12/2019 and 23/08/2022 (n=464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical and microbiologic features. RESULTS: Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14·4% of cohort), metastatic SAB (without attributable mortality, 22·2%), neither complication (56·7%), and overlapping fatal/metastatic SAB (6·7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteraemia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset. CONCLUSIONS: Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality vs. improve clinical response in patients with metastatic SAB.

Ultrasound Measurement of Femoral Articular Cartilage Thickness Before and After Marathon Running.

OBJECTIVE: The purpose of this study was to use ultrasonography to measure femoral articular cartilage thickness changes during marathon running, which could support MRI studies showing that deformation of knee cartilage during long-distance running is no greater than that for other weight-bearing activities. MATERIALS AND METHODS: Participants included 38 marathon runners with no knee pain or history of knee injury, aged 18-39. Ultrasound images of the femoral articular cartilage were taken two hours before and immediately after the race. Femoral articular cartilage thickness was measured at both the medial and lateral femoral condyles. RESULTS: The maximum change in femoral articular cartilage thickness, measured at the left outer lateral femoral condyle, was 6.94% (P=.006). All other femoral articular cartilage thickness changes were not significant. CONCLUSION: A change in femoral articular cartilage thickness of 6.94% supports our hypothesis that long-distance running does not induce deformational changes greater than that of regular daily activities. This study using ultrasonography supports MRI evidence that knee cartilage tolerates marathon running well.

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AMs and MDMs from donors with COPD and healthy donors underwent functional, metabolic, and transcriptional profiling. Measurements and Main Results: We observed that AMs and MDMs from donors with COPD display a critical depletion in glycolytic- and mitochondrial respiration-derived energy reserves and an overreliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH-generating enzyme, ME1 (malic enzyme 1), a known target of the antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2). Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance, and recovery of macrophage function. Conclusions: In COPD, an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity, which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

Slab to back-arc to arc: Fluid and melt pathways through the mantle wedge beneath the Lesser Antilles.

Volatiles expelled from subducted plates promote melting of the overlying warm mantle, feeding arc volcanism. However, debates continue over the factors controlling melt generation and transport, and how these determine the placement of volcanoes. To broaden our synoptic view of these fundamental mantle wedge processes, we image seismic attenuation beneath the Lesser Antilles arc, an end-member system that slowly subducts old, tectonized lithosphere. Punctuated anomalies with high ratios of bulk-to-shear attenuation (Qκ-1/Qµ-1 > 0.6) and VP/VS (>1.83) lie 40 km above the slab, representing expelled fluids that are retained in a cold boundary layer, transporting fluids toward the back-arc. The strongest attenuation (1000/QS ~ 20), characterizing melt in warm mantle, lies beneath the back-arc, revealing how back-arc mantle feeds arc volcanoes. Melt ponds under the upper plate and percolates toward the arc along structures from earlier back-arc spreading, demonstrating how slab dehydration, upper-plate properties, past tectonics, and resulting melt pathways collectively condition volcanism.

Sleep and the Young Athlete.

CONTEXT: Sleep plays a vital role in cognitive and physical performance. Teenage athletes (ages 13-19 years) are considered especially at risk for disordered sleep and associated negative cognitive, physical, and psychosomatic effects. However, there is a paucity of evidence-based recommendations to promote sleep quality and quantity in athletes who fall within this age range. We performed a review of the literature to reveal evidence-based findings and recommendations to help sports instructors, athletic trainers, physical therapists, physicians, and other team members caring for young athletes provide guidance on sleep optimization for peak sports performance and injury risk reduction. METHODS: PubMed, Scopus, and Cochrane CENTRAL were searched on May 11, 2016, and then again on September 1, 2020, for relevant articles published to date. STUDY DESIGN: Narrative review. LEVEL OF EVIDENCE: Level 4. RESULTS: Few studies exist on the effects disordered sleep may have on teenage athletes. By optimizing sleep patterns in young athletes during training and competitions, physical and mental performance, and overall well-being, may be optimized. Adequate sleep has been shown to improve the performance of athletes, although further studies are needed. CONCLUSION: Twenty-five percent of total sleep time should be deep sleep, with a recommended sleep time of 8 to 9 hours for most young athletes. Screen and television use during athletes' bedtime should be minimized to improve sleep quality and quantity. For young athletes who travel, jet lag can be minimized by allowing 1 day per time zone crossed for adjustment, limiting caffeine intake, planning meals and onboard sleeping to coincide with destination schedules, timing arrivals in the morning whenever possible, and using noise-canceling headphones and eyeshades. STRENGTH-OF-RECOMMENDATION TAXONOMY (SORT): B.

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Autologous versus synthetic bone grafts for the surgical management of tibial plateau fractures: a systematic review and meta-analysis of randomized controlled trials.

AIMS: Our objective was to conduct a systematic review and meta-analysis, to establish whether differences arise in clinical outcomes between autologous and synthetic bone grafts in the operative management of tibial plateau fractures. METHODS: A structured search of MEDLINE, EMBASE, the online archives of Bone & Joint Publishing, and CENTRAL databases from inception until 28 July 2021 was performed. Randomized, controlled, clinical trials that compared autologous and synthetic bone grafts in tibial plateau fractures were included. Preclinical studies, clinical studies in paediatric patients, pathological fractures, fracture nonunion, or chondral defects were excluded. Outcome data were assessed using the Risk of Bias 2 (ROB2) framework and synthesized in random-effect meta-analysis. The Preferred Reported Items for Systematic Review and Meta-Analyses guidance was followed throughout. RESULTS: Six studies involving 353 fractures were identified from 3,078 records. Following ROB2 assessment, five studies (representing 338 fractures) were appropriate for meta-analysis. Primary outcomes showed non-significant reductions in articular depression at immediate postoperative (mean difference -0.45 mm, p = 0.25, 95%confidence interval (CI) -1.21 to 0.31, I2 = 0%) and long-term (> six months, standard mean difference -0.56, p = 0.09, 95% CI -1.20 to 0.08, I2 = 73%) follow-up in synthetic bone grafts. Secondary outcomes included mechanical alignment, limb functionality, and defect site pain at long-term follow-up, perioperative blood loss, duration of surgery, occurrence of surgical site infections, and secondary surgery. Mean blood loss was lower (90.08 ml, p < 0.001, 95% CI 41.49 to 138.67) and surgery was shorter (16.17 minutes, p = 0.04, 95% CI 0.39 to 31.94) in synthetic treatment groups. All other secondary measures were statistically comparable. CONCLUSION: All studies reported similar methodologies and patient populations; however, imprecision may have arisen through performance variation. These findings supersede previous literature and indicate that, despite perceived biological advantages, autologous bone grafting does not demonstrate superiority to synthetic grafts. When selecting a void filler, surgeons should consider patient comorbidity, environmental and societal factors in provision, and perioperative and postoperative care provision. Cite this article: Bone Jt Open 2022;3(3):218-228.

Sex-Specific Effects of Plastic Caging in Murine Viral Myocarditis.

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Subduction history of the Caribbean from upper-mantle seismic imaging and plate reconstruction.

The margins of the Caribbean and associated hazards and resources have been shaped by a poorly understood history of subduction. Using new data, we improve teleseismic P-wave imaging of the eastern Caribbean upper mantle and compare identified subducted-plate fragments with trench locations predicted from plate reconstruction. This shows that material at 700-1200 km depth below South America derives from 90-115 Myr old westward subduction, initiated prior to Caribbean Large-Igneous-Province volcanism. At shallower depths, an accumulation of subducted material is attributed to Great Arc of the Caribbean subduction as it evolved over the past 70 Ma. We interpret gaps in these subducted-plate anomalies as: a plate window and tear along the subducted Proto-Caribbean ridge; tearing along subducted fracture zones, and subduction of a volatile-rich boundary between Proto-Caribbean and Atlantic domains. Phases of back-arc spreading and arc jumps correlate with changes in age, and hence buoyancy, of the subducting plate.

Mortality risk of surgically managing orthopaedic trauma during the COVID-19 pandemic.

AIMS: It is imperative to understand the risks of operating on urgent cases during the COVID-19 (SARS-Cov-2 virus) pandemic for clinical decision-making and medical resource planning. The primary aim was to determine the mortality risk and associated variables when operating on urgent cases during the COVID-19 pandemic. The secondary objective was to assess differences in the outcome of patients treated between sites treating COVID-19 and a separate surgical site. METHODS: The primary outcome measure was 30-day mortality. Secondary measures included complications of surgery, COVID-19 infection, and length of stay. Multiple variables were assessed for their contribution to the 30-day mortality. In total, 433 patients were included with a mean age of 65 years; 45% were male, and 90% were Caucasian. RESULTS: Overall mortality was 7.6% for all patients and 15.9% for femoral neck fractures. The mortality rate increased from 7.5% to 44.2% in patients with fracture neck of femur and a COVID-19 infection. The COVID-19 rate in the 30-day postoperative period was 11%. COVID-19 infection, age, and Charlson Comorbidity Index were independent risk factor for mortality. CONCLUSION: There was a significant risk of contracting COVID-19 due to being admitted to hospital. Using a site which was not treating COVID-19 respiratory patients for surgery did not identify a difference with respect to mortality, nosocomial COVID-19 infection, or length of stay. The COVID-19 pandemic significantly increases perioperative mortality risk in patients with fractured neck of femora but patients with other injuries were not at increased risk. Cite this article: Bone Jt Open 2021;2(5):330-336.

Morbidity and mortality in patients undergoing lower limb arthroplasty surgery during the initial surge of the COVID-19 pandemic in the UK at a single-speciality orthopaedic hospital.

AIMS: The COVID-19 pandemic posed significant challenges to healthcare systems across the globe in 2020. There were concerns surrounding early reports of increased mortality among patients undergoing emergency or non-urgent surgery. We report the morbidity and mortality in patients who underwent arthroplasty procedures during the UK first stage of the pandemic. METHODS: Institutional review board approval was obtained for a review of prospectively collected data on consecutive patients who underwent arthroplasty procedures between March and May 2020 at a specialist orthopaedic centre in the UK. Data included diagnoses, comorbidities, BMI, American Society of Anesthesiologists grade, length of stay, and complications. The primary outcome was 30-day mortality and secondary outcomes were prevalence of SARS-CoV-2 infection, medical and surgical complications, and readmission within 30 days of discharge. The data collated were compared with series from the preceding three months. RESULTS: There were 167 elective procedures performed in the first three weeks of the study period, prior to the first national lockdown, and 57 emergency procedures thereafter. Three patients (1.3%) were readmitted within 30 days of discharge. There was one death (0.45%) due to SARS-CoV-2 infection after an emergency procedure. None of the patients developed complications of SARS-CoV-2 infection after elective arthroplasty. There was no observed spike in complications during in-hospital stay or in the early postoperative period. There was no statistically significant difference in survival between pre-COVID-19 and peri-COVID-19 groups (p = 0.624). We observed a higher number of emergency procedures performed during the pandemic within our institute. CONCLUSION: An international cohort has reported 30-day mortality as 28.8% following orthopaedic procedures during the pandemic. There are currently no reports on clinical outcomes of patients treated with lower limb reconstructive surgery during the same period. While an effective vaccine is developed and widely accepted, it is very likely that SARS-CoV2 infection remains endemic. We believe that this report will help guide future restoration planning here in the UK and abroad. Cite this article: Bone Jt Open 2021;2(5):323-329.

Author Correction: Variable water input controls evolution of the Lesser Antilles volcanic arc.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A transdisciplinary and community-driven database to unravel subduction zone initiation.

Subduction zones are pivotal for the recycling of Earth's outer layer into its interior. However, the conditions under which new subduction zones initiate are enigmatic. Here, we constructed a transdisciplinary database featuring detailed analysis of more than a dozen documented subduction zone initiation events from the last hundred million years. Our initial findings reveal that horizontally forced subduction zone initiation is dominant over the last 100 Ma, and that most initiation events are proximal to pre-existing subduction zones. The SZI Database is expandable to facilitate access to the most current understanding of subduction zone initiation as research progresses, providing a community platform that establishes a common language to sharpen discussion across the Earth Science community.

Pyruvate Aldol Condensation Product: A Metabolite That Escaped Synthetic Preparation for Over a Century.

The homoaldol condensation product of pyruvate, 2-methyl-4-oxopent-2-enedioic acid (OMPD), has been recently implicated as a catabolic intermediate in the bacterial degradation of lignin and previously identified from other biological sources in reports ranging over 60 years. Yet, while a preparation of the pyruvate homoaldol product precursor, 4-hydroxy-4-methyl-2-oxoglutaric acid (HMOG/Parapyruvate), was first reported in 1901, there has not been a complete published synthesis of OMPD. Analyses of reaction mixtures have helped identify zymonic acid, the lactone of HMOG, as the direct precursor to OMPD. The reaction appears to proceed through an acid- or base-mediated ring opening that does not involve formal lactone hydrolysis. In addition to a preparative protocol, we provide a proposed mechanism for the formation of methylsuccinic acid that arises from the nonoxidative decarboxylation of OMPD. Finally, we calculated the relative stability of the isomers of OMPD and found Z-OMPD to be the lowest in energy. These computations also support our observations that Z-OMPD is the most abundant isomer across a range of pH values.

Variable water input controls evolution of the Lesser Antilles volcanic arc.

Oceanic lithosphere carries volatiles, notably water, into the mantle through subduction at convergent plate boundaries. This subducted water exercises control on the production of magma, earthquakes, formation of continental crust and mineral resources. Identifying different potential fluid sources (sediments, crust and mantle lithosphere) and tracing fluids from their release to the surface has proved challenging1. Atlantic subduction zones are a valuable endmember when studying this deep water cycle because hydration in Atlantic lithosphere, produced by slow spreading, is expected to be highly non-uniform2. Here, as part of a multi-disciplinary project in the Lesser Antilles volcanic arc3, we studied boron trace element and isotopic fingerprints of melt inclusions. These reveal that serpentine-that is, hydrated mantle rather than crust or sediments-is a dominant supplier of subducted water to the central arc. This serpentine is most likely to reside in a set of major fracture zones subducted beneath the central arc over approximately the past ten million years. The current dehydration of these fracture zones coincides with the current locations of the highest rates of earthquakes and prominent low shear velocities, whereas the preceding history of dehydration is consistent with the locations of higher volcanic productivity and thicker arc crust. These combined geochemical and geophysical data indicate that the structure and hydration of the subducted plate are directly connected to the evolution of the arc and its associated seismic and volcanic hazards.

Retrospective Summary of Erysipelothrix rhusiopathiae Diagnosed in Avian Species in California (2000-19).

Erysipelas is a bacterial disease caused by Erysipelothrix rhusiopathiae that affects multiple mammalian and avian species. In poultry, the disease is of sporadic prevalence and more often observed in older birds, leading to decreased egg production and mortality. Among avian species, turkey breeders seem to be the most affected, but outbreaks have been reported in ducks, layer chickens, quails, geese, and various captive and free-range birds. Sixty-seven cases of erysipelas have been diagnosed in animals submitted for necropsy evaluation at the California Animal Health and Food Safety Laboratory System from January 2000 to December 2019. Of these, 38 cases (56.72%) were in avian species, and a retrospective analysis of these avian cases was performed. The majority of the avian cases were in turkeys (17/38, 44.74%). Most of the turkey breeder cases reported performing artificial insemination prior to the increase in mortality. In other birds, mortality was often observed without observing previous clinical signs. The majority of cases presented with coinfections with other pathogens (23/38, 60.53%), which might have affected the clinical outcome. Despite the occasional occurrence in avian species, erysipelas is an important pathogen in poultry and should be considered as a differential diagnosis in other avian species when acute septicemia is suspected as the cause of mortality.

BPA Alters Estrogen Receptor Expression in the Heart After Viral Infection Activating Cardiac Mast Cells and T Cells Leading to Perimyocarditis and Fibrosis.

Myocarditis is an inflammatory heart disease that leads to dilated cardiomyopathy (DCM) and heart failure. Sex hormones play an important role in the development of myocarditis with testosterone driving disease in males and estrogen being cardioprotective in females. The human population is widely exposed to the endocrine disruptor bisphenol A (BPA) from plastics such as water bottles, plastic food containers, copy paper, and receipts. Several clinical and numerous animal studies have found an association between elevated BPA levels and cardiovascular disease. A recent report found elevated levels of BPA in the serum of patients with DCM compared to healthy controls. In this study we examined whether exposure to BPA for 2 weeks prior to viral infection and leading up to myocarditis at day 10 altered inflammation in female BALB/c mice housed in standard plastic cages/water bottles with soy-free food and bedding. We found that a human relevant dose of BPA (25 µg/L) in drinking water, with an estimated exposure of 5 µg BPA/kg BW, significantly increased myocarditis and pericarditis compared to control water without altering viral genome levels in the heart. BPA exposure activated ERα and ERß in the spleen 24 h after infection and phosphorylated ERα and ERß during myocarditis, but decreased ERα and increased ERß mRNA in the heart as measured by qRT-PCR. Exposure to BPA significantly increased CD4+ T cells, IFNγ, IL-17A, TLR4, caspase-1, and IL-1ß in the heart. BPA exposure also increased cardiac fibrosis compared to controls. Mast cells, which are associated with cardiac remodeling, were found to increase in number and degranulation, particularly along the pericardium. Interestingly, plastic caging/water bottle exposure alone led to increased mast cell numbers, pericardial degranulation and fibrosis in female BALB/c mice compared to animals housed in glass cages/water bottles with soy-free food and bedding. These data suggest that BPA exposure may increase the risk of developing myocarditis after a viral infection in women.

Chemiosmotic energy for primitive cellular life: Proton gradients are generated across lipid membranes by redox reactions coupled to meteoritic quinones.

Transmembrane proton gradients coupled to, and maintained by, electron transport are ubiquitous sources of chemiosmotic energy in all life today, but how this system first emerged is uncertain. Here we report a model liposome system in which internal ferricyanide serves as an oxidant and external ascorbate or dithionite provide a source of electrons to electron carriers embedded in liposome membranes. Quinones linked the donor to the acceptor in a coupled redox reaction that released protons into the vesicle internal volume as electrons were transported across the membranes, thereby producing substantial pH gradients. Using this system, we found that one or more quinones in extracts from carbonaceous meteorites could serve as coupling agents and that substantial pH gradients developed in the acidic interior of liposomes. If amphiphilic compounds present on the prebiotic Earth assembled into membranous compartments that separate reduced solutes in the external medium from an encapsulated acceptor, quinones can mediate electron and proton transport across the membranes, thereby providing a source of chemiosmotic energy for primitive metabolic reactions.