In vitro antifungal activity of Cinnamomum zeylanicum bark and leaf essential oils against Candida albicans and Candida auris.

Candida infections are a significant source of patient morbidity and mortality. Candida albicans is the most common pathogen causing Candida infections. Candida auris is a newly described pathogen that is associated with multi-drug-resistant candidiasis and candidaemia in humans. The antifungal effects of various essential oils and plant compounds have been demonstrated against human pathogenic fungi. In this study, the effect of cinnamon leaf and bark essential oils (CEOs) was determined against both C. albicans and C. auris. The disc diffusion (direct and vapour) and broth microdilution method was used to determine antifungal activity of the EOs against selected strains (C. albicans ATCC 10231, C. albicans ATCC 2091 and C. auris NCPF 8971) whilst the mode of action and haemolysin activity of the CEOs were determined using electron microscopy and light microscopy. Direct and vapour diffusion assays showed greater inhibitory activity of bark CEO in comparison with leaf CEO. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of bark CEO for all tested strains was below 0.03% (v/v), which was lower than the MICs of the leaf CEO (0.06-0.13%, v/v) dependent on the strain and the MFCs at 0.25% (v/v). In the morphological interference assays, damage to the cell membrane was observed and both CEOs inhibited hyphae formation. The haemolysin production assay showed that CEOs can reduce the haemolytic activity in the tested C. albicans and C. auris strains. At low concentrations, CEOs have potent antifungal and antihaemolytic activities in vitro against C. albicans and C. auris.Key points• Essential oils from Cinnamomum zeylanicum Blume bark and leaf (CBEO and CLEO) demonstrated fungicidal properties at very low concentrations.• The antifungal activity of CBEO was greater than that of CLEO consistent with other recent published literature.• The mode of action of CBEO and CLEO was damage to the membrane of C. albicans and C. auris.• Both CBEO and CLEO inhibited the formation of hyphae and reduced haemolysin production in C. albicans and C. auris. Graphical abstract.

A Flexible Lunar Architecture for Exploration (FLARE) supporting NASA's Artemis Program.

The Flexible Lunar Architecture for Exploration (FLARE) is a concept to deliver four crew to the lunar surface for a minimum of seven days and then return them safely to Earth. FLARE can be implemented whenever the component vehicles are operational. FLARE was developed as an alternative to NASA's Human Landing System (HLS) reference architecture from the Design Analysis Cycle (DAC) #2 created in 2019. The DAC2 guidelines required utilization of the Gateway vehicle in a Near- Rectilinear Halo Orbit (NRHO). Instead, FLARE chooses a Low Lunar Frozen Polar Orbit (LLFPO) for lunar rendezvous of components, and an optional Gateway vehicle. The LLFPO provides a stable orbit that overflies the south pole every 2 h, ensuring easy access to the lunar surface for surface aborts with a much lower propellant requirement than NRHO. The minimum FLARE concept uses one Space Launch System (SLS) launch, one Orion, one European Service Module (ESM), and one human lander (launched on commercial vehicle(s)). FLARE adds the SpaceTug, based upon the mature and successful ULA "Common" Centaur Upper Stage vehicle, with modifications to create an Earth-Moon transfer vehicle. In the FLARE baseline mission, the SpaceTug provides propulsion needed to return the Orion + ESM from LLFPO to Earth. The SpaceTug also provides propulsion to deliver the separate human lander components - the Descent Element (DE) and the Ascent Element (AE) - from Low Earth Orbit (LEO) to LLFPO. The SLS Block 1 then launches the Orion + ESM and completes a rendezvous with the mated DE + AE components in LLFPO. FLARE offers optional phases beyond the baseline mission. The SpaceTug can deliver components of the planned Gateway, including the Power and Propulsion Element (PPE) and the Habitable and Logistics Outpost (HALO), to LLFPO. FLARE provides an option to deliver precursor equipment to the lunar surface to enhance and extend the human mission. With these components, including an inflatable habitation module and airlock, individual crew mobility vehicle(s), an In-Situ Resource Utilization (ISRU) demonstration, and science and technology experiments, the crew can explore and conduct science on the lunar surface for up to 14 days.

Incidental significant arrhythmia in scleroderma associates with cardiac magnetic resonance measure of fibrosis and hs-TnI and NT-proBNP.

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers. METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion. RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia. CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.

Prediction of Fluoroquinolone Susceptibility Directly from Whole-Genome Sequence Data by Using Liquid Chromatography-Tandem Mass Spectrometry To Identify Mutant Genotypes.

Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis, using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms for fluoroquinolone nonsusceptibility using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquinolone susceptibility.

Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis.

Objective: Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods: The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results: A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion: The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

AIMS: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. METHODS AND RESULTS: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). CONCLUSIONS: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

OH production from the photolysis of isoprene-derived peroxy radicals: cross-sections, quantum yields and atmospheric implications.

In environments with high concentrations of biogenic volatile organic compounds and low concentrations of nitrogen oxides (NOx = NO + NO2), significant discrepancies have been found between measured and modeled concentrations of hydroxyl radical (OH). The photolysis of peroxy radicals from isoprene (HO-Iso-O2) in the near ultraviolet represents a potential source of OH in these environments, yet has not been considered in atmospheric models. This paper presents measurements of the absorption cross-sections for OH formation (σRO2,OH) from the photolysis of HO-Iso-O2 at wavelengths from 310-362.5 nm, via direct observation by laser-induced fluorescence of the additional OH produced following laser photolysis of HO-Iso-O2. Values of σRO2,OH for HO-Iso-O2 ranged from (6.0 ± 1.6) × 10-20 cm2 molecule-1 at 310 nm to (0.50 ± 0.15) × 10-20 cm2 molecule-1 at 362.5 nm. OH photodissociation yields from HO-Iso-O2 photolysis, ϕOH,RO2, were determined via comparison of the measured values of σRO2,OH to the total absorption cross-sections for HO-Iso-O2 (σRO2), which were obtained using a newly-constructed spectrometer. ϕOH,RO2 was determined to be 0.13 ± 0.04 at wavelengths from 310-362.5 nm. To determine the impact of HO-Iso-O2 photolysis on atmospheric OH concentrations, a modeling case-study for a high-isoprene, low-NOx environment (namely, the 2008 Oxidant and Particle Photochemical Processes above a South-East Asian Tropical Rainforest (OP-3) field campaign, conducted in Borneo) was undertaken using the detailed Master Chemical Mechanism. The model calculated that the inclusion of HO-Iso-O2 photolysis in the model had increased the OH concentration by only 1% on average from 10:00-16:00 local time. Thus, HO-Iso-O2 photolysis alone is insufficient to resolve the discrepancy seen between measured OH concentrations and those predicted by atmospheric chemistry models in such environments.

Being a family systems thinker: a psychiatrist's personal odyssey.

This account traces the development of family systems thinking from early pioneering thinking and practices, through the development of institutions and professional definitions, and through challenges to family systems thinking and practice from the biomedical points of view. Throughout there is a strong conviction that "thinking family" is an essential core of effective mental health treatment, because families can heal.

Normal heart ventricular tachycardia associated with pregnancy: successful treatment with catheter ablation.

BACKGROUND: Normal heart ventricular arrhythmia occurring during pregnancy has been previously described. Whilst there are established reports of catheter ablation to treat supraventricular arrhythmia during pregnancy, there are no reports of ablation to treat ventricular tachycardia. CASE: We present the case of a 36 year old women, 31 weeks into an otherwise uncomplicated pregnancy, experiencing significant, troublesome and drug refractory tachycardia emanating from the right ventricular outflow tract. CONCLUSION: We describe a successful radio frequency ablation in the third trimester of pregnancy.

Left Atrial Appendage Occlusion: British Cardiovascular Intervention Society and British Heart Rhythm Society Position Statement.

Percutaneous left atrial appendage occlusion aims to reduce the risk of stroke in patients with AF, particularly those who are not good candidates for systemic anticoagulation. The procedure has been studied in large international randomised trials and registries and was approved by the National Institute for Health and Care Excellence in 2014 and by NHS England in 2018. This position statement summarises the evidence for left atrial appendage occlusion and presents the current indications. The options and consensus on best practice for pre-procedure planning, undertaking a safe and effective implant and appropriate post-procedure management and follow-up are described. Standards regarding procedure volume for implant centres and physicians, the role of multidisciplinary teams and audits are highlighted.

Left Atrial Appendage Occlusion: British Cardiovascular Intervention Society and British Heart Rhythm Society Position Statement.

Percutaneous left atrial appendage occlusion aims to reduce the risk of stroke in patients with AF, particularly those who are not good candidates for systemic anticoagulation. The procedure has been studied in large international randomised trials and registries and was approved by the National Institute for Health and Care Excellence in 2014 and by NHS England in 2018. This position statement summarises the evidence for left atrial appendage occlusion and presents the current indications. The options and consensus on best practice for pre-procedure planning, undertaking a safe and effective implant and appropriate post-procedure management and follow-up are described. Standards regarding procedure volume for implant centres and physicians, the role of multidisciplinary teams and audits are highlighted.

Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH. METHODS: We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999-2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn's disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison's disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55). CONCLUSIONS: Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.

Characterization of novel recombinant mycobacteriophages derived from homologous recombination between two temperate phages.

Comparative analyses of mycobacteriophage genomes reveals extensive genetic diversity in genome organization and gene content, contributing to widespread mosaicism. We previously reported that the prophage of mycobacteriophage Butters (cluster N) provides defense against infection by Island3 (subcluster I1). To explore the anti-Island3 defense mechanism, we attempted to isolate Island3 defense escape mutants on a Butters lysogen, but only uncovered phages with recombinant genomes comprised of regions of Butters and Island3 arranged from left arm to right arm as Butters-Island3-Butters (BIBs). Recombination occurs within two distinct homologous regions that encompass lysin A, lysin B, and holin genes in one segment, and RecE and RecT genes in the other. Structural genes of mosaic BIB genomes are contributed by Butters while the immunity cassette is derived from Island3. Consequently, BIBs are morphologically identical to Butters (as shown by transmission electron microscopy) but are homoimmune with Island3. Recombinant phages overcome antiphage defense and silencing of the lytic cycle. We leverage this observation to propose a stratagem to generate novel phages for potential therapeutic use.

Macrophages from lupus-prone MRL mice have a conditional signaling abnormality that leads to dysregulated expression of numerous genes.

Macrophages (mϕ) from pre-diseased mice of the major murine inbred models of spontaneous autoimmunity (AI), including multiple lupus-prone strains and the type I diabetes-prone NOD (non-obese diabetic) strain, have identical apoptotic target-dependent abnormalities. This characteristic feature of mϕ from AI-prone mice suggests that abnormal signaling events induced within mϕ following their interaction with apoptotic targets may predispose to AI. Such signaling abnormalities would affect predominantly the processing and presentation of self-antigen (i.e., derived from apoptotic targets), while sparing the processing and presentation of foreign antigen (i.e., derived from non-apoptotic sources). Here, we used DNA microarrays to test the hypothesis that mϕ from AI-prone mice (MRL/MpJ [MRL/+] or MRL/MpJ-Tnfrsf6 ( lpr ) [MRL/lpr]) differentially express multiple genes in comparison to non-AI mϕ (BALB/c), but do so in a largely apoptotic cell-dependent manner. Mϕ were stimulated with lipopolysaccharide, a potent innate stimulus, in the presence or absence of serum (an experimental surrogate for apoptotic targets). In accord with our hypothesis, the number of genes differentially expressed by MRL mϕ was significantly increased in the presence vs. the absence of serum, the apoptotic target surrogate (n = 401 vs. n = 201). Notably, for genes differentially expressed by MRL mϕ in the presence of serum, serum-free culture normalized their expression to a level statistically indistinguishable from that by non-AI mϕ. Comparisons of mϕ from AI-prone NOD and non-AI C57BL/6 mice corroborated these findings. Together, these data support the hypothesis that mϕ from MRL and other AI-prone mice are characterized by a conditional abnormality elicited by serum lipids or apoptotic targets.

Gender differences in sympathetic neural activation following uncomplicated acute myocardial infarction.

AIMS: To determine whether the magnitude of post-acute myocardial infarction (AMI) sympathetic activation is greater in women (F-AMI) than men (M-AMI). METHODS AND RESULTS: Both sympatho-humoral activation and female gender are associated with worse outcome in the early phase following AMI. However, women have lower sympathetic output than men. We therefore examined matched groups of F-AMI (18) and M-AMI (18) patients 2-4 days following uncomplicated AMI, then 3 monthly to 9 months; matched normal control (NC) groups comprised M-NC (18) and F-NC (18). Muscle sympathetic nerve activity (MSNA) was measured by microneurography. Muscle sympathetic nerve activity was lower in the F-NC than M-NC (at least P < 0.05) and greater in the two AMI groups than their corresponding NC groups (at least P < 0.001). Muscle sympathetic nerve activity was similar in the F-AMI and M-AMI groups indicating a post-AMI increase in women of about twice that in men (P < 0.0001). Both AMI groups returned to corresponding NC (lower in women) levels by 9 months. CONCLUSION: Following uncomplicated AMI, women developed a relatively greater magnitude of sympathetic activation lasting until its resolution at 9 months. This is consistent with reports of their worse prognosis observed during this time period, with important potential clinical implications.

Multicentre randomised trial comparing contact force with electrical coupling index in atrial flutter ablation (VERISMART trial).

INTRODUCTION: Electrical coupling index (ECI) and contact force (CF) have been developed to aid lesion formation during catheter ablation. ECI measures tissue impedance and capacitance whilst CF measures direct contact. The aim was to determine whether the presence of catheter / tissue interaction information, such as ECI and CF, reduce time to achieve bidirectional cavotricuspid isthmus block during atrial flutter (AFL) ablation. METHODS: Patients with paroxysmal or persistent AFL were randomised to CF visible (range 5-40g), CF not visible, ECI visible (change of 12%) or ECI not visible. Follow-up occurred at 3 and 6 months and included a 7 day ECG recording. The primary endpoint was time to bidirectional cavotricuspid isthmus block. RESULTS: 114 patients were randomised, 16 were excluded. Time to bidirectional block was significantly shorter when ECI was visible (median 30.0 mins (IQR 31) to median 10.5mins (IQR 12) p 0.023) versus ECI not visible. There was a trend towards a shorter time to bidirectional block when CF was visible. Higher force was applied when CF was visible (median 9.03g (IQR 7.4) vs. 11.3g (5.5) p 0.017). There was no difference in the acute recurrence of conduction between groups. The complication rate was 2%, AFL recurrence was 1.1% and at 6 month follow-up, 12% had atrial fibrillation. CONCLUSION: The use of tissue contact information during AFL ablation was associated with reduced time taken to achieve bidirectional block when ECI was visible. Contact force data improved contact when visible with a trend towards a reduction in the procedural endpoint. ClinicalTrials.gov trial identifier: NCT02490033.

Genome Sequences of Six Cluster N Mycobacteriophages, Kevin1, Nenae, Parmesanjohn, ShrimpFriedEgg, Smurph, and SpongeBob, Isolated on Mycobacterium smegmatis mc2155.

The annotation of six cluster N Mycobacterium smegmatis phages (Kevin1, Nenae, Parmesanjohn, ShrimpFriedEgg, Smurph, and SpongeBob) reveals regions of genomic diversity, particularly within the central region of the genome. The genome of Kevin1 includes two orphams (genes with no similarity to other phage genes), with one predicted to encode an AAA-ATPase.