Selective control of parasitic nematodes using bioactivated nematicides.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Helical ordering of envelope-associated proteins and glycoproteins in respiratory syncytial virus.

Human respiratory syncytial virus (RSV) causes severe respiratory illness in children and the elderly. Here, using cryogenic electron microscopy and tomography combined with computational image analysis and three-dimensional reconstruction, we show that there is extensive helical ordering of the envelope-associated proteins and glycoproteins of RSV filamentous virions. We calculated a 16 Å resolution sub-tomogram average of the matrix protein (M) layer that forms an endoskeleton below the viral envelope. These data define a helical lattice of M-dimers, showing how M is oriented relative to the viral envelope. Glycoproteins that stud the viral envelope were also found to be helically ordered, a property that was coordinated by the M-layer. Furthermore, envelope glycoproteins clustered in pairs, a feature that may have implications for the conformation of fusion (F) glycoprotein epitopes that are the principal target for vaccine and monoclonal antibody development. We also report the presence, in authentic virus infections, of N-RNA rings packaged within RSV virions. These data provide molecular insight into the organisation of the virion and the mechanism of its assembly.

PGP-14 establishes a polar lipid permeability barrier within the C. elegans pharyngeal cuticle.

The cuticles of ecdysozoan animals are barriers to material loss and xenobiotic insult. Key to this barrier is lipid content, the establishment of which is poorly understood. Here, we show that the p-glycoprotein PGP-14 functions coincidently with the sphingomyelin synthase SMS-5 to establish a polar lipid barrier within the pharyngeal cuticle of the nematode C. elegans. We show that PGP-14 and SMS-5 are coincidentally expressed in the epithelium that surrounds the anterior pharyngeal cuticle where PGP-14 localizes to the apical membrane. pgp-14 and sms-5 also peak in expression at the time of new cuticle synthesis. Loss of PGP-14 and SMS-5 dramatically reduces pharyngeal cuticle staining by Nile Red, a key marker of polar lipids, and coincidently alters the nematode's response to a wide-range of xenobiotics. We infer that PGP-14 exports polar lipids into the developing pharyngeal cuticle in an SMS-5-dependent manner to safeguard the nematode from environmental insult.

Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis-Associated Interstitial Lung Disease.

OBJECTIVE: To explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD. METHODS: There were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling. RESULTS: LVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P = 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P = 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P = 0.08). Older age (95% CI 1.0-6.4; P = 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P < 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P < 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P < 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P = 0.04). CONCLUSION: LVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

Multidisciplinary team discussion: the emerging gold standard for management of cardiopulmonary complications of connective tissue disease.

Cardiopulmonary complications of connective tissue diseases (CTDs), particularly pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), are major determinants of morbidity and mortality. Multidisciplinary meetings may improve diagnostic accuracy and optimise treatment. We review the literature regarding multidisciplinary meetings in CTD-ILD and PAH and describe our tertiary centre experience of the role of the multidisciplinary meeting in managing CTD-PAH.

Myocardial fibrosis and arrhythmic burden in systemic sclerosis.

OBJECTIVES: Cardiac complications of SSc are a leading cause of SSc-associated death. Cardiac imaging for identifying substrate abnormality may be useful in predicting risk of cardiac arrhythmias or future cardiac failure. The aim of this study was to quantify the burden of asymptomatic fibro-inflammatory myocardial disease using cardiac magnetic resonance imaging (CMR) and assess the relationship between asymptomatic myocardial fibrosis and cardiac arrhythmias in SSc. METHODS: Thirty-two patients with SSc with no documented history of pulmonary vascular or heart disease underwent CMR with gadolinium and 24-h ambulatory ECG. Focal myocardial fibrosis was assessed using post-gadolinium imaging and diffuse fibro-inflammatory myocardial disease quantified using T1- and T2-mapping. CMR results were compared with an age- and sex-matched control group. RESULTS: Post-gadolinium focal fibrosis was prevalent in SSc but not controls (30% vs 0%, p < 0.01).. T1-mapping values (as a marker of diffuse fibrosis) were greater in SSc than controls [saturated recovery single-shot acquisition (SASHA): 1584 ms vs 1515 ms, P < 0.001; shortened Modified look locker sequence (ShMOLLI): 1218 ms vs 1138 ms, p < 0.001]. More than one-fifth (22.6%) of the participants had ventricular arrhythmias on ambulatory ECG, but no associations between focal or diffuse myocardial fibrosis and arrhythmias were evident. CONCLUSION: In SSc patients without evidence of overt cardiac disease, a high burden of myocardial fibrosis and arrhythmias was identified. However, there was no clear association between focal or diffuse myocardial fibrosis and arrhythmias, suggesting CMR may have limited use as a screening tool to identify SSc patients at risk of future significant arrhythmias.

Development of a yeast whole-cell biocatalyst for MHET conversion into terephthalic acid and ethylene glycol.

BACKGROUND: Over the 70 years since the introduction of plastic into everyday items, plastic waste has become an increasing problem. With over 360 million tonnes of plastics produced every year, solutions for plastic recycling and plastic waste reduction are sorely needed. Recently, multiple enzymes capable of degrading PET (polyethylene terephthalate) plastic have been identified and engineered. In particular, the enzymes PETase and MHETase from Ideonella sakaiensis depolymerize PET into the two building blocks used for its synthesis, ethylene glycol (EG) and terephthalic acid (TPA). Importantly, EG and TPA can be re-used for PET synthesis allowing complete and sustainable PET recycling. RESULTS: In this study we used Saccharomyces cerevisiae, a species utilized widely in bioindustrial fermentation processes, as a platform to develop a whole-cell catalyst expressing the MHETase enzyme, which converts monohydroxyethyl terephthalate (MHET) into TPA and EG. We assessed six expression architectures and identified those resulting in efficient MHETase expression on the yeast cell surface. We show that the MHETase whole-cell catalyst has activity comparable to recombinant MHETase purified from Escherichia coli. Finally, we demonstrate that surface displayed MHETase is active across a range of pHs, temperatures, and for at least 12 days at room temperature. CONCLUSIONS: We demonstrate the feasibility of using S. cerevisiae as a platform for the expression and surface display of PET degrading enzymes and predict that the whole-cell catalyst will be a viable alternative to protein purification-based approaches for plastic degradation.

The clinical implications of left ventricular diastolic dysfunction in systemic sclerosis.

OBJECTIVES: We sought to quantify the burden of left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) in systemic sclerosis (SSc) and assess the progression of LVDD over time and its prognostic importance. METHODS: Two-hundred and twenty-five participants enrolled in the Australian Scleroderma Cohort Study were included and LVDD was assessed according to 2016 ASE/EACVI Guidelines. Logistic regression analyses and generalised estimating equations were performed to evaluate the relationship between LVDD and SSc disease characteristics and symptoms and signs of heart failure, respectively. The relationship between LVDD and mortality was assessed using Kaplan-Meier survival estimates. RESULTS: Thirty-four (15%) participants were diagnosed with LVDD. A further 89 (40%) participants had indeterminate diastolic function. Older age (p<0.01), hypertension (p=0.02), impaired systolic function (p=0.03) and interstitial lung disease (p=0.01) were all associated with the presence of LVDD. There was no association between the presence of LVDD and clinical signs of heart failure, however, LVDD was associated with more breathlessness and worse functional class (p=0.03). LVDD was observed to progress over time, with significant worsening of parameters of left ventricular filling pressure. There was no significant relationship between LVDD and mortality (p=0.23). CONCLUSIONS: Abnormal diastolic function is a common finding in SSc, progresses over time and is associated with more severe dyspnoea. Whilst patients with LVDD are more breathless, LVDD is not clearly associated with clinical findings of heart failure demonstrating that LVDD may be of importance in explaining symptoms even in the absence of HFpEF in SSc.

SAR11 bacteria linked to ocean anoxia and nitrogen loss.

Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N2 gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world's largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth's most abundant organismal group.

Race and Sex Are Associated With Variations in Pain Management in Patients Presenting to the Emergency Department With Undifferentiated Abdominal Pain.

BACKGROUND: Pain management is critical to the management of patients in the emergency department (ED). The clinical decision-making process for prescribing medications is complicated by its subjective nature. Historically, racial and ethnic minority groups and women have not had their pain managed as aggressively as White and male patients. OBJECTIVE: The objective of this study was to determine whether race and biological sex affect the pain management process by means of evaluating data from a large hospital system with diverse patient demographic characteristics. METHODS: This was a retrospective study of adult patients who presented an ED within the hospital system and were discharged from the ED with a diagnosis of undifferentiated abdominal pain during a single year. Patient pain was classified as mild, moderate, or severe, and patients were further stratified by race, ethnicity, sex, and insurance status. Pain management was assessed by narcotic vs non-narcotic administration. RESULTS: A total of 32,676 patients were included in the study. Narcotic administration was more likely in White patients with undifferentiated abdominal pain (22%) compared with Black patients (12%; adjusted odds ratio 0.50; 95% CI 0.46-0.54). This persists across patient-reported pain scores. In addition, women (16.99%) were prescribed narcotics less often than men (19.41%; p < 0.0001). CONCLUSIONS: Although differences in pain management practices have been explored previously, this study provided a large, updated, multifacility assessment that confirmed that race- and sex-based differences in pain management persist, specifically in the decision to treat with narcotics. Further investigation is warranted to determine the root causes of these differences.

A Universal and High-Throughput Proteomics Sample Preparation Platform.

Major advances have been made to improve the sensitivity of mass analyzers, spectral quality, and speed of data processing enabling more comprehensive proteome discovery and quantitation. While focus has recently begun shifting toward robust proteomics sample preparation efforts, a high-throughput proteomics sample preparation is still lacking. We report the development of a highly automated universal 384-well plate sample preparation platform with high reproducibility and adaptability for extraction of proteins from cells within a culture plate. Digestion efficiency was excellent in comparison to a commercial digest peptide standard with minimal sample loss while improving sample preparation throughput by 20- to 40-fold (the entire process from plated cells to clean peptides is complete in ∼300 min). Analysis of six human cell types, including two primary cell samples, identified and quantified ∼4,000 proteins for each sample in a single high-performance liquid chromatography (HPLC)-tandem mass spectrometry injection with only 100-10K cells, thus demonstrating universality of the platform. The selected protein was further quantified using a developed HPLC-multiple reaction monitoring method for HeLa digests with two heavy labeled internal standard peptides spiked in. Excellent linearity was achieved across different cell numbers indicating a potential for target protein quantitation in clinical research.

Seaweed-coral competition in the field: effects on coral growth, photosynthesis and microbiomes require direct contact.

A number of tropical reefs have transitioned from coral to macroalgal dominance, but the role of macroalgal competition in coral decline is debated. There is a need to understand the relative roles of direct coral-algal effects versus indirect, microbially mediated effects shaping these interactions, as well as the relevant scales at which interactions operate under natural field, as opposed to laboratory, conditions. We conducted a manipulative field experiment investigating how direct contact versus close proximity (approx. 1.5 cm) with macroalgae (Galaxaura rugosa, Sargassum polycystum) impacted the growth, photosynthetic efficiency, and prokaryotic microbiome of the common Indo-Pacific coral Acropora millepora. Both coral growth and photosynthetic efficiency were suppressed when in direct contact with algae or their inert mimics--but not when in close proximity to corals without direct contact. Coral microbiomes were largely unaltered in composition, variability, or diversity regardless of treatment, although a few uncommon taxa differed in abundance among treatments. Negative impacts of macroalgae were contact dependent, accounted for by physical structure alone and had minimal effects on coral microbiomes. The spatial constraints of these interactions have important implications for understanding and predicting benthic community dynamics as reefs degrade.

An Unusual Case of Shock Following an Elective Caesarean Delivery.

BACKGROUND: The differential diagnosis of peripartum chest pain and cardiogenic shock is broad and includes pulmonary embolism, amniotic fluid embolism, peripartum and Takotsubo cardiomyopathy, myocardial infarction, and anaesthetic complications. CASE: A 31-year-old woman with Addison's disease underwent an elective caesarean section that was complicated by chest pain and cardiogenic shock. After initial resuscitation, she was transferred to a tertiary hospital, and urgent transthoracic echocardiography revealed severe systolic dysfunction. She was treated with an increased dose of hydrocortisone and intravenous furosemide and improved. Follow-up imaging showed improvement of left ventricular systolic function. CONCLUSION: In patients with cardiogenic shock after delivery, early transthoracic echocardiography is a non-invasive tool that can rapidly narrow the differential diagnosis.

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Phosphodiesterase 5 inhibitors for pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) comprises a group of complex and heterogenous conditions, characterised by elevated pulmonary artery pressure, and which left untreated leads to right-heart failure and death. PH includes World Health Organisation (WHO) Group 1 pulmonary arterial hypertension (PAH); Group 2 consists of PH due to left-heart disease (PH-LHD); Group 3 comprises PH as a result of lung diseases or hypoxia, or both; Group 4 includes PH due to chronic thromboembolic occlusion of pulmonary vasculature (CTEPH), and Group 5 consists of cases of PH due to unclear and/or multifactorial mechanisms including haematological, systemic, or metabolic disorders. Phosphodiesterase type 5 (PDE5) inhibitors increase vasodilation and inhibit proliferation. OBJECTIVES: To determine the efficacy of PDE5 inhibitors for pulmonary hypertension in adults and children. SEARCH METHODS: We performed searches of CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to 26 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials that compared any PDE5 inhibitor versus placebo, or any other PAH disease-specific therapies, for at least 12 weeks. We include separate analyses for each PH group. DATA COLLECTION AND ANALYSIS: We imported studies identified by the search into a reference manager database. We retrieved the full-text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were: change in WHO functional class, six-minute walk distance (6MWD), and mortality. Secondary outcomes were haemodynamic parameters, quality of life/health status, dyspnoea, clinical worsening (hospitalisation/intervention), and adverse events. When appropriate, we performed meta-analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the GRADE approach and created 'Summary of findings' tables. MAIN RESULTS: We included 36 studies with 2999 participants (with pulmonary hypertension from all causes) in the final review. Trials were conducted for 14 weeks on average, with some as long as 12 months. Two trials specifically included children.Nineteen trials included group 1 PAH participants. PAH participants treated with PDE5 inhibitors were more likely to improve their WHO functional class (odds ratio (OR) 8.59, 95% confidence interval (CI) 3.95 to 18.72; 4 trials, 282 participants), to walk 48 metres further in 6MWD (95% CI 40 to 56; 8 trials, 880 participants), and were 22% less likely to die over a mean duration of 14 weeks (95% CI 0.07 to 0.68; 8 trials, 1119 participants) compared to placebo (high-certainty evidence). The number needed to treat to prevent one additional death was 32 participants. There was an increased risk of adverse events with PDE5 inhibitors, especially headache (OR 1.97, 95% CI 1.33 to 2.92; 5 trials, 848 participants), gastrointestinal upset (OR 1.63, 95% CI 1.07 to 2.48; 5 trials, 848 participants), flushing (OR 4.12, 95% CI 1.83 to 9.26; 3 trials, 748 participants), and muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; 4 trials, 792 participants).Data comparing PDE5 inhibitors to placebo whilst on other PAH-specific therapy were limited by the small number of included trials. Those PAH participants on PDE5 inhibitors plus combination therapy walked 19.66 metres further in six minutes (95% CI 9 to 30; 4 trials, 509 participants) compared to placebo (moderate-certainty evidence). There were limited trials comparing PDE5 inhibitors directly with other PAH-specific therapy (endothelin receptor antagonists (ERAs)). Those on PDE5 inhibitors walked 49 metres further than on ERAs (95% CI 4 to 95; 2 trials, 36 participants) (low-certainty evidence). There was no evidence of a difference in WHO functional class or mortality across both treatments.Five trials compared PDE5 inhibitors to placebo in PH secondary to left-heart disease (PH-LHD). The quality of data were low due to imprecision and inconsistency across trials. In those with PH-LHD there were reduced odds of an improvement in WHO functional class using PDE5 inhibitors compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; 3 trials, 285 participants), and those using PDE5 inhibitors walked 34 metres further compared to placebo (95% CI 23 to 46; 3 trials, 284 participants). There was no evidence of a difference in mortality. Five trials compared PDE5 inhibitors to placebo in PH secondary to lung disease/hypoxia, mostly in COPD. Data were of low quality due to imprecision of effect and inconsistency across trials. There was a small improvement of 27 metres in 6MWD using PDE5 inhibitors compared to placebo in those with PH due to lung disease. There was no evidence of worsening hypoxia using PDE5 inhibitors, although data were limited. Three studies compared PDE5 inhibitors to placebo or other PAH-specific therapy in chronic thromboembolic disease. There was no significant difference in any outcomes. Data quality was low due to imprecision of effect and heterogeneity across trials. AUTHORS' CONCLUSIONS: PDE5 inhibitors appear to have clear beneficial effects in group 1 PAH. Sildenafil, tadalafil and vardenafil are all efficacious in this clinical setting, and clinicians should consider the side-effect profile for each individual when choosing which PDE5 inhibitor to prescribe.While there appears to be some benefit for the use of PDE5 inhibitors in PH-left-heart disease, it is not clear based on the mostly small, short-term studies, which type of left-heart disease stands to benefit. These data suggest possible harm in valvular heart disease. There is no clear benefit for PDE5 inhibitors in pulmonary hypertension secondary to lung disease or chronic thromboembolic disease. Further research is required into the mechanisms of pulmonary hypertension secondary to left-heart disease, and cautious consideration of which subset of these patients may benefit from PDE5 inhibitors. Future trials in PH-LHD should be sufficiently powered, with long-term follow-up, and should include invasive haemodynamic data, WHO functional class, six-minute walk distance, and clinical worsening.

Prostacyclin for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular changes, leads to elevated pulmonary artery pressures, dyspnoea, a reduction in exercise tolerance, right heart failure, and ultimately death.Prostacyclin analogue drugs mimic endogenous prostacyclin which leads to vasodilation, inhibition of platelet aggregation, and reversal of vascular remodelling. Prostacyclin's short half-life theoretically enhances selectivity for the pulmonary vascular bed by direct (via central venous catheter) administration. Initial continuous infusion prostacyclins were efficacious, but use of intravenous access increases the risk of adverse events. Newer and safer subcutaneous, oral and inhaled preparations are now available, though possibly less potent.Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that works similarly to prostacyclin, potentially more stable, with less complex administration and titration. OBJECTIVES: To determine the efficacy and safety of prostacyclin, prostacyclin analogues or prostacyclin receptor agonists for PAH in adults and children. SEARCH METHODS: We performed searches on CENTRAL, MEDLINE, and Embase up to 16 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included any randomised controlled trials (RCTs) which compared prostacyclin, prostacyclin analogues or prostacyclin receptor agonists to control (placebo, any other treatment or usual care) for at least six weeks. DATA COLLECTION AND ANALYSIS: We used standard methods specified by Cochrane. Primary outcomes included change in World Health Organization (WHO) functional class, six-minute walk distance (6MWD), and mortality. MAIN RESULTS: Seventeen trials with 3765 mostly adult participants were included; median trial duration was 12 weeks. Fifteen trials used prostacyclin analogues: intravenous (N = 4); subcutaneous (N = 1); oral (N = 5); inhaled (N = 5); two used oral prostacyclin receptor agonists. Three intravenous and two inhaled trials were open-label.Participants using prostacyclin had 2.39 times greater odds of improving by at least one WHO functional class (95% confidence interval (CI) 1.72 to 3.32; 24 per 100 (95% CI 18.5 to 30.4) with prostacyclin compared to 12 per 100 with control; 8 trials, 1066 participants; moderate-certainty evidence). Improvement occurred with intravenous (odds ratio (OR) 14.96, 95% CI 4.76 to 47.04), and inhaled (OR 2.94, 95% CI 1.53 to 5.66), but not with oral preparations. Participants using prostacyclin increased their 6MWD by 19.50 metres (95% CI 14.82 to 24.19; 13 trials, 2283 participants; low-certainty evidence), which was clinically significant with intravenous (mean difference (MD) 91.76 metres; 95% CI 58.97 to 124.55), but not with non-intravenous preparations (subcutaneous: MD 16.00 metres, 95% CI 7.38 to 24.62; oral: MD 14.76 metres, 95% CI 7.81 to 21.70; inhaled: MD 26.97 metres, 95% CI 17.21 to 36.73). Mortality was reduced in the intravenous (OR 0.29, 95% CI 0.12 to 0.69; risk of death 6 per 100 (95% CI 2.38 to 12.31) with prostacyclin compared to 17 per 100 with control; 4 trials, 255 participants), but not in the non-intravenous studies (OR 0.82, 95% CI 0.48 to 1.40; risk of death 21 per 1000 (95% CI 12.00 to 34.20) with prostacyclin compared to 25 per 1000 with control; moderate-certainty evidence; 12 trials, 2299 participants). We reduced the certainty of evidence due to few studies per subgroup and use of open-label trials.Prostacyclins improved cardiopulmonary haemodynamics (reduction in mean pulmonary artery pressure by 3.60 mmHg (95% CI -4.73 to -2.48); pulmonary vascular resistance by 2.81 WU (95% CI -3.80 to -1.82); right atrial pressure by 1.90 mmHg (95% CI -2.58 to -1.22), and increase in cardiac index by 0.31 L/min/m2 (95% CI 0.23 to 0.38); low-certainty evidence), improved dyspnoea (low-certainty evidence, and improved quality of life (moderate-certainty evidence), when compared to control. When only subcutaneous/inhaled trials were included the effect was still significant, but the magnitude was smaller. There was no difference across oral trials.Adverse events were increased in all prostacyclin preparations, including vasodilation (OR 5.03, 95% CI 3.84 to 6.58), headache (OR 3.16, 95% CI 2.62 to 3.80), jaw pain (OR 5.25, 95% CI 3.96 to 6.98), diarrhoea (OR 2.81, 95% CI 2.29 to 3.46), nausea/vomiting (OR 2.39, 95% CI 1.98 to 2.88), myalgias (OR 2.75, 95% CI 1.65 to 4.58), upper respiratory tract events (OR 1.61, 95% CI 1.22 to 2.13), extremity pain (OR 3.36, 95% CI 2.32 to 4.85), and infusion site reactions (OR 14.41, 95% CI 9.16 to 22.66). In the intravenous trials, there was a 12%-25% risk of serious non-fatal events including sepsis, haemorrhage, pneumothorax and pulmonary embolism.Two trials (1199 participants) compared oral selexipag to placebo; no trials compared selexipag with prostacyclin. There was a small 12.62 metre improvement in 6MWD (95% CI 1.90 to 23.34; high-certainty evidence), and weak evidence for haemodynamics. The effect was uncertain for WHO functional class. The risk of death with selexipag was five per 100 compared to three per 100 with placebo, though the CI crossed zero so the true effect is uncertain (risk difference (RD) 0.02 (95% CI -0.00 to 0.04). There was less clinical worsening with selexipag (OR 0.47, 95% CI 0.37 to 0.60), though more side effects, including vasodilation (OR 2.67, 95% CI 1.72 to 4.17), headache (OR 3.91, 95% CI 3.07 to 4.98), jaw pain (OR 5.33, 95% CI 3.64 to 7.81), diarrhoea (OR 3.11, 95% CI 2.39 to 4.05), nausea/vomiting (OR 2.92, 95% CI 2.29 to 3.73), pain in the extremities (OR 2.44, 95% CI 1.69 to 3.52), and myalgias (OR 3.05, 95% CI 2.02 to 4.58). AUTHORS' CONCLUSIONS: This review demonstrates clinical and statistical benefit for intravenous prostacyclin (compared to control) with improved functional class, 6MWD, mortality, symptoms scores, and cardiopulmonary haemodynamics, but at a cost of adverse events. This may be due to a true effect, or may be overestimated due to the inclusion of small, short or open-label studies. There was a statistical and small clinical benefit in function and haemodynamics for inhaled prostacyclin, but the effect is uncertain for mortality. The effect of oral prostacyclins are less certain. Selexipag demonstrated less clinical worsening without discernable impact on survival, increased adverse events; and the effect on other outcomes is less certain. Real-world registry data may provide further information about clinical effect.

Echocardiographic Assessment of the Right Ventricle-State of the Art.

Assessment of right ventricular (RV) structure and function by echocardiography has largely been qualitative in the past. More recent approaches emphasise the quantification of RV structure from multiple echocardiographic views and quantification of multiple parameters of RV function. Current echocardiographic examinations should include at least two quantitative measures of RV function. This paper will highlight commonly used measures along with their strengths and weaknesses. With further technical developments in three-dimensional and myocardial deformation imaging and as more outcome data become available it is likely that further quantitative assessment will become routine and be used to guide diagnosis and treatment choices.

Broad Phylogenetic Diversity Associated with Nitrogen Loss through Sulfur Oxidation in a Large Public Marine Aquarium.

Denitrification by sulfur-oxidizing bacteria is an effective nitrate removal strategy in engineered aquatic systems. However, the community taxonomic and metabolic diversity of sulfur-driven denitrification (SDN) systems, as well as the relationship between nitrate removal and SDN community structure, remains underexplored. This is particularly true for SDN reactors applied to marine aquaria, despite the increasing use of this technology to supplement filtration. We applied 16S rRNA gene, metagenomic, and metatranscriptomic analyses to explore the microbial basis of SDN reactors operating on Georgia Aquarium's Ocean Voyager, the largest indoor closed-system seawater exhibit in the United States. The exhibit's two SDN systems vary in water retention time and nitrate removal efficiency. The systems also support significantly different microbial communities. These communities contain canonical SDN bacteria, including a strain related to Thiobacillus thioparus that dominates the system with the higher water retention time and nitrate removal but is effectively absent from the other system. Both systems contain a wide diversity of other microbes whose metagenome-assembled genomes contain genes of SDN metabolism. These include hundreds of strains of the epsilonproteobacterium Sulfurimonas, as well as gammaproteobacterial sulfur oxidizers of the Thiotrichales and Chromatiales, and a relative of Sedimenticolathiotaurini with complete denitrification potential. The SDN genes are transcribed and the taxonomic richness of the transcript pool varies markedly among the enzymatic steps, with some steps dominated by transcripts from noncanonical SDN taxa. These results indicate complex and variable SDN communities that may involve chemical dependencies among taxa as well as the potential for altering community structure to optimize nitrate removal.IMPORTANCE Engineered aquatic systems such as aquaria and aquaculture facilities have large societal value. Ensuring the health of animals in these systems requires understanding how microorganisms contribute to chemical cycling and waste removal. Focusing on the largest seawater aquarium in the United States, we explore the microbial communities in specialized reactors designed to remove excess nitrogen through the metabolic activity of sulfur-consuming microbes. We show that the diversity of microbes in these reactors is both high and highly variable, with distinct community types associated with significant differences in nitrogen removal rate. We also show that the genes encoding the metabolic steps of nitrogen removal are distributed broadly throughout community members, suggesting that the chemical transformations in this system are likely a result of microbes relying on other microbes. These results provide a framework for future studies exploring the contributions of different community members, both in waste removal and in structuring microbial biodiversity.

Exercise capacity in diabetes mellitus is predicted by activity status and cardiac size rather than cardiac function: a case control study.

BACKGROUND: The reasons for reduced exercise capacity in diabetes mellitus (DM) remains incompletely understood, although diastolic dysfunction and diabetic cardiomyopathy are often favored explanations. However, there is a paucity of literature detailing cardiac function and reserve during incremental exercise to evaluate its significance and contribution. We sought to determine associations between comprehensive measures of cardiac function during exercise and maximal oxygen consumption ([Formula: see text]peak), with the hypothesis that the reduction in exercise capacity and cardiac function would be associated with co-morbidities and sedentary behavior rather than diabetes itself. METHODS: This case-control study involved 60 subjects [20 with type 1 DM (T1DM), 20 T2DM, and 10 healthy controls age/sex-matched to each diabetes subtype] performing cardiopulmonary exercise testing and bicycle ergometer echocardiography studies. Measures of biventricular function were assessed during incremental exercise to maximal intensity. RESULTS: T2DM subjects were middle-aged (52 ± 11 years) with a mean T2DM diagnosis of 12 ± 7 years and modest glycemic control (HbA1c 57 ± 12 mmol/mol). T1DM participants were younger (35 ± 8 years), with a 19 ± 10 year history of T1DM and suboptimal glycemic control (HbA1c 65 ± 16 mmol/mol). Participants with T2DM were heavier than their controls (body mass index 29.3 ± 3.4 kg/m2 vs. 24.7 ± 2.9, P = 0.001), performed less exercise (10 ± 12 vs. 28 ± 30 MET hours/week, P = 0.031) and had lower exercise capacity ([Formula: see text]peak = 26 ± 6 vs. 38 ± 8 ml/min/kg, P < 0.0001). These differences were not associated with biventricular systolic or left ventricular (LV) diastolic dysfunction at rest or during exercise. There was no difference in weight, exercise participation or [Formula: see text]peak in T1DM subjects as compared to their controls. After accounting for age, sex and body surface area in a multivariate analysis, significant positive predictors of [Formula: see text]peak were cardiac size (LV end-diastolic volume, LVEDV) and estimated MET-hours, while T2DM was a negative predictor. These combined factors accounted for 80% of the variance in [Formula: see text]peak (P < 0.0001). CONCLUSIONS: Exercise capacity is reduced in T2DM subjects relative to matched controls, whereas exercise capacity is preserved in T1DM. There was no evidence of sub-clinical cardiac dysfunction but, rather, there was an association between impaired exercise capacity, small LV volumes and sedentary behavior.

Different patients, different outcomes: A case-control study of spontaneous coronary artery dissection versus acute coronary syndrome.

INTRODUCTION: There is progressive interest worldwide in spontaneous coronary artery dissection (SCAD). To identify a SCAD cohort and compare risk factors, presentation, and management outcomes compared to acute coronary syndrome (ACS) matched controls. METHODS: Retrospective analysis was performed from 2000 to 2015. Clinical data included a neuropsychiatric history, with management and clinical outcomes assessed at 12 months. Patients were matched on a 1:3 case-control basis according to type of ACS. Twenty-two SCAD patients were matched to 66 controls by ACS type (ST-elevation myocardial infarction 45%, Non-ST-elevation myocardial infarction 41%, unstable angina 14%). RESULTS: The SCAD group were more likely female (77.3% vs 19.7%, P < 0.0001), of younger age (48.7 ± 10.7 years vs 61.3 ± 10.6 years, P < 0.0001) with no cases of diabetes (0% vs 33.3%, P = 0.002), compared to controls. SCAD patients had a high prevalence of anxiety, depression or previous neuropsychiatric history (52.4% SCAD vs 1.5% ACS, P < 0.0001). A conservative revascularization strategy with stenting was performed in a minority of SCAD patients (13.6% SCAD vs 83.3% ACS, P < 0.0001), with no significant difference in cumulative major adverse cardiac or cerebrovascular events (MACCE) of death, stroke, re-admission, or repeat angiography rates between both groups (13.6% SCAD vs 27.3% ACS P = NS). CONCLUSION: SCAD affects young females with a paucity of cardiovascular risk factors. The major risk factor for SCAD was a history of anxiety, depression, or neuropsychiatric illness. A conservative approach to SCAD revascularization led to similar MACCE when compared to ACS controls undergoing guideline revascularization at 12 months.