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ObjectivesWe aimed to investigate if lesion-specific ischaemia by invasive fractional flow reserve (FFR) can be predicted by an integrated machine learning (ML) ischaemia risk score from quantitative plaque measures from coronary computed tomography angiography (CTA).MethodsIn a multicentre trial of 254 patients, CTA and invasive coronary angiography were performed, with FFR in 484 vessels. CTA data sets were analysed by semi-automated software to quantify stenosis and non-calcified (NCP), low-density NCP (LD-NCP, < 30 HU), calcified and total plaque volumes, contrast density difference (CDD, maximum difference in luminal attenuation per unit area) and plaque length. ML integration included automated feature selection and model building from quantitative CTA with a boosted ensemble algorithm, and tenfold stratified cross-validation.ResultsEighty patients had ischaemia by FFR (FFR ≤ 0.80) in 100 vessels. Information gain for predicting ischaemia was highest for CDD (0.172), followed by LD-NCP (0.125), NCP (0.097), and total plaque volumes (0.092). ML exhibited higher area-under-the-curve (0.84) than individual CTA measures, including stenosis (0.76), LD-NCP volume (0.77), total plaque volume (0.74) and pre-test likelihood of coronary artery disease (CAD) (0.63); p < 0.006.ConclusionsIntegrated ML ischaemia risk score improved the prediction of lesion-specific ischaemia by invasive FFR, over stenosis, plaque measures and pre-test likelihood of CAD.Key Points• Integrated ischaemia risk score improved prediction of ischaemia over quantitative plaque measures• Integrated ischaemia risk score showed higher prediction of ischaemia than standard approach• Contrast density difference had the highest information gain to identify lesion-specific ischaemia

ObjectivesTo obtain more powerful assessment of the prognostic value of fractional flow reserveCT testing we performed a systematic literature review and collaborative meta-analysis of studies that assessed clinical outcomes of CT-derived calculation of FFR (FFRCT) (HeartFlow) analysis in patients with stable coronary artery disease (CAD).MethodsWe searched PubMed and Web of Science electronic databases for published studies that evaluated clinical outcomes following fractional flow reserveCT testing between 1 January 2010 and 31 December 2020. The primary endpoint was defined as ‘all-cause mortality (ACM) or myocardial infarction (MI)’ at 12-month follow-up. Exploratory analyses were performed using major adverse cardiovascular events (MACEs, ACM+MI+unplanned revascularisation), ACM, MI, spontaneous MI or unplanned (>3 months) revascularisation as the endpoint.ResultsFive studies were identified including a total of 5460 patients eligible for meta-analyses. The primary endpoint occurred in 60 (1.1%) patients, 0.6% (13/2126) with FFRCT>0.80% and 1.4% (47/3334) with FFRCT ≤0.80 (relative risk (RR) 2.31 (95% CI 1.29 to 4.13), p=0.005). Likewise, MACE, MI, spontaneous MI or unplanned revascularisation occurred more frequently in patients with FFRCT ≤0.80 versus patients with FFRCT >0.80. Each 0.10-unit FFRCT reduction was associated with a greater risk of the primary endpoint (RR 1.67 (95% CI 1.47 to 1.87), p<0.001).ConclusionsThe 12-month outcomes in patients with stable CAD show low rates of events in those with a negative FFRCT result, and lower risk of an unfavourable outcome in patients with a negative test result compared with patients with a positive test result. Moreover, the FFRCT numerical value was inversely associated with outcomes.

Fractional flow reserve (FFR) has been established as gold standard to detect hemodynamically significant coronary artery disease. Non-invasive FFR derived from coronary computed tomography angiography (CTA; FFR CT ) has demonstrated higher diagnostic performance compared with FFR. However, the accuracy and potential advantages of FFR CT compared with invasive FFR in coronary arteries with serial lesions have not been examined. The aim of this study was to compare trans-lesional gradient in FFR CT to that in invasive FFR in coronary arteries with serial stenoses. Eighteen vessels with serial coronary lesions from 18 stable angina patients were evaluated with angiography, FFR, and coronary CTA. FFR CT was computed from 3-dimensional CT model and coronary flow dynamics data. Multiple FFR CT values were co-registered with measured FFR across the lesions, and trans-lesional delta were compared between FFR CT and FFR. The mean values of the most distal FFR and FFR CT in the same co-registered regions were 0.72 ± 0.10 and 0.69 ± 0.11, respectively. In 13 vessels (72.2%), FFR was ≤0.80, while in 14 vessels (77.8%), FFR CT was ≤0.80. Trans-lesional delta FFR and FFR CT were 0.10 ± 0.09 and 0.09 ± 0.10 in distal segments, while 0.17 ± 0.10 and 0.22 ± 0.13 in proximal segments, respectively. The coefficient of correlation between trans-lesional delta FFR and FFR CT in each segment was 0.92 ( p  < 0.001). Trans-lesional delta FFR and FFR CT show an excellent correlation. Further studies are required to determine the diagnostic accuracy and clinical impact of our findings.

Mycobacterium tuberculosis employs various virulence strategies to subvert host immune responses in order to persist and cause disease. Interaction of M. tuberculosis with mannose receptor on macrophages via surface-exposed lipoarabinomannan (LAM) is believed to be critical for cell entry, inhibition of phagosome-lysosome fusion, and intracellular survival, but in vivo evidence is lacking. LprG, a cell envelope lipoprotein that is essential for virulence of M. tuberculosis, has been shown to bind to the acyl groups of lipoglycans but the role of LprG in LAM biosynthesis and localization remains unknown. Using an M. tuberculosis lprG mutant, we show that LprG is essential for normal surface expression of LAM and virulence of M. tuberculosis attributed to LAM. The lprG mutant had a normal quantity of LAM in the cell envelope, but its surface was altered and showed reduced expression of surface-exposed LAM. Functionally, the lprG mutant was defective for macrophage entry and inhibition of phagosome-lysosome fusion, was attenuated in macrophages, and was killed in the mouse lung with the onset of adaptive immunity. This study identifies the role of LprG in surface-exposed LAM expression and provides in vivo evidence for the essential role surface LAM plays in M. tuberculosis virulence. Findings have translational implications for therapy and vaccine development.

Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2–4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6–1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1–2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.

The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum. We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing ≥ 2 HIV medical visits separated by ≥ 90 days in the year. Persons not retained completed ≥ 1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA ≤ 200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients' transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART. Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012 (kappa=0.437). Not counting patients not-retained/suppressed as virally suppressed, as is commonly done in the HIV care continuum, underestimated the proportion suppressed by 13%. Applying the care continuum in a longitudinal manner will enhance its utility.

Extreme heat is projected to increase in frequency and intensity. Commonly applied infrastructure-based urban heat mitigation strategies, including greenery and reflective materials, have the potential to reduce heat exposure. However, there has been limited assessment of the cooling efficacy of these strategies as a function of synoptic weather type, neighbourhood morphology, and time of day. Using a neighbourhood-resolving mesoscale meteorological model, the urbanised Weather Research and Forecasting model, the dependence of heat mitigation cooling efficacy in Toronto, Canada during daytime versus nighttime is assessed as a function of the following: 1) weather type, using the spatial synoptic classification (SSC); and 2) local built structure and cover, using the local climate zone (LCZ) scheme. Heat mitigation efficacy is quantified by changes in three metrics: land surface temperature, air temperature, and Humidex. Large increases to rooftop albedo resulted in the greatest daytime reductions in air and surface temperatures, and Humidex. Replacing impervious surfaces with low vegetation provided the greatest nighttime reductions of temperature and Humidex. These results indicate that different heat mitigation infrastructures excel for cooling during daytime, when the highest temperatures occur, versus nighttime, when the largest heat island intensity prevails. These findings are consistent for the weather type exhibiting the highest Humidex, moist tropical, when reduction of heat exposure is most critical. The greatest daytime cooling was found during the sunny dry moderate SSC type. The largest nocturnal cooling occurred during the dry polar weather conditions, which were characterised by the lowest nighttime downwelling longwave radiation. Vegetation and albedo-based heat mitigation strategies yielded the greatest cooling when implemented in LCZs with greater impervious fraction. These results highlight the potential importance of tailoring heat mitigation strategies to prevailing synoptic weather conditions, local neighbourhood morphology, and the time of day when cooling is most needed, to maximise cooling benefits.

IntroductionObstructive sleep apnea (OSA) represents a sleep-related impairment linked to upper airway function. The question of whether OSA drives obesity or if shared underlying factors contribute to both conditions remains unresolved. Hence, this present study aims to understand the interplay between obstructive sleep apnea syndrome (OSAS) and obesity through in-depth analysis of anthropometric data within control subjects and OSA patients.MethodologyA case-control study was conducted, which included 40 cases and 40 matched healthy controls. Study participants with reported symptoms of snoring, daytime drowsiness, or both were included in the study. All the study participants underwent comprehensive anthropometric assessments such as height, weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, waist-to-hip ratio, skin-fold thickness, and thickness measurements of biceps, triceps, suprailiac, and subscapular muscles.ResultsWithin the OSA group, significant disparities emerged in mean age, waist circumference, waist-to-hip ratio, and diverse fat accumulations encompassing visceral, subcutaneous, trunk, and subcutaneous leg fat. Notably, skin-fold thickness at specific sites - biceps, triceps, subscapula, and suprailiac - demonstrated considerable augmentation relative to the control group. Furthermore, mean values associated with height, weight, BMI, neck circumference, fat percentage, subcutaneous arm fat, entire arm composition, and trunk skeletal muscle either equaled or exceeded those in the control group. However, statistical significance was not attained in these comparisons.ConclusionThis investigation underscored a pronounced correlation between numerous endpoints characterizing OSA patients and markers of obesity. Consequently, addressing altered levels of obesity-linked anthropometric variables through pharmacological interventions might hold promise as a pivotal strategy for improving symptoms associated with OSA.

[This corrects the article DOI: 10.1371/journal.ppat.1004376.].

Lipid bodies (LB; lipid droplets) are cytoplasmic organdies involved in lipid metabolism. Mammalian LBs display an important role in host-pathogen interactions, but the role of parasite LBs in biosynthesis of prostaglandin F2α (PGF2α) has not been investigated. We report herein that LBs increased in abundance during development of Leishmania infantum chagasi to a virulent metacyclic stage, as did the expression of PGF2α synthase (PGFS). The amount of parasite LBs and PGF2α were modulated by exogenous arachidonic acid. During macrophage infection, LBs were restricted to parasites inside the parasitophorous vacuoles (PV). We detected PGF2α receptor (FP) on the Leishmania PV surface. The blockage of FP with AL8810, a selective antagonist, hampered Leishmania infection, whereas the irreversible inhibition of cydooxygenase with aspirin increased the parasite burden. These data demonstrate novel functions for parasite-derived LBs and PGF2α in the cellular metabolism of Leishmania and its evasion of the host immune response.