Long-Term Clinical Implications of High-Risk Cardiac Computed Tomography Findings in Patients With Acute Ischemic Stroke.

BACKGROUND: Cardiac computed tomography (CT) acquired during the initial acute stroke imaging protocol (acute cardiac CT) is increasingly used to screen for cardioembolism, but information on the long-term clinical implications of its findings is lacking. METHODS AND RESULTS: We performed a prospective, single-center cohort study in which consecutive patients with ischemic stroke underwent ECG-gated acute cardiac CT and were followed up for 2 years. The primary outcome was functional outcome assessed using the modified Rankin Scale. Secondary outcomes were death and occurrence of major adverse cardiovascular events (composite of recurrent ischemic stroke, myocardial infarction, and cardiovascular death). We compared patients with and without a high-risk structural source of embolism on acute cardiac CT. Of 452 included patients, 55 (12.2%) had a high-risk source of embolism, predominantly cardiac thrombi (38 patients) and signs of endocarditis (8 patients). Follow-up at 2 years was complete for 430 (95.1%) patients. Patients with a high-risk source of embolism had a worse functional outcome (median modified Rankin Scale, 6 [IQR, 2-6] versus 2 [IQR, 1-5]; adjusted common odds ratio, 2.92 [95% CI, 1.62-5.25]), increased mortality rate (52.7% versus 23.7%; adjusted hazard ratio [HR], 3.28 [95% CI, 1.94-5.52]), and major adverse cardiovascular events (38.9% versus 17.5%; adjusted HR, 3.20 [95% CI, 1.80-5.69]). A high-risk source of embolism was not associated with recurrent ischemic stroke (11.1% versus 9.6%; adjusted HR, 1.30 [95% CI, 0.49-3.44]). CONCLUSIONS: Structural high-risk sources of embolism on acute cardiac CT in patients with ischemic stroke were associated with poor long-term functional outcome and occurrence of major adverse cardiovascular events but not with recurrent stroke.

NT-pro-BNP is predictive of morbidity and mortality after pulmonary thromboendarterectomy and is independent of preoperative hemodynamics.

Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT-pro-BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post-PTE. For analysis, NT-pro-BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT-pro-BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5-1410.8). Of the 816 patients included, 250 had NT-pro-BNP > 1000 pg/mL. Those with NT-pro-BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III-IV) and worse preoperative hemodynamics. Patients with NT-pro-BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p < 0.001), airway hemorrhage (8.4% vs. 4.9%, p = 0.075), residual pulmonary hypertension (11.9% vs. 3.1%, p < 0.001), and 30-day mortality (4.8% vs. 1.1%, p = 0.001). Even after adjusting for confounders, patients with NT-pro-BNP > 1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45-4.00) of reaching a combined endpoint that included the above complications. Preoperative NT-pro-BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications.

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

INTRODUCTION: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). RESULTS: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

Feasibility and repeatability of ultrasound-guided surface electroenterography to measure colonic slow wave motility in healthy adults.

Surface electroenterography is a potential non-invasive alternative to current diagnostics of colonic motility disorders. However, electrode positioning in electroenterography is often based on general anatomy and may lack generalizability. Furthermore, the repeatability of electroenterography measurements is unknown. This study aimed to evaluate ultrasound-guided electrode positioning for electroenterography measurements and to determine the repeatability of those measurements. In ten healthy adults, two electroenterography procedures were performed, consisting of fasting, ultrasound-guided electrode localization and two 20-minute electroenterography recordings separated by a meal. The dominant frequency, the mean power density (magnitude of colonic motility) and the power percent difference (relative pre- to postprandial increase in magnitude) were determined. Repeatability was determined by Lin's concordance correlation coefficient. The results demonstrated that the dominant frequency did not differ between pre- and postprandial recordings and was 3 cpm, characteristic of colonic motility. The mean power density increased between the pre- and postprandial measurements, with an average difference of over 200%. The repeatability of both the dominant frequency and power density was poor to moderate, whereas the correlation coefficient of the power percent difference was poor. Concluding, ultrasound-guided surface electroenterography seems able to measure the gastrocolic reflex, but the dissatisfactory repeatability necessitates optimization of the measurement protocol.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.

Airway smooth muscle and long-term clinical efficacy following bronchial thermoplasty in severe asthma.

The mechanism of action of bronchial thermoplasty (BT) treatment for patients with severe asthma is incompletely understood. This study investigated the 2.5-year impact of BT on airway smooth muscle (ASM) mass and clinical parameters by paired data analysis in 22 patients. Our findings demonstrate the persistence of ASM mass reduction of >50% after 2.5 years. Furthermore, sustained improvement in asthma control, quality of life and exacerbation rates was found, which is in line with previous reports. An association was found between the remaining ASM and both the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for alpha smooth muscle actin (SMA)) and post-bronchodilator forced expiratory volume in 1 s predicted percentage (r=-0.69, p=0.03 for desmin, r=-0.58, p=0.08 for alpha SMA). This study provides new insight into the long-term impact of BT.

Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

INTRODUCTION: Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. RESULTS: The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. CONCLUSION: There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov .

Disease characteristics, treatments, and outcomes of patients with pulmonary arterial hypertension treated with selexipag in real-world settings from the SPHERE registry (SelexiPag: tHe usErs dRug rEgistry).

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals.

Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma.

BACKGROUND: Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling. OBJECTIVE: We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes. METHODS: This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored. RESULTS: Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 µm to 5.74 µm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV1 reversibility. CONCLUSIONS: Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV1 reversibility.

Balloon pulmonary angioplasty in the current era of CTEPH treatment: How did we get here?

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by persistent organized thromboembolic obstruction of the pulmonary arteries from incompletely resolved pulmonary embolism. The treatment of choice is pulmonary thromboendarterectomy (PTE) surgery and all patients should be evaluated for operability candidacy. Despite advancements in PTE technique allowing more segmental-subsegmental surgeries, up to a third of patients with CTEPH may still be considered inoperable. Over the past decade, there have been increasing treatment options for these inoperable CTEPH patients. Balloon pulmonary angioplasty (BPA) is a percutaneous-based interventional treatment option for select CTEPH cases. Early BPA experiences were plagued by high complication rates, but further refinements in technique and equipment pioneered by Japan led to the worldwide spread and adoption of BPA. Multiple centers have shown that patients experience significant improvements in hemodynamics, quality of life, exercise capacity, and survival with BPA treatment. There remain many questions on best practices, but BPA has evolved into a pivotal cornerstone of CTEPH treatment.

On the benefits of desulfated seawater flooding in mature hydrocarbon fields.

Removal of sulfate from the injection seawater (desulfation) in hydrocarbon reservoirs is a Modified Salinity Water (MSW) flooding method that mitigates microbial reservoir souring, improves oil recovery, and enables produced-water re-injection (PWRI). Aside from the Improved Oil Recovery (IOR) effect, desulfation results in a cleaner production of oil through enabling PWRI and reducing the environmental impacts associated with reservoir souring and nitrate treatment. However, whether desulfation is still beneficial for mature fields, after years of the injection of untreated seawater, is a valid common concern. In such cases, sulfate concentration inside the reservoir has already increased due to years of untreated seawater injection. The high sulfate concentration inside the subsurface reservoir before desulfated water flooding may render desulfation pointless. The present study investigates the potential benefits of desulfation after around 20 years of untreated seawater injection in a sector of an oil field in the Danish North Sea. The results show that depending on the cessation of production point in time and the efficiency of residual oil saturation reduction of MSW flooding, desulfation results in a significant increase in oil production. Even if improving oil recovery is no longer a priority, modification of injected seawater would still help reduce the amount of water required to support a given oil production rate. Moreover, desulfation is considerably more effective than nitrate treatment in mitigating microbial reservoir souring. Furthermore, the possibility of scale formation is decreased considerably due to desulfation, which further encourages PWRI.

Enhancing the Predictive Power of Google Trends Data Through Network Analysis: Infodemiology Study of COVID-19.

BACKGROUND: The COVID-19 outbreak has revealed a high demand for timely surveillance of pandemic developments. Google Trends (GT), which provides freely available search volume data, has been proven to be a reliable forecast and nowcast measure for public health issues. Previous studies have tended to use relative search volumes from GT directly to analyze associations and predict the progression of pandemic. However, GT's normalization of the search volumes data and data retrieval restrictions affect the data resolution in reflecting the actual search behaviors, thus limiting the potential for using GT data to predict disease outbreaks. OBJECTIVE: This study aimed to introduce a merged algorithm that helps recover the resolution and accuracy of the search volume data extracted from GT over long observation periods. In addition, this study also aimed to demonstrate the extended application of merged search volumes (MSVs) in combination of network analysis, via tracking the COVID-19 pandemic risk. METHODS: We collected relative search volumes from GT and transformed them into MSVs using our proposed merged algorithm. The MSVs of the selected coronavirus-related keywords were compiled using the rolling window method. The correlations between the MSVs were calculated to form a dynamic network. The network statistics, including network density and the global clustering coefficients between the MSVs, were also calculated. RESULTS: Our research findings suggested that although GT restricts the search data retrieval into weekly data points over a long period, our proposed approach could recover the daily search volume over the same investigation period to facilitate subsequent research analyses. In addition, the dynamic time warping diagrams show that the dynamic networks were capable of predicting the COVID-19 pandemic trends, in terms of the number of COVID-19 confirmed cases and severity risk scores. CONCLUSIONS: The innovative method for handling GT search data and the application of MSVs and network analysis to broaden the potential for GT data are useful for predicting the pandemic risk. Further investigation of the GT dynamic network can focus on noncommunicable diseases, health-related behaviors, and misinformation on the internet.

Chronic thromboembolic pulmonary hypertension: realising the potential of multimodal management.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of multimodal therapeutic options in CTEPH to improve long-term outcomes for patients.

MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins.

Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the 'Mitochondrial Contact Site and Cristae Organising System' (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function.

Straightforward model construction and analysis of multicomponent biomolecular systems in equilibrium.

Mathematical modelling of molecular systems can be extremely helpful in elucidating complex phenomena in (bio)chemistry. However, equilibrium conditions in systems consisting of more than two components, such as for molecular glues bound to two proteins, can typically not be analytically determined without assumptions and (semi-)numerical models are not trivial to derive by the non-expert. Here we present a framework for equilibrium models, geared towards molecular glues and other contemporary multicomponent chemical biology challenges. The framework utilizes a general derivation method capable of generating custom mass-balance models for equilibrium conditions of complex molecular systems, based on the simple, reversible biomolecular reactions describing these systems. Several chemical biology concepts are revisited via the framework to demonstrate the simplicity, generality and validity of the approach. The ease of use of the framework and the ability to both analyze systems and gain additional insights in the underlying parameters driving equilibria formation strongly aids the analysis and understanding of biomolecular systems. New directions for research and analysis are brought forward based on the model formation and system and parameter analysis. This conceptual framework severely reduces the time and expertise requirements which currently impede the broad integration of such valuable equilibrium models into molecular glue development and chemical biology research.

Repeat pulmonary thromboendarterectomy outcomes: A 15-year single-center retrospective review.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension is potentially curable via pulmonary thromboendarterectomy. A minority of patients experience recurrence of their symptoms and are eligible for repeat pulmonary thromboendarterectomy. However, little data exist regarding risk factors and outcomes for this patient population. METHODS: We performed a retrospective review of the University of California San Diego chronic thromboembolic pulmonary hypertension quality improvement database, including all patients who underwent pulmonary thromboendarterectomy from December 2005 to December 2020. Of the 2019 cases performed during this period, 46 were repeat pulmonary thromboendarterectomy procedures. Demographics, preoperative and postoperative hemodynamics, and surgical complications were compared between the repeat pulmonary thromboendarterectomy group and 1008 first pulmonary thromboendarterectomy group. RESULTS: Repeat pulmonary thromboendarterectomy recipients were more likely to be younger, to have an identified hypercoagulable state, and to have higher preoperative right atrial pressure. Etiologies of recurrent disease include incomplete initial endarterectomy, discontinuation of anticoagulation (noncompliance or for medical reasons), and anticoagulation treatment failure. Patients who received repeat pulmonary thromboendarterectomy had significant hemodynamic improvement, but less pronounced compared with patients who received first pulmonary thromboendarterectomy. Repeat pulmonary thromboendarterectomy was associated with an increased risk of postoperative bleeding, reperfusion lung injury, residual pulmonary hypertension, and increased ventilator, intensive care unit, and hospital days. However, hospital mortality was similar between the groups (2.2% vs 1.9%). CONCLUSIONS: This is the largest reported series of repeat pulmonary thromboendarterectomy surgery. Despite an increase in postoperative complications, this study demonstrates that repeat pulmonary thromboendarterectomy surgery can result in significant hemodynamic improvement with acceptable surgical mortality in an experienced center.

Distal vessel pulmonary thromboendarterectomy: Results from a single institution.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is primarily managed by pulmonary thromboendarterectomy (PTE). As advanced surgical techniques permit resection at the segmental and subsegmental level, PTE can now be curative for CTEPH mostly involving the distal pulmonary arteries. METHODS: Between January 2017 and June 2021, consecutive patients undergoing PTE were categorized according to the most proximal level of chronic thrombus resection: Level I (main pulmonary artery), Level II (lobar), Level III (segmental) and Level IV (subsegmental). Proximal disease patients (any Level I or II) were compared to distal disease (Level III or IV bilaterally) patients. Demographics, medical history, preoperative pulmonary hemodynamics, and immediate postoperative outcomes were obtained for each group. RESULTS: During the study period, 794 patients underwent PTE, 563 with proximal disease and 231 with distal disease. Patients with distal disease more frequently had a history of an indwelling intravenous device, splenectomy, upper extremity thrombosis or use thyroid replacement and less often had prior lower extremity thrombosis or hypercoagulable state. Despite more use of PAH-targeted medications in the distal disease group (63.2% vs 50.1%, p < 0.001), preoperative hemodynamics were similar. Both patient groups exhibited significant improvements in pulmonary hemodynamics postoperatively with comparable in-hospital mortality rates. Compared to proximal disease, a lower percentage of patients with distal disease showed residual pulmonary hypertension (3.1% vs 6.9%, p = 0.039) and airway hemorrhage (3.0% vs 6.6%, p = 0.047) postoperatively. CONCLUSIONS: Thromboendarterectomy for distal (segmental and subsegmental) CTEPH is technically feasible and may result in favorable pulmonary hemodynamic outcomes, without increased mortality or morbidity.

The spatial-temporal dynamics of pulmonary blood flow are altered in pulmonary arterial hypertension.

Global fluctuation dispersion (FDglobal), a spatial-temporal metric derived from serial images of the pulmonary perfusion obtained with MRI-arterial spin labeling, describes temporal fluctuations in the spatial distribution of perfusion. In healthy subjects, FDglobal is increased by hyperoxia, hypoxia, and inhaled nitric oxide. We evaluated patients with pulmonary arterial hypertension (PAH, 4F, aged 47 ± 15, mean pulmonary artery pressure 48 ± 7 mmHg) and healthy controls (CON, 7F, aged 47 ± 12) to test the hypothesis that FDglobal is increased in PAH. Images were acquired at ∼4-5 s intervals during voluntary respiratory gating, inspected for quality, registered using a deformable registration algorithm, and normalized. Spatial relative dispersion (RD = SD/mean) and the percent of the lung image with no measurable perfusion signal (%NMP) were also assessed. FDglobal was significantly increased in PAH (PAH = 0.40 ± 0.17, CON = 0.17 ± 0.02, P = 0.006, a 135% increase) with no overlap in values between the two groups, consistent with altered vascular regulation. Both spatial RD and %NMP were also markedly greater in PAH vs. CON (PAH RD = 1.46 ± 0.24, CON = 0.90 ± 0.10, P = 0.0004; PAH NMP = 13.4 ± 6.1%; CON = 2.3 ± 1.4%, P = 0.001 respectively) consistent with vascular remodeling resulting in poorly perfused regions of lung and increased spatial heterogeneity. The difference in FDglobal between normal subjects and patients with PAH in this small cohort suggests that spatial-temporal imaging of perfusion may be useful in the evaluation of patients with PAH. Since this MR imaging technique uses no injected contrast agents and has no ionizing radiation it may be suitable for use in diverse patient populations.NEW & NOTEWORTHY Using proton MRI-arterial spin labeling to obtain serial images of pulmonary perfusion, we show that global fluctuation dispersion (FDglobal), a metric of temporal fluctuations in the spatial distribution of perfusion, was significantly increased in female patients with pulmonary arterial hypertension (PAH) compared with healthy controls. This potentially indicates pulmonary vascular dysregulation. Dynamic measures using proton MRI may provide new tools for evaluating individuals at risk of PAH or for monitoring therapy in patients with PAH.

Lung cancer screening an asbestos exposed population: Existing lung cancer risk criteria are not sufficient.

BACKGROUND AND OBJECTIVE: Asbestos is a major risk factor for lung cancer, with or without tobacco smoke exposure. Low dose computed tomography (LDCT) screening for early lung cancer is effective but only when targeting high risk populations. This study aimed to analyse the effectiveness of LDCT screening in an asbestos exposed population and to compare lung cancer screening program (LCSP) eligibility criteria. METHODS: Participants in an asbestos health surveillance program, the Western Australia Asbestos Review Program, underwent at least one LDCT scan and lung function assessment as part of annual review between 2012 and 2017. Lung cancer cases were confirmed through linkage to the WA cancer registry. Theoretical eligibility for different screening programs was calculated. RESULTS: Five thousand seven hundred and two LDCT scans were performed on 1743 individuals. The median age was 69.8 years, 1481 (85.0%) were male and 1147 (65.8%) were ever-smokers (median pack-year exposure of 20.0). Overall, 26 lung cancers were detected (1.5% of the population; 3.5 cases per 1000 person-years of observation). Lung cancer was early stage in 86.4% and four (15.4%) cases were never smokers. Based on current lung screening program criteria, 1299 (74.5%) of this population, including the majority (17, 65.4%) of lung cancer cases, would not have been eligible for any LCSP. CONCLUSION: This population is at raised risk despite modest tobacco exposure. LDCT screening is effective at identifying early-stage lung cancer in this population and existing lung cancer risk criteria do not capture this population adequately.