Screening for obstructive sleep apnea in patients with cancer - a machine learning approach.

Background: Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder associated with daytime sleepiness, fatigue, and increased all-cause mortality risk in patients with cancer. Existing screening tools for OSA do not account for the interaction of cancer-related features that may increase OSA risk. Study Design and Methods: This is a retrospective study of patients with cancer at a single tertiary cancer institution who underwent a home sleep apnea test (HSAT) to evaluate for OSA. Unsupervised machine learning (ML) was used to reduce the dimensions and extract significant features associated with OSA. ML classifiers were applied to principal components and model hyperparameters were optimized using k-fold cross-validation. Training models for OSA were subsequently tested and compared with the STOP-Bang questionnaire on a prospective unseen test set of patients who underwent an HSAT. Results: From a training dataset of 249 patients, kernel principal component analysis (PCA) extracted eight components through dimension reduction to explain the maximum variance with OSA at 98%. Predictors of OSA were smoking, asthma, chronic kidney disease, STOP-Bang score, race, diabetes, radiation to head/neck/thorax (RT-HNT), type of cancer, and cancer metastases. Of the ML models, PCA + RF had the highest sensitivity (96.8%), specificity (92.3%), negative predictive value (92%), F1 score (0.93), and ROC-AUC score (0.88). The PCA + RF screening algorithm also performed better than the STOP-Bang questionnaire alone when tested on a prospective unseen test set. Conclusions: The PCA + RF ML model had the highest accuracy in screening for OSA in patients with cancer. History of RT-HNT, cancer metastases, and type of cancer were identified as cancer-related risk factors for OSA.

Complement C3 Reduces Apoptosis via Interaction with the Intrinsic Apoptotic Pathway.

Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Recently, we reported that myocardial necrosis was decreased in complement C3-/- mice after heart I/R. The current study used the same heart model to test the effect of C3 on myocardial apoptosis and investigated if C3 regulation of apoptosis occurred in human cardiomyocytes. Comparative proteomics analyses found that cytochrome c was present in the myocardial C3 complex of WT mice following I/R. Incubation of exogenous human C3 reduced apoptosis in a cell culture system of human cardiomyocytes that did not inherently express C3. In addition, human C3 inhibited the intrinsic apoptosis pathway in a cell-free apoptosis system. Finally, human pro-C3 was found to bind with an apoptotic factor, pro-caspase 3, in a cell-free system. Thus, we present firsthand evidence showing that C3 readily reduces myocardial apoptosis via interaction with the intrinsic apoptotic pathway.

Iron therapy as a novel treatment of scleroderma-related pulmonary hypertension: A case report and literature review.

Pulmonary arterial hypertension (PAH) is the leading cause of death in patients with systemic sclerosis (SSc), with a 3-year mortality of 40%-50% despite optimal therapy. Treatment mirrors that of idiopathic PAH and is often ineffective. This is a case report of a patient with SSc evaluated for progressive dyspnoea with exertion and found to have elevated pulmonary artery systolic pressures (PASPs). She received ferritin-targeted iron infusions as a novel treatment of suspected SSc-associated PAH, with subsequent resolution of respiratory symptoms and PASPs that normalized. We review PAH especially associated with SSc, its treatment and identify a possible novel therapeutic approach for those with PAH-SSc.

Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury.

The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB-/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB-/- mice, 20 ± 4%; WT mice, 45 ± 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB-/- mice, 0 ± 0%; WT mice, 31 ± 6%; P<0.05). Reconstitution of fB-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.

Complement factor B activation in patients with preeclampsia.

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. Bb, the active fragment of complement factor B (fB), has been reported to be a predictor of preeclampsia. However, conflicting results have been found by some investigators. We hypothesized that the disagreement in findings may be due to the racial/ethnic differences among various study groups, and that fB activation is significant in women of an ethnic minority with preeclampsia. We investigated the maternal and fetal levels of Bb (the activated fB fragment) in pregnant women of an ethnic minority with or without preeclampsia. We enrolled 291 pregnant women (96% of an ethnic minority, including 78% African-American). Thirteen percent of these were diagnosed with preeclampsia. Maternal venous blood was collected from all participants together with fetal umbilical cord blood samples from 154 deliveries in the 291 women. The results were analyzed using the Mann-Whitney U test and multivariate analyses. Maternal Bb levels were significantly higher in the preeclamptic group than in the nonpreeclamptic group. Levels of Bb in fetal cord blood were similar in both groups. Subgroup analyses of African-American patients' results confirmed the study hypothesis that there would be a significant increase in Bb in the maternal blood of the preeclamptic group and no increase in Bb in the fetal cord blood of this group. These results suggest that a maternal immune response through complement fB might play a role in the development of preeclampsia, particularly in African-American patients.