BMP-6 promotes type 2 immune response during enhancement of rat mandibular bone defect healing.

Introduction: Bone morphogenetic proteins (BMPs) are used as key therapeutic agents for the treatment of difficult fractures. While their effects on osteoprogenitors are known, little is known about their effects on the immune system. Methods: We used permutations of BMP-6 (B), vascular endothelial growth factor (V), and Hedgehog signaling pathway activator smoothened agonist (S), to treat a rat mandibular defect and investigated healing outcomes at week 8, in correlation with the cellular landscape of the immune cells in the fracture callus at week 2. Results: Maximum recruitment of immune cells to the fracture callus is known to occur at week 2. While the control, S, V, and VS groups remained as nonunions at week 8; all BMP-6 containing groups - B, BV, BS and BVS, showed near-complete to complete healing. This healing pattern was strongly associated with significantly higher ratios of CD4 T (CD45+CD3+CD4+) to putative CD8 T cells (CD45+CD3+CD4-), in groups treated with any permutation of BMP-6. Although, the numbers of putative M1 macrophages (CD45+CD3-CD11b/c+CD38high) were significantly lower in BMP-6 containing groups in comparison with S and VS groups, percentages of putative - Th1 cells or M1 macrophages (CD45+CD4+IFN-γ+) and putative - NK, NKT or cytotoxic CD8T cells (CD45+CD4-IFN-γ+) were similar in control and all treatment groups. Further interrogation revealed that the BMP-6 treatment promoted type 2 immune response by significantly increasing the numbers of CD45+CD3-CD11b/c+CD38low putative M2 macrophages, putative - Th2 cells or M2 macrophages (CD45+CD4+IL-4+) cells and putative - mast cells, eosinophils or basophils (CD45+CD4-IL-4+ cells). CD45- non-haematopoietic fractions of cells which encompass all known osteoprogenitor stem cells populations, were similar in control and treatment groups. Discussion: This study uncovers previously unidentified regulatory functions of BMP-6 and shows that BMP-6 enhances fracture healing by not only acting on osteoprogenitor stem cells but also by promoting type 2 immune response.

Overt and Occult Hypoxemia in Patients Hospitalized With COVID-19.

Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the Pao2 to the Fio2 (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously (ratio of the Spo2 to the Fio2 [S/F ratio]), but it is affected by skin color and occult hypoxemia can occur in Black patients. Oxygen dissociation curves allow noninvasive estimation of P/F ratios (ePFRs) but remain unproven. OBJECTIVES: Measure overt and occult hypoxemia using ePFR. DESIGN SETTING AND PARTICIPANTS: We retrospectively studied COVID-19 hospital encounters (n = 5,319) at two academic centers (University of Virginia [UVA] and Emory University). MAIN OUTCOMES AND MEASURES: We measured primary outcomes (death or ICU transfer within 24 hr), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score [NEWS] and Sequential Organ Failure Assessment [SOFA]). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AORs) and area under the receiver operating characteristic curves (AUROCs). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test. RESULTS: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p < 0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (0.70 [both sites]) or SOFA (0.68 [UVA]; 0.65 [Emory]) and similar to S/F ratio (0.76 [UVA]; 0.70 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p < 0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory]; p < 0.01). CONCLUSIONS AND RELEVANCE: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models. By accounting for biased oximetry as well as clinicians' real-time responses to it (supplemental oxygen adjustment), ePFRs may reveal racial disparities attributable to occult hypoxemia.

Impact of transcatheter mitral valve edge-to-edge repair on atrial fibrillation burden: Insights from a multicenter cohort.

BACKGROUND: Patients with significant mitralregurgitation (MR) often experience atrial fibrillation (AF). The effects of transcatheter edge-to-edge repair (TEER) for MR on AF burden is unknown. METHODS: Patients who underwent TEER atthree institutions who also had a cardiac implantable electronic device with aright atrial lead were retrospectively identified. In patients with baseline AF, device data onAF burden and echocardiographic changes were recorded at baseline and 3- and 12-month follow up time points when available. Data is expressed as number (%) and median (interquartile range), withpaired values analyzed using the Wilcoxon signed-rank test. RESULTS: Overall 66 patients wereidentified, of whom 54 (82%) had baseline data on AF available for review. Of these, 18 (33%) had a baseline burden ofAF (median burden 100% [54-100%]). Patients were 77 (71-83) years old, 10 (56%) male, 14 (78%) White, and 3 (17%) Black. A significant reduction in AF burdenwas observed at 3 months (11 patients, p = 0.03) which did not retainsignificance at 12 months (8 patients, p = 0.69). Indexed maximal left atrial volumes did not significantly change inthose with paired studies available (p > 0.35 for both time points). CONCLUSIONS: In this multicenter cohort, one thirdof patients with severe MR undergoing TEER had an AF burden at baseline, whichwas found to be significantly lower at 3 month follow up. Further investigation is needed to confirm thefindings of this small cohort and determine its effects on downstream sequelaeof AF.

Overt and occult hypoxemia in patients hospitalized with novel coronavirus disease 2019.

Background: Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously, but occult hypoxemia can occur in Black patients because the technique is affected by skin color. Oxygen dissociation curves allow non-invasive estimation of P/F ratios (ePFR) but this approach remains unproven. Research Question: Can ePFRs measure overt and occult hypoxemia? Study Design and methods: We retrospectively studied COVID-19 hospital encounters (n=5319) at two academic centers (University of Virginia [UVA] and Emory University). We measured primary outcomes (death or ICU transfer within 24 hours), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score (NEWS) and Sepsis-3). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AOR) and area under receiver operating characteristics curves (AUROC). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test. Results: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p<0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (AUROC: 0.70 [UVA]; 0.70 [Emory]) or Sepsis-3 (AUROC: 0.68 [UVA]; 0.65 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p<0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory], p<0.01). Interpretation: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models like NEWS and Sepsis-3. By accounting for biased oximetry as well as clinicians’ real-time responses to it (supplemental oxygen adjustment), ePFRs may enable statistical modelling of racial disparities in outcomes attributable to occult hypoxemia.

Sexual Satisfaction Changes Reported by Men After Their Partners' Robotic-Assisted Laparoscopic Sacrocolpopexies.

OBJECTIVES: This study aimed to compare the preoperative and postoperative sexual satisfaction reported by male sexual partners of women undergoing surgical correction of pelvic organ prolapse. METHODS: This was a single-center prospective cohort study. Heterosexual, sexually active English-speaking couples in which the women were planning to undergo robotic-assisted laparoscopic sacrocolpopexy for correction of pelvic organ prolapse were eligible for enrollment in the study. Validated sexual function questionnaires-the Sexual Experience Questionnaire (SEX-Q; Mulhall et al. J Sex Med. 2008) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (Rogers, et al. Int Urogynecol J Pelvic Floor Dysfunct. 2003)-were used to evaluate preoperative and postoperative male and female sexual experience, respectively. These preoperative scores were compared using paired t tests. The Student t and the Mann-Whitney tests were used to compare study-eligible couples with noneligible couples and to compare study participants with nonparticipants. RESULTS: During the study enrollment period, 92 couples met the inclusion criteria and 45 of those were enrolled. Complete data sets of preoperative and postoperative questionnaires were obtained for 36 couples. After their partners' successful reconstructive surgery, male study subjects reported improved total SEX-Q scores (mean ± SD, 71 ± 16.7 vs 76.5 ± 17.8; P = 0.025). Within the subscales of the SEX-Q, there was significant improvement between preoperative and postoperative "individual satisfaction" scores (mean ± SD, 65.7 ± 16.8 vs 78.9 ± 17.5; P < 0.0001), but not within the "erectile dysfunction" or "couple satisfaction" subscales. Female partners reported improved Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 scores after surgery (mean ± SD, 36.6 ± 5.5 vs 40.0 ± 4.6; P = 0.003). CONCLUSIONS: Sexually active heterosexual men and women reported improved sexual experience after successful prolapse repair.

Molecular rearrangement reactions in the gas phase triggered by electron attachment.

Bond formation and rearrangement reactions in gas phase electron attachment were studied through dissociative electron attachment (DEA) to pentafluorotoluene (PFT), pentafluoroaniline (PFA) and pentafluorophenol (PFP) in the energy range 0-14 eV. In the case of PFA and PFP, the dominant processes involve formation of [M - HF](-) through the loss of neutral HF. This fragmentation channel is most efficient at low incident electron energy and for PFP it is accompanied by a substantial conformational change of the anionic fragment. At higher energy, HF loss is also observed as well as a number of other fragmentation processes. Thermochemical threshold energies have been computed for all the observed fragments and classical trajectories of the electron attachment process were calculated to elucidate the fragmentation mechanisms. For the dominant reaction channel leading to the loss of HF from PFP, the minimum energy path was calculated using the nudged elastic band method.

Dissociative electron attachment to C2F5 radicals.

Dissociative electron attachment to the reactive C(2)F(5) molecular radical has been investigated with two complimentary experimental methods; a single collision beam experiment and a new flowing afterglow Langmuir probe technique. The beam results show that F(-) is formed close to zero electron energy in dissociative electron attachment to C(2)F(5). The afterglow measurements also show that F(-) is formed in collisions between electrons and C(2)F(5) molecules with rate constants of 3.7 × 10(-9) cm(3) s(-1) to 4.7 × 10(-9) cm(3) s(-1) at temperatures of 300-600 K. The rate constant increases slowly with increasing temperature, but the rise observed is smaller than the experimental uncertainty of 35%.