Endoscopic-Assisted Cochlear Implantation in Far Advanced Otosclerosis.

OBJECTIVES: To evaluate the effectiveness of cochlear implantation (CI) in case of far advanced otosclerosis and to evaluate the value of using intraoperative otoendoscopy to facilitate the identification of the round window membrane and the scala tympani without the need to remove the posterior canal wall or to perform a subtotal petrosectomy. STUDY DESIGN: Retrospective case-series study. SETTING: Tertiary academic CI center. PATIENTS AND METHODS: This study was conducted on patients with far advanced otosclerosis who underwent endoscopic-assisted CI between January 2010 and June 2020 at the same CI center. The minimum follow-up period was 2 years after surgery. RESULTS: Fourteen patients were included in the study. Ten patients had undergone a previous stapedotomy. Electrode insertion in the scala tympani was successfully accomplished in all cases included in the study. There was a statistically significant improvement in pure-tone average and speech discrimination scores in all cases of the study group (p < 0.0001). There were no statistically significant differences in postoperative pure-tone average or speech discrimination scores between cases with and without cochlear ossification or between cases with and without a previous stapedotomy (p > 0.05). CONCLUSION: Endoscopic-assisted CI is an effective option for hearing restoration in patients with far advanced otosclerosis. Otoendoscopy can facilitate visualization and access to the scala tympani without the need to remove the posterior canal wall or to perform a subtotal petrosectomy.

Unconventional activation of PRKDC by TNF-α: deciphering its crucial role in Th1-mediated inflammation beyond DNA repair as part of the DNA-PK complex.

BACKGROUND: The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID. METHODS: We investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC+/-, or Ku70+/- mice used in this study. RESULTS: A ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α - induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system. CONCLUSIONS: This study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions.

Endoscopic ossiculoplasty in traumatic conductive hearing loss with intact tympanic membrane: a five-year experience.

BACKGROUND: Exploratory tympanotomy in cases of traumatic ossicular disruption with intact tympanic membrane is crucial for both diagnostic and therapeutic purposes. Performing this procedure using the endoscope is gaining popularity. Hence, this study aimed to demonstrate varieties of ossicular pathology and their management in our institution. METHODS: A retrospective evaluation was conducted of 136 ears in patients with traumatic ossicular disruption with an intact tympanic membrane, who underwent endoscopic exploratory tympanotomy. A proposed algorithm was followed, to incorporate different traumatic ossicular possibilities. Assessment of hearing outcomes and surgical complications was performed six months post-operatively. RESULTS: Incudostapedial dislocation was the most commonly encountered type of traumatic ossicular disruption (35.3 per cent). Air conduction threshold improved significantly following endoscopic ossiculoplasty, from 50.9 ± 6.35 dB pre-operatively to 22.35 ± 3.27 dB post-operatively, with successful air-bone gap closure. CONCLUSION: Endoscopic ear surgery is effective in the diagnosis and management of challenging cases of post-traumatic ossicular disruption with an intact tympanic membrane.

Pulmonary inflammation and fibroblast immunoregulation: from bench to bedside.

In recent years, there has been an explosion of interest in how fibroblasts initiate, sustain, and resolve inflammation across disease states. Fibroblasts contain heterogeneous subsets with diverse functionality. The phenotypes of these populations vary depending on their spatial distribution within the tissue and the immunopathologic cues contributing to disease progression. In addition to their roles in structurally supporting organs and remodeling tissue, fibroblasts mediate critical interactions with diverse immune cells. These interactions have important implications for defining mechanisms of disease and identifying potential therapeutic targets. Fibroblasts in the respiratory tract, in particular, determine the severity and outcome of numerous acute and chronic lung diseases, including asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and idiopathic pulmonary fibrosis. Here, we review recent studies defining the spatiotemporal identity of the lung-derived fibroblasts and the mechanisms by which these subsets regulate immune responses to insult exposures and highlight past, current, and future therapeutic targets with relevance to fibroblast biology in the context of acute and chronic human respiratory diseases. This perspective highlights the importance of tissue context in defining fibroblast-immune crosstalk and paves the way for identifying therapeutic approaches to benefit patients with acute and chronic pulmonary disorders.

Spatiotemporal development of the human T follicular helper cell response to Influenza vaccination.

We profiled blood and draining lymph node (LN) samples from human volunteers after influenza vaccination over two years to define evolution in the T follicular helper cell (TFH) response. We show LN TFH cells expanded in a clonal-manner during the first two weeks after vaccination and persisted within the LN for up to six months. LN and circulating TFH (cTFH) clonotypes overlapped but had distinct kinetics. LN TFH cell phenotypes were heterogeneous and mutable, first differentiating into pre-TFH during the month after vaccination before maturing into GC and IL-10+ TFH cells. TFH expansion, upregulation of glucose metabolism, and redifferentiation into GC TFH cells occurred with faster kinetics after re-vaccination in the second year. We identified several influenza-specific TFH clonal lineages, including multiple responses targeting internal influenza proteins, and show each TFH state is attainable within a lineage. This study demonstrates that human TFH cells form a durable and dynamic multi-tissue network.

Discriminant Analysis of the Prognostic Factors for Hearing Outcomes in Patients with Idiopathic Sudden Sensorineural Hearing Loss.

BACKGROUND: This study aims to determine and assess prognostic variables that might affect the hearing result in patients with idiopathic sudden sensorineural hearing loss following intratympanic steroid injection. METHODS: In total, 190 patients with idiopathic sudden sensorineural hearing loss received intratympanic steroid injection. Two hearing indices (recovery and nonrecovery) will be analyzed as dependent variables; patient's age, time period between the onset of hearing loss and treatment, initial level of hearing (hearing loss pre), type of audiogram curve (upsloping, downsloping, and flat), presence of vertigo, presence of tinnitus, and diabetes) will be analyzed as prognostic factor variables. RESULTS: Recovery was seen in 72% of the patients. Different preinjection audiogram curves and hearing grades had a significant effect on recovery, absence of vestibular symptoms and no diabetic history were noted to have a good prognosis. Delay in treatment by more than 30 days from the onset of hearing loss was associated with a worse prognosis. CONCLUSION: Idiopathic sudden sensorineural hearing loss associated with late treatment plan more than 1 month, presence of vertigo, diabetes, and profound prehearing loss were negative prognostic factors. Whereas age, gender, and presence of tinnitus did not affect prognosis. More stable response was obtained when intratympanic steroids were added within 1 month after diagnosis, and the patient presented with mild or moderate hearing loss grade, flat or downsloping pure tone audiometery curve, and absence of vertigo and nondiabetic with significantly good results.

Promotion of a synthetic degradation of activated STAT6 by PARP-1 inhibition: roles of poly(ADP-ribosyl)ation, calpains and autophagy.

BACKGROUND: We reported that PARP-1 regulates genes whose products are crucial for asthma, in part, by controlling STAT6 integrity speculatively through a calpain-dependent mechanism. We wished to decipher the PARP-1/STAT6 relationship in the context of intracellular trafficking and promoter occupancy of the transcription factor on target genes, its integrity in the presence of calpains, and its connection to autophagy. METHODS: This study was conducted using primary splenocytes or fibroblasts derived from wild-type or PARP-1-/- mice and Jurkat T cells to mimic Th2 inflammation. RESULTS: We show that the role for PARP-1 in expression of IL-4-induced genes (e.g. gata-3) in splenocytes did not involve effects on STAT6 phosphorylation or its subcellular trafficking, rather, it influenced its occupancy of gata-3 proximal and distal promoters in the early stages of IL-4 stimulation. At later stages, PARP-1 was crucial for STAT6 integrity as its inhibition, pharmacologically or by gene knockout, compromised the fate of the transcription factor. Calpain-1 appeared to preferentially degrade JAK-phosphorylated-STAT6, which was blocked by calpastatin-mediated inhibition or by genetic knockout in mouse fibroblasts. The STAT6/PARP-1 relationship entailed physical interaction and modification by poly(ADP-ribosyl)ation independently of double-strand-DNA breaks. Poly(ADP-ribosyl)ation protected phosphorylated-STAT6 against calpain-1-mediated degradation. Additionally, our results show that STAT6 is a bonafide substrate for chaperone-mediated autophagy in a selective and calpain-dependent manner in the human Jurkat cell-line. The effects were partially blocked by IL-4 treatment and PARP-1 inhibition. CONCLUSIONS: The results demonstrate that poly(ADP-ribosyl)ation plays a critical role in protecting activated STAT6 during Th2 inflammation, which may be synthetically targeted for degradation by inhibiting PARP-1.

The impact of bolgerization versus partial resection of the middle turbinate on frontal sinusotomy patency outcome: A randomised controlled study.

OBJECTIVES: This study aimed to compare the effects of middle turbinate resection vs bolgerization on the incidence of middle meatus synechia and their prognostic value on the patency outcomes after frontal sinusotomy. DESIGN: A randomised controlled study. SETTING: Tertiary centre hospital. MAIN OUTCOME MEASURES: Thirty-eight patients undergoing bilateral frontal sinusotomy for chronic frontal sinusitis were included. Partial middle turbinate resection was alternated with bolgerization in both nasal cavities of every patient. The Lund-Kennedy endoscopic scores (LKESs) for both sides were compared at the first, third and sixth months postoperatively. Middle meatus synechia was assessed using the visual analogue score (VAS). Sinus patency was assessed at the end of the sixth month using a 70° nasal endoscope. RESULTS: The sinus patency outcome was significantly higher in the resected group (34\38) than the bolgerized group (26\38), (P = .047*). The VAS scores suggested that the middle turbinate bolgerization group showed a significantly higher incidence of middle meatal synechia than the partial middle turbinate resection group (4.47 ± 2.617 vs 3.29 ± 2.301; P = .040*). CONCLUSION: Middle turbinate resection showed more favourable results than bolgerization concerning the sinus patency outcome after frontal sinusotomy. It also showed a lower incidence of middle meatus synechia postoperatively.

The prognostic variables affecting the frontal sinusotomy patency outcome and how to manage: A prospective study.

OBJECTIVES: The study aimed to assess the factors affecting the frontal sinus patency after endoscopic frontal sinusotomy. DESIGN: A prospective cohort study. SETTING: Tertiary centre hospital. MAIN OUTCOME MEASURES: Fifty patients with refractory chronic frontal sinusitis (83 operated frontal sinuses) had frontal sinusotomy and followed up for six months. Multiple operative factors were included the type of the procedure, intraoperative sinus findings, degree of mucosal preservation and middle turbinate stability. Other factors were also assessed, including smoking, the presence of allergic rhinitis, asthma, gastroesophageal reflux and other associated medical comorbidities. RESULTS: The sinus patency success rate was 75.9%. There was a significant difference regarding the intraoperative anteroposterior sinus ostium diameter (5.36 ± 1.45 mm vs 8.88 ± 2.38 mm, P-value: .001* in the failed group and the success group, respectively). There was a significant association between the patency outcome and the presence of associated medical comorbidities (P-value: .001*), the presence of allergic rhinitis (P-value: .001*), the degree of sinus mucosal preservation (P-value: .012*) and the degree of middle turbinate stability (P-value: .001*). The multivariate analysis showed that the intraoperative anteroposterior diameter of the sinus ostium, middle turbinate stability and presence of allergic rhinitis were significant predictors (P-value: .012*, .042* and .013*, respectively). CONCLUSION: Sinuses with anteroposterior ostium diameters less than 5.36 mm are more susceptible to restenosis. The flail middle turbinate increases the risk of postoperative middle meatus synechia and frontal sinus patency failure. The presence of allergic rhinitis has a negative impact on the patency outcome.

Comparison between the endoscopic scores of bolgerization versus partial resection of the middle turbinate for management of the postoperative lateralization in the early follow-up period after endoscopic frontal sinusotomy: A randomized controlled study.

BACKGROUND: Frontal sinusotomy is a challenging procedure that needs meticulous handling due to its unique anatomical position. Postoperative middle turbinate lateralization is critical comorbidity for the success rate, and many techniques are adopted to prevent it. The study aimed to compare the effect of middle turbinate bolgerization and partial resection on the postoperative endoscopic scores and assess their impact on the middle meatus and the frontal recess outcome. PATIENT AND METHODS: This prospective study was conducted on forty-one patients undergoing bilateral frontal sinusotomy for chronic frontal sinusitis. Nasal cavities were randomized so that partial middle turbinate resection technique was done alternately with bolgerization approach in every patient. Each participant acted as their control. Both sides were compared using Lund Kennedy Endoscopic Score (LKES) and Perioperative Sinus Endoscopy Score (POSE) at the baseline, 1st, 3rd, and 12th-month intervals postoperatively. Also, middle turbinate status was assessed at the end of the 12th-month interval using POSE score. RESULTS: The total frontal sinus patency rate was 82.9% (63/76 operated sinus). Baseline scores, LKES (3.79 ± 0.777 vs 4.05 ± 0.769, p = 0.142, for the side of resection and the side for bolgerization respectively) and POSE (1.79 ± 0.413 vs 1.82 ± 0.393, p = 0.777, for the side of resection and the side for bolgerization respectively). Regarding LKES, the differences between both operated sides were fluctuating with p values: 0.001*, 0.171, and 0.044* for the 1st, 3rd, and 12th months follow-up intervals, respectively. Regarding the POSE score of the frontal sinus, the difference between both groups was steadily increasing with p values: 0.318, 0.119, and 0.017* for the 1st, 3rd, and 12th months follow-up intervals. The middle turbinate's POSE score at the 12th month was significantly higher in the side allocated for bolgerization (p-value = 0.008*). CONCLUSION: Partial middle turbinate resection showed favorable endoscopic outcomes than bolgerization at the 12th month follow up period in patients undergoing primary ESS for chronic frontal sinusitis.

Acute effect of inhaled iloprost on exercise dynamic hyperinflation in COPD patients: A randomized crossover study.

BACKGROUND AND OBJECTIVE: We tested whether the prostacyclin analog inhaled iloprost modulates dead space, dynamic hyperinflation (DH), and systemic inflammation/oxidative stress during maximal exercise in subjects with chronic obstructive pulmonary disease (COPD) who were not selected based on pulmonary hypertension (PH). METHODS: Twenty-four COPD patients with moderate-severe obstruction (age 59 ± 7 years, FEV1 53 ± 13% predicted) participated in a randomized, double-blind, placebo-controlled crossover trial. Each subject received a single nebulized dose of 5.0 µg iloprost or placebo on non-consecutive days followed by maximal cardiopulmonary exercise tests. The primary outcome was DH quantified by end-expiratory lung volume/total lung capacity ratio (EELV/TLC) at metabolic isotime. RESULTS: Inhaled iloprost was well-tolerated and reduced submaximal alveolar dead-space fraction but did not significantly reduce DH (0.70 ± 0.09 vs 0.69 ± 0.07 following placebo and iloprost, respectively, p = 0.38). Maximal exercise time (9.1 ± 2.3 vs 9.3 ± 2.2 min, p = 0.31) and peak oxygen uptake (17.4 ± 6.3 vs 17.9 ± 6.9 mL/kg/min, p = 0.30) were not significantly different following placebo versus iloprost. CONCLUSIONS: A single dose of inhaled iloprost was safe and reduced alveolar dead space fraction; however, it was not efficacious in modulating DH or improving exercise capacity in COPD patients who were not selected for the presence of PH.

The preoperative radiological findings associated with failure of frontal sinusotomy: A prospective study.

OBJECTIVES: The study aimed to assess the association between the preoperative CT findings and the patency outcome of the frontal sinus after endoscopic frontal sinusotomy in the early follow-up period. DESIGN: A prospective cohort study. SETTING: Tertiary hospital centre. MAIN OUTCOME MEASURES: The study measures the association between the frontal sinusotomy outcome and the standard preoperative radiological scores, including Harvard, Kennedy and Lund-Mackay. It also measures the impact of the degree of sinus mucosal thickness on the outcome. Furthermore, it measures the effect of the anteroposterior lengths of both the frontal sinus ostium and the frontal recess on postoperative frontal sinus patency. RESULTS: Harvard, Kennedy and modified Lund-Mackay scores showed no evidence of association with the frontal sinusotomy patency outcome (P-values .397, .487 and .501), respectively. Still, the Lund-Mackay score showed a negative correlation with symptom improvement. Sinuses with a high-grade mucosal thickness on CT scan were associated with high failure rates (P-value: .009*). The anteroposterior length of the frontal sinus ostium significantly affects the outcome (P-value: .001*). In contrast, there was no association between the anteroposterior length of the frontal recess and the outcome (P-value: .965). CONCLUSION: The Harvard, Kennedy and Lund-Mackay scores could not predict the frontal sinusotomy patency outcome. Failed cases were associated with advanced degrees of mucosal pathology in the preoperative CT scan. Sinuses ostia with anteroposterior diameters less than 5.36 mm showed more susceptibility for sinus restenosis postoperatively. The variability of the anteroposterior length of the frontal recess did not affect the surgical outcome.

Targeting PARP-1 with metronomic therapy modulates MDSC suppressive function and enhances anti-PD-1 immunotherapy in colon cancer.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored. METHODS: Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or APCMin/+ mice bred into PARP-1+/- or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSIhigh) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy. RESULTS: Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/APCMin -mediated intestinal tumorigenesis and APCMin -associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSIhigh or reduction of MSS tumors in mice. CONCLUSIONS: These results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer.

Combined preoperative HRCT parameters for prediction of round window visibility in pediatric cochlear implant patient.

OBJECTIVE: To evaluate the add value of combined analysis of high resolution computed tomography (HRCT) temporal bone parameters in accurate prediction of round window (RW) visibility through posterior tympanotomy. PATIENTS AND METHODS: a retrospective observational study was held in a tertiary center, conducted on 45 cochlear implant pediatric candidates between January 2017 and September 2019. Candidates were referred for CT temporal bone. They were classified into fully visible RW cases and partially or non-visible RW cases. Radiological measurements were compared between the two groups for prediction of RW visibility separate and in combination. RESULTS: 45 patients were included in the study (26 males (57.8%) and 19 females (42.2%)). Their median age was 4 years (2-12 years). There were 38 (84.4%) fully visible and 7 (15.6%) partially or non-visible RW cases. Kashio posterior line (n:32/3), fascial recess width (FRW) (mean: 4.9 (3.5-7.5)/4.2 (4-4.7) mm) and round window location (RWL) (3 (1-4)/2.8 (1-3)mm) measurements significantly differentiated between the two groups; (P value 0.034, 0.012 & 0.025 respectively). Posterior kashio line and cut off values of ≥4.75 mm of FRW & 2.95 mm of RWL were showed sensitivity 84.2%, 63.2% & 65.8%, and accuracy 80%, 68.9% &68.9% in prediction of RW visibility respectively. Combination of Kashio prediction line with cut off value ≥ 7.45 mm (sum of FRW & RWL) showed P value 0.003 with further improve in the sensitivity and overall accuracy in prediction of RW visibility from 84.2% to 80% up to 91.4% and 88.6% respectively. CONCLUSION: combined parameters using Kashio line with FRW and RWL increases sensitivity and overall accuracy in prediction of RW visibility rather than single parameter.

Are direct oral anticoagulants preferable to warfarin for the treatment of left ventricular thrombi? A Bayesian meta-analysis of randomized controlled trials.

Background: There is no clear consensus on the optimal choice of anticoagulant in patients with left ventricular thrombi (LVT). Given the potentially fatal complications associated with this disease entity, we performed a systematic review and meta-analysis of recent randomized clinical trials (RCTs) to synthesize the latest evidence on this topic. Methods: We performed a comprehensive search of electronic databases to identify RCTs comparing warfarin to direct oral anticoagulants (DOACs) in patients with LVT. A random-effects Bayesian analysis using a binomial-normal hierarchical model was performed to compare the two treatment options with regards to the risk of mortality, stroke, LVT resolution, and major bleeding. Results: In an analysis comprising 3 RCTs (N = 139), there were no statistically significant differences regarding mortality (OR: 0.68; 95% CrI: 0.10 to 4.43), stroke (OR: 0.14; 95% CrI: 0.01 to 1.27), or LVT resolution (OR: 1.17; 95% CrI: 0.37 to 3.45). Major bleeding was significantly lower in the DOAC group (OR: 0.16; 95% CrI: 0.02 to 0.82). Conclusion: In patients with LVT, the currently available evidence from RCTs supports the use of DOACs rather than warfarin due to lower major bleeding risks and no evidence of inferiority with respect to mortality, stroke or LVT resolution.

PARP-1 Is Critical for Recruitment of Dendritic Cells to the Lung in a Mouse Model of Asthma but Dispensable for Their Differentiation and Function.

Dendritic cells (DCs) are critical in asthma and many other immune diseases. We previously demonstrated a role for PARP-1 in asthma. Evidence on PARP-1 playing a role in Th2-associated DC function is not clear. In this study, we examined whether PARP-1 is critical for DC differentiation and function using bone marrow progenitors and their migration to the lung in an ovalbumin-based mouse model of asthma. Results show that changes in PARP-1 levels during GM-CSF-induced DC differentiation from bone marrow progenitors were cyclic and appear to be part of an array of changes that included STAT3/STAT5/STAT6/GRAIL/RAD51. Interestingly, PARP-1 gene deletion affected primarily STAT6 and γH2AX. PARP-1 inhibition significantly reduced the migration of DCs to the lungs of ovalbumin-challenged mice, which was associated with a concomitant reduction in lung levels of the adhesion molecule VCAM-1. The requirement of PARP-1 for VCAM-1 expression was confirmed using endothelial and lung smooth muscle cells. PARP-1 expression and activity were also required for VCAM-1 in differentiated DCs. An assessment of CD11b+/CD11c+/MHCIIhigh DCs in spleens and lymph nodes of OVA-sensitized mice revealed that PARP-1 inhibition genetically or by olaparib exerted little to no effect on DC differentiation, percentage of CD80+/CD86+/CD40+-expressing cells, or their capacity to promote proliferation of ovalbumin-primed (OTII) CD4+ T cells. These findings were corroborated using GM-CSF-induced differentiation of DCs from the bone marrow. Surprisingly, the PARP-1-/- DCs exhibited a higher intrinsic capacity to induce OTII CD4+ T cell proliferation in the absence of ovalbumin. Overall, our results show that PARP-1 plays little to no role in DC differentiation and function and that the protective effect of PARP-1 inhibition against asthma is associated with a prevention of DC migration to the lung through a reduction in VCAM-1 expression. Given the current use of PARP inhibitors (e.g., olaparib) in the clinic, the present results may be of interest for the relevant therapies.

A systematic review and meta-analysis of ulipristal acetate for symptomatic uterine fibroids.

BACKGROUND: Uterine fibroids cause menorrhagia and adversely affect quality of life. Ulipristal acetate (UPA) can improve fibroid symptoms. OBJECTIVES: To assess the effectiveness of UPA in women with symptomatic uterine fibroids. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, Embase, and CINHAL on December 31, 2018, using relevant search terms. Clinical trials registries were searched for ongoing trials and there were no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing UPA with placebo/no treatment/any pharmacological intervention for symptomatic uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials, extracted data, and assessed the risk of bias in included studies. We used risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, plus their 95% confidence intervals (CIs). MAIN RESULTS: We identified six RCTs (1121 participants). Five studies (882 participants) compared UPA with placebo. UPA significantly achieved amenorrhea (RR 24.54; 95% CI, 10.82-55.64), reduced blood loss, and improved quality of life with insufficient evidence from RCTs for adverse events. There was insufficient evidence for improved outcomes when UPA was compared with leuprolide acetate. CONCLUSION: Compared with placebo, oral UPA significantly induces amenorrhea, reduces heavy menses, and improves quality-of-life in women with uterine fibroids.

Microparticles in systemic sclerosis: Potential pro-inflammatory mediators and pulmonary hypertension biomarkers.

BACKGROUND AND OBJECTIVE: Endothelial microparticles (EMP) are submicron vesicles released from endothelial cells. We aimed to determine the utility of EMP as biomarkers of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients and the pathogenic role of microparticles (MP) in vascular inflammation. METHODS: Levels of EMP (CD144+, CD31+, CD62E+ and CD143+) were compared between three groups (10 SSc patients with PAH, 10 SSc patients without pulmonary hypertension (no-PH) and 10 healthy age- and sex-matched controls). Human pulmonary artery endothelial cells (HPAEC) were exposed in vitro to MP obtained from SSc patients or healthy controls, and levels of cytokines and inflammatory adhesion molecules were compared. RESULTS: CD144+ EMP were significantly higher in the SSc-PAH group compared to either the SSc-no PH or healthy controls (diagnostic accuracy 80%, P = 0.02). Compared to controls, SSc patients had higher CD31+/CD62E+ ratios, indicating larger contributions of apoptosis to EMP release (P = 0.04). Patients with limited SSc had significantly higher levels of CD143+ EMP compared to those with diffuse subtype (P = 0.008). When HPAEC were exposed to MP from SSc patients, there was a significant increase in inflammatory cytokines and adhesion molecules. Interestingly, exposure to healthy control MP caused a reduction in inflammatory markers. CONCLUSION: EMP (particularly CD144+) are promising biomarkers of PAH in SSc but require further study. MP isolated from SSc patients induced an increase in endothelial cell inflammation and may be an important pathogenic factor in SSc.