Intimate partner violence and its correlates in middle-aged and older adults during the COVID-19 pandemic: A multi-country secondary analysis.

Intimate partner violence (IPV) may have been exacerbated during the COVID-19 pandemic. Middle-aged and older adults, ages 45 years or older, are at higher risk of COVID-19 mortality and social isolation. However, most studies on IPV during the pandemic do not focus on this important subpopulation. Informed by the social-ecological theory, this study examines individual, household, community, and country-level correlates of IPV among middle-aged and older adults in multiple countries using a cross-sectional online survey. Data from 2867 participants aged 45 or older in the International Sexual Health and Reproductive Health (I-SHARE) survey from July 2020 to February 2021 were described using univariate analysis. IPV was defined using four validated WHO measures. Individual characteristics included self-isolation and food security. At the country-level, we examined social distancing stringency. Logistic regression models with a random intercept for country were conducted to explore IPV correlates among 1730 eligible individuals from 20 countries with complete data. Most participants were heterosexual (2469/2867), cisgender (2531/2867) females (1589/2867) between the ages of 45-54 (1539/2867). 12.1% (346/2867) of participants experienced IPV during social distancing measures. After adjustment, participants who self-isolated experienced 1.4 (95% CI 1.0, 2.0, p = 0.04) times the odds of IPV compared to those who had not isolated. Those who reported an increase in food insecurity compared to pre-pandemic experienced 2.2 times the odds (95% CI 1.6, 3.0, p<0.0001) of IPV compared to those who did not report increased food insecurity. People in countries with more stringent social distancing policies were less likely to experience IPV compared to people in countries with lower levels of stringency (aOR = 0.6, 95% CI 0.4, 0.9, p = 0.04). IPV was common among middle-aged and older adults during the COVID-19 pandemic. Our data suggest the need for further crisis management and social protection measures for middle-aged and older adults who have intersecting vulnerabilities to IPV to mitigate COVID-19 impact.

Ecto-5'-nucleotidase (Nt5e/CD73)-mediated adenosine signaling attenuates TGFß-2 induced elastin and cellular contraction.

Arterial calcification due to deficiency of CD73 (ACDC) is a rare genetic disease caused by a loss-of-function mutation in the NT5E gene encoding the ecto-5'-nucleotidase (cluster of differentiation 73, CD73) enzyme. Patients with ACDC develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that patients with ACDC vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor ß (TGFß) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGFß regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGFß signaling in vascular smooth muscle cells (SMCs). We show that Nt5e-/- SMCs have elevated contractile markers and elastin gene expression compared with Nt5e+/+ SMCs. Ecto-5'-nucleotidase (Nt5e)-deficient SMCs exhibit increased TGFß-2 and activation of small mothers against decapentaplegic (SMAD) signaling, elevated elastin transcript and protein, and potentiate SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGFß signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGFß signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis.

Isolation of Human Primary Valve Cells for In vitro Disease Modeling.

Calcific aortic valve disease (CAVD) is present in nearly a third of the elderly population. Thickening, stiffening, and calcification of the aortic valve causes aortic stenosis and contributes to heart failure and stroke. Disease pathogenesis is multifactorial, and stresses such as inflammation, extracellular matrix remodeling, turbulent flow, and mechanical stress and strain contribute to the osteogenic differentiation of valve endothelial and valve interstitial cells. However, the precise initiating factors that drive the osteogenic transition of a healthy cell into a calcifying cell are not fully defined. Further, the only current therapy for CAVD-induced aortic stenosis is aortic valve replacement, whereby the native valve is removed (surgical aortic valve replacement, SAVR) or a fully collapsible replacement valve is inserted via a catheter (transcatheter aortic valve replacement, TAVR). These surgical procedures come at a high cost and with serious risks; thus, identifying novel therapeutic targets for drug discovery is imperative. To that end, the present study develops a workflow where surgically removed tissues from patients and donor cadaver tissues are used to create patient-specific primary lines of valvular cells for in vitro disease modeling. This protocol introduces the utilization of a cold storage solution, commonly utilized in organ transplant, to reduce the damage caused by the often-lengthy procurement time between tissue excision and laboratory processing with the benefit of greatly stabilizing cells of the excised tissue. The results of the present study demonstrate that isolated valve cells retain their proliferative capacity and endothelial and interstitial phenotypes in culture upwards of several days after valve removal from the donor. Using these materials allows for the collection of control and CAVD cells, from which both control and disease cell lines are established.

Dysregulation of FOXO1 (Forkhead Box O1 Protein) Drives Calcification in Arterial Calcification due to Deficiency of CD73 and Is Present in Peripheral Artery Disease.

OBJECTIVE: The recessive disease arterial calcification due to deficiency of CD73 (ACDC) presents with extensive nonatherosclerotic medial layer calcification in lower extremity arteries. Lack of CD73 induces a concomitant increase in TNAP (tissue nonspecific alkaline phosphatase; ALPL), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increased ALPL expression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification. Approach and Results: We previously developed a patient-specific disease model using ACDC primary dermal fibroblasts that recapitulates the calcification phenotype in vitro. We found that lack of CD73-mediated adenosine signaling reduced cAMP production and resulted in increased activation of AKT. The AKT/mTOR (mammalian target of rapamycin) axis blocks autophagy and inducing autophagy prevented calcification; however, we did not observe autophagy defects in ACDC cells. In silico analysis identified a putative FOXO1 (forkhead box O1 protein) binding site in the human ALPL promoter. Exogenous AMP induced FOXO1 nuclear localization in ACDC but not in control cells, and this was prevented with a cAMP analogue or activation of A2a/2b adenosine receptors. Inhibiting FOXO1 reduced ALPL expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced ALPL promoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries. CONCLUSIONS: These data show that lack of CD73-mediated cAMP signaling promotes expression of the human ALPL gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.

Features of Urrets-Zavalia syndrome after descemet stripping automated endothelial keratoplasty.

PURPOSE: To report a case series of pupil abnormalities consistent with features of Urrets-Zavalia syndrome (UZS) after Descemet stripping automated endothelial keratoplasty (DSAEK) for corneal edema secondary to corneal endothelial cell dysfunction. METHODS: Retrospective chart analysis of subjects who developed UZS after DSAEK at the University of Texas Southwestern Medical Center. RESULTS: We present a series of 7 eyes with features consistent with UZS, after undergoing DSAEK. Elevated intraocular pressures (IOP) were noted in the early postoperative period in all cases. Five of 7 had graft dislocation in the postoperative period and required rebubbling or repeat DSAEK to obtain a well-apposed graft. Patients were followed for 3 to 14 months and showed improvement in visual acuity and IOP, but fixed dilated pupils persisted. CONCLUSION: A fixed irregular or dilated pupil is a rare complication that can be associated with DSAEK surgery. Patients with an elevated IOP and complicated postoperative course seem to be at greater risk for developing iris ischemia and pupil abnormalities consistent with the diagnosis of UZS.

Laser in situ keratomileusis for residual refractive errors after apodized diffractive multifocal intraocular lens implantation.

PURPOSE: To evaluate the visual and refractive outcomes of laser in situ keratomileusis (LASIK) to correct residual refractive error after apodized diffractive multifocal intraocular lens (IOL) implantation. SETTING: University of Texas Southwestern Medical Center, Dallas, Texas, USA. METHODS: This retrospective study reviewed eyes of consecutive patients who had LASIK using the IntraLase FS60 femtosecond laser and Visx Star S4 excimer laser to correct residual refractive error after AcrySof ReSTOR IOL implantation. RESULTS: The review comprised 85 eyes of 59 patients. Thirty-six eyes (42.3%) had myopic correction, 35 (41.2%) had mixed astigmatic correction, and 14 (16.5%) had hyperopic correction; 45 eyes (52.9%) also had neodymium:YAG (Nd:YAG) capsulotomy. Six months after LASIK, 91.8% of eyes had an uncorrected distance visual acuity (UCVA) of 20/25 or better, 92.9% had an uncorrected near visual acuity (UCNVA) of J1 or better, and 85.9% had 20/25 or better UCVA concurrent with J1 or better UCNVA. No eye lost more than 1 line of best spectacle-corrected visual acuity; 2 eyes (2.4%) lost 1 line. Ninety-nine percent of eyes were within +/-1.00 diopter (D) of emmetropia, and 98% of eyes were within +/-1.00 D cylinder. There was no significant difference in postoperative UCVA or UCNVA between the 3 refraction groups (P >.05) or between eyes that had Nd:YAG capsulotomy and those that did not (P >.05). CONCLUSION: Laser in situ keratomileusis for residual ametropia after apodized diffractive multifocal IOL implantation was predictable, effective, and safe.

Targeted inhibition of p57 and p15 blocks transforming growth factor beta-inhibited proliferation of primary cultured human limbal epithelial cells.

PURPOSE: To evaluate the role of cyclin-dependent kinase inhibitors p57 and p15 in transforming growth factor (TGF)-beta1 or TGF-beta2 inhibited proliferation of primary cultured human limbal epithelial cells using short interfering RNA (siRNA). METHODS: Primary cultured human limbal epithelial cells were treated with TGF-beta1 or TGF-beta2 for 6 and 24 h, and total RNA extracted for RT-PCR and real-time PCR using primers for p21, p27, and p57 (CipP/Kip family) and p15 and p19 (INK4 family). Proteins were extracted for western blot analysis of p57 and p15. For RNA interference, primary cultured human limbal epithelial cells were transfected with annealed double-stranded siRNA (67 nM) specific for p57, p15, or siRNA-Fluorescein (siRNA-F; as a negative control) followed by treatment with TGF-beta1 or TGF-beta2 at 1 ng/ml. P57 and p15 were quantitatively detected by real-time PCR and western blot; and immunolocalized by immunofluorescent staining. The effects of TGF-beta1 or TGF-beta2 on cell proliferation were evaluated by BrdU incorporation and MTT assay. RESULTS: TGF-beta1 or TGF-beta2 significantly inhibited primary cultured human limbal epithelial cell proliferation measured by BrdU incorporation and MTT assay. TGF-beta1 or TGF-beta2 upregulated the expression of p57 and p15 mRNA and protein, but did not effect the expression of p19, p21, or p27. The siRNA transfection efficiency of these cells was 75% and no cellular toxicity was observed by 24 h. The TGF-beta1 or TGF-beta2 stimulated expression of p57 and p15 mRNA were markedly blocked by siRNA-p57 or siRNA-p15, respectively, but not by siRNA-F. The TGF-beta1 or TGF-beta2 suppression of epithelial proliferation measured by BrdU incorporation and MTT generation was increased to near normal levels by siRNA-p57 or siRNA-p15. Western blot and immunofluorescent staining showed that levels of p57 and p15 proteins were equally reduced in the cytoplasm and nucleus. CONCLUSIONS: These findings demonstrate that TGF-beta1 and/or TGF-beta2 inhibit proliferation of primary cultured human limbal epithelial cells and that p57 and p15 play roles in this process.

Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.

SCF complexes are the largest family of E3 ubiquitin-protein ligases and mediate the ubiquitination of diverse regulatory and signalling proteins. Here we present the crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex, which shows that Cul1 is an elongated protein that consists of a long stalk and a globular domain. The globular domain binds the RING finger protein Rbx1 through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the ubiquitin-conjugating enzyme. The long stalk, which consists of three repeats of a novel five-helix motif, binds the Skp1-F boxSkp2 protein substrate-recognition complex at its tip. Cul1 serves as a rigid scaffold that organizes the Skp1-F boxSkp2 and Rbx1 subunits, holding them over 100 A apart. The structure suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold.