Citations

Abstract Objective: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

BACKGROUND The midface is an area of high demand for minimally invasive cosmetic procedures, that is, soft-tissue filler injections. OBJECTIVE To investigate the functional anatomy behind the facial overfilled syndrome observed after soft-tissue filler injections. MATERIALS AND METHODS The clinical part of the study enrolled 25 volunteers (12 men and 13 women, Caucasians); the anatomical part included 72 fresh frozen cephalic specimens obtained from 32 male and 40 female body donors. 3D surface scanning procedures were applied to calculate the maximal anterior projection of the midface. RESULTS Upon smiling, the point of maximal anterior projection shifted cranially in men by 12.43 ± 8.8 mm (difference between resting and smiling; p < .001) and by 8.75 ± 4.1 mm in women (p < .001). Cadaveric dissections identified a septum originated from the underside of the zygomaticus major muscle forming a transversely running boundary between the buccal space and the deep midfacial fat compartments. CONCLUSION Facial overfilled syndrome can potentially be explained by the presence of the transverse facial septum. Dynamic filling—injecting small amounts of filler and asking the patient to smile repeatedly during the procedure—seems to be a viable way to avoid this adverse event during soft-tissue filler injection.

Abstract Background The arrangement of the facial soft tissue layers is different with respect to the line of ligaments: medially oblique and laterally in parallel. Aims This split‐face study was designed to investigate the effects on midfacial volumization if the same medial vs lateral injection points are targeted in various sequences. Methods Twelve patients (3 males, 9 females; 46.67 years ± 4.5) were included in this interventional study. On the right side of the face, lateral injection points were performed first, whereas on the left side, medial injection points were executed first. The infraorbital hollowness score, the upper cheek fullness score, the global aesthetic improvement scale, and the injected volume were assessed. Results No side differences were observed after the intervention with P = 1.00 for all scores. When the lateral injection points were performed first, the volume injected into the medially located injection points (0.46 ± 0.26 cc vs 0.73 ± 0.31 cc [ P = .037]), into the lateral injection points (0.79 ± 0.40 cc vs 1.15 ± 0.28 cc [ P = .017]), and overall (1.26 ± 0.64 cc vs 1.88 ± 0.57 cc [ P = .02]) was significantly reduced. Conclusion The results of the present study emphasize the importance of respecting the layered arrangement of the facial soft tissues when performing minimally invasive soft tissue filler injections. Targeting injection points lateral to the line of ligaments first reduces the volume needed to symmetrically and aesthetically appealing manner and volumizes the infraorbital and upper cheek regions.

AbstractObjectiveNeuromodulator injections of the forehead are often performed using standardized protocols. This study was designed to identify the individual skin motion pattern of the forehead and to relate this pattern to the underlying frontalis muscle morphology to offer guidance for neuromodulator placement.Material and MethodsThirty‐seven healthy volunteers (29 Caucasians, six African Americans, two Asians) with a mean age of 39.84 ± 14.4 years [range: 22‐73] were enrolled. 3D images of the forehead were analyzed using a Vectra H1 camera system computing skin displacement vectors between the noncontracted and the maximally contracted forehead of the volunteers. Relationships between the shape of the horizontal forehead lines (straight vs wavy) and the forehead motion pattern were calculated.ResultsIndependent of age or gender, a greater forehead motion angle was associated with the presence of wavy forehead lines 21.34°± 5.9 with P < 0.001, whereas straight forehead lines were associated with a smaller forehead motion angle 6.68°± 2.9 P < 0.001. Females had more frequently straight horizontal forehead lines versus males: 68.4% vs 44.4% (P = 0.037). Young volunteers (<39.8 years) did not differ in their mean forehead motion angle when compared to older volunteers (>39.8 years): 13.70°± 9.0 vs 12.39°± 8.0 with P = 0.530.ConclusionInjections of neuromodulators in the forehead can be individualized by respecting the shape of the horizontal forehead lines. Wavy lines require injection points that are located more laterally, whereas straight lines require more centrally located injection points.

Background: The deep intramuscular approach during buttock augmentation with fat grafting has been associated with a significantly increased risk for pulmonary fat embolism. This study was designed to provide guidance for injection into the subcutaneous fat. Methods: The authors investigated 150 Caucasian individuals with an equal distribution of men and women (n = 75 each) and a balanced distribution of age (n = 30 per decade: 20 to 29, 30 to 39, 40 to 49, 50 to 59, and 60 to 69 years) and body mass index (n = 50 per group: ≤24.9 kg/m2, between 25.0 and 29.9kg/m2, and ≥30 kg/m2). Ultrasound-based measurements were conducted of the thickness of the total, superficial, and deep gluteal fatty layers. Results: An increase in body mass index of 1.0 kg/m2 corresponded to an increase of 3 mm of the total gluteal subcutaneous fat of men and a 4-mm increase of the total gluteal subcutaneous fat in women. With increasing age, the thickness of the deep fatty layer increased, whereas with increasing body mass index the thickness of the superficial layer primarily increased. Formulas were generated to estimate the total thickness of the gluteal subcutaneous fatty layer for men [total thickness (in millimeters) = −33.56 + (age × 0.078) + (body mass index × 3.042)] and women [total thickness (in millimeters) = −56.997 + (age × 0.1) + (body mass index × 3.86)]. Conclusions: Knowing the total thickness of the gluteal subcutaneous fat (i.e., the safe space) allows surgeons to estimate their operating range for cannula motion even if no ultrasound machine is available during buttock augmentation with fat grafting. This can increase safety, potentially reducing the number of adverse events.

Abstract Background The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. Methods We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy‐confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. Results Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. Conclusions The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P &lt; 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Abstract Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439

IntroductionDepressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment.MethodsThe pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE), randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery‐Asberg Depression Rating Scale (MADRS). Growth mixture modeling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors.ResultsFour distinct trajectories of depressive symptoms were identified. The responding class (60.3%) with a rapid reduction and subsequent low level; the partial‐responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the fluctuating class (11.6%) with a fluctuation in depressive symptoms; and the non‐responding class (9.7%) with sustained moderate‐severe depressive symptoms. Bipolar type I predicted membership of the non‐responding class and randomization to quetiapine predicted membership of either the responding or the non‐responding class.ConclusionApproximately 30% experienced a partial or fluctuating course, and almost 10% had a chronic course with moderate‐severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses.