ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum.

Intracellular Mg2+ (iMg2+) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major iMg2+ compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases. However, ERMA uniquely combines a P-type ATPase domain and a GMN motif for ERMg2+ uptake. Experiments reveal that a tyrosine residue is crucial for Mg2+ binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg2+ ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca2+ cycling in mouse Erma+/- cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of ERMg2+ uptake in eukaryotes.

Changes in receipt of adjuvant brachytherapy for endometrial cancer patients before and after affordable care act: The impact of Medicaid expansion.

Purpose: For patients with high-intermediate risk (HIR) endometrial cancer, adjuvant radiation (RT) reduces the risk of recurrence, but many patients do not receive RT. Under the Affordable Care Act (ACA), most states expanded Medicaid coverage. Our hypothesis was patients would be more likely to receive indicated adjuvant RT in states that expanded Medicaid compared with patients in states that did not expand Medicaid. Material and methods: National Cancer Database (NCDB) was used to identify patients aged 40-64 years with HIR endometrial adenocarcinoma, stage IA and grade 3 or stage IB and grade 1 or 2, diagnosed from 2010-2018. We conducted a difference-in-differences (DID) cross-sectional retrospective analysis comparing receipt of adjuvant RT among patients residing in Medicaid expansion and non-expansion states before and after ACA implementation (January 2014). Results: Expansion states had higher rates of adjuvant RT prior to January 2014 compared with non-expansion states (49.21% vs. 36.46%), and the proportion of patients who received adjuvant RT increased over the study period across both Medicaid expansion and non-expansion states. After Medicaid expansion, the non-expansion states had a larger absolute increase in adjuvant radiation resulting in a non-significant change in the difference in adjuvant radiation rates compared with baseline (crude increase: 9.63% vs. 7.45%, adjusted DID: -2.68 [95% CI: -7.12-1.75], p = 0.236). Conclusions: Medicaid expansion is likely not the most significant factor affecting access or receipt of adjuvant RT for HIR endometrial cancer patients. Further study could help inform policy and efforts to ensure all patients have access to guideline-recommended RT.

Patient characteristics and clinical factors affecting lumpectomy cavity volume: implications for partial breast irradiation.

Introduction: Partial breast irradiation (PBI) has increased in utilization, with the postoperative lumpectomy cavity and clips used to guide target volumes. The ideal timing to perform computed tomography (CT)-based treatment planning for this technique is unclear. Prior studies have examined change in volume over time from surgery but not the effect of patient characteristics on lumpectomy cavity volume. We sought to investigate patient and clinical factors that may contribute to larger postsurgical lumpectomy cavities and therefore predict for larger PBI volumes. Methods: A total of 351 consecutive women with invasive or in situ breast cancer underwent planning CT after breast-conserving surgery at a single institution during 2019 and 2020. Lumpectomy cavities were contoured, and volume was retrospectively computed using the treatment planning system. Univariate and multivariate analyses were performed to evaluate the associations between lumpectomy cavity volume and patient and clinical factors. Results: Median age was 61.0 years (range, 30-91), 23.9% of patients were Black people, 52.1% had hypertension, the median body mass index (BMI) was 30.4 kg/m², 11.4% received neoadjuvant chemotherapy, 32.5% were treated prone, mean interval from surgery to CT simulation was 54.1 days ± 45.9, and mean lumpectomy cavity volume was 42.2 cm3 ± 52.0. Longer interval from surgery was significantly associated with smaller lumpectomy cavity volume on univariate analysis, p = 0.048. Race, hypertension, BMI, the receipt of neoadjuvant chemotherapy, and prone position remained significant on multivariate analysis (p < 0.05 for all). Prone position vs. supine, higher BMI, the receipt of neoadjuvant chemotherapy, the presence of hypertension, and race (Black people vs. White people) were associated with larger mean lumpectomy cavity volume. Discussion: These data may be used to select patients for which longer time to simulation may result in smaller lumpectomy cavity volumes and therefore smaller PBI target volumes. Racial disparity in cavity size is not explained by known confounders and may reflect unmeasured systemic determinants of health. Larger datasets and prospective evaluation would be ideal to confirm these hypotheses.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress.

The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-µM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, ß-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2-/- mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.

Differences in personal care product use by race/ethnicity among women in California: implications for chemical exposures.

BACKGROUND: Personal care products may contain many chemicals, some of which are suspected endocrine disrupters. This is an important source of chemical exposure for women, but little is known about how chemical exposure differs among different races/ethnicities. OBJECTIVE: This study examines differences in personal care product use among Black, Latina, Vietnamese, Mixed Race, and White women in California. METHODS: We used a community-based participatory process to create and administer a personal care product usage survey to 321 Black, Latina, Vietnamese, Mixed Race, and White women. We used multivariate regression models with pairwise comparisons to examine the frequency of product use by race/ethnicity. RESULTS: We found distinct trends of personal care product use by race/ethnicity: Latina women typically used makeup most frequently; Black women used certain hair products or styles most frequently; and Vietnamese women were most likely to use facial cleansing products compared to other races/ethnicities. Latina and Vietnamese women were less likely to try to avoid certain ingredients in their products. SIGNIFICANCE: These findings can help estimate disparities in chemical exposure from personal care product use and complement future research on health inequities due to chemical exposures in the larger environmental and social context.

Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review.

Melanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review (SLR) including a total of 39 articles to evaluate the proportion of melanoma patients who are diagnosed with, or develop, brain metastases, and summarize the risk factors of MBM. The average proportion of MBM was calculated and weighted by the sample size of each study. Meta-analyses were conducted for the selected risk factors using a random-effects model. The proportion of MBM at diagnosis was 33% (975 with MBM out of 2948 patients) among patients with cutaneous melanoma (excluding acral) and 23% (651/2875) among patients with cutaneous mixed with other types of melanoma. The proportion at diagnosis was lower among populations with mucosal (9/96, 9%) or uveal (4/184, 2%) melanoma and among populations outside the United States and Europe. Meta-analysis demonstrated that male vs. female gender and left-sided tumors vs. right-sided were significantly associated with increased risk of melanoma brain metastases. These data may help clinicians to assess an individual patient's risk of developing melanoma brain metastases.

Systematic literature review and meta-analysis of clinical outcomes and prognostic factors for melanoma brain metastases.

Background: More than 60% of all stage IV melanoma patients develop brain metastases, while melanoma brain metastases (MBM) is historically difficult to treat with poor prognosis. Objectives: To summarize clinical outcomes and prognostic factors in MBM patients. Methods: A systematic review with meta-analysis was conducted, and a literature search for relevant studies was performed on November 1, 2020. Weighted average of median overall survival (OS) was calculated by treatments. The random-effects model in conducting meta-analyses was applied. Results: A total of 41 observational studies and 12 clinical trials with our clinical outcomes of interest, and 31 observational studies addressing prognostic factors were selected. The most common treatments for MBM were immunotherapy (IO), MAP kinase inhibitor (MAPKi), stereotactic radiosurgery (SRS), SRS+MAPKi, and SRS+IO, with median OS from treatment start of 7.2, 8.6, 7.3, 7.3, and 14.1 months, respectively. Improved OS was observed for IO and SRS with the addition of IO and/or MAPKi, compared to no IO and SRS alone, respectively. Several prognostic factors were found to be significantly associated with OS in MBM. Conclusion: This study summarizes pertinent information regarding clinical outcomes and the association between patient characteristics and MBM prognosis.

Chemicals of concern in personal care products used by women of color in three communities of California.

BACKGROUND: Personal care products (PCPs) may contain chemicals associated with adverse health effects. Prior studies found differences in product use by race/ethnicity and suggest some women are disproportionately exposed to chemicals of concern (CoCs). OBJECTIVE: We quantified chemicals linked to cancer, reproductive or developmental harm, or endocrine disruption in PCPs used by women of color. METHODS: We documented PCPs in stores frequented by Black, Latina, and Vietnamese women in their communities in California and CoCs on ingredient labels of 546 unique hair, skin, makeup, nail, deodorant/perfume, and intimate care products. Community partners chose 31 products for a combined targeted and suspect screen (National Institute of Standards and Technology mass spectral library search) two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOFMS) analysis to detect chemicals not on ingredient labels. RESULTS: We found that 65% of labels included CoCs, and 74% of labels had undisclosed ingredients listed as "fragrance." The most prevalent chemicals were parabens, cyclosiloxanes, and formaldehyde releasers. GCxGC-TOFMS found additional CoCs, including fragrances, solvents, preservatives, ultraviolet filters, and contaminants. SIGNIFICANCE: These findings contribute to awareness of potentially hazardous chemicals in PCPs, can help estimate disparities in chemical exposure, and complement research on health inequities due to chemical exposures from various contributors. IMPACT STATEMENT: This study is one of the first detailed assessments of chemicals of concern found in various types of PCPs used by several racial/ethnic groups. We found that over half of the 546 products selected by community partners as marketed to and/or used by them contained ingredients linked to cancer, reproductive or developmental harm, or endocrine disruption. Laboratory analysis identified additional chemicals in a subset of products, including unlabeled fragrance chemicals and contaminants. Elucidating exposures to chemicals in PCPs is important for risk assessment and health inequity research.

Adding a Clinical Hemophilia Pharmacist to the Hemophilia Comprehensive Care Model Improves Health Care-Related Outcomes and Drug-Related Costs in an Integrated Health Care System.

IntroductionThe National Hemophilia Foundation has advocated for a comprehensive care model in caring for patients with hemophilia. Currently pharmacists are not included as part of the team, and the impact of specific team members on patient outcomes is unknown. The authors designed an intervention to add a clinical pharmacist to this care model. The authors evaluated the impact of this intervention on bleeding outcomes, medication access and adherence, and cost within an integrated health care system. MethodsThe authors performed a multicenter, retrospective analysis of all hemophilia A and B patients enrolled in the hemophilia pharmacy service between March 2017 and February 2019. The authors analyzed data prior to and after this quality improvement project, encompassing the period between March 2016 and February 2020. Primary outcomes included an evaluation of the annualized bleed rates, emergency department visits, and hospitalizations. ResultsIn the cohort of patients with hemophilia A and B, the overall bleed rate was reduced from 40 per 100 patient-years to 37.6 per 100 patient-years. Similarly, emergency department visits were reduced from 22.7 to 18.3 per 100 patient-years, and hospitalizations reduced from 6.4 to 3.0 per 100 patient-years (p values >.05). This was augmented by the use of a unique factor recycling program that saved $900,000 in medication costs over a 12-month period. DiscussionThis study shows that the addition of a clinical pharmacist to the core hemophilia team leads to positive trends toward improved bleeding outcomes for patients, improved medication access and adherence, and substantial cost savings to the health system.

Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma.

Background: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.

Local and distant brain control in melanoma and NSCLC brain metastases with concurrent radiosurgery and immune checkpoint inhibition.

INTRODUCTION: The treatment of brain metastases with stereotactic radiosurgery (SRS) in combination with immune checkpoint inhibitors (ICI) has become more common in recent years, but there is a lack of prospective data on cancer control outcomes when these therapies are administered concurrently. METHODS: Data were retrospectively reviewed for patients with non-small cell lung cancer (NSCLC) and melanoma brain metastases treated with SRS at a single institution from May 2008 to January 2017. A parametric proportional hazard model is used to detect the effect of concurrent ICI within 30, 60, or 90 days of ICI administration on local control and distant in-brain control. Other patient and lesion characteristics are treated as covariates and adjusted in the regression. A frailty term is added in the baseline hazard to capture the within-patient correlation. RESULTS: We identified 144 patients with 477 total lesions, including 95 NSCLC patients (66.0%), and 49 (34.0%) melanoma patients. On multivariate analysis, concurrent SRS and ICI (SRS within 30 days of ICI administration) was not associated with local control but was associated with distant brain control. When controlling for prior treatment to lesion, number of lesions, and presence of extracranial metastases, patients receiving this combination had a statistically significant decrease in distant brain failure compared to patients that received non-concurrent ICI or no ICI (HR 0.15; 95% CI 0.05-0.47, p = 0.0011). CONCLUSION: Concurrent ICI can enhance the efficacy of SRS. Prospective studies would allow for stronger evidence to support the impact of concurrent SRS and ICI on disease outcomes.

Literature review of management of brain metastases from germ cell tumors.

OBJECTIVE: In this review article, we discuss the role of chemotherapy, surgery, and radiation therapy in the treatment of brain metastases from germ cell tumors (GCT). BACKGROUND: GCT rarely metastasize to the brain and there is limited data to guide management. Most instances of brain metastases occur in patients with non-seminomatous germ cell tumors (NSGCT). METHODS: We searched PubMed using the terms 'central nervous system (CNS) metastases' or 'brain metastases' and 'germ cell' from 2011 through August 2021. Review articles and prospective trials related to the treatment of brain metastases in GCT were included in addition to articles obtained by hand search of the references and clinical practice guidelines. CONCLUSIONS: We highlight the importance of using chemotherapy as first-line therapy in most situations. We discuss the very minimal data regarding surgery and its primary role when there is significant mass effect or brain shift. We also compare whole brain radiation therapy (WBRT) with the use of radiosurgery. We then provide overall recommendations based on the reviewed data and our experience as a referral center for GCT.

Minimally invasive myomectomy: practice trends and differences between Black and non-Black women within a large integrated healthcare system.

BACKGROUND: Although multiple professional organizations encourage minimally invasive surgical approaches whenever feasible, nationally, fewer than half of myomectomies are performed via minimally invasive routes. Black women are less likely than their non-Black counterparts to have minimally invasive surgery. OBJECTIVE: This study aimed to assess the trends in surgical approach among women who underwent minimally invasive myomectomies for uterine leiomyomas within a large integrated healthcare system as initiatives were implemented to encourage minimally invasive surgery, particularly evaluating differences in the proportion of minimally invasive surgery performed in Black vs non-Black women. STUDY DESIGN: We conducted a retrospective cohort study of women, aged ≥18 years, who underwent a myomectomy for a uterine leiomyoma within Kaiser Permanente Northern California between 2009 and 2019. Generalized estimating equations and Cochran-Armitage testing were used to assess myomectomy incidence and linear trend in the proportions of myomectomy by surgical route-abdominal myomectomy and minimally invasive myomectomy. Multivariable logistic regression analyses were used to assess the associations between surgical route and (1) race and ethnicity and (2) complications, controlling for patient demographic, clinical, and surgical characteristics. RESULTS: A total of 4033 adult women underwent a myomectomy during the study period. Myomectomy incidence doubled from 0.12 (95% confidence interval, 0.12-0.13) per 1000 women in 2009 to 0.25 (95% confidence interval, 0.24-0.25) per 1000 women in 2019 (P<.001). During the 11-year study period, the proportion of minimally invasive myomectomy increased from 6.0% to 89.5% (a 15-fold increase). The proportion of minimally invasive myomectomy in Black women remained lower than in non-Black women (54.5% vs 64.7%; P<.001). Black women undergoing myomectomy were younger (36.4±5.6 vs 37.4±5.8 years; P<.001), had a higher mean fibroid weight (436.0±505.0 vs 324.7±346.1 g; P<.001), and had a higher mean body mass index (30.8±7.3 vs 26.6±5.9 kg/m2; P<.001) than their non-Black counterparts. In addition to patient race, surgery performed between 2016 and 2019 compared with surgery performed between 2009 and 2012 and higher surgeon volume compared with low surgeon volume were associated with an increased proportion of minimally invasive myomectomy (adjusted relative risks, 12.58 [95% confidence interval, 9.96-15.90] and 6.63 [95% confidence interval, 5.35-8.21], respectively). Black race and fibroid weight of >500 g each independently conferred lower rates of minimally invasive myomectomy. In addition, there was an interaction between race and fibroid weight such that Black women with a fibroid weight of ≤500 g or >500 g were both less likely to have minimally invasive myomectomy than non-Black women with a fibroid weight of ≤500 g (adjusted relative risks, 0.74 [95% confidence interval, 0.58-0.95] and 0.26 [95% confidence interval, 0.18-0.36], respectively). Operative, perioperative, and medical complications were low during the 11-year study period. In regression analyses, after controlling for race, age, fibroid weight, parity, low-income residence, body mass index, surgeon volume, and year of myomectomy, the risk of complications was not markedly different comparing abdominal myomectomy with minimally invasive myomectomy. Similar results were found comparing laparoscopic minimally invasive myomectomy with robotic-assisted minimally invasive myomectomy except for women who underwent laparoscopic minimally invasive myomectomy had a lower risk of experiencing any medical complications than those who underwent robotic-assisted minimally invasive myomectomy (adjusted relative risk, 0.27; 95% confidence interval, 0.09-0.83; P=.02). CONCLUSION: Within an integrated healthcare delivery system, although initiatives to encourage minimally invasive surgery were associated with a marked increase in the proportion of minimally invasive myomectomy, Black women continued to be less likely to undergo minimally invasive myomectomy than their non-Black counterparts. Race and fibroid weight alone did not explain the disparities in minimally invasive myomectomy.

Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients.

Major depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of "chronic stress" using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.

Electronic Family History Screening Tool for Detection of Inherited Cancer Risk: A Prospective Pilot Study.

Family history screening to identify individuals at increased risk for hereditary cancers could be a powerful strategy to prevent cancer but is used inconsistently in primary care. The objective was to improve identification of women with at-risk family histories using a point-of-care family history screening tool administered on an electronic tablet device during well-woman appointments. A total of 288 women were invited to participate and 136 women (47.2%) completed the electronic family history screening tool. Significantly more women were identified and referred to the genetics department with the electronic family history screening tool than the standard-of-care paper questionnaire (11.8% versus 0.8%, P < 0.001). There were no statistically significant differences in the proportion of referred women who were evaluated by the genetic counselors, and no pathogenic variants were found with either family history screening method. Implementing innovative self-reporting tools may improve inherited cancer risk detection.

Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury.

BACKGROUND: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcusaureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. METHODS: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O'Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. CONCLUSION: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.

Sexual function, menopausal symptoms, depression and cancer worry in women with BRCA mutations.

OBJECTIVES: Assess sexual function, menopausal symptoms, and depression in women with BRCA mutations associated with oophorectomy and menopause status. METHODS: Women age 40 and older with BRCA mutations completed a questionnaire with validated measures of sexual activity, menopausal symptoms, depression, and cancer worry. These measures were compared between those with intact ovaries and those who had undergone pre- or post-menopausal risk-reducing salpingo-oophorectomy (RRSO). RESULTS: Of the 244 women, 21 had intact ovaries and 223 had undergone RRSO. Women with intact ovaries had less menopausal symptoms (Menopausal Symptom Checklist (MSCL) score 14 versus 23, P = .01) but more cancer worry than women who had undergone RRSO (median Cancer Worry Scale (CWS) score 5 versus 4, P < .0001) with no significant difference in sexual activity or function. Compared with women with postmenopausal RRSO, women with premenopausal RRSO were more likely to be sexually active (56.3% versus 42.0%, P =.04) but had similar sexual functioning, including frequency, pleasure and discomfort. Women with premenopausal RRSO were also more likely to report menopausal symptoms (MSCL score 26 versus 19, P = .04) and depression (PHQ-8 score 4 versus 2, P < .001). Factors associated with sexual activity included younger age, lower BMI, living with a partner, and lower depression scores. Higher current depression score was associated with history of depression and more menopausal symptoms. CONCLUSIONS: Risk-reducing surgery decreases cancer risk and worry in women with BRCA mutations. Among women undergoing oophorectomy, factors such as age and history of depression were related to reduced sexual activity and increased depression, but menopausal status was not related.

Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons.

Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.