Host response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1.

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.

Liquid Thyroxine Improves Outcomes in Hypothyroid Patients With Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome.

OBJECTIVE: Malabsorption of levothyroxine (LT4) is often seen in patients with hypothyroidism and gastrointestinal (GI) conditions. Our study was designed to establish the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with hypothyroidism and irritable bowel syndrome (IBS), and to demonstrate that liquid LT4 is more consistently absorbed vs tablet, leading to improvement in thyroid and GI symptoms. METHODS: This was a single-center, open label, prospective cohort study of liquid LT4 in 75 adult patients with hypothyroidism and IBS. Patients were transitioned from LT4 tablets to solution at equivalent dosing. Patients returned at 6 and 12 weeks for repeat thyroid levels and completion of validated questionnaires. A standard 2-hour SIBO breath test was administered at Week 6. Patients recorded daily stool appearance and frequency. RESULTS: Prevalence of SIBO was 65.3%. Liquid LT4 normalized thyroid stimulating hormone (TSH) in a higher percentage of patients vs tablet (77.55% vs 57.14%); significantly decreased TSH in subjects with SIBO; improved hypothyroid symptoms, IBS symptoms, stool appearance in all groups, and significantly altered bowel frequency among those with SIBO. CONCLUSION: Small intestinal bacterial overgrowth (SIBO) is common in patients with hypothyroidism and IBS. Among SIBO patients, LT4 tablets were inefficiently absorbed, leading to suboptimal thyroid control; however, transitioning from LT4 tablets to solution normalized TSH and improved hypothyroid symptoms. Liquid LT4 also significantly improved GI symptoms in all patients with hypothyroidism and IBS, regardless of SIBO status. Additionally, 1 in 5 patients had complete resolution of IBS symptoms after switching from LT4 tablets to solution, independent of changes in TSH.

Steroid Drugs Inhibit Bacterial Respiratory Oxidases and Are Lethal Toward Methicillin-Resistant Staphylococcus aureus.

BACKGROUND: Cytochrome bd complexes are respiratory oxidases found exclusively in prokaryotes that are important during infection for numerous bacterial pathogens. METHODS: In silico docking was employed to screen approved drugs for their ability to bind to the quinol site of Escherichia coli cytochrome bd-I. Respiratory inhibition was assessed with oxygen electrodes using membranes isolated from E. coli and methicillin-resistant Staphylococcus aureus strains expressing single respiratory oxidases (ie, cytochromes bd, bo', or aa3). Growth/viability assays were used to measure bacteriostatic and bactericidal effects. RESULTS: The steroid drugs ethinylestradiol and quinestrol inhibited E. coli bd-I activity with median inhibitory concentration (IC50) values of 47 ± 28.9 µg/mL (158 ± 97.2 µM) and 0.2 ± 0.04 µg/mL (0.5 ± 0.1 µM), respectively. Quinestrol inhibited growth of an E. coli "bd-I only" strain with an IC50 of 0.06 ± 0.02 µg/mL (0.2 ± 0.07 µM). Growth of an S. aureus "bd only" strain was inhibited by quinestrol with an IC50 of 2.2 ± 0.43 µg/mL (6.0 ± 1.2 µM). Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli. CONCLUSIONS: Quinestrol inhibits cytochrome bd in E. coli and S. aureus membranes and inhibits the growth of both species, yet is only bactericidal toward S. aureus.

Single-Cell Transcription Mapping of Murine and Human Mammary Organoids Responses to Female Hormones.

During female adolescence and pregnancy, rising levels of hormones result in a cyclic source of signals that control the development of mammary tissue. While such alterations are well understood from a whole-gland perspective, the alterations that such hormones bring to organoid cultures derived from mammary glands have yet to be fully mapped. This is of special importance given that organoids are considered suitable systems to understand cross species breast development. Here we utilized single-cell transcriptional profiling to delineate responses of murine and human normal breast organoid systems to female hormones across evolutionary distinct species. Collectively, our study represents a molecular atlas of epithelial dynamics in response to estrogen and pregnancy hormones.

Single-cell transcription mapping of murine and human mammary organoids responses to female hormones.

During female adolescence and pregnancy, rising levels of hormones result in a cyclic source of signals that control the development of mammary tissue. While such alterations are well understood from a whole-gland perspective, the alterations that such hormones bring to organoid cultures derived from mammary glands have yet to be fully mapped. This is of special importance given that organoids are considered suitable systems to understand cross species breast development. Here we utilized single-cell transcriptional profiling to delineate responses of murine and human normal breast organoid systems to female hormones across evolutionary distinct species. Collectively, our study represents a molecular atlas of epithelial dynamics in response to estrogen and pregnancy hormones.

Controlling the structure of supramolecular fibre formation for benzothiazole based hydrogels with antimicrobial activity against methicillin resistant Staphylococcus aureus.

Antimicrobial resistance is one of the greatest threats to human health. Gram-positive methicillin resistant Staphylococcus aureus (MRSA), in both its planktonic and biofilm form, is of particular concern. Herein we identify the hydrogelation properties for a series of intrinsically fluorescent, structurally related supramolecular self-associating amphiphiles and determine their efficacy against both planktonic and biofilm forms of MRSA. To further explore the potential translation of this hydrogel technology for real-world applications, the toxicity of the amphiphiles was determined against the eukaryotic multicellular model organism, Caenorhabditis elegans. Due to the intrinsic fluorescent nature of these supramolecular amphiphiles, material characterisation of their molecular self-associating properties included; comparative optical density plate reader assays, rheometry and widefield fluorescence microscopy. This enabled determination of amphiphile structure and hydrogel sol dependence on resultant fibre formation.

Immature natural killer cells promote progression of triple-negative breast cancer.

Natural killer (NK) cells are cytotoxic lymphocytes that accumulate within the tumor microenvironment and are generally considered to be antitumorigenic. Using single-cell RNA sequencing and functional analysis of multiple triple-negative breast cancer (TNBC) and basal tumor samples, we observed a unique subcluster of Socs3highCD11b-CD27- immature NK cells that were present only in TNBC samples. These tumor-infiltrating NK cells expressed a reduced cytotoxic granzyme signature and, in mice, were responsible for activating cancer stem cells through Wnt signaling. NK cell-mediated activation of these cancer stem cells subsequently enhanced tumor progression in mice, whereas depletion of NK cells or Wnt ligand secretion from NK cells by LGK-974 decreased tumor progression. In addition, NK cell depletion or inhibition of their function improved anti-programmed cell death ligand 1 (PD-L1) antibody or chemotherapy response in mice with TNBC. Furthermore, tumor samples from patients with TNBC and non-TNBC revealed that increased numbers of CD56bright NK cells were present in TNBC tumors and were correlated to poor overall survival in patients with TNBC. Together, our findings identify a population of protumorigenic NK cells that may be exploited for both diagnostic and therapeutic strategies to improve outcomes for patients with TNBC.

Developing a Culturally Competent Neuropsychological Assessment Battery for Farsi-speaking Patients with Suspected Dementia.

OBJECTIVE: To assemble a comprehensive neuropsychological battery appropriate for differential diagnosis of dementia in Farsi-speaking Iranian adults in the United States. METHOD: Systematic searches of PubMed, PsychInfo, and Google Scholar databases were conducted to obtain test instruments relevant to Farsi speakers in consultation with a Farsi-speaking cultural broker. RESULTS: A proposed battery assessing the domains of attention, executive function, verbal and visual episodic memory, language, visuospatial/visuoconstruction abilities, and mood/anxiety was assembled that includes core measures developed, either specifically for a Farsi-speaking Iranian population or validated/normed with a Farsi-speaking Iranian sample. Though not ideal, additional measures were selected that can be administered using translated instructions with English normative data to supplement the limited tests available for use in this population. The rationale for test selection and caveats for their clinical use are presented along with a case study. CONCLUSIONS: The number of neuropsychological measures available in Farsi and/or with normative data for Farsi speakers is extremely limited. Cognitive tests either developed for or validated with a bilingual Farsi-English sample also represent a significant gap in the literature. Appropriate measures for these populations are urgently needed to provide a culturally competent assessment of a growing older adult segment of an underserved community.

Re-Engaging Individuals & Societies for Structural Evolution: A Brain Health Equity Neuropsychology Research Framework.

OBJECTIVE: A brain health equity neuropsychology research framework (NRF) is crucial to the anti-racist movement in cognitive assessments. Universalist interpretation of neuropsychological tools contributes to systemic disparities, and there is a need for a clear conceptual framework for disentangling the direct and indirect impact of social determinants of health (SDH) on brain-behavior relationships and neuropsychological performance. The aim of this paper is to present a NRF anchored in the principles of brain health and health equity that is inclusive, and can be implemented across racially and ethnically diverse communities. METHODS: The Re-engaging Individuals and societies for Structural Evolution (RISE) NRF aims to address this via a two-pronged approach: 1. Focusing on community engagement and recruitment and retention of individuals and societies typically not equitably represented in brain health studies, and 2. Integrating the conceptual structure of individual, community, and SDH, while considering the broader historical and current structures that differentially shape these. RESULTS: The proposed RISE NRF is dynamic and multidirectional. It identifies barriers and proposes strategies to engage communities and diversify recruitment. It identifies evidence-based guidance on non-cognitive determinants of health to include, consider or explore in brain health research. CONCLUSION: The RISE NRF can guide the development of culturally and linguistically responsive methodologies and assist with clearly conceptualized and contextualized interpretation of neuropsychological tools to foment a transformative science that benefits the brain health of marginalized communities.

The Measurement of Acculturation in Neuropsychological Evaluations of Hispanic/Latino Individuals across the Lifespan: A Scoping Review of the Literature.

OBJECTIVE: Acculturation has been linked to health outcomes in Hispanics/Latinos (H/Ls). However, there is equivocal evidence of a relationship between acculturation and neuropsychological outcomes. Various factors limit the ability to subject the evidence to systematic/meta-analytic review. We sought to examine the current state of the literature in the context of H/Ls and neuropsychology and describe the various limitations of measuring acculturation across the lifespan. METHOD: Applying a scoping review approach, we identified unique stand-alone (e.g., questionnaires) measures of acculturation. We focused on psychometric (e.g., internal consistency) and other characteristics (e.g., language, structure/format) and description of the validation samples (e.g., cultural background/country of origin). RESULTS: A total of 40 unique acculturation measures were identified. Measures spanned various domains (e.g., language proficiency, food preference, music choice), and relied heavily on linguistic behavioral characteristics. Internal consistency varied from unacceptable to clinically acceptable ranges. Variable approaches to development and validation were reported. Validation samples varied from 22 to 2,048 respondents (median = 380), most of which represented a general adult population. Only eight measures were validated for use in pediatric populations; none were developed specifically for use with older adults. CONCLUSIONS: Published measures are outdated, evidence highly variable psychometric and methodological weaknesses, and lack a lifespan perspective. Several themes in the types of items considered elemental to the acculturative process are revealed and findings are summarized via an "ABC" framework, categorizing items as antecedents, behaviors, and consequent acculturative changes, that lends itself to clinical and research settings.

Characterization of Gene Expression Signatures for the Identification of Cellular Heterogeneity in the Developing Mammary Gland.

The developing mammary gland depends on several transcription-dependent networks to define cellular identities and differentiation trajectories. Recent technological advancements that allow for single-cell profiling of gene expression have provided an initial picture into the epithelial cellular heterogeneity across the diverse stages of gland maturation. Still, a deeper dive into expanded molecular signatures would improve our understanding of the diversity of mammary epithelial and non-epithelial cellular populations across different tissue developmental stages, mouse strains and mammalian species. Here, we combined differential mammary gland fractionation approaches and transcriptional profiles obtained from FACS-isolated mammary cells to improve our definitions of mammary-resident, cellular identities at the single-cell level. Our approach yielded a series of expression signatures that illustrate the heterogeneity of mammary epithelial cells, specifically those of the luminal fate, and uncovered transcriptional changes to their lineage-defined, cellular states that are induced during gland development. Our analysis also provided molecular signatures that identified non-epithelial mammary cells, including adipocytes, fibroblasts and rare immune cells. Lastly, we extended our study to elucidate expression signatures of human, breast-resident cells, a strategy that allowed for the cross-species comparison of mammary epithelial identities. Collectively, our approach improved the existing signatures of normal mammary epithelial cells, as well as elucidated the diversity of non-epithelial cells in murine and human breast tissue. Our study provides a useful resource for future studies that use single-cell molecular profiling strategies to understand normal and malignant breast development.

Executive function in individuals with clinically significant weight loss via behavioral intervention.

BACKGROUND: Executive function (EF) is associated with obesity development and self-management. Individuals who demonstrate or self-report poorer EF performance tend to have poorer short-term outcomes in obesity treatment. There may be distinct behavioral self-management strategies and EF domains related to initial weight loss as compared to weight loss maintenance. OBJECTIVE: To characterize EF in individuals who achieved clinically significant weight loss via behavioral intervention and examine potential differences in EF between those who maintained versus regained lost weight. METHODS: Participants who previously achieved ≥5% weight loss via lifestyle intervention were included (N = 44). "Maintainers" (n = 16) maintained this minimum level of weight loss for ≥1 year. "Regainers" (n = 28) regained some or all initially lost weight. Performance-based EF, intelligence quotient, health literacy, depression, anxiety, binge eating, demographics, and medical/weight history were assessed using a cross-sectional design. Descriptive statistics and age-, gender-, education-adjusted reference ranges were used to characterize EF. Analyses of covariance were conducted to examine EF differences between maintainers and regainers. RESULTS: The sample consisted primarily of females with obesity over age 50. Approximately half self-identified as African-American. Decision-making performance was better in maintainers than regainers (p = 0.003, partη2 = 0.19). There were no differences between maintainers and regainers in inhibitory control, verbal fluency, planning/organization, cognitive flexibility, or working memory (ps > 0.05, partη2s = 0.003-0.07). At least 75% of the sample demonstrated average-above average EF test performance, indicated by scaled scores ≥13 or t-scores > 60. CONCLUSIONS: Most individuals with obesity who achieved clinically significant weight loss via behavioral intervention had average to above average EF. Individuals who maintained (vs. regained) their lost weight performed better on tests of decision-making.

Patient and Provider Communication Regarding Exercise during Pregnancy in a Rural Setting.

Women in rural settings are at increased risk for adverse pregnancy outcomes. One potential way to improve pregnancy outcomes in rural settings is through physical activity promotion. However, given the disparities in prenatal care, women in rural areas may not receive information from their health care provider regarding physical activity during pregnancy. Therefore, the purpose of this study was to examine patient and provider communication in a rural setting (both patients' and providers' perspectives) regarding physical activity during pregnancy. A mixed methods study was performed among patients and providers in an obstetrical practice in a rural setting. During early pregnancy, patients were asked questions about their current physical activity levels and intentions for physical activity during their pregnancy. During late pregnancy, patients completed a survey regarding communication from their obstetric provider about exercise during pregnancy. Providers responsible for the patients' prenatal care were surveyed regarding communication with patients about physical activity. Seventy-one pregnant women and five providers participated. 58.2% of patients reported their provider did not discuss physical activity during pregnancy with them at all. Meanwhile, all providers (100%) reported discussing physical activity with all of their patients. Similarly, only 21.8% of patients reported their provider discussed the benefits of exercise during pregnancy, while 100% of providers reported telling their patients about the benefits of exercise during pregnancy. Our study suggests ineffective patient-provider communication regarding physical activity during pregnancy in a rural setting. Improved communication strategies could reduce disparities in health outcomes among pregnant women in rural settings.

Determining the optimal clinical cutoff on the CES-D for depression in a community corrections sample.

BACKGROUND: Screening instruments are urgently needed to rapidly and efficiently identify those in need of mental health treatment, particularly among underserved populations. Although designed initially for use in research, the CES-D has become a widely used clinical screening tool for the presence of major depression. Despite four decades and three major revisions to the DSM since the CES-D was first introduced, the cutoff score of 16 remains the marker by which individuals are assessed. The present study aims to examine an optimal cutoff score in a low-income, high-risk sample of ethnically diverse adults involved in some phase of the criminal justice system. The utility of the CES-D to detect depression in this population is unknown as these individuals are unlikely to be included in community studies of mental health. METHODS: A diverse sample of participants under criminal justice supervision (n = 500, ages 19-72) completed the CES-D at up to six time points and the MINI-D at two time-points over a year. RESULTS: Using receiver operating characteristic (ROC) curves, a cut point of 21 on the CES-D was determined to produce the best overall screening characteristics (sens = 0.82, spec = 0.76) using an efficiency calculation when compared with the gold standard MINI-D, though these results varied by race and gender. The optimal cutoff for women in this sample was determined to be 23 as opposed to 15 for men, and 20 for nonwhites versus 23 for whites. LIMITATIONS: This study is limited in its generalizability to low-income individuals without criminal justice involvement or those without substance use. CONCLUSION: Results suggest that the CES-D is a useful screening measure for depressive symptoms among high-risk individuals under criminal justice supervision. However, the current cutoff score of 16 is inadequate for optimizing true positives and false negatives. Possible gender and racial/ethnic bias may limit the utility of this instrument in this population. The current study contributes to the understanding of mental health needs in underserved populations.

Effect of elastic bandage wraps on leg edema in patients before and after liver transplant.

CONTEXT: Few studies have evaluated the benefits of short-term use of compression therapy to prevent or minimize edema and/or pain in the legs of acutely ill, hospitalized patients without venous leg ulcers. OBJECTIVE: To determine if the use of elastic bandage wraps of the leg in patients before and after liver transplant decreases edema formation and pain in the leg. Study Population-A convenience sample of inpatients before and after liver transplant. STUDY DESIGN: Pretest, posttest, randomized controlled trial with each participant serving as his or her own control. Intervention-Elastic bandage wrap applied to leg for 8 hours. OUTCOME MEASURES: Edema and pain in leg. RESULTS: In 13 patients before and 11 patients after liver transplant, the mean (SD) change in leg circumference after a single 8-hour application of an elastic bandage wrap was -2.6 (2.2) cm at the ankle and -3.1 (2.9) cm at midcalf for wrapped legs, as opposed to -0.4 (1.6) cm at the ankle and 1.0 (2.8) cm at midcalf for unwrapped legs (P<.001). Leg pain, measured on a visual analog scale, was significantly lower for the wrapped (mean [SD], 10.3 [26.5] mm) versus the unwrapped (20.3 [33.5] mm) leg (P=.04). CONCLUSION: In inpatients before and after liver transplant, the application of elastic bandage wraps to 1 leg for an 8-hour period led to significantly less edema formation and pain compared with the unwrapped leg. These results support the use of elastic bandage wraps in liver transplant patients to reduce leg edema and improve comfort.