Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.

PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone receptor-positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone receptor-positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. RESULTS: In 8985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR 1.43, 95% CI 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR 1.37, 95% CI 1.05-1.80), dyslipidemia (HR 1.58, 95% CI 1.29-1.92), and hypertension (HR 1.50, 95% CI 1.24-1.82) compared with non-endocrine therapy users. CONCLUSION: Hormone receptor-positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.

Determinants, circumstances and consequences of injurious falls among older women living in the community.

OBJECTIVE: To identify the risk factors of women who fell with injury relative to women who did not fall or fell without injury and to describe the circumstances and consequences of injurious and non-injurious falls. METHODS: We analysed 5074 older women from the Objective Physical Activity and Cardiovascular Health Study who prospectively tracked their falls using a 13-month calendar. Women with a reported fall were phone interviewed about fall-related details, including injuries. Risk factors were identified from surveys and clinical home visits. Logistic regression models were used to calculate adjusted ORs and 95% CIs for injurious falls relative to not falling or falling without injury. Circumstances of injurious and non-injurious falls were compared. RESULTS: At least one fall was experienced by 1481 (29%) participants. Of these, 1043 were phone interviewed, of whom 430 (41%) reported at least one injurious fall. Relative to not falling, the risk factor most strongly associated with experiencing an injurious fall was having fallen ≥2 times (OR 4.0, CI 2.7 to 5.8) in the past year. Being black was protective for fall-related injury (OR 0.6, CI 0.4 to 0.9). No strong associations in risk factors were observed for injurious relative to non-injurious falls. Injurious falls were more likely to occur away from and outside of the home (p<0.05). Over half of those who injured self-managed their injury. CONCLUSION: Falling repeatedly is a powerful risk factor for injurious falls. Those who have fallen more than once should be prioritised for interventions to mitigate the risk of an injurious fall.

Participation and engagement of a rural community in Ciclovía: progressing from research intervention to community adoption.

BACKGROUND: Open streets events, where roads are temporarily closed to motorized vehicles, can provide safe spaces for physical activity (PA) and become sustainable community infrastructure. Since 2016, we have collaborated with a rural community to implement an open streets event, named ciclovía. In 2019, ciclovía was adopted as a community-wide program. This paper describes the process of building and progressing a ciclovía from a research intervention to a community-adopted program and participation of a rural community in ciclovía. METHODS: We used community-based participatory research to foster bidirectional learning on how to optimize the content and implementation of ciclovía to be feasible and acceptable for rural communities. The community-academic partnership focused on: 1) understanding the science of ciclovía; 2) learning the implementation process; 3) creating tools to facilitate planning, implementation, and evaluation of ciclovía; and 4) developing transition steps from a research intervention to a community-adopted program. RESULTS: The progression of the research intervention to community adoption spanned 2 years. First, the partnership met quarterly to discuss the science of ciclovía, its utility, and its adaptation for rural communities. Second, the partnership studied processes that facilitated ciclovía implementation. Third, the partnership created the ciclovía planning guide and tools for communities to establish their own ciclovía. The guide included forming a planning committee, setting meeting and communication plans, marketing and promotion, and selecting evaluation tools. Fourth, the transition steps from research intervention to community adoption included creating roles and responsibilities, implementing ciclovía using the planning guide, and convening listening sessions for improvement on implementation. Community attendance at ciclovía doubled from 189 individuals (126 children and 63 adults) when it was a research intervention to 394 individuals (277 children and 117 adults) when it was a community program. CONCLUSIONS: The progression from a research intervention to a community-adopted program encompasses multiple steps that involve bidirectional learning and partnership with the community. Lessons learned from this study are integrated into a disseminatable ciclovía planning guide.

Sedentary behavior and cardiovascular disease in older women: The Objective Physical Activity and Cardiovascular Health (OPACH) Study.

Background: Evidence that higher sedentary time is associated with higher risk for cardiovascular disease (CVD) is based mainly on self-reported measures. Few studies have examined whether patterns of sedentary time are associated with higher risk for CVD. Methods: Women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study (n=5638, aged 63-97, mean age=79±7) with no history of myocardial infarction (MI) or stroke wore accelerometers for 4-to-7 days and were followed for up to 4.9 years for CVD events. Average daily sedentary time and mean sedentary bout duration were the exposures of interest. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CVD using models adjusted for covariates and subsequently adjusted for potential mediators (body mass index (BMI), diabetes, hypertension, and CVD-risk biomarkers [fasting glucose, high-density lipoprotein, triglycerides, and systolic blood pressure]). Restricted cubic spline regression characterized dose-response relationships. Results: There were 545 CVD events during 19,350 person-years. Adjusting for covariates, women in the highest (≥ ~11 hr/day) vs. the lowest (≤ ~9 hr/day) quartile of sedentary time had higher risk for CVD (HR=1.62; CI=1.21-2.17; p-trend <0.001). Further adjustment for potential mediators attenuated but did not eliminate significance of these associations (p-trend<.05, each). Longer vs. shorter mean bout duration was associated with higher risks for CVD (HR=1.54; CI=1.27-2.02; p-trend=0.003) after adjustment for covariates. Additional adjustment for CVD-risk biomarkers attenuated associations resulting in a quartile 4 vs. quartile 1 HR=1.36; CI=1.01-1.83; p-trend=0.10). Dose-response associations of sedentary time and bout duration with CVD were linear (P-nonlinear >0.05, each). Women jointly classified as having high sedentary time and long bout durations had significantly higher risk for CVD (HR=1.34; CI=1.08-1.65) than women with both low sedentary time and short bout duration. All analyses were repeated for incident coronary heart disease (MI or CVD death) and associations were similar with notably stronger hazard ratios. Conclusions: Both high sedentary time and long mean bout durations were associated in a dose-response manner with increased CVD risk in older women, suggesting that efforts to reduce CVD burden may benefit from addressing either or both component(s) of sedentary behavior.

Accelerometer-Measured Physical Activity Levels and Fatigue in Older Women.

The authors examined whether the associations between physical activity (PA) levels and fatigue vary by body mass index and physical performance, and whether substituting sedentary time (ST) with low light PA, high light PA, and moderate to vigorous PA (MVPA) was associated with better mean fatigue scores. In total, 6,111 participants (aged 65 years and older) were from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. PA levels were from a hip-worn GT3X accelerometer. Overall fatigue, energy, and weariness subdomains were from the RAND-36 Vitality subscale. Isotemporal substitution models examined the time-substitution effects. Interactions were observed between MVPA and short physical performance battery performance measure (p < .05). Substituting ST with 34.3 min of MVPA was associated on average with a 1.63-point improvement in fatigue score. Substituting ST with 50.2 min of low light PA and 34.3 min of MVPA was associated on average with an energy score improvement of 1.18 and 2.06 points respectively. Substituting ST with 34.3 min of MVPA was associated on average with a 1.08-point improvement in weariness score (p < .05 for all).

Cryo-Electron Microscopy Structure of Seneca Valley Virus Procapsid.

Seneca Valley virus (SVV), like some other members of the Picornaviridae, forms naturally occurring empty capsids, known as procapsids. Procapsids have the same antigenicity as full virions, so they present an interesting possibility for the formation of stable virus-like particles. Interestingly, although SVV is a livestock pathogen, it has also been found to preferentially infect tumor cells and is being explored for use as a therapeutic agent in the treatment of small-cell lung cancers. Here we used cryo-electron microscopy to investigate the procapsid structure and describe the transition of capsid protein VP0 to the cleaved forms of VP4 and VP2. We show that the SVV receptor binds the procapsid, as evidence of its native antigenicity. In comparing the procapsid structure to that of the full virion, we also show that a cage of RNA serves to stabilize the inside surface of the virus, thereby making it more acid stable.IMPORTANCE Viruses are extensively studied to help us understand infection and disease. One of the by-products of some virus infections are the naturally occurring empty virus capsids (containing no genome), termed procapsids, whose function remains unclear. Here we investigate the structure and formation of the procapsids of Seneca Valley virus, to better understand how they form, what causes them to form, how they behave, and how we can make use of them. One potential benefit of this work is the modification of the procapsid to develop it for targeted in vivo delivery of therapeutics or to make a stable vaccine against SVV, which could be of great interest to the agricultural industry.

Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes.

Picornaviruses are non-enveloped RNA viruses that enter cells via receptor-mediated endocytosis. Because they lack an envelope, picornaviruses face the challenge of delivering their RNA genomes across the membrane of the endocytic vesicle into the cytoplasm to initiate infection. Currently, the mechanism of genome release and translocation across membranes remains poorly understood. Within the enterovirus genus, poliovirus, rhinovirus 2, and rhinovirus 16 have been proposed to release their genomes across intact endosomal membranes through virally induced pores, whereas one study has proposed that rhinovirus 14 releases its RNA following disruption of endosomal membranes. For the more distantly related aphthovirus genus (e.g. foot-and-mouth disease viruses and equine rhinitis A virus) acidification of endosomes results in the disassembly of the virion into pentamers and in the release of the viral RNA into the lumen of the endosome, but no details have been elucidated as how the RNA crosses the vesicle membrane. However, more recent studies suggest aphthovirus RNA is released from intact particles and the dissociation to pentamers may be a late event. In this study we have investigated the RNase A sensitivity of genome translocation of poliovirus using a receptor-decorated-liposome model and the sensitivity of infection of poliovirus and equine-rhinitis A virus to co-internalized RNase A. We show that poliovirus genome translocation is insensitive to RNase A and results in little or no release into the medium in the liposome model. We also show that infectivity is not reduced by co-internalized RNase A for poliovirus and equine rhinitis A virus. Additionally, we show that all poliovirus genomes that are internalized into cells, not just those resulting in infection, are protected from RNase A. These results support a finely coordinated, directional model of viral RNA delivery that involves viral proteins and cellular membranes.

Reproductive Risk Factors and Coronary Heart Disease in the Women's Health Initiative Observational Study.

BACKGROUND: Reproductive factors provide an early window into a woman's coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain. METHODS AND RESULTS: In the Women's Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of <5%, 5 to <10%, and ≥10% 10-year risk of CHD), and integrated discriminatory index were assessed. Among 72 982 women (CHD events, n=4607; median follow-up,12.0 [interquartile range, 8.3-13.7] years; mean [standard deviation] age, 63.2 [7.2] years), an age-adjusted reproductive risk factor model had a C statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages, and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P<0.0001). Net reclassification for women with events was not improved (net reclassification index events, 0.007; P=0.18); and, for women without events, net reclassification was marginally improved (net reclassification index nonevents, 0.002; P=0.04) CONCLUSIONS: Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination, and do not materially improve net reclassification.

The Objective Physical Activity and Cardiovascular Disease Health in Older Women (OPACH) Study.

BACKGROUND: Limited evidence exists to inform physical activity (PA) and sedentary behavior guidelines for older people, especially women. Rigorous evidence on the amounts, intensities, and movement patterns associated with better health in later life is needed. METHODS/DESIGN: The Objective PA and Cardiovascular Health (OPACH) Study is an ancillary study to the Women's Health Initiative (WHI) Program that examines associations of accelerometer-assessed PA and sedentary behavior with cardiovascular and fall events. Between 2012 and 2014, 7048 women aged 63-99 were provided with an ActiGraph GT3X+ (Pensacola, Florida) triaxial accelerometer, a sleep log, and an OPACH PA Questionnaire; 6489 have accelerometer data. Most women were in their 70s (40%) or 80s (46%), while approximately 10% were in their 60s and 4% were age 90 years or older. Non-Hispanic Black or Hispanic/Latina women comprise half of the cohort. Follow-up includes 1-year of falls surveillance with monthly calendars and telephone interviews of fallers, and annual follow-up for outcomes with adjudication of incident cardiovascular disease (CVD) events through 2020. Over 63,600 months of calendar pages were returned by 5,776 women, who reported 5,980 falls. Telephone interviews were completed for 1,492 women to ascertain the circumstances, injuries and medical care associated with falling. The dataset contains extensive information on phenotypes related to healthy aging, including inflammatory and CVD biomarkers, breast and colon cancer, hip and other fractures, diabetes, and physical disability. DISCUSSION: This paper describes the study design, methods, and baseline data for a diverse cohort of postmenopausal women who wore accelerometers under free-living conditions as part of the OPACH Study. By using accelerometers to collect more precise and complete data on PA and sedentary behavior in a large cohort of older women, this study will contribute crucial new evidence about how much, how vigorous, and what patterns of PA are necessary to maintain optimal cardiovascular health and to avoid falls in later life. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00000611 . Registered 27 October 1999.

Dual function of CD81 in influenza virus uncoating and budding.

As an obligatory pathogen, influenza virus co-opts host cell machinery to harbor infection and to produce progeny viruses. In order to characterize the virus-host cell interactions, several genome-wide siRNA screens and proteomic analyses have been performed recently to identify host factors involved in influenza virus infection. CD81 has emerged as one of the top candidates in two siRNA screens and one proteomic study. The exact role played by CD81 in influenza infection, however, has not been elucidated thus far. In this work, we examined the effect of CD81 depletion on the major steps of the influenza infection. We found that CD81 primarily affected virus infection at two stages: viral uncoating during entry and virus budding. CD81 marked a specific endosomal population and about half of the fused influenza virus particles underwent fusion within the CD81-positive endosomes. Depletion of CD81 resulted in a substantial defect in viral fusion and infection. During virus assembly, CD81 was recruited to virus budding site on the plasma membrane, and in particular, to specific sub-viral locations. For spherical and slightly elongated influenza virus, CD81 was localized at both the growing tip and the budding neck of the progeny viruses. CD81 knockdown led to a budding defect and resulted in elongated budding virions with a higher propensity to remain attached to the plasma membrane. Progeny virus production was markedly reduced in CD81-knockdown cells even when the uncoating defect was compensated. In filamentous virus, CD81 was distributed at multiple sites along the viral filament. Taken together, these results demonstrate important roles of CD81 in both entry and budding stages of the influenza infection cycle.

Global quality of life modifies terminal change in physical functioning among older adult women.

BACKGROUND: the factors that moderate decline in physical functioning as death approaches are understudied. This study aimed to assess death-related decline in global quality of life (QoL) and physical functioning and to test whether baseline QoL moderates terminal decline in physical functioning. METHODS: four thousand six hundred and fifty-one decedents from the Women's Health Initiative Study (WHI) rated QoL and physical functioning each year throughout 5 years of follow-up. RESULTS: both QoL and physical functioning showed a steeper decline as a function of years to death than as a function of chronological age. Moreover, decedents with higher QoL at baseline showed a less steep decline in physical functioning as death approached than those with lower QoL at baseline. CONCLUSION: although QoL strongly decreases across the terminal years, its beneficial influence on physical functioning is evident till the very end of life.

Dissecting the role of COPI complexes in influenza virus infection.

As an obligate pathogen, influenza virus requires host cell factors and compartments to mediate productive infection and to produce infectious progeny virus. Recently, several small interfering RNA (siRNA) knockdown screens revealed influenza virus host dependency proteins, all of which identified at least two subunits of the coat protein I (COPI) complex. COPI proteins oligomerize to form coated vesicles that transport contents between the Golgi apparatus and the endoplasmic reticulum, and they have also been reported to mediate endosomal trafficking. However, it remains unclear which steps in the influenza virus infection cycle rely on the COPI complex. Upon systematic dissection of the influenza virus infection cycle, from entry to progeny virion production, we found that prolonged exposure to COPI complex disruption through siRNA depletion resulted in significant defects in virus internalization and trafficking to late endosomes. Acute inhibition of COPI complex recruitment to the Golgi apparatus with pharmacological compounds failed to recapitulate the same entry defects as observed with the COPI-depleted cells but did result in specific decreases in viral membrane protein expression and assembly, leading to defects in progeny virion production. Taken together, our findings suggest that COPI complexes likely function indirectly in influenza virus entry but play direct roles in viral membrane protein expression and assembly.

Association of the selected dimensions of eudaimonic well-being with healthy survival to 85 years of age in older women.

BACKGROUND: Aspects of eudaimonic well-being, such as personal growth (PG) and purpose in life (PL), have been highlighted as important to older adults' health. We investigated the relationship of PG and PL with patterns of survival to the age of 85 years and older. METHODS: The sample included 8,880 women from the Women's Health Initiative cohort who reached 85 years of age by December 1, 2013, and for whom data on the PG and PL constructs were available. Women were classified into mutually exclusive outcomes: Healthy, Prevalent, Incident, Disabled, and Deceased. PG and PL were each assessed using a modified seven-item measure derived from the Psychological Well-Being scale. RESULTS: Women were most commonly classified as Healthy (38.2%, n = 3,395), followed by Incident (24.4%, n = 2,163), Disabled (19.0%, n = 1,685), Prevalent (14.3%, 1,273), and Deceased (4.1%, n = 364). Women with low PL and PG levels were more likely to have prevalent mobility disability and disease or incident death before the age of 85 years. Specifically, those who reported low levels of PG and PL had a 2.1- and 3.6-fold higher risk, respectively, of death. CONCLUSIONS: These findings indicate that even among the oldest old, experience of purposeful life engagement and continuing PG may contribute to better health outcomes.

Grandmothers' smoking in pregnancy and grandchildren's birth weight: comparisons by grandmother birth cohort.

This study examined whether grandmothers' smoking behavior during pregnancy was associated with birth weights in their grandchildren, considering possible birth cohort effects in the grandmothers' generation. The birth weights of 935 singleton children were compared by grandmothers' and mothers' smoking status during pregnancy. In 2008, women (n = 397) from the Michigan Bone Health and Metabolism Study were interviewed about their own birth history, including whether their own mother smoked while pregnant with them, and the birth histories of their offspring. While also accounting for family clustering, linear mixed models were used to evaluate whether birth weight differences in the grandchildren were associated with grandmothers' and mothers' smoking behavior during pregnancy. Associations were compared among grandmothers born from 1904 to 1928 versus grandmothers born from 1929 to 1945 to determine potential birth cohort effects. Forty-six (5 %) grandchildren had grandmothers and mothers who smoked while pregnant, while 455 (49 %) had grandmothers and mothers who did not smoke during pregnancy. After adjustment, birth weight was an average of 346 (95 % confidence interval 64-628) grams higher in grandchildren whose grandmother and mother both smoked during pregnancy relative to grandchildren whose grandmother and mother both did not smoke during pregnancy, but only among grandmothers who were born from 1929 to 1945. For grandmothers born from 1904 to 1928, grandchildren birth weights did not differ by grandmother and mother smoking status. Birth weight may be associated with grandmother and mother smoking behaviors during pregnancy, but birth cohort effects should be considered.

Social Support, Diet, and Physical Activity among Latina/Hispanic Women Breast Cancer Survivors.

Diet and physical activity guidelines for cancer survivorship are less likely to be followed by populations of minority cancer survivors, such as Latina/Hispanic women, compared to non-Hispanic White women. It is important to understand psychosocial mechanisms that may increase adherence to healthy lifestyle habits, especially in populations at risk for poorer cancer outcomes. This cross-sectional study examined the relationships between overall social support (SS) and SS from three sources (family, friends, and significant other) with diet (fruit and vegetables, fat, energy density, and diet quality), and moderate-to-vigorous physical activity (MVPA) behaviors in Latina/Hispanic women with a history of breast cancer (n = 85; M age = 55.2; SD = 9.2). Linear regression models and odds ratios were used to examine associations and adjusted for age, income, and acculturation. Family, significant other, and total SS were positively related to total fruit and vegetable intake but SS from friends was not. Higher levels of SS from all sources were each related to a low energy density diet. A higher quality diet was only related to SS from family. SS was not related to fat intake or MVPA. Higher SS from family and a significant other were associated with higher odds of meeting the fruit/vegetable guidelines; (family, OR = 3.72, 95% CI [1.21, 11.39]; significant other, OR = 3.32, 95% CI [1.08, 10.30]). Having more SS from family or a significant other may contribute to Latina/Hispanic women breast cancer survivors meeting national guidelines for a diet high in fruits and vegetables and low in energy density.

Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study.

BACKGROUND: Women with breast cancer are at higher risk of cardiovascular disease (CVD) compared with women without breast cancer. Whether higher diet quality at breast cancer diagnosis lowers this risk remains unknown. We set out to determine if higher diet quality at breast cancer diagnosis was related to lower risk of CVD and CVD-related death. METHODS: This analysis included 3415 participants from the Pathway Study, a prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013 and followed through December 31, 2021. Scores from 5 diet quality indices consistent with healthy eating were obtained at the time of breast cancer diagnosis. Scores were categorized into ascending quartiles of concordance for each diet quality index, and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. P values were 2-sided. RESULTS: The Dietary Approaches to Stop Hypertension diet quality index was associated with lower risk of heart failure (HR = 0.53, 95% CI = 0.33 to 0.87; Ptrend = .03), arrhythmia (HR = 0.77, 95% CI = 0.62 to 0.94; Ptrend = .008), cardiac arrest (HR = 0.77, 95% CI = 0.61 to 0.96; Ptrend = .02), valvular heart disease (HR = 0.79, 95% CI = 0.64 to 0.98; Ptrend = .046), venous thromboembolic disease (HR = 0.75, 95% CI = 0.60 to 0.93; Ptrend = .01), and CVD-related death (HR = 0.70, 95% CI = 0.50 to 0.99; Ptrend = .04), when comparing the highest with lowest quartiles. Inverse associations were also found between the healthy plant-based dietary index and heart failure (HR = 0.60, 95% CI = 0.39 to 0.94; Ptrend = .02), as well as the alternate Mediterranean dietary index and arrhythmia (HR = 0.74, 95% CI = 0.60 to 0.93; Ptrend = .02). CONCLUSION: Among newly diagnosed breast cancer patients, higher diet quality at diagnosis was associated with lower risk of CVD events and death.

Phosphine quenching of cyanine dyes as a versatile tool for fluorescence microscopy.

We report that the cyanine dye Cy5 and several of its structural relatives are reversibly quenched by the phosphine tris(2-carboxyethyl)phosphine (TCEP). Using Cy5 as a model, we show that the quenching reaction occurs by 1,4-addition of the phosphine to the polymethine bridge of Cy5 to form a covalent adduct. Illumination with UV light dissociates the adduct and returns the dye to the fluorescent state. We demonstrate that TCEP quenching can be used for super-resolution imaging as well as for other applications, such as differentiating between molecules inside and outside the cell.

Efzofitimod: a novel anti-inflammatory agent for sarcoidosis.

Efzofitimod is a first-in-class biologic based on a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that downregulates immune responses via selective modulation of neuropilin-2 (NRP2). Preclinical data found high expression of NRP2 in sarcoidosis granulomas. Treatment with efzofitimod reduced the granulomatous inflammation induced by P. acnes in an animal model of sarcoidosis. A dose escalating trial of efzofitimod in sarcoidosis with chronic symptomatic pulmonary disease found that treatment with efzofitimod was associated with improved quality of life with a trend towards reduced glucocorticoid use and stable to improved pulmonary function. These studies have led to a large Phase 3 trial of efzofitimod in symptomatic pulmonary sarcoidosis.

Development of an Assessment Tool to Measure Healthy Eating in Navajo Children and Their Families.

Background: To estimate the efficacy of interventions to improve healthy eating, valid measures are essential. Although simple dietary intake tools have been developed with other populations, few have been culturally tailored and assessed for validity and reliability among Navajo. Objectives: This study aimed to develop a simple dietary intake tool tailored to Navajo culture, derive healthy eating indices, and assess their validity and reliability in Navajo children and adults and to describe the process used to develop this tool. Methods: A picture-sort tool using typically consumed foods was developed. Elementary school children and family members provided qualitative feedback in focus groups, used to refine the tool. Next, school-aged children and adults completed assessments at baseline and follow-up. Baseline behavior measures including child self-efficacy for fruits and vegetables (F&V) were examined for internal consistency. Healthy eating indices were derived from intake frequencies from picture sorting. The convergent validity of the indices and behavior measures for children and adults were examined. The reliability of the indices at the 2 time points was derived using Bland-Altman plots. Results: The picture-sort was refined from feedback provided by the focus groups. Baseline measures from 25 children and 18 adults were obtained. In children, a modified Alternative Healthy Eating Index (AHEI) and 2 other indices from the picture-sort were correlated with self-efficacy for eating F&V and had good reliability. In adults, the modified AHEI and 3 other indices from the picture-sort had significant correlations with adult abbreviated food frequency of F&V or obesogenic dietary index and had good reliability. Conclusions: The Navajo foods picture-sort tool developed for Navajo children and adults is proven to be acceptable and feasible to implement. Indices derived from the tool has good convergent validity and repeatability, supporting use in evaluating dietary change interventions in Navajo, with the potential for broader use of the approach in other underserved populations.

Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.

PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone-receptor positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone-receptor positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. RESULTS: In 8,985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR: 1.43, 95% CI: 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR: 1.37, 95% CI: 1.05-1.80), dyslipidemia (HR: 1.58, 95% CI: 1.29-1.92) and hypertension (HR: 1.50, 95% CI: 1.24-1.82) compared with non-endocrine therapy users. CONCLUSION: Hormone-receptor positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.