Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and ...induce apoptosis in TNBC cell lines.
Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4-7 days prior to neoadjuvant anthracycline-taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics.
Forty-two patients were recruited with a median age of 51 years (28-72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% 95% confidence interval (CI), 52.8-87.3 in FASN+ patients and 74.4% (95% CI, 57.9-87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC
for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy mean change 0.12 (SD, 0.25);
= 0.02. Omeprazole was well tolerated with no grade ≥ 3 toxicities.
FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.
Sex steroid hormones may play a role in insulin resistance and glucose dysregulation. However, evidence regarding associations between early-pregnancy sex steroid hormones and hyperglycemia during ...pregnancy is limited. The primary objective of this study was to assess the relationships between first trimester sex steroid hormones and the subsequent development of hyperglycemia during pregnancy; with secondary evaluation of sex steroid hormones levels in mid-late pregnancy, concurrent with and subsequent to diagnosis of gestational diabetes.
Retrospective analysis of a prospective pregnancy cohort study was conducted. Medically low-risk participants with no known major endocrine disorders were recruited in the first trimester of pregnancy (n=319). Sex steroid hormones in each trimester, including total testosterone, free testosterone, estrone, estradiol, and estriol, were assessed using high-performance liquid chromatography and tandem mass spectrometry. Glucose levels of the 1-hour oral glucose tolerance test and gestational diabetes diagnosis were abstracted from medical records. Multivariable linear regression models were fitted to assess the associations of individual first trimester sex steroids and glucose levels.
In adjusted models, first trimester total testosterone (β=5.24, 95% CI: 0.01, 10.46, p=0.05) and free testosterone (β=5.98, 95% CI: 0.97, 10.98, p=0.02) were positively associated with subsequent glucose concentrations and gestational diabetes diagnosis (total testosterone: OR=3.63, 95% CI: 1.50, 8.78; free testosterone: OR=3.69; 95% CI: 1.56, 8.73). First trimester estrone was also positively associated with gestational diabetes (OR=3.66, 95% CI: 1.56, 8.55). In mid-late pregnancy, pregnant people with gestational diabetes had lower total testosterone levels (β=-0.19, 95% CI: -0.36, -0.02) after adjustment for first trimester total testosterone.
Early-pregnancy sex steroid hormones, including total testosterone, free testosterone, and estrone, were positively associated with glucose levels and gestational diabetes in mid-late pregnancy. These hormones may serve as early predictors of gestational diabetes in combination with other risk factors.
To test the hypothesis that our motivational sexual health intervention (SexHealth) would increase health service uptake when compared with control.
In a randomized controlled trial at a pediatric ...emergency department, sexually active adolescents received either the SexHealth intervention or printed materials (control). SexHealth, delivered by a health educator, was a tablet-based, interactive intervention that included motivational techniques to promote sexual health, condom skills training, and tailored service recommendations. We assessed feasibility (eg, intervention completion, recommendations discussed, intervention duration), acceptability (ie, proportion enrolled and rating intervention as satisfactory), and efficacy; secondary outcomes were sexual and care-seeking behaviors at 6 months. The efficacy outcome was completion of ≥1 service at the index visit (ie, counseling, condoms, emergency contraception for immediate or future use, pregnancy/sexually transmitted infection/HIV testing, sexually transmitted infection treatment, and clinic referral).
We enrolled 91 participants (intervention = 44; control = 47). The intervention demonstrated high feasibility: 98% completed the intervention; 98% of recommendations were discussed; duration was 24.6 minutes, and acceptability: 87% of eligible adolescents enrolled and 93% rated the intervention as fairly to very satisfactory. Compared with controls, intervention participants were more likely to complete ≥1 service (98% vs 70%, P < .001) including HIV testing (33% vs 6%, P = .02) and emergency contraception (80% vs 0%, P = .01). There were no meaningful differences between arms in behaviors at follow-up.
SexHealth was feasible to implement, acceptable to youth, and resulted in increased uptake of health services during the emergency department visit. Additional strategies may be needed to extend intervention effects over time.
ClinicalTrials.gov; NCT03341975.
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Hearing loss is associated with higher health care spending and use, but little is known about the unmet health care needs of people with hearing loss or difficulty. Analysis of 2016 Medicare Current ...Beneficiary Survey data for beneficiaries ages sixty-five and older reveals that those who reported a lot of trouble hearing in the past year were 49 percent more likely than those who reported no trouble hearing to indicate not having a usual source of care. Compared with those who reported no trouble hearing, those who reported some trouble hearing were more likely to indicate not having obtained medical care in the past year when they thought it was needed, as well as not filling a prescription, with the risk for both behaviors being greater among those reporting a lot of trouble hearing versus a little. Interventions that improve access to hearing services and aid communication may help older Medicare beneficiaries meet their health care needs.
Using telehealth in pulmonary rehabilitation (telerehabilitation) is a new field of health-care practice. To successfully implement a telerehabilitation program, measures of acceptance of this new ...type of program need to be assessed among potential users. The purpose of this study was to develop a scale to measure acceptance of using telerehabilitation by health-care practitioners and patients.
Three objectives were met (a) constructing a modified scale of the technology acceptance model, (b) judging the items for content validity, and (c) judging the scale for face validity. Nine experts agreed to participate and evaluate item relevance to theoretical definitions of domains. To establish face validity, 7 health-care practitioners and 5 patients were interviewed to provide feedback about the scale's clarity and ease of reading.
The final items were divided into 2 scales that reflected the health-care practitioner and patient responses. Each scale included 3 subscales: perceived usefulness, perceived ease of use, and behavioral intention.
The 2 scales, each with 3 subscales, exhibited evidence of content validity and face validity. The 17-item telerehabilitation acceptance scale for health-care practitioners and the 13-item telerehabilitation acceptance scale among patients warrant further psychometric testing as valuable measures for pulmonary rehabilitation programs.
Prior investigations attempted to determine the relative influence of advection and convective processes on ozone and water vapor distributions in the tropical tropopause layer (TTL) through analyses ...of tracers, related physical parameters (e.g., outgoing long-wave radiation, precipitable water, and temperature), or with models. In this study, stable laminae in Southern Hemisphere Additional Ozonesonde Network (SHADOZ) ozone profIles from 1998 to 2007 are interpreted in terms of gravity waves (GW) or Rossby waves (RW) that are identified with vertical and quasi-horizontal displacements, respectively. Using the method of Pierce and Grant (1998) as applied by Thompson et al. (2007a, 2007b, 2010, 2011), amplitudes and frequencies in ozone laminae are compared among representative SHADOZ sites over Africa and the Pacific, Indian, and Atlantic oceans. GW signals maximize in the TTL and lower stratosphere. Depending on site and season, GW are identified in up to 90% of the soundings. GW are most prevalent over the Pacific and eastern Indian oceans, a distribution consistent with vertically propagating equatorial Kelvin waves. Ozone laminae from RW occur more often below the tropical tropopause and with lower frequency 20%). Gravity wave and Rossby wave indices (GWI, RWI) are formulated to facilitate analysis of interannual variability of wave signatures among sites. GWI is positively correlated with a standard ENSO (El Nino-Southern Oscillation) index over American Samoa (14degS, 171degW) and negatively correlated at Watukosek, Java (7.5degS, 114degE), Kuala Lumpur (3degN, 102degE), and Ascension Island (80degS, 15degW). Generally, the responses of GW and RW to ENSO are consistent with prior studies.
Previous studies have shown that interference between fast waves and slow waves can lead to observed negative dispersion in cancellous bone. In this study, the effects of overlapping fast and slow ...waves on measurements of the apparent attenuation as a function of propagation distance are investigated along with methods of analysis used to determine the attenuation properties. Two methods are applied to simulated data that were generated based on experimentally acquired signals taken from a bovine specimen. The first method uses a time-domain approach that was dictated by constraints imposed by the partial overlap of fast and slow waves. The second method uses a frequency-domain log-spectral subtraction technique on the separated fast and slow waves. Applying the time-domain analysis to the broadband data yields apparent attenuation behavior that is larger in the early stages of propagation and decreases as the wave travels deeper. In contrast, performing frequency-domain analysis on the separated fast waves and slow waves results in attenuation coefficients that are independent of propagation distance. Results suggest that features arising from the analysis of overlapping two-mode data may represent an alternate explanation for the previously reported apparent dependence on propagation distance of the attenuation coefficient of cancellous bone.
We know that there are cross-cultural differences in psychological variables, such as individualism/collectivism. But it has not been clear which of these variables show relatively the greatest ...differences. The Survey of World Views project operated from the premise that such issues are best addressed in a diverse sampling of countries representing a majority of the world’s population, with a very large range of item-content. Data were collected online from 8,883 individuals (almost entirely college students based on local publicizing efforts) in 33 countries that constitute more than two third of the world’s population, using items drawn from measures of nearly 50 variables. This report focuses on the broadest patterns evident in item data. The largest differences were not in those contents most frequently emphasized in cross-cultural psychology (e.g., values, social axioms, cultural tightness), but instead in contents involving religion, regularity-norm behaviors, family roles and living arrangements, and ethnonationalism. Content not often studied cross-culturally (e.g., materialism, Machiavellianism, isms dimensions, moral foundations) demonstrated moderate-magnitude differences. Further studies are needed to refine such conclusions, but indications are that cross-cultural psychology may benefit from casting a wider net in terms of the psychological variables of focus.
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In 2015, a laboratory of the United States Department of Defense (DoD) inadvertently shipped preparations of gamma-irradiated spores of
that contained live spores. In response, a systematic ...evidence-based method for preparing, concentrating, irradiating, and verifying the inactivation of spore materials was developed. We demonstrate the consistency of spore preparations across multiple biological replicates and show that two different DoD institutions independently obtained comparable dose-inactivation curves for a monodisperse suspension of
spores containing 3 × 10
CFU. Spore preparations from three different institutions and three strain backgrounds yielded similar decimal reduction (D
) values and irradiation doses required to ensure sterility (D
) to the point at which the probability of detecting a viable spore is 10
Furthermore, spores of a genetically tagged strain of
strain Sterne were used to show that high densities of dead spores suppress the recovery of viable spores. Together, we present an integrated method for preparing, irradiating, and verifying the inactivation of spores of
for use as standard reagents for testing and evaluating detection and diagnostic devices and techniques.
The inadvertent shipment by a U.S. Department of Defense (DoD) laboratory of live
(anthrax) spores to U.S. and international destinations revealed the need to standardize inactivation methods for materials derived from biological select agents and toxins (BSAT) and for the development of evidence-based methods to prevent the recurrence of such an event. Following a retrospective analysis of the procedures previously employed to generate inactivated
spores, a study was commissioned by the DoD to provide data required to support the production of inactivated spores for the biodefense community. The results of this work are presented in this publication, which details the method by which spores can be prepared, irradiated, and tested, such that the chance of finding residual living spores in any given preparation is 1/1,000,000. These irradiated spores are used to test equipment and methods for the detection of agents of biological warfare and bioterrorism.
With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria breakdown and the heart becomes less efficient. Heart failure is ...linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the three-dimensional (3-D) networks in cardiac muscle samples of male mice at aging intervals of 3 mo, 1 yr, and 2 yr. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the three-dimensional (3-D) volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of
(some members of the MICOS complex), and
, which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes.
This article shows how mitochondria in murine cardiac changes, importantly elucidating age-related changes. It also is the first to show that the MICOS complex may play a role in outer membrane mitochondrial structure.
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