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The All of Us Research Program seeks to advance precision medicine and reduce health disparities by recruiting people in demographic categories that are underrepresented in biomedical research. Asian Americans, Native Hawaiians and Pacific Islanders are the most understudied of all racial/ethnic groups in the United States. We propose a national engagement strategy for the recruitment of Asian Americans, Native Hawaiians and Pacific Islanders into biomedical research using a community-based participatory research approach.We partnered with Asian serving community-based organizations across the United States to increase education and awareness and developed a culturally and linguistically tailored approach for the engagement of AANHPIs into All of Us Research Program.In the first year, our national engagement strategy reached more than 35,000 AANHPIs through promotional events and educational sessions.Our success is a result of our equal and mutually beneficial partnership with community-based organizations who have access to rich, local knowledge and hold a unique role within the community.

In Parkinson’s disease (PD), reduced cerebral cortical thickness may reflect network-based degeneration. This study performed cognitive assessment and brain MRI in 30 PD participants and 41 controls at baseline and 18 months later. We hypothesized that cerebral cortical thickness and volume, as well as change in these metrics, would differ between PD participants who remained cognitively stable and those who experienced cognitive decline. Dividing the participant sample into PD-stable, PD-decline, and control-stable groups, we compared mean cortical thickness and volume within segments that comprise the prefrontal cognitive-control, memory, dorsal spatial, and ventral object-based networks at baseline. We then compared the rate of change in cortical thickness and volume between the same groups using a vertex-wise approach. We found that the PD-decline group had lower cortical thickness within all 4 cognitive networks in comparison with controls, as well as lower cortical thickness within the prefrontal and medial temporal networks in comparison with the PD-stable group. The PD-decline group also experienced a greater rate of volume loss in the lateral temporal cortices in comparison with the control group. This study suggests that lower thickness and volume in prefrontal, medial, and lateral temporal regions may portend cognitive decline in PD.

Background Although Korean American women have one of the highest cervical cancer incidence and mortality rates among all Asian American and non-Hispanic White women, they are less likely to receive the human papillomavirus (HPV) vaccine to prevent cervical cancer. Objectives This study aimed to examine Korean American women's HPV literacy and factors related to HPV literacy to identify targeted intervention strategies. Methods A quota sampling strategy was used to recruit 243 Korean American women aged 19-85 years in the Atlanta, Georgia, metropolitan area. Multiple linear regression analysis was conducted using Andersen's Behavioral Model of Health Services Use to examine factors associated with HPV literacy. Findings HPV literacy of Korean American immigrant women was moderate, and knowledge about HPV detection items was particularly low. Age was the only predisposing factor that had a significantly negative association with HPV literacy, whereas education level and English proficiency had a significant positive relationship with HPV literacy. Health status as a need factor was significantly positively associated with HPV literacy.

Value for money is a growing necessity in today's U.S. health care system in which drug spending is expected to increase by an average rate of 6.7% yearly through 2025. In response to uncertainty about real-world clinical and economic outcomes for many drugs, health insurers and pharmacy benefit managers (PBMs) have implemented various contracts and arrangements with drug manufacturers that can collectively be described as performance-based risk-sharing arrangements (PBRSAs). Little is known about U.S.-specific PBRSAs for drugs.To conduct a systematic review of U.S.-specific PBRSAs for drugs to describe (a) trends over time and (b) key aspects including outcome measures and terms of arrangements between stakeholders.A systematic review was conducted in MEDLINE (January 1, 1946-April 1, 2017), Embase (January 1, 1988-April 1, 2017), and the grey literature (up to April 1, 2017) to identify publicly disclosed PBRSAs. Articles and conference abstracts were included if they were published in English and described a U.S.-specific PBRSA for a drug. Articles and conference abstracts were excluded if they only described a PBRSA similar to a money-back guarantee to patients. They were also excluded if they only described a PBRSA between a PBM and a health insurer in which the latter would receive a discount for patients nonadherent to a drug. Results were summarized as counts and percentages.From the literature review, 26 publicly disclosed PBRSAs were identified. Of these, 16 (62%) were announced or initiated from 2015 to 2017, and 10 (38%) were announced or initiated from 1997 to 2012. Thirteen (50%) PBRSAs involved cardiometabolic indications; 5 (19%) involved oncology indications; and 8 (31%) involved other indications. Categorized by health insurer or PBM, 10 (38%) PBRSAs involved large multistate insurers; 5 (19%) involved the Centers for MedicareMedicaid Services; 7 (27%) involved regional insurers; 3 (12%) involved PBMs; and 1 (4%) involved multiple unspecified insurers. Regarding the most active drug manufacturers, Amgen initiated 5 (19%) PBRSAs and Novartis initiated 4 (15%). Relative to the initial FDA approval of a treatment, 15 (58%) PBRSAs were announced or initiated within 5 years, and 11 (42%) were announced or initiated more than 5 years later. For data collection, electronic medical record (EMR) data would have been an appropriate source for 12 (46%) PBRSAs; claims data would have been an appropriate source for 11 (42%) PBRSAs; and EMR and claims data would have been appropriate sources for 2 (8%) PBRSAs; no description of the outcome measures was available for 1 (4%) PBRSA.The number of publicly disclosed U.S.-specific PBRSAs for drugs has increased over the years. This review's findings confirm the interest of stakeholders in such arrangements and their confidence in the use of the selected outcome measures. Each PBRSA represents a timely collaboration among stakeholders to provide access to a drug while generating evidence to better elucidate its clinical and economic value.No funding supported this systematic review. Yu is an employee and shareholder of Allergan. Chin reports personal fees from Formulary Resources. Oh and Farias have nothing to disclose. Study concept and design were primarily contributed by Yu, along with the other authors. All authors contributed to the collection and interpretation of the data. The manuscript was written by Yu, Chin, Oh, and Farias and revised by Yu and Chin, along with the other authors.

Korean-American women experience a higher incidence of cervical cancer than non-Hispanic White women as well as other Asian-American women. A prominent cause of such a disproportional health risk among Korean-American women is a lack of awareness and knowledge of cervical cancer screening. Identifying factors related to cervical cancer screening awareness and literacy is critical for increasing cervical cancer screening among this population. Researchers surveyed 230 Korean-American women in a metro area in a Southeastern state, USA. Based on Anderson’s Behavioral Model of Health Services Use, predisposing, enabling, and need factors were explored to predict cervical cancer screening awareness and literacy. Monthly income, education, English proficiency, and annual checkups had significantly positive associations with cervical cancer screening awareness. Having an acquaintance giving support and receiving an annual checkup had significantly positive relationships with cervical cancer screening literacy. This study recommends culture specific guidelines to promote annual checkups through primary care physicians and the transfer of information about cervical cancer screening through acquaintances giving support.

Relationships among bully victimization, bully perpetration, ethnic identity, and subjective well-being (i.e., life satisfaction, positive affect, and negative affect) were examined in a group of urban, ethnically diverse early adolescents. Indices of subjective well-being correlated with participants' scores on bully victimization and perpetration measures but bully perpetration was not significantly related to negative affect. The authors used cluster analysis to determine participants' status as either bully-victims, perpetrators, non-participants, or victim-perpetrators. They found significant analysis of variance differences on the variables of interest between bully participants vs. non-participants. This article discusses implications for bully prevention efforts with ethnic minority youth.

Sarcospan (SSPN) is a core component of the major adhesion complexes in skeletal muscle, the dystrophin- and utrophin (Utr)-glycoprotein complexes (DGC and UGC). We performed a rigorous analysis of SSPN-null mice and discovered that loss of SSPN decreased DGC and UGC abundance, leading to impaired laminin-binding activity and susceptibility to eccentric contraction-induced injury in skeletal muscle. We show that loss of SSPN increased levels of α7β1 integrin. To genetically test whether integrin compensates for the loss of DGC and UGC function in SSPN-nulls, we generated mice lacking both SSPN and α7 integrin (DKO, double knockout). Muscle regeneration, sarcolemma integrity and fibrosis were exacerbated in DKO mice and were remarkably similar to muscle from Duchenne muscular dystrophy (DMD) patients, suggesting that secondary loss of integrin contributes significantly to pathogenesis. Expression of the DGC and UGC, laminin binding and Akt signaling were negatively impacted in DKO muscle, resulting in severely diminished specific force properties. We demonstrate that SSPN is a necessary component of dystrophin and Utr function and that SSPN modulation of integrin signaling is required for extracellular matrix attachment and muscle force development.

Background Postoperative urinary retention (POUR) is a relatively common complication after total joint arthroplasty (TJA). Based on the findings of a randomized, prospective study from our institution, we abandoned the routine use of indwelling urinary catheters in patients undergoing elective TJA using opioid-free spinal anesthesia. The aim of this study was to determine the incidence of and the risk factors for POUR in this patient population. Patients and Methods A total of 842 consecutive patients underwent TJA between January 2012 and September 2014 using opioid-free spinal anesthesia in whom indwelling urinary catheters were not used. Postoperative urinary retention was defined as the inability of a patient to void that necessitated the placement of either an indwelling urinary catheter or straight catheterization. Multivariate logistic regression analysis was used to determine risk factors for developing POUR. Results In this cohort, 79 patients (79/842; 9.3%) developed POUR. Independent risk factors for POUR were history of a benign prostatic hyperplasia ( P = .02), renal disease ( P = .001), longer operative time ( P = .003), and age older than 67 years ( P = .02). No patients in this cohort developed neurogenic bladder. Conclusion This study confirms that the routine use of indwelling urinary catheters for patients undergoing TJA using an opioid-free spinal anesthesia may not be warranted. Urinary catheters may be used selectively in patients at risk for subsequent urinary retention.

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of α7β1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of α7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or α7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and α7β1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and α7β1 integrin.

The TAM receptor tyrosine kinases Tyro3, Axl, and Mer regulate key features of cellular physiology, yet the differential activities of the TAM ligands Gas6 and Protein S are poorly understood. We have used biochemical and genetic analyses to delineate the rules for TAM receptor–ligand engagement and find that the TAMs segregate into two groups based on ligand specificity, regulation by phosphatidylserine, and function. Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl. Optimal TAM signaling requires coincident TAM ligand engagement of both its receptor and the phospholipid phosphatidylserine (PtdSer): Gas6 lacking its PtdSer-binding ‘Gla domain’ is significantly weakened as a Tyro3/Mer agonist and is inert as an Axl agonist, even though it binds to Axl with wild-type affinity. In two settings of TAM-dependent homeostatic phagocytosis, Mer plays a predominant role while Axl is dispensable, and activation of Mer by Protein S is sufficient to drive phagocytosis. DOI: http://dx.doi.org/10.7554/eLife.03385.001, eLife digest Cells send out and receive signals to communicate with other cells. Detecting these signals is largely carried out by proteins called receptors that span the cell surface membrane. These proteins typically have extracellular domains outside of the cell that can bind to specific signaling molecules and an intracellular domain inside the cell that relays the information inwards to trigger a response. Three such receptor proteins are collectively known as the TAM receptors. Each day, many billions of cells in the human body die and are engulfed by other cells and broken down so that their building blocks can be reused. TAM receptors are required for this process; and the TAM receptors also help prevent the immune system from going out of control, which would damage the body's own tissues. Two different signaling proteins, called Gas6 and Protein S, can bind to and activate TAM receptors. Both of the signaling proteins can also bind to a phospholipid molecule that is found on the surface membrane of dead cells. However, it is not known if all three TAM receptors bind to both signaling proteins equally, and the importance of the phospholipid-binding domain in the signaling proteins remains unclear. To shed light on the workings of these receptors, Lew et al. created mouse cells that each only express one out of the three TAM receptors. These cells were then exposed to intact Gas6 and Protein S, or shortened versions that lacked the phospholipid-binding domain. Lew et al. found that Gas6 could trigger a response through all three TAM receptors but that Protein S was specific for only two out of the three receptors. Signaling proteins with or without their phospholipid-binding domains bound equally well to the receptors, but the maximum level of response was only triggered when both signaling proteins were intact and the phospholipid molecule was present. This is important since the phospholipid can be thought of as an ‘eat-me’ signal by which the dead cells are recognized by the TAM receptor-expressing cells that will engulf them. Using mice that only produce a TAM receptor called Mer, Lew et al. show that Protein S alone can trigger the process that engulfs and breaks down cells in a living organism. These data and previous work suggest that two TAM receptors—including Mer—are involved in the daily engulfment of dying cells, whereas the third mediates this process during infection and tissue damage. Molecules that inhibit or activate the function of TAM receptors are currently being developed to treat cancer and other diseases. By revealing which receptors respond to which signaling molecules, the findings of Lew et al. will serve to guide these efforts. DOI: http://dx.doi.org/10.7554/eLife.03385.002

Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval.Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables.Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (P0.001, uncorrected for multiple comparisons).Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases.

Due to the importance of vascular endothelial growth factor (VEGF) in the neovascularization of solid tumors, a clear understanding of how VEGF is regulated in normal and tumor cells is warranted. We investigated insulin-like growth factor (IGF)-I-stimulated signaling pathways that increase the rate of VEGF synthesis in primary cultures of normal prostate epithelial cells (PrEC). IGF-I increased the secretion of VEGF(165) into PrEC growth medium and stimulated transcription of a reporter gene driven by a 1.5-kb region of the VEGF promoter. Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I-induced increase in VEGF secretion and promoter activity, indicating a dependence on coordinate signaling from both pathways to produce this effect. Levels of the transcription factors hypoxia-inducible factor (HIF)-1 and Fos were elevated in response to IGF-I in a PI3-K-dependent and Mek1/2-dependent manner, respectively. The expression of an activator protein (AP)-1 dominant negative in an immortalized prostate epithelial cell line PZ-HPV-7 suppressed the IGF-I-induced increase in VEGF promoter activity. Mutation of the hypoxia response element (HRE), which mediates hypoxic stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the VEGF promoter, despite the fact that this mutation inhibited PI3-K-stimulated VEGF promoter activity in prostate cancer cells. These data indicate that PI3-K signaling does not increase VEGF transcription through transactivation by HIF-1 at the HRE in normal PrEC. This work also suggests that an additional signal, not stimulated by IGF-I in PrEC, is needed for HIF-1 to stimulate transcription from the VEGF HRE.

Duchenne muscular dystrophy is a progressive muscle wasting disorder caused by loss of the predominant adhesion complex at the muscle membrane, the dystrophin–glycoprotein complex. Over-expression of compensatory adhesion complexes, α 7 β 1 integrin or the utrophin–glycoprotein complex, rescues dystrophic pathology in the mdx mouse model of Duchenne muscular dystrophy. The utrophin–glycoprotein complex is normally localized to the neuromuscular junction and is comprised of utrophin, dystroglycan, and the sarcoglycan–sarcospan subcomplex. We have recently demonstrated that sarcospan amelioration of mdx muscular dystrophy increases protein abundance of the utrophin–glycoprotein complex and α 7 β 1 integrin around the extra-synaptic membrane; however, the mechanism of sarcospan-mediated rescue is unknown. Here, we show that the rescue effect is dependent on both α 7 integrin and utrophin, which in turn determine muscle cell binding to laminin in the extracellular matrix. Since sarcospan over-expression stabilizes the utrophin–glycoprotein complex and α 7 β 1 integrin at the sarcolemma, we investigated the possibility that sarcospan acts synergistically between both complexes. We biochemically isolated a macromolecular complex containing α 7 β 1 integrin and the utrophin–glycoprotein complex. Using several double- and triple-knockout mice, we discovered that integrin and sarcospan synergistically contribute to utrophin-glycoprotein complex function by promoting interactions between α - and β -dystroglycan, thereby disturbing laminin connections. Our data highlights the importance of both α 7 β 1 integrin and utrophin for sarcospan rescue of mdx dystrophic pathology.