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An incomplete Freund's adjuvant elicited an overt pathogenesis in vaccinated mice following the intranasal challenge of A/California/07/2009 (H1N1) virus despite the induction of a higher specific antibody titer than other adjuvanted formulations. Aluminum hydroxide adjuvants have not induced any pathogenic signs in a variety of formulations with glycolipids. A glycolipid, α-galactosyl ceramide, improved a stimulatory effect of distinct adjuvanted formulations on an anti-influenza A antibody response. In contrast to α-galactosyl ceramide, its synthetic analogue C34 was antagonistic toward a stimulatory effect of an aluminum hydroxide adjuvant on a specific antibody response. The aluminum hydroxide adjuvant alone could confer complete vaccine-induced protection against mortality as well as morbidity caused by a lethal challenge of the same strain of an influenza A virus. The research results indicated that adjuvants could reshape immune responses either to improve vaccine-induced immunity or to provoke an unexpected pathogenic consequence. On the basis of these observations, this research connotes the prominence to develop a precision adjuvant for innocuous vaccination aimed at generating a protective immunity without aberrant responses. [ABSTRACT FROM AUTHOR]

Background: Associations have been found between single nucleotide polymorphisms (SNPs) in the MTHFR gene and cognitive outcomes in cancer survivors. Prior research has demonstrated that the presence of MTHFR SNPs (rs1801131 and rs1801133) in survivors of acute lymphoblastic leukemia (ALL) corresponds to impairments in attention and executive functioning. The current study examines the associations between rs1801131 and/or rs1801133 SNPs and cognitive performance in long-term survivors of medulloblastoma. Procedure: Eighteen pediatric medulloblastoma survivors, on average 12.42 years post-diagnosis, completed the Digit Span Forward, Digit Span Backward, California Verbal Learning Test Trial 1, and Auditory Consonant Trigrams tests. MTHFR SNPs were detected using whole genome sequencing data and custom scripts within R software. Results: Survivors with a rs1801131 SNP performed significantly worse on Digit Span Backward than survivors without this SNP exhibiting a large effect (p = 0.049; d = 0.95). Survivors with a rs1801131 SNP performed worse on Digit Span Forward (d = 0.478) and the CVLT Trial 1 (d = 0.417) with medium effect sizes. In contrast to rs1801131, relationships were not identified between a rs1801133 SNP and these performance measures. Conclusions: Our findings demonstrate the potential links between MTHFR SNPs and cognitive outcomes following treatment in brain tumor survivors. The current findings establish a novel relationship between rs1801131 and working memory in medulloblastoma. Increases in homocysteine levels and oxidative damage from radiation may lead to adverse long-term outcomes. This establishes the need to look beyond leukemia and methotrexate treatment to consider the risk of MTHFR SNPs for medulloblastoma survivors. [ABSTRACT FROM AUTHOR]

Background: Fusions are increasingly pursued as oncology therapeutic targets. The current study evaluated differences in outcomes for fusion versus nonfusion targets.Methods: Outcomes were compared for patients with fusions versus those with other alterations for US Food and Drug Administration-approved single agents (from package inserts) and for patients treated at the University of California at San Diego.Results: A total of 28 drugs approved by the US Food and Drug Administration (6189 patients) were included in the analysis. The median response rate was 68% versus 50% for fusions versus nonfusion matches (odds ratio [OR], 1.67; P < .0001); solid tumor therapies had an OR of 2.07 (P < .0001) and hematologic therapies had an OR of 3.35 (P < .0001) for fusion versus nonfusion targets. The University of California at San Diego analysis included 79 patients in whom fusions were treated of the 2455 patients screened. Patients matched to fusions were found to have a longer median progression-free survival (PFS) (11.6 months; 95% CI, 4.0-35.4 months) compared with those unmatched to fusions (4.9 months; 95% CI, 3.5-8.8 months) (P = .034). Patients with fusions matched to other alterations present in the tumor had a median PFS that was indistinguishable from that of those patients with fusions who were treated with unmatched therapy (4.0 months vs 5.0 months; P = .75).Conclusions: Significantly higher response rates and a longer PFS were observed when targeting fusions compared with nonfusions. The observations reported in the current study suggest that fusions are important targets and that additional studies are needed to confirm that optimized therapy may require targeting fusions, even in the presence of other alterations. [ABSTRACT FROM AUTHOR]

Background: Patient and community engagement in under-resourced communities is a key issue for precision medicine research. We report proceedings from a community-academic partnered conference in Los Angeles to promote community understanding of precision medicine and generate engagement recommendations.Methods: Planning group review of planning, presentations, and audience discussions from facilitator notes and participant survey data from a one-day conference.Findings: Community-academic planning broadened community participation and presentations. More than 80% of survey participants indicated they would participate in the national precision medicine initiative, and most were willing to share diverse sources of data. Discussions identified trust concerns related to historical research abuses, data privacy, potential effects of findings on health care, personal safety, research procedures, the time-frame for benefit, and confusion about different initiatives. Concerns were balanced by belief in science to improve health. Recommendations included a community partnered participatory approach with support for local community and academic teams to engage stakeholders with written/online resources and partnered workgroups addressing key concerns.Conclusion: Conference participants expressed high willingness to participate in precision medicine studies, but discussions highlighted trust and transparency issues and suggested community partnered research with local capacity building. [ABSTRACT FROM AUTHOR]

Precision cancer care has reduced cancer-related mortality. However, minorities remain less likely to receive precision medicine than White populations with cancer due to language and system-level barriers. Precision medicine knowledge increases involvement in treatment decisions and receipt of such treatment. Few interventions exist that seek to improve precision medicine knowledge among low-income and racial and ethnic minorities with cancer. We designed a randomized controlled trial to evaluate the effectiveness of a community health worker (CHW)-delivered intervention on patients' knowledge of precision medicine in partnership with a community oncology clinic in Monterey County, California. Eligibility includes adults with newly diagnosed, progression or recurrence of cancer, low-income, or racial and ethnic minorities, or uninsured, insured by Medicaid or by a local agricultural employer. We will randomize 110 patients with cancer to the intervention or usual cancer care. The intervention group will be assigned to a CHW who will deliver culturally tailored and personalized education on precision medicine and advance care planning, screen for social determinants of health barriers and connect patients to community resources. The primary outcome is precision medicine knowledge measured by a 6-item survey adapted from Davies at baseline, 3-, 6- and 12-months post-enrollment. Exploratory outcomes include patient satisfaction with decision, activation, health care utilization, and receipt of evidence-based precision medicine care. This trial will assess whether the CHW-led intervention can increase knowledge of precision medicine as well as several exploratory outcomes including receipt of evidence-based cancer care among low-income and racial and ethnic minority adults with cancer. ClinicalTrials.gov Registration # NCT04843332 [ABSTRACT FROM AUTHOR]

Background: Older populations are increasing and comprise a substantial portion of high-altitude travelers. Aging physiology may influence susceptibility to acute mountain sickness, though prior research remains inconclusive. The goal of this study was to investigate the relationship between increasing age and acute mountain sickness.Methods: This study was a pooled analysis of 5 prospective randomized controlled trials conducted at White Mountain, California from 2010, 2016-2019 with identical 4-hour rapid ascent from 1242 m to overnight sojourn at 3810 m. Acute mountain sickness was defined by the 2018 Lake Louise Questionnaire criteria.Results: There were 491 participants analyzed, 234 (48%) diagnosed with acute mountain sickness and 71 (14%) with moderate acute mountain sickness. Mean age was 37 years (±13). There was no significant correlation between Lake Louise Questionnaire severity and age (r = -0.02; 95% confidence interval [CI], -0.11-0.07, P = .7), 40-year-old dichotomy (t = -0.6; 95% CI, -0.53-0.28, P = .6), or decade of life (P = .4). Logistic regression found no increased odds of acute mountain sickness for increasing age by decade of life (odds ratio [OR] 1.0; 95% CI, 0.97-1.0) or 40-year-old dichotomy (OR 1.4; 95% CI, 0.97-2.1). A history of acute mountain sickness increased odds of acute mountain sickness (OR 3.2; 95% CI, 1.5-7.7).Conclusions: Older age was not associated with incidence nor severity of acute mountain sickness. A history of altitude illness increased odds of acute mountain sickness and should be used for pre-ascent risk stratification. [ABSTRACT FROM AUTHOR]

Despite an ever-expanding number of analytics with the potential to impact clinical care, the field currently lacks point-of-care technological tools that allow clinicians to efficiently select disease-relevant data about their patients, algorithmically derive clinical indices (eg, risk scores), and view these data in straightforward graphical formats to inform real-time clinical decisions. Thus far, solutions to this problem have relied on either bottom-up approaches that are limited to a single clinic or generic top-down approaches that do not address clinical users' specific setting-relevant or disease-relevant needs. As a road map for developing similar platforms, we describe our experience with building a custom but institution-wide platform that enables economies of time, cost, and expertise. The BRIDGE platform was designed to be modular and scalable and was customized to data types relevant to given clinical contexts within a major university medical center. The development process occurred by using a series of human-centered design phases with extensive, consistent stakeholder input. This institution-wide approach yielded a unified, carefully regulated, cross-specialty clinical research platform that can be launched during a patient's electronic health record encounter. The platform pulls clinical data from the electronic health record (Epic; Epic Systems) as well as other clinical and research sources in real time; analyzes the combined data to derive clinical indices; and displays them in simple, clinician-designed visual formats specific to each disorder and clinic. By integrating an application into the clinical workflow and allowing clinicians to access data sources that would otherwise be cumbersome to assemble, view, and manipulate, institution-wide platforms represent an alternative approach to achieving the vision of true personalized medicine. [ABSTRACT FROM AUTHOR]

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RAS-altered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation., (© 2019 UICC.)

The North American Menopause Society (NAMS) held the 2018 Utian Translational Science Symposium on October 2, 2018, in San Diego, California, to discuss new therapeutic approaches to uterine leiomyomas when surgery is not the optimal choice.Uterine leiomyomas arise from a single clonal cell and are the most common gynecologic disorder affecting reproductive and perimenopausal women worldwide. The prevalence of this disorder is approximately 40% to 70% in white women and 60% to 80% in black women. Recent research suggests that both estrogen and progesterone modulate the growth of leiomyomas, with progesterone being a major stimulator of leiomyoma growth.Women with symptomatic uterine leiomyomas experience heavy uterine bleeding, bulk symptoms, miscarriages, and pregnancy complications. Surgical therapies such as myomectomy or hysterectomy are highly effective; however, medical therapy with progestin-predominant contraceptives or gonadotropin-releasing hormone (GnRH) agonists are in many ways inadequate to address the unmet need for better, noninvasive, and cost-effective treatments.Recent advances in medical treatment, such as selective progesterone receptor modulators, new oral GnRH analogs, and clinical trials that provide new therapeutic approaches, were presented by speakers at the symposium. Research on why there is a prevalence of leiomyomas in black women, the racial and genetic effects on leiomyoma growth, and potential molecular mechanisms also were discussed.

Sharing massive amounts of medical data is critical to precision medicine. The California Department of Public Health recently started to partner with certain hospitals in the state to better understand cancer trends by collecting and securely sending standardized cancer data directly to the California Cancer Registry. This initiative is the first of its kind in the United States. This has afforded the cancer registry the opportunity to perform real-time surveillance on data reported via participating hospitals, and researchers can use advanced methods to analyze these data. Other states are likely to follow California's lead. However, there are barriers to increased data-sharing efforts. How these barriers can be addressed to facilitate data sharing while protecting individual privacy, reducing the risk of data misuse, and enhancing public trust becomes critical as precision medicine moves forward.

A goal of the Precision Medicine Initiative All of Us Research Program (AoURP) is recruitment of participants who reflect the diversity of the US. Recruitment from among blood bank donors, which may better reflect the demographic makeup of local communities, is one proposed strategy. We evaluated this strategy by analyzing the results of a survey of San Diego Blood Bank donors conducted in November 2015. Whites were more likely than nonwhites to respond to the survey (7.1 percent versus 3.9 percent). However, race was not a significant predictor of interest in participating in precision medicine research. Using census data linked to donors' ZIP codes, we also found that people who indicated interest in research participation were more likely to come from regions with higher educational attainment. Although blood banks represent a viable recruitment strategy for AoURP, our findings indicate that bias toward inclusion of whites and more highly educated people persists.

Many Americans are attempting to lose weight with the help of healthcare professionals. Clinicians can improve weight loss results by using technology. Accurate dietary assessment is crucial to effective weight loss. The aim of this study was to validate a computer-led dietary assessment method in overweight/obese women. Known dietary intake was compared to Automated Self-Administered 24-h recall (ASA24) reported intake in women ( n = 45), 19-50 years, with body mass index of 27-39.9 kg/m². Participants received nutrition education and reduced body weight by 4%-10%. Participants completed one unannounced dietary recall and their responses were compared to actual intake. Accuracy of the recall and characteristics of respondent error were measured using linear and logistic regression. Energy was underreported by 5% with no difference for most nutrients except carbohydrates, vitamin B12, vitamin C, selenium, calcium and vitamin D ( p = 0.002, p < 0.0001, p = 0.022, p = 0.010, p = 0.008 and p = 0.001 respectively). Overall, ASA24 is a valid dietary assessment tool in overweight/obese women participating in a weight loss program. The automated features eliminate the need for clinicians to be trained, to administer, or to analyze dietary intake. Computer-led dietary assessment tools should be considered as part of clinician-supervised weight loss programs.

Purpose: In this article, we examine the effectiveness of a variety of HIV diagnosis interventions in recently HIV-diagnosed men who have sex with men (MSM). These interventions use the preventive potential of postdiagnosis behavior change (PDBC), as measured by the reduction in the number of new infections. Empirical evidence for PDBC was presented in the behavioral substudy of the Southern California Acute Infection and Early Disease Research Program. In previous modeling work, we demonstrated the existing preventive effects of PDBC. However, a large proportion of new infections among MSM are either undiagnosed or diagnosed late, and the preventive potential of PDBC is not fully utilized., Methods: We derive empirical, stochastic, network-based models to examine the effectiveness of several diagnosis interventions that account for PDBC among MSM over a 10-year period. These interventions involve tests with shorter detection windows, more frequent testing, and individualized testing regimens., Results: We find that individualized testing interventions (i.e., testing individuals every three partners or 3 months, whichever is first, or every six partners or 6 months, whichever is first) result in significantly fewer new HIV infections than the generalized interventions we consider., Conclusions: This work highlights the potential of individualized interventions for new public health policies in HIV prevention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Molecular testing of patients with advanced non-small cell lung cancer for personalized therapy often is limited by insufficient specimen from nonsurgical biopsies. We measured the feasibility, patient safety, and clinical impact of thoracic surgical tumor biopsy in patients with stage IV non-small cell lung cancer., Methods: This is a single institution retrospective analysis. Patients with stage IV non-small cell lung cancer undergoing elective surgical tissue biopsy for molecular analysis were evaluated from March 2011 to November 2012. Perioperative specific variables were measured., Results: Twenty-five patients with known or suspected stage IV non-small cell lung cancer undergoing surgical biopsy were identified. All cases were discussed at a multidisciplinary thoracic oncology conference or a multidisciplinary thoracic oncology clinic. Preoperative histologies included adenocarcinoma in 20 patients (80.0%) and squamous cell carcinoma in 2 patients (8.0%). Surgical procedures consisted of video-assisted thoracic surgery wedge biopsy (16, 64%), video-assisted thoracic surgery pleural biopsy (4, 16.0%), mediastinoscopy (2, 8.0%), supraclavicular/cervical lymph node excisional biopsy (3, 12.0%), and rib/chest wall resection (2, 8.0%). There were no deaths and 5 postoperative complications (20.0%). Surgery identified potentially targetable molecular information in 19 of the total patients undergoing operation (76.0%) and changed the treatment strategy in 14 patients (56.0%); 10 of the total cohort (40.0%) were enrolled into therapeutic targeted clinical trials., Conclusions: These data suggest that thoracic surgical biopsy can be safely performed in appropriately selected patients with stage IV non-small cell lung cancer and direct personalized therapy and enrollment into relevant clinical trials. Patients with advanced-stage non-small cell lung cancer should be discussed in a multidisciplinary setting to determine the need and strategy for thoracic surgical biopsy for molecular analysis., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Rapidly evolving genetic and genomic technologies for genetic cancer risk assessment (GCRA) are revolutionizing the approach to targeted therapy and cancer screening and prevention, heralding the era of personalized medicine. Although many academic medical centers provide GCRA services, most people receive their medical care in the community setting. However, few community clinicians have the knowledge or time needed to adequately select, apply, and interpret genetic/genomic tests. This article describes alternative approaches to the delivery of GCRA services, profiling the City of Hope Cancer Screening & Prevention Program Network (CSPPN) academic and community-based health center partnership as a model for the delivery of the highest-quality evidence-based GCRA services while promoting research participation in the community setting. Growth of the CSPPN was enabled by information technology, with videoconferencing for telemedicine and Web conferencing for remote participation in interdisciplinary genetics tumor boards. Grant support facilitated the establishment of an underserved minority outreach clinic in the regional County hospital. Innovative clinician education, technology, and collaboration are powerful tools to extend GCRA expertise from a National Cancer Institute-designated Comprehensive Cancer Center, enabling diffusion of evidenced-base genetic/genomic information and best practice into the community setting.