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BackgroundAlthough colorectal cancer (CRC) is traditionally considered to be immunologically inert, some subsets of colorectal cancer, particularly mismatch repair-deficient (MMRd) tumors, can be highly responsive to immune checkpoint blockade (ICB). Recent studies show -that even mismatch repair-proficient (MMRp) tumors can respond to combined PD-1/CTLA-4 ICB. Tumor-associated macrophages (TAMs) are an influential component of the tumor microenvironment (TME), although the exact role of these immune cells in tumor pathogenesis and progression remains enigmatic. TAMs are highly heterogenous and can be either pro-inflammatory or anti-inflammatory, and thus exhibit anti-tumorigenic or pro-tumorigenic effects respectively. Signal regulatory protein α (SIRPα) is a transmembrane protein expressed on TAMs that binds to CD47 on target cells, eliciting a ‘don’t-eat-me’ signal that inhibits phagocytosis by macrophages. In preclinical studies, anti-SIRPα antibodies have been shown to induce macrophage-dependent anti-tumor activity and skew macrophages towards an anti-tumorigenic phenotype. Since colorectal cancer lesions are often dominated by both T cells and anti-inflammatory TAMs, combination therapy with an anti-SIRPα antibody and an anti-PD-1 antibody may result in synergistic killing of tumor cells by TAMs and T cells.MethodsThis phase I, open-label, parallel-cohort, single-center trial (NCT05446129) was designed to assess the safety, feasibility, clinical efficacy, and biological activity of BI-765063 (an anti-SIRPα antibody) in combination with either ezabenlimab (Cohort A) or pembrolizumab (Cohort B), both anti-PD-1 antibodies, in patients with early-stage, resectable CRC (figure 1). Each cohort will enroll 25 patients. Treatment will be given as a single-dose in the neoadjuvant setting. All patients will then be scheduled to undergo surgical resection 2 to 6 weeks after treatment administration. The primary endpoint is a composite safety and feasibility endpoint, defined as the proportion of patients exhibiting any grade-3 or higher treatment-related adverse event or any treatment-related adverse event delaying surgery more than 6 weeks after treatment administration. The secondary endpoints include pathological response, defined as 50% or greater tumor regression, time from treatment administration to surgery, and radiographic response. Tissue, blood, and stool will be collected prior to treatment administration and at the time of resection. Immune monitoring will be performed using multiplex and single-cell analysis platforms to define the immunodynamic effects of these therapies.Trial RegistrationClinicalTrials.gov Identifier: NCT05446129Ethics ApprovalOn 9/23/2022 an Institutional Review Board of the Mount Sinai School of Medicine, in accordance with Mount Sinai’s Federal Wide Assurances (FWA#00005656, FWA#00005651) to the Department of Health and Human Services approved the human subject research (ID 1502–0001; PRMC-22–037; STUDY-22–00928) from 9/23/2022 to 9/19/2023.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 650 Figure 1Trial schema for neoadjuvant ezabenlimab or pembrolizumab with anti-SlRPα antibody

In Philadelphia, more than 70,000 adults have started college, earned some college credit, but never completed a degree; in the greater Philadelphia region, over 320,000 adults have started college but never finished. In 2005, recognizing the significance of this population, Sallie Glickman, CEO of the Philadelphia Workforce Investment Board; David Thornburgh, then Executive Director of the Pennsylvania Economy League; and Hadass Sheffer, then Director of Higher Education Fellowships and Program Development at the Woodrow Wilson Foundation, combined their backgrounds in workforce development, economic development, and higher education to create Graduate! Philadelphia (G!P), an innovative organization that is committed to increasing the number of adults with college degrees in the greater Philadelphia region.G!P’s innovation is to create a general awareness messaging campaign and targeted outreach to adults (“Comebackers”) with some college credit but no degree, matching these adults with a dedicated advisor in order to create a plan for completing a college degree efficiently and expeditiously, and providing continuous comprehensive support to these individuals until degree attainment. G!P succeeds in supporting these adults through the creation of strategic partnerships with colleges, workforce and economic development organizations, and other support resources that have historically been separated by institutional and theoretical boundaries around an adult-focused college completion agenda. Finally, G!P pursues systematic public policy initiatives that will better support higher education learners of all ages, but in particular the population G!P is targeting.G!P aligns systems and fills in gaps in resources to enable adults to go through college more efficiently and successfully. Adults are an important regional focus in three ways. First, they have a more immediate impact on the workforce, as they may be already employed or of an age to join the workforce; second, they tend to have stronger local connections and therefore are more apt to look for work in the region; and third, they are role models for their children and peers in their families and communities and tend to create a multiplier effect by helping others get to and through college.Focusing first on adults with some college credit but no degree helps a region and the individuals achieve faster outcomes because these students have a shorter path to completion than those who have not yet started college. The systems and practices perfected for the Comebackers can then be adapted into more productive pathways for adults who have never attended college. By partnering with employers, organized labor, community-based organizations, colleges, foundations, and government agencies in the greater Philadelphia region, G!P is improving not only the earning potential of those who participate in its programs, but also the region’s competitive advantage by developing a labor pool. With every graduate that G!P supports, this innovative model is proving that the competitive educational position of the United States can be advanced. By applying the G!P model and helping Comebackers graduate, other regions can achieve better economic outcomes for their populations.David Fair is co-managing partner of Graduate! Philadelphia. As Senior Vice President for Community Impact at the United Way of Southeastern Pennsylvania, David was uniquely positioned to support the formation of G!P. When Graduate! Philadelphia was first evolving, United Way was expanding its work from its well-known fundraising campaigns to include the mobilization of communities in Philadelphia. G!P’s mission aligned perfectly with this shift in focus. David is excited about G!P because never before have business and higher education been brought together quite like they have in this model. He suggests that although building this partnership seems so obvious in retrospect, no one had attempted it. David highlights the sophisticated multifaceted approach: “This problem is not hard to fix or expensive to fix…we just had never thought to mobilize these different sectors of society to support individuals to build a better and stronger Philadelphia.”Sallie Glickman is a co-founder and co-managing partner of Graduate! Philadelphia. As the Chief Executive Officer of the Philadelphia Workforce Development Board, Sallie focuses on achieving social justice through the development of the workforce, which Sallie calls a fundamental human right. Providing opportunities for people to succeed in higher education best fosters this development. Sallie calls G!P a “game changer” because of its focus on college completion, rather than focusing simply on access. In order for individual and community economic vitality to exist, Sallie believes “everyone who aspires to have a college degree should have that opportunity.” G!P is helping people connect to and take full advantage of such opportunities. Sallie suggests that in order for G!P to be effective, the movement must continue to focus on three aspects: awareness and advocacy, public policy, and practice. “You need to keep the stool balanced in this higher education movement,” she says.Hadass Sheffer is Founding Executive Director of Graduate! Philadelphia. Hadass is the “glue” of G!P, pushing the initiative ever-forward, often shepherding partnerships across difficult terrain. “Graduate! Philadelphia is more than a good concept and implementation.” she says. “It is proof that collaboration done well can be a powerful tool for innovation and positive change.” She is most proud of the college and employer partners G!P has brought together, the G!P team, and the Comebackers who overcome huge barriers in order to earn their degrees. She sees the work as having just begun, however. “In order to start moving toward the change we envision, we have to work on many levels: institutional, policy, public attitudes, and we must get more individuals everywhere through the system so that while we’re working on changing it, they can help their families and friends get through too.” Once a “tipping point” has been reached, where enough people interested in going to college can find the guidance and supports within their immediate social circle and programs like G!P’s services are needed less urgently, she believes this market of new, savvy, empowered adult learners will itself help drive the necessary changes.Kimberly Stephens was Graduate! Philadelphia’s second employee. In her first few months with G!P she translated the vision of a practice component for G!P into a first-of-its-kind comprehensive program that guides adults from the early decision to return to college to successful graduation. The program she built had to seamlessly integrate institutional structures that had been designed for cutthroat competition; then it had to be introduced to a population that had deep doubts about re-investing in a system that had failed them in the past. “Working in a community college for 16 years,” Kim says, “I met many adults who spoke about their desire to return to school and their internal conflict about making the often-necessary family sacrifices. It was always difficult convincing them that they should focus on themselves and return to school immediately. Had there been a Graduate! Philadelphia at the time, it would have been more convincing to forward them to a reliable resource or articulate to them that there was an organization committed to providing them with supports and services to return to school. And all for free.” In ten years, Kim foresees G!P becoming a national model for attaining the college completion goal set by President Obama, a “Graduate! America” active in all 50 states.David Thornburgh is one of the three co-founders of Graduate! Philadelphia. As Executive Director of the Pennsylvania Economy League, he was interested in exploring ways to develop the human capital potential in Philadelphia to more quickly improve the workforce and economy. David recognized the importance of increasing the number of college graduates for the Philadelphia region. In the early, pre-design phase of G!P, David asked two questions: Is this worth doing, and is this doable? To the first question, David suggests that perhaps the single most important component of the regional economy is an educated workforce. And to the second question, David suggests that for a long time, people have been working to transform the educational system and have failed to make any significant impact. Therefore, David thought, let’s work within the system and help individuals navigate it. David serves as the Chair of the Board of Advisors of Graduate! Philadelphia and is the Executive Director of the Fels Institute of Government at the University of Pennsylvania.

How sad that the provincial government sees fit to spend $5.5 million improving the road between Lake Cowichan and Port Renfrew. The future plan is to link Lake Cowichan and Port Alberni.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = –.48 and –.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function—GSH—and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

BackgroundMetabolomic dysregulation following a meal in overweight individuals with the Metabolic Syndrome (MetS) involves multiple pathways of nutrient storage and oxidation.ObjectiveThe aim of the current study was to perform an acute cross-over intervention to examine the interactive actions of meal glycaemic load (GL) on the dynamic responses of the plasma metabolome in overweight females.MethodsPostmenopausal women [63 ± 1.23y; Healthy (n = 20) and MetS (n = 20)] ingested two differing high-carbohydrate test meals (73 g carbohydrate; 51% energy) composed of either low glycemic index (LGI) or high (HGI) foods in a randomised sequence. Plasma metabolome was analysed using liquid chromatography–mass spectrometry (LC–MS).ResultsIn the overweight women with MetS, there were suppressed postprandial responses for several amino acids (AAs), including phenylalanine, leucine, valine, and tryptophan, p < 0.05), irrespective of the meal type. Meal GL exerted a limited impact on the overall metabolomic response, although the postprandial levels of alanine were higher with the low GL meal and uric acid was greater following the high GL meal (p < 0.05).ConclusionsMetS participants exhibited reduced differences in the concentrations of a small set of AAs and a limited group of metabolites implicated in energy metabolism following the meals. However, the manipulation of meal GL had minimal impact on the postprandial metabolome. This study suggests that the GL of a meal is not a major determinant of postprandial response, with a greater impact exerted by the metabolic health of the individual.Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12615001108505 (21/10/2015)

Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22 degrees C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37 degrees C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22 degrees C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22 degrees C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens.

Background Blast injury emerged as a primary source of morbidity among US military personnel during the recent conflicts in Iraq and Afghanistan, and led to an array of adverse health outcomes. Multimorbidity, or the presence of two or more medical conditions in an individual, can complicate treatment strategies. To date, there is minimal research on the impact of multimorbidity on long-term patient-reported outcomes. We aimed to define multimorbidity patterns in a population of blast-injured military personnel, and to examine these patterns in relation to long-term quality of life (QOL). Methods A total of 1972 US military personnel who sustained a blast-related injury during military operations in Iraq and Afghanistan were identified from clinical records. Electronic health databases were used to identify medical diagnoses within the first year postinjury, and QOL was measured with a web-based assessment. Hierarchical cluster analysis methods using Ward’s minimum variance were employed to identify clusters with related medical diagnosis categories. Duncan’s multiple range test was used to group clusters into domains by QOL. Results Five distinct clusters were identified and grouped into three QOL domains. The lowest QOL domain contained one cluster with a clinical triad reflecting musculoskeletal pain, concussion, and mental health morbidity. The middle QOL domain had two clusters, one with concussion/anxiety predominating and the other with polytrauma. The highest QOL domain had two clusters with little multimorbidity aside from musculoskeletal pain. Conclusions The present study described blast-related injury profiles with varying QOL levels that may indicate the need for integrated health services. Implications exist for current multidisciplinary care of wounded active duty and veteran service members, and future research should determine whether multimorbidity denotes distinct post-blast injury syndromes.

During the Millennium Development Goal (MDG) era, many countries in Africa achieved marked reductions in under-5 and neonatal mortality. Yet the pace of progress toward these goals substantially varied at the national level, demonstrating an essential need for tracking even more local trends in child mortality. With the adoption of the Sustainable Development Goals (SDGs) in 2015, which established ambitious targets for improving child survival by 2030, optimal intervention planning and targeting will require understanding of trends and rates of progress at a higher spatial resolution. In this study, we aimed to generate high-resolution estimates of under-5 and neonatal all-cause mortality across 46 countries in Africa. We assembled 235 geographically resolved household survey and census data sources on child deaths to produce estimates of under-5 and neonatal mortality at a resolution of 5 × 5 km grid cells across 46 African countries for 2000, 2005, 2010, and 2015. We used a Bayesian geostatistical analytical framework to generate these estimates, and implemented predictive validity tests. In addition to reporting 5 × 5 km estimates, we also aggregated results obtained from these estimates into three different levels—national, and subnational administrative levels 1 and 2—to provide the full range of geospatial resolution that local, national, and global decision makers might require. Amid improving child survival in Africa, there was substantial heterogeneity in absolute levels of under-5 and neonatal mortality in 2015, as well as the annualised rates of decline achieved from 2000 to 2015. Subnational areas in countries such as Botswana, Rwanda, and Ethiopia recorded some of the largest decreases in child mortality rates since 2000, positioning them well to achieve SDG targets by 2030 or earlier. Yet these places were the exception for Africa, since many areas, particularly in central and western Africa, must reduce under-5 mortality rates by at least 8·8% per year, between 2015 and 2030, to achieve the SDG 3.2 target for under-5 mortality by 2030. In the absence of unprecedented political commitment, financial support, and medical advances, the viability of SDG 3.2 achievement in Africa is precarious at best. By producing under-5 and neonatal mortality rates at multiple levels of geospatial resolution over time, this study provides key information for decision makers to target interventions at populations in the greatest need. In an era when precision public health increasingly has the potential to transform the design, implementation, and impact of health programmes, our 5 × 5 km estimates of child mortality in Africa provide a baseline against which local, national, and global stakeholders can map the pathways for ending preventable child deaths by 2030. Bill & Melinda Gates Foundation.

Purpose To examine the relationship between deployment-related concussion and long-term health-related quality of life (HRQoL) among injured US military personnel. Methods The study sample included 810 service members with deployment-related injuries between 2008 and 2012 who responded to a web-based longitudinal health survey. Participants were categorized into three injury groups: concussion with loss of consciousness (LOC; n  = 247), concussion without LOC ( n  = 317), or no concussion ( n  = 246). HRQoL was measured using the 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS) scores. Current post-traumatic stress disorder (PTSD) and depression symptoms were examined. Multivariable linear regression models assessed the effects of concussion on PCS and MCS scores, while controlling for covariates. Results A lower PCS score was observed in participants with concussion with LOC ( B  =  − 2.65, p  = 0.003) compared with those with no history of concussion. Symptoms of PTSD (PCS: B  =  − 4.84, p  < 0.001; MCS: B  =  − 10.53, p  < 0.001) and depression (PCS: B  =  − 2.85, p  < 0.001; MCS: B  =  − 10.24, p  < 0.001) were the strongest statistically significant predictors of lower HRQoL. Conclusion Concussion with LOC was significantly associated with lower HRQoL in the physical domain. These findings affirm that concussion management should integrate physical and psychological care to improve long-term HRQoL and warrant a more detailed examination of causal and mediating mechanisms. Future research should continue to incorporate patient-reported outcomes and long-term follow-up of military service members to further define the lifelong impact of deployment-related concussion.