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Background Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. Results Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608–0.707, OR 2.37–5.71) than for African individuals (AUC 0.502–0.585, OR 0.95–2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. Conclusions Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

INTRODUCTION AND OBJECTIVE:Men of African descent have the highest burden of aggressive prostate cancer (PCa). However, the clinical features of PCa within sub-Saharan Africa (SSA) are understudied...

Author(s): Sun, Matthew Z; Babayan, Diana; Chen, Jia-Shu; Wang, Maxwell M; Naik, Priyanka K; Reitz, Kara; Li, Jingyi Jessica; Pouratian, Nader; Kim, Won | Abstract: BackgroundThe neurointensive care unit (NICU) has traditionally been the default recovery unit after elective craniotomies.ObjectiveTo assess whether admitting adult patients without significant comorbidities to the neuroscience ward (NW) instead of NICU for recovery resulted in similar clinical outcome while reducing length of stay (LOS) and hospitalization cost.MethodsWe retrospectively analyzed the clinical and cost data of adult patients undergoing supratentorial craniotomy at a university hospital within a 5-yr period who had a LOS less than 7 d. We compared those admitted to the NICU for 1 night of recovery versus those directly admitted to the NW.ResultsThe NICU and NW groups included 340 and 209 patients, respectively, and were comparable in terms of age, ethnicity, overall health, and expected LOS. NW admissions had shorter LOS (3.046nvs 3.586 d, Pnln.001), and independently predicted shorter LOS in multivariate analysis. While the NICU group had longer surgeries (6.8nvs 6.4 h), there was no statistically significant difference in the cost of surgery. The NW group was associated with reduced hospitalization cost by $3193 per admission on average (Pnln.001). Clinically, there were no statistically significant differences in the rate of return to Operating Room, Emergency Department readmission, or hospital readmission within 30 d.ConclusionAdmitting adult craniotomy patients without significant comorbidities, who are expected to have short LOS, to NW was associated with reduced LOS and total cost of admission, without significant differences in postoperative clinical outcome.

Background: Allogeneic HCT continues to be the optimal consolidation strategy for many patients with AML. Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes. We tested the prognostic ability of a modified (mELN) classification system based on available CIBMTR genetic data, to predict post-transplant outcomes. Methods: Adult patients with a diagnosis of AML in first complete remission (CR1) with available pre-transplant cytogenetic and molecular mutational data, receiving a first allogeneic HCT from 2013-2017, were included. Patients were stratified according to mELN genetic classification in three distinct groups: favorable (Fav), intermediate (IM) and adverse (Adv). Clinical outcomes following HCT were compared among groups after adjusting for significant patient, disease, and transplant-related variables. The primary endpoint was disease free survival (DFS). Secondary endpoints were overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse, acute GVHD, and chronic GVHD. Cox proportional hazard models were used to compare endpoints among mELN risk groups, age groups and genetic subsets within the adverse-risk group. Results: Demographic characteristics are summarized in Table 1. 2289 patients (Fav, n=181; IM n=1185; and Adv n=923) met the inclusion criteria. Median follow-up for survivors was 35 months. Importantly, 41% of transplant recipients (n=936) were >60 years, 76% (n=1743) had de novo AML and 48% (n=1111) received a myeloablative conditioning regimen. Univariate analysis (UVA) demonstrated significant differences in 2-year OS (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p Initial multivariate analysis (MVA) of mELN risk groups indicated that there was no significant difference in clinical outcomes between the Fav and IM risk groups. Thus, these groups were combined for subsequent analyses. Adv risk (vs. Fav/IM) led to significantly worse OS (HR 1.39 [1.24-1.57] p= This mELN classification effectively stratified both younger (60 y/o) patients for OS (Adv vs. Fav/IM HR for 60: 1.44 [1.21-1.72] p60: 1.41 [1.19-1.66] p60: 1.42 [1.15-1.76] p=0.001). NRM was higher for older patients (>60 y/o) in both the Fav/IM (HR 1.40 [1.10-1.78] p=0.007) and Adv-risk cohorts (HR 1.59 [1.18-2.13] p=0.002). Genetic subset comparisons within the adverse-risk group showed that patients carrying monosomy 5, del(5q) or monosomy 7 had inferior 2-year OS (42.6%, p Conclusion: Stratification using mELN criteria resulted in clear prognostic separation of OS, DFS and relapse in this large cohort of AML patients undergoing allogeneic HCT. While Fav and IM groups had similar OS, DFS and relapse rates; patients in the Adv risk group had the highest risk of relapse and inferior DFS/OS. However, the majority of patients in all cohorts had favorable outcomes for HCT in CR1. Our findings confirm the value of a combined genetic prognostic model in the AML HCT setting and justify the use of this stratification system in future HCT trials. Correlation of genetic subtypes with other important transplant variables, such as conditioning intensity and pre-transplant MRD status deserves further evaluation. There remains a subset of Adv-risk patients for which post-transplant outcomes continue to be poor, even when transplanted in CR1. Novel peri-transplant pre-emptive/therapeutic strategies are urgently needed for this high-risk cohort. Disclosures de Lima: Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Komanduri:Kiadis: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Ziopharm: Other: Research Support; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Bhatt:National Marrow Donor Program: Research Funding; Rigel Pharmaceuticals: Other; Jazz: Research Funding; Agios: Other: Personal Fees; Incyte: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees; Partner Therapeutics: Other: Personal Fees; Pfizer: Other, Research Funding; CSL Behring: Other; Tolero Pharmaceuticals: Research Funding; Oncoceutics: Other: Drug support for a trial; Partnership for health analytic research, LLC: Other: Personal Fees; Omeros: Other: Personal Fees; Abbvie: Other: Personal Fees, Research Funding. Saad:Orcabio: Other: research support; Kadmon: Other: research support; Amgen: Other: research support; Incyte Pharmaceuticals: Other: Personal Fees; Magenta Therapeutics: Other: Personal Fees. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy.

Current scar surveys have included many questions to evaluate the physical characteristics of scars, with some expanding to include physical implications and patient opinions. This review provides an analysis of frequently used scar assessment methods to date and highlights potential areas for improvement. We build the case that a new assessment tool is necessary, specifically one that centers on psychosocial consequences of scars that influence patient decision making for treatment, allowing physicians to individualize treatment conversations with patients. We postulate that survey techniques used in consumer product marketing, such as choice-based conjoint analysis, may be effective in determining the factors strongly influencing patient decision making and spending in scar treatment; therefore, more research in this area is warranted. By incorporating these psychosocial and economic considerations driving scar treatment decisions, future scar assessment tools may accomplish much more than characterizing/documenting the clinical aspects of scars. Rather, these patient-centered, holistic tools may be implemented by plastic surgeons and other clinicians specifically to provide patients with personalized treatment options that maximize long-term patient satisfaction.

The field of remote sensing is undergoing rapid changes through the utilization of unmanned aerial vehicle (UAV) technology. The rise of this new technology and the corresponding growth in the application of digital aerial photogrammetric point clouds (DAP) require renewed investigation into individual tree detection (ITD) routines; most of which have been developed for airborne laser scanning (ALS) and traditional aerial imagery. This article analyzes the application of a well-known ALS-ITD routine to UAV-acquired DAP. In particular, specific modifications are proposed and evaluated aimed at improving its applicability to DAP, with particular emphasis on the incorporation of spectral information through subcrown scale k-means clustering. The new routine, which utilizes point-level spectral information in the clustering process, improved overall true positive detection by ∼6.3%, with the most significant improvements in true positive detection found in lower canopy class stems. The new routine was also tested without the inclusion of spectral information and was shown to produce poorer results by ∼4.1%, indicating that the inclusion of these data is beneficial for ITD approaches. This new routine represents an advancement of processing approaches incorporating both structural and spectral components for ITD in the era of UAV remote sensing in forested environments.

Aim: To determine the relationship between maternal serum 25(OH) D concentrations and development of preeclampsia. Study Design: A cross sectional comparative study. Place and Duration of Study: Department of Obstetrics and Gynaecology, University of Abuja Teaching Hospital, Abuja, between March 2016 and February 2017. Methodology: We included 55 women with preeclampsia and 55 healthy women. Data obtained included sociodemographic characteristics, clothing style and duration of exposure to sun light. ELISA method was used for evaluation of serum vitamin D levels. Results: The prevalence of VD deficiency in the population was 15%, while 16.8% and 73% of the participants had insufficient and normal levels respectively. The prevalence of VD deficiency in women with preeclampsia was 20.4% while that in healthy pregnant women was 9.4% (P=.19). The mean serum 25-OH-D level of women with pre-eclampsia was significantly lower than that of healthy women (34.5±14.9 vs. 43.5±15.1, P = .003). Preeclamptic women with vitamin D insufficiency delivered at a higher gestational age than those with vitamin D deficiency (37.67(2.77) weeks vs. 33.55(2.38) weeks respectively, P = .007). In the adjusted analysis of cases with vitamin D defficiency, the odds of developing preeclampsia was not statistically significant [odds ratio (OR) = 3.27, CI = 0.99-10.83, P =.05]. However, the odds of developing preeclampsia in women with Vitamin D insufficiency was statistically significant (OR = 3.20, CI = 1.02–10.06, = 0.046). Conclusion: In conclusion, an association between vitamin D deficiency and preeclampsia was not demonstrated in this study. The results however suggest that maternal vitamin D insufficiency in late pregnancy is an independent risk factor for preeclampsia.

A sustained policy press to improve quality and reduce disparities in public education is driving U.S. public school districts to organize and manage instruction for excellence and equity. The purpose of this analysis is to elaborate and to animate patterns and dilemmas in this work. The analysis identifies five domains of work central to this transformation, four patterns in the distribution of this work among central offices and schools, and four dilemmas endemic to the work. It then uses the preceding to frame vignettes of that work and those dilemmas as playing out in four different public school districts.

Long-term cooperation between individuals necessitates repairing damage arising from inevitable competing interests. How two members of a valuable relationship switch from competing to cooperating constitutes an important problem for any social species. Observations of non-human animals suggest that affiliative contact immediately following a contest facilitates continued cooperation. Behavioral studies further indicate that winners and losers frequently differ in hormonal changes following a competition. We tested the hypothesis that immediate contact with increases in cortisol (and testosterone for men) for winners following competition would facilitate subsequent cooperation between adult same-sex friends. Results show that contact (versus no contact) immediately following competition enhanced subsequent cooperation between female friends. During contact, increases in winner's cortisol for both sexes, and in testosterone for men, predicted future cooperation. Our results suggest two mechanisms that maintain social bonds following competition between established allies.

Online technologies hold promise to support more personalized teacher professional development (PD) experiences, but fulfilling this promise requires heightened attention to what teachers value about the outcomes of their learning. This paper uses the example of the Creative Computing Online Workshop (CCOW) to explore outcomes that teachers described as valuable: exposure to new ideas, rethinking classroom practice, and new relationships with their surrounding world. We discuss how the diversity, specificity, and nonlinearity of these outcomes extend teacher PD research, and suggest implications of this expanded framework for the design and evaluation of PD in both in-person and online contexts.

A comprehensive database of the optical response in the form of complex dielectric function (e) spectra of magnetron co-sputtered CdSe1−xSx alloy thin films is developed spanning the full 0 ≤ x ≤ 1 range of compositions. A parametric model is presented and used to determine e describing each film while in both as-deposited and thermally annealed states. This model combines a critical point electronic transition lineshape and an Urbach tail in the above- and below-bandgap portions of the measured spectrum, respectively, while maintaining first derivative continuity. Additionally, this hybrid parametric description of e automatically determines the Urbach energy (EU) describing the width of the sub-bandgap absorption tail, thereby providing a relative measure of the defect density of the modeled material. These as-deposited CdSe1−xSx films are generally found to be the most defective at intermediate compositions with some EU reaching energies > 200 meV. Annealing reduces EU in all films to a relatively uniform value

A critical part of the development of CXCR4 modulators is to have a simple and sensitive assay system to complement the search by screening and evaluating the binding affinity. Herein, a NanoBRET assay system was developed, and its feasibility as a high-throughput screening tool for potent CXCR4 ligands was ascertained. TAMRA-Ac-TZ14011, a fluorescent-labeled CXCR4 antagonist, was adopted as a fluorescent acceptor of bioluminescent energy from N-terminally fused NanoLuc-CXCR4 stably expressed in CHO cells. The ratio of fluorescence at 620 nm to the luminescence at 460 nm represents the interaction between test compounds and CXCR4. We have demonstrated in the present study that the NanoBRET assay system is applicable for the evaluation of CXCR4 ligands using the combination of TAMRA-Ac-TZ14011 as an acceptor and NanoLuc tagged to CXCR4 as a bioluminescent donor expressed in living cells. IC50 values of known CXCR4 ligands were determined and found to be compatible with the values obtained by other existing and sensitive methods, such as SDF-1:3.2 nM, Ac-TZ14011:15.3 nM, and FC131:4.5 nM, which confirmed the feasibility of our system ( Z' values ≥0.5). The introduction of an IL-6 secretory signaling peptide (secNluc-CXCR4) further enhanced the expression and trafficking of the tagged receptor, which, in turn, increased the dynamic range of the NanoBRET assay system. Thus, we have successfully developed a NanoBRET system in living cells, which is simple, homogeneous, and useful in multiwell plate screening of potent CXCR4 ligands.

In the early 1990s, the logic and policies of systemic reform launched a press to coordinate the pursuit of excellence and equity in U.S. public education, with each other and with classroom instruction. There was little in that policy moment to predict that these reforms would sustain, and much to predict otherwise. Yet, nearly three decades hence, many public school districts are working earnestly to pursue the central aims of the reforms: all students engaging rich instructional experiences to master ambitious content and tasks at the same high standards. That begs a question: What happens when new educational ambitions collide with legacy educational institutions—not in a policy moment but across a historical moment? This chapter takes up that question by reviewing the rise of mass public schooling in pursuit of universal access, a historic pivot toward instructionally focused education systems in pursuit of excellence and equity, and changing patterns in instructional organization and management that follow. The lesson we draw is that, even amid incoherence and turbulence in education environments, sustained public, political, and policy support for new educational ambitions opens up new opportunities for those ambitions to manifest in the structures and the work of public school districts.

The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5–7.5 A showed potent binding affinity selective for CXCR4 with IC50 values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC50s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.

IMPORTANCE: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P

The fungal plasma membrane H+-ATPase Pma1 is a vital enzyme, generating a proton-motive force that drives the import of essential nutrients. Auto-inhibited Pma1 hexamers in starving fungi are activated by glucose signalling resulting in phosphorylation of the auto-inhibitory domain. As related P-type ATPases are not known to oligomerise, the physiological relevance of Pma1 hexamers remains unknown. We have determined the structure of hexameric Pma1 from Neurospora crassa by cryo-EM at 3.3 Å resolution, elucidating the molecular basis for hexamer formation and auto-inhibition, and providing a basis for structure-based drug development. Coarse-grained molecular dynamics simulations in a lipid bilayer suggest lipid-mediated contacts between monomers and a substantial protein-induced membrane deformation that could act as a proton-attracting funnel.

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P.0001) and the eGFR45 mL/min group (HR, 3.09; P.0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR45 mL/min was associated with an increased overall mortality (HR, 1.63; P.0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.

Additional file 1. Supplementary appendix REMAH Survey Questionnaire.

Chronic graft-versus-host disease (cGvHD) is the most significant late complication of allogeneic hematopoietic cell transplantation (allo-HCT). cGvHD has protean manifestations and impacts long-term mortality, morbidity, disease control, and quality of life. Its worst manifestations may cause irreversible disfigurement, disability, and death. Early recognition and intervention is critical; however, proven treatment options remain limited.