Recent publications
This paper presents a systematic literature review and bibliometric analysis focusing on Biased Random-Key Genetic Algorithms (BRKGA). BRKGA is a metaheuristic framework that uses random-key-based chromosomes with biased, uniform, and elitist mating strategies alongside a genetic algorithm. This review encompasses around 250 papers, covering a diverse array of applications ranging from classical combinatorial optimization problems to real-world industrial scenarios, and even non-traditional applications like hyperparameter tuning in machine learning and scenario generation for two-stage problems. In summary, this study offers a comprehensive examination of the BRKGA metaheuristic and its various applications, shedding light on key areas for future research.
In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10⁻³⁴, OR = 8.65, 95% CI 6.11–12.25), but not with CL/P (P = 7.2 × 10⁻⁵), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10⁻²⁸) and Estonia (P = 1.25 × 10⁻⁵). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.
BACKGROUND
Mitral annular calcification with valve dysfunction remains a challenging syndrome. Operative risk is high, and available transcatheter therapies are limited.
METHODS
This study describes our initial experience with a novel procedure to address large mitral annuli when no surgical or trial-based transcatheter mitral valve replacement device is available. The rationale was to shorten the intercommissural distance using commissural mitral transcatheter edge-to-edge repair (TEER) followed by valve-in-mitral annular calcification transcatheter mitral valve replacement with a balloon-expandable aortic valve platform. Patients with long intercommissural distances and large mitral annulus areas were selected based on a high perceived risk of transcatheter valve embolization. Patients underwent mitral TEER with MitraClip in a commissural position, followed immediately by transseptal transcatheter mitral valve replacement with a 29 mm SAPIEN 3 valve.
RESULTS
Thirteen patients were included. Median intercommissural distance and annular area were 39.1 mm and 930 mm ² , respectively. Commissural mitral TEER was successful in all patients with no instances of single leaflet detachment. In 10 of 13 instances, an NTW device size was used. In 12 of 13 patients, valve implantation was successful, including 1 case that required a second valve for atrial positioning of the first valve. In 1 case, frank valve embolization into the left atrium occurred. Among the 12 successful cases, paravalvular leak was 1+ or less, and there were no instances of paravalvular leak adjacent to the TEER device.
CONCLUSIONS
In patients with large annuli and sufficient annular calcium, a hybrid mitral TEER and valve replacement with the SAPIEN platform can be successfully used to facilitate transcatheter mitral valve replacement.
Objective
To quantify recent trends in access to timely, high-quality, affordable surgical care in the US.
Background
Insufficient access to surgical care remains an ongoing concern in the US. Previous attempts to understand and quantify barriers in access to surgical care in the US lack a comprehensive, policy-relevant lens.
Methods
This observational cross-sectional study evaluates multiple domains of access to surgical care across the US from 2011-2015 and 2016-2020. Our stepwise model included timeliness (<60-minute drive time), quality (surgically capable hospital with ≥3 CMS stars), and affordability (neither uninsured nor underinsured) of access to surgical care using a novel combination of data from the American Hospital Association, Medicare claims, CMS’s Five-Star Quality Rating System, the American Community Survey, and the Medical Expenditure Panel Survey.
Results
The number of Americans lacking access to timely, high-quality, affordable surgical care increased from 97.7 million in 2010-2015 to 98.7 million in 2016-2020. Comparing these two periods, we found improvements in the number of Americans lacking access due to being uninsured (decrease from 38.5 to 26.5 million). However, these improvements were offset by increasing numbers of Americans for whom timeliness (increase from 9.5 to 14.1 million), quality (increase from 3.4 to 4.9 million), and underinsured status (increase from 46.3 to 53.1 million) increased as barriers to access. Multiple sensitivity analyses using alternative thresholds for each access domain demonstrated similar trends. Those with insufficient access to care tended to be more rural (6.7% vs. 2.0%, P <0.001), lower income (40.7% vs. 30.0%, P <0.001), and of Hispanic ethnicity (35.9% vs. 15.8%, P <0.001).
Conclusions
Nearly one-in-three Americans lack access to surgical care that is timely, high-quality, and affordable. This study identifies the multiple actionable drivers of access to surgical care that notably can each be addressed with specific policy interventions.
Decisions to initiate long-term ventilation (LTV) in children with severe neurologic impairment have recently been subject to candidacy determinations by home ventilation teams that exclude patients based on their neurologic status alone. Determinations of whether decisions are inappropriate require careful analysis of specific clinical circumstances and attention to the family’s values. In this Ethics Rounds, we present a case of a previously healthy child who sustained an acute severe anoxic brain injury and was assessed by the medical team to have a high likelihood of remaining minimally conscious or unconscious. It was determined that he was not a candidate for LTV based on the severity of neurologic impairment. The family disagreed and declined withdrawal of ventilatory support. Drawing upon our backgrounds in intensive care, pulmonology, and bioethics, we offer commentary on utilizing a candidacy-based approach for LTV decisions in children with severe neurologic impairment from variable perspectives, including clinical determinations of inappropriate care, ablest biases and discrimination, and obligations to maintain a just process.
Lipoarabinomannan (LAM) is a promising target biomarker for diagnosing subclinical and clinical tuberculosis (TB). Urine LAM (uLAM) testing using rapid diagnostic tests (RDTs) has been approved for people living with HIV (PLWH), however there is limited data regarding uLAM levels in HIV-negative (HIV-ve) adults with clinical TB. We conducted a clinical study of adults presenting with clinical TB-related symptoms at the National Lung Hospital in Hanoi, Vietnam. The uLAM concentrations were measured using electrochemiluminescent (ECL) immunoassays and compared to a microbiological reference standard (MRS) using GeneXpert Ultra and TB culture testing. Estimated uLAM concentrations above plate specific calculated limit of detection (LOD) were considered uLAM positive. Additional microbiological testing was conducted for possible extrapulmonary TB (EPTB). Among 745 participants enrolled, 335 (44.9%) participants with presumptive pulmonary TB (PTB) and 6 (11.3%) participants with presumptive EPTB had confirmed TB disease. Overall, the S/A antibody pair had a sensitivity of 39% (95% Confidence Interval [CI] 0.33, 0.44) and a specificity of 97% (95% CI 0.96, 0.99) compared to the MRS. The F/A antibody pair had a sensitivity of 41% (95% CI 0.35, 0.47) and a specificity of 79% (95% CI 0.75, 0.84). S/A provided greater discriminatory ability compared to F/A for both individuals with presumptive PTB (AUROC: 0.74 vs 0.63, p<0.0001) and presumptive EPTB (0.76 vs 0.54, p = 0.045) when using the MRS. Among HIV-ve participants in an adult cohort in Vietnam, the concentrations of uLAM remained relatively low for people with clinical TB, which may present challenges for improving RDT sensitivity.
Identifying sources of air pollution exposure is crucial for addressing their health impacts and associated inequities. Researchers have developed modeling approaches to resolve source‐specific exposure for application in exposure assessments, epidemiology, risk assessments, and environmental justice. We explore six source‐specific air pollution exposure assessment approaches: Photochemical Grid Models (PGMs), Data‐Driven Statistical Models, Dispersion Models, Reduced Complexity chemical transport Models (RCMs), Receptor Models, and Proximity Exposure Estimation Models. These models have been applied to estimate exposure from sources such as on‐road vehicles, power plants, industrial sources, and wildfires. We categorize these models based on their approaches for assessing emissions and atmospheric processes (e.g., statistical or first principles), their exposure units (direct physical measures or indirect measures/scaled indices), and their temporal and spatial scales. While most of the studies we discuss are from the United States, the methodologies and models are applicable to other countries and regions. We recommend identifying the key physical processes that determine exposure from a given source and using a model that sufficiently accounts for these processes. For instance, PGMs use first principles parameterizations of atmospheric processes and provide source impacts exposure variability in concentration units, although approaches within PGMs for source attribution introduce uncertainties relative to the base model and are difficult to evaluate. Evaluation is important but difficult—since source‐specific exposure is difficult to observe, the most direct evaluation methods involve comparisons with alternative models.
Background
Recovery from SARS CoV-2 infection is expected within 3 months. Long COVID occurs after SARS-CoV-2 when symptoms are present for more than 3 months that are continuous, relapsing and remitting, or progressive. Better understanding of Long COVID illness trajectories could strengthen patient care and support.
Methods
We characterized functional impairments, quality of life (QoL), and cognition among patients who recovered from SARS-CoV-2 infection within 3 months (without Long COVID), after 3 months (Recovered Long COVID), or remained symptomatic (Long COVID). Among 7305 patients identified with previous SARS-CoV-2 infection between March 2020 and December 2021, confirmed in the medical record with laboratory test or physician diagnosis, 435 (6%) completed a single self-administered survey between March 2022 and September 2022. Multi-domain QoL and cognitive concerns were evaluated using PROMIS-29 and the Cognitive Change Index-12.
Results
Nearly half the participants (47.7%) were surveyed more than 2 years from initial infection (median = 23.3 months; IQR = 18.6, 26.7) and 86.7% were surveyed more than 1 year from infection. A significantly greater proportion of the Long COVID (n = 215) group, (Current and Recovered combined), had moderate-to-severe impairment in all health domains assessed compared to those Without Long COVID (n = 220; all p < 0.05). The Recovered Long COVID group (n = 34) had significantly lower prevalence of fatigue, pain, depression, and physical and social function impairment compared to those with Current Long COVID (n = 181; all p < 0.05). However, compared to patients Without Long COVID, the Recovered Long COVID group had greater prevalences of fatigue, pain (p ≤ 0.06) and subjective cognitive decline (61.8% vs 29.1%; p < 0.01). Multivariate relative risk (RR) regression indicated Long COVID risk was greater for older age groups (RR range 1.46–1.52; all p ≤ 0.05), those without a bachelor’s degree (RR = 1.33; 95% CI = 1.03–1.71; p = 0.03), and those with 3 or more comorbidities prior to SARS-CoV-2 infection (RR = 1.45; 95% CI = 1.11–1.90; p < 0.01).
Conclusions
Long COVID is associated with long-term subjective cognitive decline and diminished quality of life. Clinically significant cognitive complaints, fatigue, and pain were present even in those who reported they had recovered from Long COVID. These findings have implications for the sustainability of participation in work, education, and social activities.
The living tumor cell vaccine (TCV) holds a promise for cancer immunotherapy. Microneedle arrays provide a tool to improve the immune response of vaccines by the intradermal administration in a painless manner. However, it remains challenges for microneedle arrays to deliver the living TCV intradermally. Here, an ice microneedle array delivered living TCVs is shown with sustained granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) secretion for cancer treatment. The ice microneedle array is composed of ice microneedles and a matching polymer holder, which are customized fabricated by a static optical projection lithography (SOPL) technique. The living TCV consisted of irradiated melanoma cells transfected with nanoparticle‐mediated GM‐CSF plasmids. After the living TCV is readily loaded into the ice microneedle via a cryopreservation process, it could be efficiently delivered into the dermis by the microneedle device. Compared to the subcutaneous injection, intradermal administration led to the recruitment of more dendritic cells at the vaccination site and the increased infiltration of CD8⁺ T cells in the tumor. The ice microneedle array deliveres intradermal TCVs significantly inhibited melanoma growth and effectively prevented melanoma recurrence without obvious side effects. This work demonstrates a promising TCVs for melanoma treatment, which will inspire the future of cancer immunotherapy.
Background
Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein and 4 molecules of attenuated human interleukin-2 (IL-2), to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers.
Methods
CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic HPV16+ head and neck squamous cell cancer
(
R/M HNSCC). Escalating doses of CUE-101 monotherapy from 0.06 to 8 mg/kg were evaluated in R/M HNSCC refractory to ≥ 1 platinum or checkpoint inhibitor (CPI) based therapy, while CUE-101 doses from 1 to 4 mg/kg combined with pembrolizumab 200 mg Q3W were evaluated as first line treatment of PD-L1+ R/M HNSCCs. Therapy was administered every 3 weeks (Q3W) until disease progression or intolerable toxicity.
Results
Enrollment is now completed (N = 80 patients, 49 in monotherapy and 31 in CUE-101 plus pembrolizumab). Following dose escalation, 4 mg/kg Q3W of CUE-101 was selected for RP2D for both monotherapy and pembrolizumab combination cohorts. Adverse events (AEs) have been manageable and the most frequent grade ≥3 AEs reported include lymphocyte count decreased (8%), anemia (6%), decreased appetite and infusion-related reaction (5%). Among the 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) and mOS of 20.8 months [95% CI 10.0; NA] were observed. Among the 24 evaluable patients treated at the CUE-101 RP2D plus pembrolizumab, an ORR of 46% (1 CR, 10 PRs), Disease Control Rate (ORR + durable SDs) of 75%, and mPFS of 5.8 months [95% CI 4.0; NA] were observed. Objective responses were observed in 50% (6/12) of patients with CPS 1-19 and 42% (5/12) with CPS ≥ 20. 12-month OS rate of 96% was observed and median OS has not been reached.
Conclusions
An ORR of 46%, mPFS of 5.8 months and 12-month OS of 96% were observed in R/M HNSCC patients treated with CUE-101 4 mg/kg + pembrolizumab as 1L therapy. A median OS of 20.8 months was observed in patients treated with CUE-101 monotherapy as post-platinum/CPI therapy. CUE-101 continues to demonstrate safety, tolerability and clinical benefit in patients with HPV16+ R/M HNSCC.
Acknowledgements
The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea.
Ethics Approval
This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), HRPO# 201905108 (Washington University School of Medicine), DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB STUDY00008948 (University of Washington, Seattle), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), 2019-087 Karmanos Cancer Institute, WIRB 2000026098 (Yale Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), IRB0001113 (US Oncology Inc./Affiliated Oncologists, LLC), WCG IRB00000533 (Gabrail Cancer Center), IRB000001113 (George Washington University Cancer Center).
Background
Significant sex disparities exist in cancer, with underlying molecular mechanisms remaining largely unexplored. This understudied area holds promise for improved therapeutic strategies. Medulloblastoma (MB), the most frequent pediatric malignant brain tumor, exemplifies this sexual dimorphism. Males exhibit a higher incidence rate across all age groups and a poorer prognosis compared to females, particularly after the age of three.
Methods
This study investigates the functional role of the Yap1 oncogene in the context of Sonic Hedgehog (SHH)-MB. We employed a sex-disaggregated approach, analyzing survival outcomes in Yap1-deleted male and female mice harboring SmoM2-driven SHH MB. Furthermore, we utilized an integrated multi-omics approach to elucidate the impact of YAP1 on cancer stem cells and the immune evasion within both sexes.
Results
Yap1 deletion significantly extends overall survival in male mice harboring SHH medulloblastoma, but not in females. This suggests a sex-specific role for Yap1. We found that YAP1 is essential for maintaining cancer stem cells in both sexes by activating stemness genes (e.g., Sox2) and repressing differentiation genes (e.g., Neurod1 and Zic1/2). However, single-cell transcriptomics and functional assays revealed a more critical role for Yap1 in male immune evasion. Specifically, Yap1 promotes cytotoxic T cell suppression within the MB tumor microenvironment by regulating Cd276/B7-H3, a key immune checkpoint molecule. Interestingly, CD276 blockade or Yap1 deletion effectively restores T cell function in sex-matched male tumor:T cell co-cultures, while females require the combination of both approaches to reverse T cell suppression.
Conclusions
Our findings transcend MB, suggesting a potentially conserved mechanism across diverse species. We provide evidence that YAP1’s directly regulated transcriptional targets, including CD276, manifest a signature predictive of survival outcomes in male patients across a spectrum of human cancers. These observations underscore the potential for sex-dependent efficacy of Yap1 or Cd276 inhibitors and provide novel mechanistic insights into sexually dimorphic cancer immune evasion.
Background
TOPACIO was a phase I/II study evaluating the PARP inhibitor (PARPi) niraparib in combination with the anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic triple-negative breast cancer (TNBC, n=55), irrespective of BRCA mutation status. In the efficacy-evaluable population (n=47) the objective response rate (ORR) was 21% and disease control rate (DCR) 49%. Although activity was greater in BRCA-MUT patients (7/15, ORR=47% and 12/15, DCR=80%), durable clinical benefit was seen in patients with BRCA-WT tumors (3/27, ORR=11% and 9/27, DCR=33%). Patients with PD-L1+ tumors (28/47, 60%) achieved higher ORR (9/28, 32%) than those with PD-L1neg tumors (1/13, 8%). It remains unstudied whether tumor gene expression or immune composition in baseline biospecimens is predictive of treatment response. Therefore, we conducted exploratory biomarker analyses to uncover gene expression patterns and immune states associated with treatment response.
Methods
Transcriptional profiling of baseline samples was performed using the BC360 (n=41) and PanCancer IO360 (n=42) panels (Nanostring) and multigene signatures were used to measure tumor and immune activities. Transcriptional analysis was paired with high-dimensional, single-cell cyclic immunofluorescence (CyCIF) of samples with adequate tissue for analysis (n=22) to characterize the immune microenvironment at single-cell resolution.
Results
BRCA-MUT tumors showed increased downstream interferon signaling and immune infiltration relative to BRCA-WT tumors (p < 0.05). Downstream interferon and immunoproteasome scores were elevated in objective responders (p < 0.05). Genes involved in WNT signaling (TANKS1, TANKS2, PARP4, and NETO2) associated with long-term response, defined by those still on therapy and responding at data cut off. Low NETO2 gene expression strongly associated with better ORR (p = 0.01). CyCIF analysis performed on whole tissue sections accounting for 2.97x10⁶ single cells revealed that in BRCA-WT patients, baseline infiltration of immune cells – cells expressing CD45, CD3 (T cells), CD20 (B cells) or CD68/CD163 (macrophages) positively correlated with PFS (R=0.81, p=0.0004, Spearman’s correlation). Further, elevated fractions of CD8+ and PD-1+ CD4+ T cells strongly associated with favorable PFS (R > 0.71, p < 0.0041). In BRCA-MUT patients, baseline immune composition did not correlate with clinical outcome by any metric studied.
Conclusions
NETO2 expression, WNT pathway, and interferon signaling associate with response to niraparib plus pembrolizumab. While BRCA-MUT tumors showed higher baseline immune cell abundance compared to BRCA-WT, immune and T cell infiltration was predictive of PFS duration only in BRCA-WT patients, suggesting divergent mechanisms of response to PARPi and ICB dependent on BRCA status.
Trial Registration
ClinicalTrials.gov identifier: NCT02657889.
Ethics Approval
The study was performed according to the ethical principles of the Declaration of Helsinki. The study protocol and/or other relevant documents received central approval by the Dana-Farber institutional review board and/or relevant competent authorities at each site. All patients supplied written informed consent for their participation in the study.
Background
We and others have shown that validated neoantigen-specific CD8+ TIL from several cancer types express high levels of CXCL13 and ENTPD1 (CD39), and low level of IL7R. Notably, among a small number of functionally validated tumor-reactive TIL, those from ICB-resistant tumors were transcriptionally distinct. A major limitation impeding assessment of this observation in a larger cohort is the expensive and cumbersome nature of functional T cell assays detecting human tumor-reactive TIL. We therefore developed a conserved, 3-gene score to distinguish tumor-specific from bystander TIL, providing insights into tumor-reactive TIL biology independent of functional assays.
Methods
Neoantigen- and CEF-specific TIL from 3 melanoma specimens (Oliveira et al, Nature, 2021) were used to train a gene score weighted for CXCL13, ENTPD1 and IL7R, which was validated with neoantigen- and CEF-specific TIL from 2 lung cancers (Caushi et al, Nature, 2021). SAVER was used to recover missing data. Single patient models were constructed initially with linear regression and random forest algorithm on imputed and non-imputed data. Combined voting models were built. ROC curves and AUC were used for model evaluation. Due to strong inter-patient heterogeneity, patient-specific cutoffs for defining MANAscorehi TIL were set based on MANAscore distributions.
Results
Our three-gene MANAscore algorithm out-performed other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ TIL. Most MANAscorehi TIL expressed a tissue resident memory (TRM) program, consistent with validated neoantigen-specific TIL. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung cancers had higher expression of immune checkpoint and cytotoxicity-related genes relative to non-pTRC, and their frequency was significantly correlated with ICB response. pTRC in pathologically responding tumors showed higher IL7R expression, lower checkpoint expression, and shared trajectories originating from high expression of GZMK and moving toward a stem-like phenotype. Moreover, MANAscore accurately identified T cells specific for multiple classes of tumor antigens across different cancer types, including cancer-testis antigen-specific TIL from oral cancers, neoantigen-specific TIL in metastatic cancers (including breast cancer, colorectal cancer, melanoma), and viral oncogene-specific TIL in virus-driven Merkel cell carcinomas. Application of MANAscore on larger scRNAseq datasets integrating additional melanomas and lung, oral, sinonasal, and head and neck cancers revealed shared expression patterns of pTRC across tumor types, which provides a unique opportunity to discover novel T cell-specific therapeutic targets and biomarkers.
Conclusions
MANAscore is a robust tool for enriching candidate tumor-specific TIL. It can be used to understand the functional programming and underlying biology of tumor-reactive TIL in different antigen-specific contexts.
Acknowledgements
The Mark Foundation for Cancer Research, Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Mark Foundation Center for Advanced Genomics and Imaging, Cancer Research Institute, Lung Cancer Foundation of America, LUNGevity, American Lung Association, Swim Across America, Commonwealth Foundation, Bristol-Myers Squibb, National Institutes of Health grants R37CA251447 (K.N.S.), R01HG010889 (H.J.), R01HG009518 (H.J.), P01 CA255517, T32 CA080416, and P30 CA006973, Kelsey Dickson Team Science Courage Research Award: Advancing New Therapies for Merkel Cell Carcinoma (MCC), MCC Patient Gift Fund, National Foundation for Cancer Research.
The proportions of carbon (C), nitrogen (N), and phosphorus (P) in surface ocean particulate matter deviate greatly from the canonical Redfield Ratio (C:N:P = 106:16:1) in space and time with significant implications for global carbon storage as this matter reaches the deep ocean. Recent work has revealed clear latitudinal patterns in C:N:P, yet the relative importance of ecological, physiological, or biochemical processes in creating these patterns is unclear. We present high-resolution, concurrent measurements of particulate C:N:P, macromolecular composition, environmental conditions, and plankton community composition from a transect spanning a subtropical-subpolar boundary, the North Pacific Transition Zone. We find that the summed contribution of macromolecules to particulate C, N, and P is consistent with, and provides interpretation for, particulate C:N:P patterns. A decline in particulate C:N from the subtropical to subpolar North Pacific largely reflects an increase in the relative contribution of protein compared to carbohydrate and lipid, whereas variation in C:P and N:P correspond to shifts in protein relative to polyphosphate, DNA, and RNA. Possible causes for the corresponding trends in C:N and macromolecular composition include physiological responses and changes in community structure of phytoplankton, which represented approximately 1/3 rd of particulate C across the transect. Comparison with culture experiments and an allocation-based model of phytoplankton macromolecular composition suggest that physiological acclimation to changing nutrient supply is the most likely explanation for the latitudinal trend in C:N, offering both a mechanistic interpretation and biochemical basis for large-scale patterns in C:N:P.
Background
Implementation strategies are key to enhancing the translation of new innovations but there is a need to systematically design and tailor strategies to match the targeted implementation context and address determinants. There are increasing methods to inform the development and tailoring of implementation strategies to maximize their usability, feasibility, and appropriateness in new settings such as the Cognitive Walkthrough for Implementation Strategies (CWIS) approach. The aim of the current project is to apply the CWIS approach to inform the redesign of a multifaceted selection-quality implementation toolkit entitled Adoption of Curricular supports Toolkit: Systematic Measurement of Appropriateness and Readiness for Translation in Schools (ACT SMARTS) for use in middle and high schools.
Methods
We systematically applied CWIS as the second part of a community-partnered iterative redesign of ACT SMARTS for schools to evaluate the usability and inform further toolkit redesign areas. We conducted three CWIS user testing sessions with key end users of school district administrators (n = 3), school principals (n = 6), and educators (n = 6).
Results
Our CWIS application revealed that end users found ACT SMARTS acceptable and relevant but anticipate usability issues engaging in the ACT SMARTS process. Results informed the identification of eleven usability issues and corresponding redesign solutions to enhance the usability of ACT SMARTS for use in middle and high schools.
Conclusions
Results indicated the utility of CWIS in assessing implementation strategy usability in service of informing strategy modification as part of our broader redesign to improve alignment with end user, end recipient, and setting needs. Recommendations regarding the use of this participatory approach are discussed.
We investigated how long-term visual experience with habitual spherical aberration (SA) influences subjective depth of focus (DoF). Nine healthy cycloplegic eyes with habitual SAs of different signs and magnitudes were enrolled. An adaptive optics (AO) visual simulator was used to measure through-focus high-contrast visual acuity after correcting all monochromatic aberrations and imposing + 0.5 μm and − 0.5 μm SAs for a 6-mm pupil. The positive (n = 6) and negative (n = 3) habitual SA groups ranged from 0.17 to 0.8 μm and from − 1.2 to – 0.12 μm for a 6-mm pupil, respectively. Although all optical conditions were identical, and the subjective DoFs were expected to be the same for all participants, the DoFs of individuals differed between the positive and negative habitual SA groups. For the positive habitual SA group, the mean DoF with positive AO-induced SA (2.14 D) was larger than that with negative AO-induced SA (1.88 D); for the negative habitual SA group, a smaller DoF was measured with positive AO-induced SA (1.94 D) than that with negative AO-induced SA (2.14 D). Subjective DoF tended to be larger when the induced SA in terms of sign and magnitude was closer to the participant’s habitual SA. Our findings suggest that neural adaptation to habitual SA compensated for optical blur at multiple object distances, perceptually expanding DoF. As a result, the outcomes of optical treatments for presbyopia may differ due to the neural compensation mechanism influenced by an individual’s visual experience with their habitual optics.
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