Protein biomarkers for subtyping breast cancer and implications for future research: a 2024 update.

INTRODUCTION: Breast cancer subtyping is used clinically for diagnosis, prognosis, and treatment decisions. Subtypes are categorized by cell of origin, histomorphology, gene expression signatures, hormone receptor status, and/or protein levels. Categorizing breast cancer based on gene expression signatures aids in assessing a patient's recurrence risk. Protein biomarkers, on the other hand, provide functional data for selecting therapies for primary and recurrent tumors. We provide an update on protein biomarkers in breast cancer subtypes and their application in prognosis and therapy selection. AREAS COVERED: Protein pathways in breast cancer subtypes are reviewed in the context of current protein-targeted treatment options. PubMed, Science Direct, Scopus, and Cochrane Library were searched for relevant studies between 2017 and 17 August 2024. EXPERT OPINION: Post-translationally modified proteins and their unmodified counterparts have become clinically useful biomarkers for defining breast cancer subtypes from a therapy perspective. Tissue heterogeneity influences treatment outcomes and disease recurrence. Spatial profiling has revealed complex cellular subpopulations within the breast tumor microenvironment. Deciphering the functional relationships between and within tumor clonal cell populations will further aid in defining breast cancer subtypes and create new treatment paradigms for recurrent, drug resistant, and metastatic disease.

Proteomics based selection achieves complete response to HER2 therapy in HER2 IHC 0 breast cancer.

Recent trials have shown the efficacy of trastuzumab deruxtecan (T-DXd) in HER2-negative patients, but there is not yet a way to identify which patients will best respond, especially with the inability of current HER2 IHC and FISH assays to accurately determine HER2 expression in the unamplified setting. Here, we present a heavily pre-treated patient with triple-negative breast cancer (HER2 IHC 0 who had a complete response to T-DXd. In this case, we used a CLIA-certified reverse-phase protein array-based proteomic assay (RPPA) to determine that the patient had moderate HER2 protein expression (HER2Total 2+, 42%) and activation (HER2Y1248 1+, 23%). Using these results, we determined that the patient may benefit from T-Dxd despite being traditionally qualified as HER2 IHC 0. These findings highlight the potential for proteomics-based assays that may more accurately quantitate HER2 and (its activation) in the HER2 unamplified/IHC 0 setting to better select patients whose tumors are classically molecularly defined as HER2 IHC 0, but still could respond to HER2-directed therapy, and give patients access to therapies which for which they otherwise would not be eligible.

Functional activation of the AKT-mTOR signalling axis in a real-world metastatic breast cancer cohort.

BACKGROUND: Mutations of the PIK3CA/AKT/mTOR axis are common events in metastatic breast cancers (MBCs). This study was designed to evaluate the extent to which genetic alterations of the PIK3CA/AKT/mTOR can predict protein activation of this signalling axis in MBCs. METHODS: Molecular profiles were generated by CLIA-certified laboratories from a real-world evidence cohort of 171 MBC patients. Genetic alterations of the PIK3CA pathway were measured using next-generation sequencing. Activation levels of AKT and downstream signalling molecules were quantified using two orthogonal proteomic methods. Protein activity was correlated with underlying genomic profiles and response to CDK4/6 inhibition in combination with endocrine treatment (ET). RESULTS: Oncogenic alterations of the PIK3CA/AKT/PTEN pathway were identified in 49.7% of cases. Genomic profiles emerged as poor predictors of protein activity (AUC:0.69), and AKT phosphorylation levels mimicked those of mutant lesions in 76.9% of wild-type tumours. High phosphorylation levels of the PI3K/AKT/mTOR downstream target p70S6 Kinase (T389) were associated with shorter PFS in patients treated with CDK4/6 inhibitors in combination with ET (HR:4.18 95%CI:1.19-14.63); this association was not seen when patients were classified by mutational status. CONCLUSIONS: Phosphoprotein-based measurements of drug targets and downstream substrates should be captured along with genomic information to identify MBCs driven by the PI3K/AKT/mTOR signalling.

Molecular and Evolutionary Analysis of RNA-Protein Interactions in Telomerase Regulation.

Telomerase is an enzyme involved in the maintenance of telomeres. Telomere shortening due to the end-replication problem is a threat to the genome integrity of all eukaryotes. Telomerase inside cells depends on a myriad of protein-protein and RNA-protein interactions to properly assemble and regulate the function of the telomerase holoenzyme. These interactions are well studied in model eukaryotes, like humans, yeast, and the ciliated protozoan known as Tetrahymena thermophila. Emerging evidence also suggests that deep-branching eukaryotes, such as the parasitic protist Trypanosoma brucei require conserved and novel RNA-binding proteins for the assembly and function of their telomerase. In this review, we will discuss telomerase regulatory pathways in the context of telomerase-interacting proteins, with special attention paid to RNA-binding proteins. We will discuss these interactors on an evolutionary scale, from parasitic protists to humans, to provide a broader perspective on the extensive role that protein-protein and RNA-protein interactions play in regulating telomerase activity in eukaryotes.

Variations in Management and Clinical Outcomes for Children With Diabetic Ketoacidosis in an Academic Pediatric Versus Community Emergency Department Setting.

OBJECTIVES: Our objectives were to characterize variations from standardized, evidence-based guidelines in the management of pediatric patients with diabetic ketoacidosis (DKA) based on initial presentation to a tertiary pediatric emergency department (PED) versus a community emergency department (OSH) and compare clinical outcomes. METHODS: We conducted a retrospective study on children 18 years and younger with DKA who presented to an OSH or PED over a 3-year period. Treatments monitored for variation included intravenous fluid management, insulin delivery, and sodium bicarbonate administrations. Clinical outcomes included time to anion gap correction and on insulin infusion, hypokalemia, hypoglycemia, rapid serum glucose decline, cerebral edema, mechanical ventilation, mortality, and time from initial presentation to hospital discharge. RESULTS: Children with DKA who presented to an OSH (n = 250) were more acidotic (pH 7.11 vs. 7.13, P = 0.001) and had larger anion gaps (28.8 vs. 25.5, P < 0.001) compared with children presenting to the PED (n = 237). The OSH patients were more likely to receive larger fluid boluses (>20 cc/kg or >1000 ml, 43% vs. 4%, P < 0.001), sodium bicarbonate (5% vs. 0%, P < 0.001), and intravenous bolus insulin (28% vs. 0%, P < 0.001). The OSH group were less likely to be started on maintenance intravenous fluids (70% vs. 99%, P < 0.001) or receive potassium in maintenance intravenous fluids (14% vs. 42%, P < 0.001). The OSH group had longer anion gap correction times (754 vs. 541 mins, P < 0.001), insulin infusion times (1018 vs. 854 min, P = 0.003), and times to hospital discharge (3358 vs. 3045 mins, P < 0.001). Incidence of hypokalemia, hypoglycemia, rapid glucose decline, cerebral edema, and deaths were similar between the 2 groups. CONCLUSIONS: Our study demonstrated significant variations in the initial management of pediatric DKA patients by OSH facilities that deviated from an evidence-based treatment pathway utilized by a PED. Statewide quality improvement initiatives could help improve the overall clinical care provided to pediatric DKA patients.

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors.

Metastatic pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 11%, necessitating identification of novel treatment paradigms. Tumor tissue specimens from patients with PDAC, breast cancer, and other solid tumor malignancies were collected and tumor cells were enriched using laser microdissection (LMD). Reverse phase protein array (RPPA) analysis was performed on enriched tumor cell lysates to quantify a 32-protein/phosphoprotein biomarker panel comprising known anticancer drug targets and/or cancer-related total and phosphorylated proteins, including HER2Total, HER2Y1248, and HER3Y1289. RPPA analysis revealed significant levels of HER2Total in PDAC patients at abundances comparable to HER2-positive (IHC 3+) and HER2-low (IHC 1+ /2+ , FISH-) breast cancer tissues, for which HER2 screening is routinely performed. These data support a critical unmet need for routine clinical evaluation of HER2 expression in PDAC patients and examination of the utility of HER2-directed antibody-drug conjugates in these patients.

IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas.

INTRODUCTION: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. MATERIALS AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. CONCLUSIONS: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

Effects of Tourniquet Features on Application Processes.

BACKGROUND: We investigated emergency-use limb tourniquet design features effects on application processes (this paper) and times to complete those processes (companion paper). METHODS: Sixty-four appliers watched training videos and then each applied all eight tourniquets: Combat Application Tourniquet Generation 7 (CAT7), SOF™ Tactical Tourniquet-Wide Generation 3 (SOFTTW3), SOF™ Tactical Tourniquet-Wide Generation 5 (SOFTTW5), Tactical Mechanical Tourniquet (TMT), OMNA Marine Tourniquet (OMT), X8T tourniquet (X8T), Tactical Ratcheting Medical Tourniquet (Tac RMT), and RapidStop™ Tourniquet (RST). Application processes were scored from videos. RESULTS: Thirty-three appliers had no prior tourniquet experience. All 512 applications were placed proximal to the recipient's simulated distal thigh injury. Thirty-one appliers (13 with no experience) had 66 problem-free applications (18 by no experience appliers). Tightening-system mechanical problems were more frequent with windlass rod systems (26 losing hold of the rod, 27 redoing rod turns, and 58 struggling to secure the rod) versus ratchet systems (3 tooth skips and 16 advance failures). Thirty-five appliers (21 with no experience) had 68 applications (45 by no experience appliers) with an audible Doppler pulse when stating "Done"; causes involved premature stopping (53), inadequate strap pull (1 SOFTTW3, 1 RST), strap/redirect understanding problem (1 SOFTTW5, 1 X8T, 4 Tac RMT, 1 RST), tightening-system understanding problem (2 CAT7, 1 SOFTTW3, 1 TMT, 1 RST), and physical inability to secure (1 SOFTTW3). Fifty-three appliers (32 no experience) had 109 applications (64 by no experience appliers) not correctly secured. Six involved strap/redirect understanding problems: 4 Tac RMT, 1 X8T, 1 SOFTTW5; 103 involved improper securing of non-self-securing design features: 47 CAT7 (8 strap, 45 rod), 31 TMT (17 strap, 19 rod), 22 OMT (strap), and 3 SOFTTW3 (rod). CONCLUSION: Self-securing systems have process advantages. Because most emergent tourniquet recipients require transport, we believe tourniquet security is a critical design aspect. Decisions regarding tourniquet choices may become very different when both occlusion and tourniquet security are considered.

Effects of Tourniquet Features on Application Processes Times.

BACKGROUND: We investigated emergency-use limb tourniquet design features effects on application processes (companion paper) and times to complete those processes (this paper). METHODS: Sixty-four appliers watched training videos then each applied all eight tourniquets: Combat Application Tour- niquet Generation 7 (CAT7), SOF™ Tactical Tourniquet-Wide Generation 3 (SOFTTW3), SOF™ Tactical Tourniquet-Wide Generation 5 (SOFTTW5), Tactical Mechanical Tourniquet (TMT), OMNA Marine Tourniquet (OMT), X8T-Tourniquet (X8T), Tactical Ratcheting Medical Tourniquet (Tac RMT), and RapidStop Tourniquet (RST). Application processes times were captured from videos. RESULTS: From "Go" to "touch tightening system" was fastest with clips and self-securing redirect buckles and without strap/redirect application process problems (n, median seconds: CAT7 n=23, 26.89; SOFTTW3 n=11, 20.95; SOFTTW5 n=16, 20.53; TMT n=5, 26.61; OMT n=12, 25.94; X8T n=3, 18.44; Tac RMT n=15, 30.59; RST n=7, 22.80). From "touch tightening system" to "last occlusion" was fastest with windlass rod systems when there were no tightening system understanding or mechanical problems (seconds: CAT7 n=48, 4.21; SOFTTW3 n=47, 5.99; SOFTTW5 n=44, 4.65; TMT n=38, 6.21; OMT n=51, 6.22; X8T n=48, 7.59; Tac RMT n=52, 8.44; RST n=40, 8.02). For occluded, tightening system secure applications, from "touch tightening system" to "Done" was fastest with self-securing tightening systems tightening from a tight strap (occluded, secure time in seconds from a tight strap: CAT7 n=17, 14.47; SOFTTW3 n=22, 10.91; SOFTTW5 n=38, 9.19; TMT n=14, 11.42; OMT n=44, 7.01; X8T n=12 9.82; Tac RMT n=20, 6.45; RST n=23, 8.64). CONCLUSIONS: Suboptimal processes in- crease application times. Optimal design features for fast, occlusive, secure tourniquet applications are self-securing strap/ redirect systems with an easily identified and easily used clip and self-securing tightening systems.

Changes in post-PCI physiology based on anatomical vessel location: a DEFINE PCI substudy.

BACKGROUND: Anatomical vessel location affects post-percutaneous coronary intervention (PCI) physiology. AIMS: We aimed to compare the post-PCI instantaneous wave-free ratio (iFR) in left anterior descending (LAD) versus non-LAD vessels and to identify the factors associated with a suboptimal post-PCI iFR. METHODS: DEFINE PCI was a multicentre, prospective, observational study in which a blinded post-PCI iFR pullback was used to assess residual ischaemia following angiographically successful PCI. RESULTS: Pre- and post-PCI iFR recordings of 311 LAD and 195 non-LAD vessels were compared. Though pre-PCI iFR in the LAD vessels (median 0.82 [0.63, 0.86]) were higher compared with those in non-LAD vessels (median 0.72 [0.49, 0.84]; p<0.0001), post-PCI iFR were lower in the LAD vessels (median 0.92 [0.88, 0.94] vs 0.98 [0.95, 1.00]; p<0.0001). The prevalence of a suboptimal post-PCI iFR of <0.95 was higher in the LAD vessels (77.8% vs 22.6%; p<0.0001). While the overall frequency of residual physiological diffuse disease (31.4% vs 38.6%; p=0.26) and residual focal disease in the non-stented segment (49.6% vs 50.0%; p=0.99) were similar in both groups, residual focal disease within the stented segment was more common in LAD versus non-LAD vessels (53.7% vs 27.3%; p=0.0009). Improvement in iFR from pre- to post-PCI was associated with angina relief regardless of vessel location. CONCLUSIONS: After angiographically successful PCI, post-PCI iFR is lower in the LAD compared with non-LAD vessels, resulting in a higher prevalence of suboptimal post-PCI iFR in LAD vessels. This difference is, in part, due to a greater frequency of a residual focal pressure gradient within the stented segment which may be amenable to more aggressive PCI.

RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells.

RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.

Proteomic analysis defines the interactome of telomerase in the protozoan parasite, Trypanosoma brucei.

Telomerase is a ribonucleoprotein enzyme responsible for maintaining the telomeric end of the chromosome. The telomerase enzyme requires two main components to function: the telomerase reverse transcriptase (TERT) and the telomerase RNA (TR), which provides the template for telomeric DNA synthesis. TR is a long non-coding RNA, which forms the basis of a large structural scaffold upon which many accessory proteins can bind and form the complete telomerase holoenzyme. These accessory protein interactions are required for telomerase activity and regulation inside cells. The interacting partners of TERT have been well studied in yeast, human, and Tetrahymena models, but not in parasitic protozoa, including clinically relevant human parasites. Here, using the protozoan parasite, Trypanosoma brucei (T. brucei) as a model, we have identified the interactome of T. brucei TERT (TbTERT) using a mass spectrometry-based approach. We identified previously known and unknown interacting factors of TbTERT, highlighting unique features of T. brucei telomerase biology. These unique interactions with TbTERT, suggest mechanistic differences in telomere maintenance between T. brucei and other eukaryotes.

The Role of Reconstruction on Desmoid Tumor Recurrence: A Systematic Review and Technical Considerations.

BACKGROUND: Desmoid tumors occur throughout the body, presenting as aggressive, locally invasive lesions that can impede quality of life. Many controversies remain regarding the optimal surgical treatment of desmoid. This article presents a systematic review and meta-analysis on surgical management, focusing on risk of recurrence and the utility of reconstruction within this unique patient population. METHODS: A systematic review was conducted to search for articles. The clinical course of patients diagnosed with desmoid tumors and treated by our institution's multidisciplinary team was retrospectively reviewed over a 13-year period. Meta-analysis study findings were compared with our cohort. RESULTS: From the systematic review, 10 studies with level of evidence III were found, which resulted in 981 patients. Twenty patients from our institution met the inclusion criteria for our study. In both our study cohort and the pooled results, recurrence was significantly higher in patients with positive microscopic margin after resection. In our study cohort, patients with recurrence had higher rates of positive margins compared with those without recurrence (83.3% vs 7.1%, P = 0.004), whereas the pooled study showed a difference of margin positivity of 50% vs 40% ( P = 0.01). No patients who underwent reconstruction in our study cohort had a recurrence during the study period. CONCLUSION: In both our cohort and pooled results, recurrence was significantly higher in patients with positive margins after initial resection. Reconstruction was not found to be a risk factor for recurrence. Reconstruction following desmoid tumor resection should be considered a viable option if a large and aggressive resection is required to obtain negative margins.

Feasibility of outpatient robot assisted minimally invasive transforaminal lumbar interbody fusion.

Introduction: Lumbar interbody fusion is a common spine procedure. 199,140 elective lumbar fusions were performed in the United States in 2015. Robot assisted (RA) pedicle screw placement has advanced minimally invasive spine surgery (MIS) making short stay transforaminal lumbar interbody fusions (TLIF) with same day or next day discharge a possibility for select patients. Methods: This study is a retrospective case series of a single surgeon's experience with RA MIS TLIF using the Globus ExcelsiusGPS system. Patients undergoing RA MIS TLIF at an outpatient surgery center between August 2020 and February 2021 were included in the study. Results: Twenty-three patients met inclusion criteria. Ninety-six RA pedicle screws and 25 interbody cages were placed. 96/96 (100%) pedicle screws and 25/25 (100%) interbodies were found to be in satisfactory position using intraoperative x-ray. None of the instrumentation required re-placement or revision intraoperatively. 20/23 (87%) patients were able to discharge within 24 hours of the procedure. 2/23 (8.7%) patients discharged on the day of surgery. One patient of 23 (4.3%) required discharge to an inpatient rehabilitation facility post operatively. 0/23 (0%) patients required readmission for pain control. Conclusions: Our study demonstrates the safety and feasibility of outpatient RA MIS TLIF for select patients. Future directions include a larger study to elucidate characteristics of the best candidates for outpatient RA MIS TLIF.

The Clinical Response of Upadacitinib and Risankizumab Is Associated With Reduced Inflammatory Bowel Disease Anti-TNF-α Inadequate Response Mechanisms.

BACKGROUND: Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis factor (anti-TNF)-α inadequate responders (TNF-IRs). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab. METHODS: Eight tissue transcriptomic data sets from IBD patients treated with anti-TNF-α therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. The RNAseq colon tissue data from clinical studies of TNF-IR Crohn's disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab. RESULTS: We found 7 TNF-IR upregulated modules related to innate/adaptive immune responses, interferon signaling, and tissue remodeling and 6 TNF-IR upregulated cell types related to inflammatory fibroblasts, postcapillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR upregulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, 4 of the 6 TNF-IR upregulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab. CONCLUSIONS: Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR upregulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.

We identified molecular and cellular mechanisms associated with and potentially mediating the response of upadacitinib and risankizumab for IBD patients that inadequately responded to anti-TNF-α treatment.

Ecological validity reconsidered: the Night Out Task versus the D-KEFS.

INTRODUCTION: Although executive functioning (EF) correlates with execution of instrumental activities of daily living (IADLs), tests of EF have been criticized for having poor ecological validity. Attempts have been made to develop new tests that approximate naturalistic daily tasks. However, the incremental utility of such tests has not been convincingly demonstrated. The Night Out Task (NOT) is a novel measure designed to increase ecological validity. This study examined whether the NOT correlates with traditional lab- and home-based measures of EF and IADLs, and whether it outperforms traditional measures of EF in predicting IADLs. METHOD: Participants (50 adults aged 60 to 95) completed (1) the Delis Kaplan Executive Function System (D-KEFS) and IADLs in the laboratory, and (2) ecological momentary assessment of EF and daily IADL tasks at home across three weeks (using the Daily Assessment of Independent Living and Executive Skills protocol; DAILIES). RESULTS: The NOT correlated with a lab-based measure of EF beyond covariates, and lab-based IADLs beyond covariates and beyond the D-KEFS. However, it was unrelated to at-home variables beyond covariates. In contrast, the D-KEFS was a significant predictor of at-home IADLs, and this association was mediated by at-home EF performance. CONCLUSION: This study provides a preliminary validation of the NOT as a correlate of office-based performances in a primarily college educated white sample. Despite its high face validity, the NOT does not appear to sufficiently tap EF processes needed for home-based IADLs as measured by the DAILIES, although small sample size limits the interpretability of this negative finding.

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

Introduction: The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD. Methods: We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers. Results: WGCNA identified five modules associated with biological clocks, with the module designated as "purple" showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers. Conclusion: Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD. Highlights: Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes.Weighted gene co-expression network analysis (WGCNA) found five modules related to biological aging.Among the hub genes of the module, CX3CR1 was downregulated in AD.The CX3CR1 expression level was associated with cognitive performance and brain atrophy.

Integrated Forecasts Based on Public Health Surveillance and Meteorological Data Predict West Nile Virus in a High-Risk Region of North America.

BACKGROUND: West Nile virus (WNV), a global arbovirus, is the most prevalent mosquito-transmitted infection in the United States. Forecasts of WNV risk during the upcoming transmission season could provide the basis for targeted mosquito control and disease prevention efforts. We developed the Arbovirus Mapping and Prediction (ArboMAP) WNV forecasting system and used it in South Dakota from 2016 to 2019. This study reports a post hoc forecast validation and model comparison. OBJECTIVES: Our objective was to validate historical predictions of WNV cases with independent data that were not used for model calibration. We tested the hypothesis that predictive models based on mosquito surveillance data combined with meteorological variables were more accurate than models based on mosquito or meteorological data alone. METHODS: The ArboMAP system incorporated models that predicted the weekly probability of observing one or more human WNV cases in each county. We compared alternative models with different predictors including a) a baseline model based only on historical WNV cases, b) mosquito models based on seasonal patterns of infection rates, c) environmental models based on lagged meteorological variables, including temperature and vapor pressure deficit, d) combined models with mosquito infection rates and lagged meteorological variables, and e) ensembles of two or more combined models. During the WNV season, models were calibrated using data from previous years and weekly predictions were made using data from the current year. Forecasts were compared with observed cases to calculate the area under the receiver operating characteristic curve (AUC) and other metrics of spatial and temporal prediction error. RESULTS: Mosquito and environmental models outperformed the baseline model that included county-level averages and seasonal trends of WNV cases. Combined models were more accurate than models based only on meteorological or mosquito infection variables. The most accurate model was a simple ensemble mean of the two best combined models. Forecast accuracy increased rapidly from early June through early July and was stable thereafter, with a maximum AUC of 0.85. The model predictions captured the seasonal pattern of WNV as well as year-to-year variation in case numbers and the geographic pattern of cases. DISCUSSION: The predictions reached maximum accuracy early enough in the WNV season to allow public health responses before the peak of human cases in August. This early warning is necessary because other indicators of WNV risk, including early reports of human cases and mosquito abundance, are poor predictors of case numbers later in the season. https://doi.org/10.1289/EHP10287.

Size and Perception of Facial Features with Selfie Photographs, and Their Implication in Rhinoplasty and Facial Plastic Surgery.

BACKGROUND: Patients increasingly use photographs taken with a front-facing smartphone camera-"selfies"-to discuss their goals with a plastic surgeon. The purpose of this study was to quantify changes in size and perception of facial features when taking a selfie compared to the gold standard of clinical photography. METHODS: Thirty volunteers took three series of photographs. A 12-inch and 18-inch series were taken with a front-facing smartphone camera, and the 5-foot clinical photography series was taken with a digital single-lens reflex camera. Afterward, subjects filled out the FACE-Q inventory, once when viewing their 12-inch selfies and once when viewing their clinical photographs. Measurements were taken of the nose, lip, chin, and facial width. RESULTS: Nasal length was, on average, 6.4 percent longer in 12-inch selfies compared to clinical photography, and 4.3 percent longer in 18-inch selfies compared to clinical photography. The alar base width did not change significantly in either set of selfies compared to clinical photography. The alar base to facial width ratio represents the size of the nose in relation to the face. This ratio decreased 10.8 percent when comparing 12-inch selfies to clinical photography (p < 0.0001) and decreased 7.8 percent when comparing 18-inch selfies to clinical photography (p < 0.0001). CONCLUSIONS: This study quantifies the change in facial feature size/perception seen in previous camera-to-subject distance studies. With the increasing popularity of front-facing smartphone photographs, these data allow for a more precise conversation between the surgeon and the patient. In addition, the authors' findings provide data for manufacturers to improve the societal impact of smartphone cameras. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, III.