[18F]TFB PET/CT misses intense [124I]iodine-avid metastases after redifferentiation therapy in metastatic thyroid cancer.

BACKGROUND: Fluorine 18-labelled tetrafluoroborate ([18F]TFB) is a substrate for the sodium/iodide symporter. In thyroid cancer, [18F]TFB-PET/CT may be an alternative to iodine imaging to evaluate the extent of disease, eligibility for radioiodine treatment, and success of redifferentiation therapies. We report the results of a pilot study to determine tumor uptake of [18F]TFB and compare its properties to [124I]IodinePET/CT in patients with metastatic thyroid cancer. METHODS: Five patients were included in a prospective study. All patients received PET/CT 1 h after injection of 356 ± 12 MBq [18F]TFB and were given 230 ± 9 MBq [124I]Iodine orally on the same day, followed by PET/CT after 48 h. Before redifferentiation therapy, patients underwent an additional baseline [124I]Iodine PET/CT. Cases were analyzed by two board-certified specialists. Detection rates and Spearman correlation for [18F]TFB and [124I]Iodine were calculated. RESULTS: Three patients had poorly differentiated thyroid cancer and received trametinib in a redifferentiation trial. Two patients had papillary thyroid cancer and did not receive redifferentiation therapy. Of the 33 lesions seen before/without redifferentiation therapy, 19 (58%) were visible on [18F]TFB and 30 (91%) on [124I]Iodine imaging. In the patients who underwent redifferentiation therapy, 48 lesions were newly seen on [124I]Iodine PET/CT with a median SUVmax of 3.3 (range, 0.4-285.0). All of these lesions were [18F]TFB-negative. CONCLUSION: [18F]TFB failed to predict radioactive iodine uptake in patients with poorly differentiated thyroid cancer who underwent redifferentiation therapy with trametinib. It is unclear whether such discrepancies may also occur in other redifferentiation therapies or may even be encountered in redifferentiation-naïve thyroid cancer. TRIAL REGISTRATION NUMBER: NCT03196518, registered on June 22, 2017.

Water dispersible carbon nanomaterials reduced N, P, and K leaching potential in sandy soils: A column leaching study.

Carbon nanomaterials (CNMs) - amendments with carbon in nanoscale form -could potentially enhance fertilizer delivery efficiency in agriculture, but their interaction with soil properties and nutrient co-mobility, especially in coarse-textured soils, remain poorly understood. We conducted a column leaching study in repacked soil columns to compare the co-leaching of novel water-dispersible CNMs and soil nutrients across two levels of CNMs applications (200 & 400 mg kg-1), two fertilization rates (low:80 mg kg-1 of N, P and K and high: 200 mg N kg-1, 100 mg P kg-1, 200 mg K kg-1, applied as ammonium nitrate, potassium phosphate, and potassium nitrate) and two soils (Spodosol with pH = 5.1, Alfisol with pH = 6.5). We imposed 12 leaching events to each column, with each leaching event adding water equivalent to the soil-pore volume (250 mL), resulting in cumulative leaching of 3000 mL of water through each column. CNMs applications reduced cumulative leaching losses of NO3-N (Spodosol: 8-12 %, Alfisol: 9-19 %), NH4-N (Spodosol: 2-14 %, Alfisol: 9-14 %), P (Spodosol: 23-27 %, Alfisol: 23-36 %) and K (Spodosol: 17-23 %, Alfisol: 24-26 %) compared to fertilized columns without CNMs. CNMs increased soil pH by up to 0.3 units (Spodosol) or 0.5 units (Alfisol), while lowering electrical conductivity by 15-20 % at the high fertilization rate in both soils. Columns with water-dispersible CNMs accumulated 25-30 % more total C in the base sections of the Alfisol compared to the Spodosol, indicating faster downward movement through the soil profile. Overall, we demonstrated that CNMs have the potential to reduce nutrient leaching in coarse-textured soils, which could be particularly beneficial in high-input intensive agricultural systems.

The αvß6 integrin specific virotherapy, Ad5NULL-A20.FCU1, selectively delivers potent "in-tumour" chemotherapy to pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvß6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvß6 integrin by incorporation of an A20 peptide. METHODS: Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20. RESULTS: We show that Ad5NULL-A20 enables the transfer of suicide genes to αvß6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC. CONCLUSION: Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate "in-tumour chemotherapy" and merits further investigation for the treatment of PDAC patients.

Phase 2 trial of regorafenib in recurrent or metastatic adenoid cystic carcinoma.

BACKGROUND: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multi-targeted, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. METHODS: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The primary endpoints were best overall response (BOR) and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. RESULTS: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR-TKIs. No objective responses were observed. Six-month PFS was 45%, and median PFS was 7.2 months (95%CI 5.2-11.9 months). Presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS (HR 2.6, 95%CI 1.1-6.1, p=0.03). Bulk RNA sequencing of pre-treatment tumors revealed that regorafenib clinical benefit (CB; PFS≥6 months; n=11) was associated with native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS<6 months; n=9) had greater expression of signatures related to cell cycle progression (E2F targets, G2/M checkpoint). CONCLUSION: The trial failed to meet the pre-specified 6-month PFS and BOR targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, while programs promoting cell cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR-TKI should be considered.

Cognitive Stimulation and Maternal Feeding Styles in Families with Low Incomes: Impacts from a Randomized Clinical Trial.

OBJECTIVE: To examine associations between cognitive stimulation in the home at 6 months and maternal feeding styles at 24 months, direct intervention effects of Smart Beginnings (SB) on feeding styles, and potential indirect effects of SB on feeding styles via earlier intervention effects on cognitive stimulation. STUDY DESIGN: Single-blind, two-site randomized clinical trial (RCT) of the SB intervention. SB integrates PlayReadVIP, a universal, pediatric primary care-based program, and Family Check-Up (FCU), a targeted secondary home-based parenting intervention. Mother-infant dyads (N=327) were randomized at birth to standard pediatric care or the SB intervention. Linear regression analyses determined associations between cognitive stimulation at 6 months and maternal feeding styles at 24 months, a secondary data analysis. Direct intervention impacts on feeding styles, a secondary RCT outcome, were also assessed and mediation analyses explored intervention effects on feeding styles via earlier intervention impacts on cognitive stimulation. RESULTS: Cognitive stimulation was significantly associated with higher responsive and lower indulgent feeding styles. SB mothers were less likely to exhibit pressuring styles compared with controls (Effect Size [ES]=-0.12, p=0.02). Although no direct intervention effects were found on responsive or indulgent feeding styles, indirect effects of SB were evident on these feeding styles through intervention-induced increases in cognitive stimulation in the SB group. CONCLUSION: This study found positive linkages between cognitive stimulation in the home and later feeding styles. Additionally, the SB intervention was associated with less pressured feeding and indirect pathways mediated by intervention effects on cognitive stimulation. Implications for early childhood parenting interventions are discussed.

Editorial Commentary: Prolonged Joint Effusion After Hip Arthroscopy May Be Associated With Persistent Symptoms.

Research to investigate causes for continued symptoms in patients who undergo hip arthroscopic treatment is an opportunity to improve outcomes. A disconcertingly large number of patients (47%-66%) show a joint effusion/synovitis on magnetic resonance imaging at 6 to 12 months after hip arthroscopy for femoroacetabular impingement syndrome, and a recent study shows that this is associated with inferior 2-year clinical outcomes compared to patients without effusions. Perhaps the effusions are associated with comorbid structural abnormalities such as cartilage degeneration, capsule defect, labral reinjury, adhesions, or microinstability/hyperlaxity. In theory, interventions to treat the effusion, such as intra-articular injections or anti-inflammatory medications (which also prophylax against heterotopic ossification), will produce sustained clinical improvement.

Investigative power of Genomic Informational Field Theory (GIFT) relative to GWAS for genotype-phenotype mapping.

Identifying associations between phenotype and genotype is the fundamental basis of genetic analyses. Inspired by frequentist probability and the work of R.A. Fisher, genome-wide association studies (GWAS) extract information using averages and variances from genotype-phenotype datasets. Averages and variances are legitimated upon creating distribution density functions obtained through the grouping of data into categories. However, as data from within a given category cannot be differentiated, the investigative power of such methodologies is limited. Genomic Informational Field Theory (GIFT) is a method specifically designed to circumvent this issue. The way GIFT proceeds is opposite to that of GWAS. Whilst GWAS determines the extent to which genes are involved in phenotype formation (bottom-up approach), GIFT determines the degree to which the phenotype can select microstates (genes) for its subsistence (top-down approach). Doing so requires dealing with new genetic concepts, a.k.a. genetic paths, upon which significance levels for genotype-phenotype associations can be determined. By using different datasets obtained in ovis aries related to bone growth (Dataset-1) and to a series of linked metabolic and epigenetic pathways (Dataset-2), we demonstrate that removing the informational barrier linked to categories enhances the investigative and discriminative powers of GIFT, namely that GIFT extracts more information than GWAS. We conclude by suggesting that GIFT is an adequate tool to study how phenotypic plasticity and genetic assimilation are linked.

Literacy Promotion: An Essential Component of Primary Care Pediatric Practice: Technical Report.

Early literacy promotion in pediatric primary care supports parents and caregivers reading with their children from birth, offering counseling in interactive, developmentally appropriate strategies and providing developmentally and culturally appropriate and appealing children's books. This technical report reviews the evidence that reading with young children supports language, cognitive, and social-emotional development. Promoting early literacy in pediatric primary care offers a strengths-based strategy to support families in creating positive childhood experiences, which strengthen early relational health. An increasing body of evidence, reviewed in this report, shows that clinic-based literacy promotion, provided with fidelity to an evidence-based model, has benefits for children, for parents and caregivers, and for pediatric physicians and advanced care providers as well. Reading with young children supports early brain development and the neural "reading network," and improves school readiness. High-quality literacy promotion is especially essential for children who face disparities and inequities because of social factors, systemic racism, and socioeconomic risk. All families benefit from high-quality and diverse books and from developmentally appropriate guidance supporting interactions around books and stories. Thus, literacy promotion can be a universal primary prevention strategy to strengthen families and support healthy development. Partnerships at community, local, and state levels offer opportunities for integration with other programs, services, and platforms. Literacy promotion in primary care pediatric practice, recognized by the AAP as an essential component since 2014, has become increasingly common. There are successful models for public funding at federal, state, county, and municipal levels, but sustainable funding, including payment to pediatric physicians and advanced care providers, remains a need so that the benefits of pediatric early literacy promotion and the joys of books and shared reading can truly be offered on a population level.

Reconciling heterogeneous dengue virus infection risk estimates from different study designs.

Uncovering rates at which susceptible individuals become infected with a pathogen, i.e. the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology are considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, have not been assessed. Using 26 years of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence was 2.46 to 4.33-times higher than case-derived FOI. Correlation between seroprevalence-derived and case-derived FOI was moderate (correlation coefficient=0.46) and no systematic bias. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.

The relationship between intraocular pressure and glaucoma: An evolving concept.

Intraocular pressure (IOP) is the most important modifiable risk factor for glaucoma and fluctuates considerably within patients over short and long time periods. Our field's understanding of IOP has evolved considerably in recent years, driven by tonometric technologies with increasing accuracy, reproducibility, and temporal resolution that have refined our knowledge regarding the relationship between IOP and glaucoma risk and pathogenesis. The goal of this article is to review the published literature pertinent to the following points: 1) the factors that determine IOP in physiologic and pathologic states; 2) technologies for measuring IOP; 3) scientific and clinical rationale for measuring diverse IOP metrics in patients with glaucoma; 4) the impact and shortcomings of current standard-of-care IOP monitoring approaches; 5) recommendations for approaches to IOP monitoring that could improve patient outcomes; and 6) research questions that must be answered to improve our understanding of how IOP contributes to disease progression. Retrospective and prospective data, including that from landmark clinical trials, document greater IOP fluctuations in glaucomatous than healthy eyes, tendencies for maximal daily IOP to occur outside of office hours, and, in addition to mean and maximal IOP, an association between IOP fluctuation and glaucoma progression that is independent of mean in-office IOP. Ambulatory IOP monitoring, measuring IOP outside of office hours and at different times of day and night, provides clinicians with discrete data that could improve patient outcomes. Eye care clinicians treating glaucoma based on isolated in-office IOP measurements may make treatment decisions without fully capturing the entire IOP profile of an individual. Data linking home blood pressure monitors and home glucose sensors to dramatically improved outcomes for patients with systemic hypertension and diabetes and will be reviewed as they pertain to the question of whether ambulatory tonometry is positioned to do the same for glaucoma management. Prospective randomized controlled studies are warranted to determine whether remote tonometry-based glaucoma management might reduce vision loss and improve patient outcomes.

Detection of SEZ6, a therapeutic target, in medullary thyroid carcinoma.

PURPOSE: Seizure-related 6 homolog (SEZ6) is a cDNA that strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody drug conjugate targeting SEZ6 has been developed and is currently in clinical trial in treating SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC). We herein presented the first evidence that SEZ6 was highly expressed in MTC. METHODS: SEZ6 immunoexpression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile. RESULTS: SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using two different SEZ6 antibody clones SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immunoexpression determined using H score was associated with male sex, advance stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations were 83%. MAIN CONCLUSIONS: SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targetted antibody-drug conjugate therapy a promising targeted therapy for MTCs.

Alterations in circulating immunoregulatory proteins discriminate poor CD4 T lymphocyte trajectories in people with HIV on suppressive antiretroviral therapy.

Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation, and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/µl, n = 34 or immune competent: CD4 >500 cells/µl, n = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantly higher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significant after adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classification of individuals with poor CD4 trajectories. In summary, we identified a novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART. IMPORTANCE: It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.

Trends in smoking initiation and cessation over a century in two Australian cohorts.

BACKGROUND: Historical data on smoking can enhance our comprehension of the effectiveness of past tobacco control policies and play a key role in developing targeted public health interventions. This study was undertaken to assess trends in smoking initiation and cessation in Australia for the period 1910-2005. METHODS: Rates of smoking initiation and cessation were calculated for participants in two population-based cohorts, the Busselton Health Study and the Tasmanian Longitudinal Health Study. The effects of time trends, gender and age group were evaluated. RESULTS: Of the 29,971 participants, 56.8% ever smoked. In males, over the period 1910-1999, the rate of smoking initiation in young adolescents remained high with a peak in the 1970s; in older adolescents it peaked in the 1940s and then declined; in young adults it showed a steady decline. In females, the rate of smoking initiation in young adolescents rose sharply in the 1960s and peaked in the 1970s, in older adolescents it increased throughout the period, and in young adults it declined after 1970. In the period 1930-2005, 27.3% of 9,605 people aged 36-50 years who smoked ceased smoking. Rates of cessation in this age group increased throughout but decreased in males after 1990 and plateaued around 2000 in females. CONCLUSION: Our findings show substantial variation in the efficacy of tobacco control policies across age groups, with a notable lack of success among the younger population.

Preoperative Hip Injection Response Does Not Reliably Predict 2-Year Postoperative Outcomes After Hip Arthroscopy for Femoroacetabular Impingement.

PURPOSE: To determine whether response to preoperative local anesthetic or corticosteroid intra-articular injections can predict 2-year postoperative outcomes in patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS). METHODS: We performed a retrospective analysis of patients undergoing hip arthroscopy for FAIS at a single institution from 2014 to 2020. Patients who underwent preoperative intra-articular hip injections were classified based on injection type (local anesthetic or corticosteroid) and whether they experienced pain relief after injection (responders or nonresponders). Responders were matched 2:1 to nonresponders by age, body mass index, and sex. Patient-reported outcomes (PROs) including the Hip Disability and Osteoarthritis Outcome Score (HOOS), 12-Item Short-Form Health Survey (SF-12) Mental Component Summary score, SF-12 Physical Component Summary score, and visual analog scale pain score were collected preoperatively and 2 years postoperatively. Mean score change and minimal clinically important difference (MCID) achievement were calculated and compared between groups. RESULTS: The matched cohort included 126 total patients (42 nonresponders and 84 responders; 74.6% female sex; age [mean ± standard deviation], 30.9 ± 9.9 years; body mass index, 24.7 ± 3.7) with no differences in demographic or radiographic hip variables. Both groups showed significant 2-year postoperative score improvements across all PROs, except the SF-12 Mental Component Summary score, which remained unchanged. There was no difference in mean score change or MCID achievement across all PROs between the corticosteroid injection responder and nonresponder groups. In the local anesthetic group, MCID achievement was similar across all PROs, except the visual analog scale pain score, which showed a greater percentage of MCID achievement among local anesthetic nonresponders (89.5%) than in responders (55.0%, P = .03). Significant ceiling effects were most readily apparent within the injection responder group, with greater percentages of patients achieving maximal 2-year postoperative survey scores (HOOS-Activities of Daily Living, 36.9%; HOOS-Pain, 19.0%; HOOS-Quality of Life, 15.5%; and HOOS-Sport, 32.1%). CONCLUSIONS: Response to preoperative injection with either corticosteroid or local anesthetic did not predict 2-year outcomes after hip arthroscopy in patients with FAIS. LEVEL OF EVIDENCE: Level III, retrospective matched-cohort study.

Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors.

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

Comparison Study of the Bio-Plex and Meso Scale Multiplexed SARS-CoV-2 Serology Assays Reveals Evidence of Diminished Host Antibody Responses to SARS-CoV-2 after Monoclonal Antibody Treatment.

Background: Assessing the breadth and duration of antigen-specific binding antibodies provides valuable information for evaluating interventions to treat or prevent SARS-CoV-2 infection. Multiplex immunoassays are a convenient method for rapid measurement of antibody responses but can sometimes provide discordant results, and antibody positive percent agreement for COVID-19 diagnosis can vary depending on assay type, disease severity, and population sampled. Therefore, we compared two assays marked for research applications, MSD and Bio-Plex Pro, to evaluate qualitative interpretation of serostatus and quantitative detection of antibodies of varying isotypes (IgG, IgM, and IgA) against receptor binding domain (RBD) and nucleocapsid (N) antigens. Methods: Specimens from ACTIV-2/A5401, a placebo-controlled clinical trial of the SARSCoV-2 monoclonal antibody (mAb) bamlanivimab to prevent COVID-19 disease progression, were used to evaluate the concordance of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 Serology Assay and the Meso Scale Discovery (MSD) V-PLEX COVID-19 Panel 1 serology assay in detecting and quantifying IgG, IgA, and IgM binding anti-SARS-CoV-2 antibody responses against the RBD and N antigens. Data were disaggregated by study arm, bamlanivimab dose, days post-enrollment, and presence of emerging resistance. Results: We observed 90.5% (412 of 455 tests) concordance for anti-RBD IgG and 87% (396 of 455) concordance for anti-N IgG in classifying samples as negative or positive based on assay-defined cutoffs. Antibody levels converted to the WHO standard BAU/mL were significantly correlated for all isotypes (IgG, IgM, and IgA) and SARS-CoV-2 antigen targets (RBD and N) tested that were common between the two assays (Spearman r 0.65 to 0.92, P < 0.0001). Both assays uncovered evidence of diminished host-derived IgG immune responses in participants treated with bamlanivimab compared to placebo. Assessment of immune responses in the four individuals treated with the 700 mg of bamlanivimab with emerging mAb resistance demonstrated a stronger anti-N IgG response (MSD) at day 28 (median 2.18 log BAU/mL) compared to participants treated with bamlanivimab who did not develop resistance (median 1.55 log BAU/mL). Conclusions: These data demonstrate the utility in using multiplex immunoassays for characterizing the immune responses with and without treatment in a study population and provide evidence that monoclonal antibody treatment in acute COVID-19 may have a modest negative impact on development of host IgG responses.

Effect of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19.

OBJECTIVE: To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-ß2-Glycoprotein-I (aß2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS: Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION: These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.

An evaluation of the associations among posttraumatic stress disorder, depression, and complicated grief in active duty military personnel with traumatic loss.

Between 44% and 87% of active duty service members and veterans who deployed following the September 11, 2001, terrorist attacks know someone who was killed or seriously injured in combat. Considering the high frequency and known impact of traumatic loss, it is important to understand if and how traumatic loss may impede posttraumatic stress disorder (PTSD) treatment progress in military personnel. Additionally, experiencing a traumatic loss elevates the risk of developing prolonged grief disorder (PGD), which is associated with higher levels of PTSD symptoms, more functional impairment, and more lifetime suicide attempts among military personnel. Given what is known about the association between PGD and PTSD in treatment-seeking service members and veterans, it is also important to understand whether grief-related symptom severity negatively impacts PTSD treatment response. The current study examined associations among traumatic loss, complicated grief, depressive symptoms, and PTSD treatment response among military personnel (N = 127) who participated in variable-length cognitive processing therapy (CPT). There was no direct, F(2, 125) = 0.77, p = .465, or indirect, ß = .02, p = .677, association between a traumatic loss index event and PTSD treatment response compared with other trauma types. Prior assessments of depressive symptom severity were directly related to PTSD at later assessments across two models, ps < .001-p = .021 Participants with a traumatic loss index trauma demonstrated significant reductions in complicated grief, depressive symptoms, and PTSD following CPT, ps < .001, ds = -0.61--0.83. Implications, study limitations, and suggestions for future research are presented.

Factor Eight Inhibitor Bypass Activity use in cardiac surgery: A propensity matched analysis of safety outcomes.

BACKGROUND: Bleeding during cardiac surgery may be refractory to standard interventions. Off-label use of Factor Eight Inhibitor Bypass Activity (FEIBA) has been described to treat such bleeding. However, reports of safety, particularly thromboembolic outcomes, show mixed results and reported cohorts have been small. METHODS: Adult patients undergoing cardiac surgery on cardiopulmonary bypass between July 1, 2018 and June 30, 2023 at Stanford Hospital were reviewed (n=3335). Patients who received FEIBA to treat post-cardiopulmonary bypass bleeding were matched with those who did not by propensity scores in a 1:1 ratio using nearest neighbor matching (n= 352 per group). The primary outcome was a composite outcome of thromboembolic complications including any one of deep vein thrombosis (DVT), pulmonary embolism (PE), unplanned coronary artery intervention, ischemic stroke, and acute limb ischemia, in the postoperative period. Secondary outcomes included renal failure, reoperation, postoperative transfusion, ICU length of stay (LOS), and 30-day mortality. RESULTS: 704 encounters were included in our propensity matched analysis. The mean dose of FEIBA administered was 7.3 ±5.5 units/kg. In propensity matched multivariate logistic regression models there was no statistically significant difference in odds ratios for thromboembolic outcomes, ICU LOS, or mortality. Patients who received >750 units of FEIBA had an increased odds ratio for acute renal failure (OR 4.14; 95% CI 1.61 to 10.36, p <0.001). In multivariate linear regression, patients receiving FEIBA were transfused more plasma and cryoprecipitate postoperatively. However, only the dose range of 501-750 units was associated with an increase in transfusion of RBCs (ß 2.73; 95% CI 0.68 to 4.78; p=0.009), and platelets (ß 1.74; 95% CI 0.85 to 2.63; p <0.001). CONCLUSIONS: Low dose FEIBA administration during cardiac surgery does not increase risk of thromboembolic events, ICU LOS, or mortality in a propensity matched cohort. Higher doses were associated with increased acute renal failure and postoperative transfusion. Further studies are required to establish the efficacy of activated factor concentrates to treat refractory bleeding during cardiac surgery.

PANDA: a self-driving lab for studying electrodeposited polymer films.

We introduce the polymer analysis and discovery array (PANDA), an automated system for high-throughput electrodeposition and functional characterization of polymer films. The PANDA is a custom, modular, and low-cost system based on a CNC gantry that we have modified to include a syringe pump, potentiostat, and camera with a telecentric lens. This system can perform fluid handling, electrochemistry, and transmission optical measurements on samples in custom 96-well plates that feature transparent and conducting bottoms. We begin by validating this platform through a series of control fluid handling and electrochemistry experiments to quantify the repeatability, lack of cross-contamination, and accuracy of the system. As a proof-of-concept experimental campaign to study the functional properties of a model polymer film, we optimize the electrochromic switching of electrodeposited poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) films. In particular, we explore the monomer concentration, deposition time, and deposition voltage using an array of experiments selected by Latin hypercube sampling. Subsequently, we run an active learning campaign based upon Bayesian optimization to find the processing conditions that lead to the highest electrochromic switching of PEDOT:PSS. This self-driving lab integrates optical and electrochemical characterization to constitute a novel, automated approach for studying functional polymer films.