Background We investigated whether partner (spouse or intimate partner) engagement in colorectal cancer (CRC) surveillance is associated with patient receipt of surveillance. Methods From 2019 to ...2020 we surveyed Stage III CRC survivors diagnosed 2014-2018 at an academic cancer center, a community oncology practice and the Georgia SEER registry, and their partners. Partner engagement was measured across 3 domains: Informed about; Involved in; and Aware of patient preferences around surveillance. We evaluated bivariate associations between domains of partner engagement and independent partner variables. Analysis of variance and multivariable logistic regression were used to compare domains of engagement with patient-reported receipt of surveillance. Results 501 patients responded (51% response rate); 428 had partners. 311 partners responded (73% response rate). Partners were engaged across all domains. Engagement varied by sociodemographics. Greater partner involvement was associated with decreased odds of receipt of composite surveillance (OR 0.67, 95% CI 0.48-0.93) and trended towards significance for decreased odds of receipt of endoscopy (OR 0.60, 95% CI 0.34-1.03) and CEA (OR 0.75, 95% CI 0.55-1.04). Greater partner awareness was associated with increased odds of patients' receipt of endoscopy (OR 2.18, 95% CI 1.15-4.12) and trended towards significance for increased odds of receipt of composite surveillance (OR 1.30, 95% CI 0.91-2.04). Conclusion Partners are engaged (informed, involved, and aware) in CRC surveillance. Future research to develop dyadic interventions that capitalize on the positive aspects of partner engagement may help partners effectively engage in surveillance to improve patient care. Keywords: Colorectal cancer, Surveillance, Dyadic, Partner
Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic ...fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed.
To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics.
We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes.
In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.
Cardiomyocytes (CMs) generated from human induced pluripotent stem cells are an evolving platform to understand molecular disease mechanism and evaluate cardiovascular drugs. A major limitation of ...this system is that they represent a heterogeneous mix of ventricular-, atrial-, and nodal-like CMs. By expressing a voltage-sensitive fluorescent protein under the control of lineage-specific promoters, we developed a convenient system allowing high-throughput subtype-specific optical action potential (AP) imaging in these cells. This enables not only quantification of electrical phenotypes in patient-specific CMs but also subtype-specific investigation of drug effects, which may aid both drug development and safety pharmacology in the cardiovascular field.
Regulatory T‐cell (Treg) therapy is under clinical investigation for the treatment of transplant rejection, autoimmune disease, and graft‐versus‐host disease. With the advent of genome editing, ...attention has turned to reinforcing Treg function for therapeutic benefit. A hallmark of Tregs is dampened activation of PI3K‐AKT signaling, of which PTEN is a major negative regulator. Loss‐of‐function studies of PTEN, however, have not conclusively shown a requirement for PTEN in upholding Treg function and stability. Using CRISPR‐based genome editing in human Tregs, we show that PTEN ablation does not cause a global defect in Treg function and stability; rather, it selectively blocks their ability to suppress antigen‐presenting cells. PTEN‐KO Tregs exhibit elevated glycolytic activity, upregulate FOXP3, maintain a Treg phenotype, and have no discernible defects in lineage stability. Functionally, PTEN is dispensable for human Treg‐mediated inhibition of T‐cell activity in vitro and in vivo but is required for suppression of costimulatory molecule expression by antigen‐presenting cells. These data are the first to define a role for a signaling pathway in controlling a subset of human Treg activity. Moreover, they point to the functional necessity of PTEN‐regulated PI3K‐AKT activity for optimal human Treg function.
PTEN ablation in human Tregs and consequent increased PI3K‐AKT activity does not cause a global defect in Treg function and stability, in contrast to mice. Rather, it selectively blocks their ability to suppress antigen‐presenting cells.
Surveillance, Epidemiology, and End Results (SEER) public research database does not include chemotherapy data due to concerns for incomplete ascertainment. To compensate for perceived lack of data ...quality many researchers use SEER-Medicare linked data, limiting studies to persons over age 65. We sought to determine current SEER ascertainment of chemotherapy receipt in two relatively large SEER registries compared to patient-reported receipt and to assess patterns of under-ascertainment.
In 2011-14, we surveyed patients with Stage III colorectal cancer reported to the Georgia and Metropolitan Detroit SEER registries. 1301/1909 eligible patients responded (68% response rate). Survey responses regarding treatment and sociodemographic factors were merged with SEER data. We compared patient-reported chemotherapy receipt with SEER recorded chemotherapy receipt. We estimated multivariable regression models to assess associations of under-ascertainment in SEER.
Eighty-five percent of patients reported chemotherapy receipt. Among those, 10% (n = 104) were under-ascertained in SEER (coded as not receiving chemotherapy). In unadjusted analyses, under-ascertainment was more common for older patients (11.8% age 76+ vs. < 9% for all other ages, p = 0.01) and varied with SEER registries (10.2% Detroit vs. 6.8% Georgia; p = 0.04). On multivariable analyses, chemotherapy under-ascertainment did not vary significantly by any patient attributes.
We found a 10% rate of under-ascertainment of adjuvant chemotherapy for resected, stage III colorectal cancer in two SEER registries. Chemotherapy under-ascertainment did not disproportionately affect any patient subgroups. Use of SEER data from select registries is an important resource for researchers investigating contemporary chemotherapy receipt and outcomes.
Compared to other states in the United States, Mississippi has the lowest uptake of PrEP relative to the number of people newly diagnosed with HIV in the state. Open Arms Healthcare Center is the ...largest provider of PrEP in Mississippi, and has systematically documented PrEP eligibility, offers, and acceptance (ie, agreed to undergo a clinical PrEP evaluation) from 2017 to mid-2020. In encounter-based analyses, we examined factors associated with PrEP acceptance. Among 721 encounters where patients were eligible for PrEP, staff offered PrEP at 680 (94%) of encounters (526 unique individuals); individuals accepted a PrEP offer at 58% of encounters. Accepting a PrEP offer was lowest (15.8%) among transgender/non-binary individuals and highest (93.3%) among individuals who reported having sex partners living with HIV. This clinic's model worked to offer PrEP to a highly impacted population, though there is a need to enhance PrEP acceptance for key groups such as transgender/non-binary individuals.
The role of age and sex in mediating coagulation characteristics in injured children is not well defined. We hypothesize that thromboelastography (TEG) profiles are equivalent across sex in younger ...children and diverge after puberty.
Consecutive trauma patients younger than 18 years were identified from a university-affiliated, Level I, pediatric trauma center (2016-2020) database. Demographics, injury characteristics, and TEG parameters were recorded. Children were categorized by sex and age (younger, ≤10 years; older, ≥11 years). Baseline characteristics, outcomes, and TEG parameters were compared using nonparametric tests as appropriate. To account for the effects of confounding variables, analysis of covariance was performed controlling for Injury Severity Score (ISS), admission Glasgow Coma Scale score, and pediatric age-adjusted shock index.
Six hundred forty-seven subjects were identified (70.2% male, median ISS, 10; interquartile range, 5-24; blunt mechanism, 75.4%). Among 395 younger children (≤10 years), there were no differences in TEG characteristics between sexes. Among 252 adolescents (≥11 years), males had greater kinetic times (1.8 vs. 1.4 min; p < 0.001), decreased alpha angles (69.6° vs73.7°; p < 0.001), and lower maximum amplitudes (59.4 vs. 61.5 mm; p = 0.01). Fibrinolysis was significantly lower in older females compared with younger females (0.4% vs. 1.5%, p < 0.001) and age-matched males (0.4% vs. 1.0%, p = 0.02). Compared with younger male children, adolescent males had greater kinetic times (1.8 vs. 1.4 min; p < 0.001), decreased alpha angles (73.5° vs. 69.6°, p < 0.001), lower maximum amplitudes (59.4 vs. 62 mm, p < 0.001), and less fibrinolysis (1.0% vs. 1.3%, p = 0.03). This interaction persisted after controlling for ISS, Glasgow Coma Scale, and pediatric age-adjusted shock index.
Sex dimorphisms in TEG coagulation profiles appear after puberty. This divergence appears to be driven by a shift in male coagulation profiles to a relatively hypocoagulable state and female coagulation profiles to a relatively hypercoagulable state after puberty.
Prognostic and Epidemiologic, Level III.
Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental ...window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6–14 years‐old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole‐brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone‐related effects in theta (4–7 Hz) and alpha (8–14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left‐lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex‐specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.
During puberty, endogenous testosterone levels rise. We examined whether these increases in testosterone are associated with developmental changes, controlling for age, in the neural oscillatory dynamics serving verbal working memory. Results showed that alpha and theta oscillatory responses were modulated by testosterone levels across multiple regions critical for task performance.
Introduction. The purpose of this study was to evaluate change in motor function, gait speed, dynamic balance, balance confidence, and quality of life (QoL) in nine participants with Parkinson’s ...disease (PwPD) completing Lee Silverman Voice Treatment BIG (LSVT-BIG), an external cueing and task-based intervention. Although supported as an efficacious treatment in PwPD, there is limited research examining clinically meaningful change in outcome measures related to external cueing and task-based interventions. Materials and Methods. This was a case series of nine PwPD (age range 64-76 years, 55% male) who completed the LSVT-BIG protocol. Disease duration ranged from 1 to 17 years and was classified as moderate in all participants (Hoehn and Yahr=2 or 3). Outcome measures included motor function (MDS-UPDRS Part III Motor), gait speed, dynamic balance (MiniBEST), Activities-specific Balance Confidence (ABC), and Summary Index for PD Quality of Life 39 (PDQ-SI). Assessments were completed at baseline (BASE), end of treatment (EOT), and 4 weeks after EOT (EOT+4). Results. Minimal detectable change (MDC) or minimal clinical important difference (MCID) was observed in one or more outcome measures in 8 of 9 participants at EOT and EOT+4 across domains of motor function (67%, 78%), gait speed (78%, 67%), balance confidence (44%, 33%), quality of life (44%, 78%), and dynamic balance (22%, 22%). Discussion. In this case series, 8 of 9 participants showed MDC or MCID changes across multiple functional domains. Improvements were observed immediately post (EOT) and 4-week post-treatment (EOT+4) suggesting a temporal component of the LSVT-BIG impact on functional change. Future research should include clinical trials to examine additional external cueing and task-based intervention efficacy with consideration of intensity, frequency, and mode of delivery across disease severity.
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