Effect of Socioeconomic Status and Comorbidities on Thyroid Cancer Survival Outcomes

Purpose/Objectives: Thyroid cancer ranks among the most common head and neck malignancies and makes up 3% of new cancer cases per year, having increased in overall incidence in the last several decades. This study investigates patient characteristics, socioeconomic status (SES), and medical comorbidities as independent predictors of survival in patients with thyroid cancer, treated at a tertiary care hospital with a diverse, primarily low SES patient population. Materials/Methods: The Henry Ford Health System’s Virtual Data Warehouse Tumor Registry was used to identify patients with thyroid cancers from 1997 to 2016. Socioeconomic data was obtained from 2010 US Census. Comorbidities were quantified using the Charlson Comorbidity Index (CCI). Statistical analysis was performed using Kaplan-Meier estimator and Cox proportional hazards models. Results: There were 1042 patients with thyroid cancer. 5- and 10-year survival probabilities decreased with age \u3e=60 years (p\u3c0.001), stage 3/4 (p\u3c0.001), clinical N stage 1-3 (p\u3c0.001), black race (p=0.001), CCI\u3e1 (p\u3c0.001), and lowest quartile median household income (p\u3c0.001). In multivariate analysis, age (1-year increase HR: 1.97, 95% CI: 1.06-1.09), sex (female vs. male HR: 0.67, 95% CI: 0.48-0.95), and CCI (1-point increase HR: 1.26, 95% CI: 1.19-1.34) were significantly associated with survival outcomes. A CCI cutoff of \u3e1 was a reliable predictor of mortality (AUC: 0.759, 95% CI: 0.716-0.801). CCI was significantly correlated with stage (r=0.166, p=0.004) and median household income (r=-0.175, p\u3c0.001). Conclusion: Increased age, male sex, and medical comorbidities predicted significantly worse survival in thyroid cancer. Race and median household income were not independent significant prognostic indicators

30-Day Mortality and Cardiopulmonary Complication Rates in Patients Undergoing Emergency Surgery with Perioperative SARS-CoV-2 Infection

INTRODUCTION AND OBJECTIVE: Continued vigilance of operative outcomes in COVID-19 patients is important given the relative novelty of the SARS-CoV-2 infection. We sought to evaluate the 30-day mortality and cardiopulmonary complication rates in patients undergoing emergency surgery with perioperative COVID-19, in comparison to a control group of medically managed COVID-19 patients that did not require a surgical intervention. METHODS: A retrospective chart review at a single tertiary-care hospital in Michigan was undertaken. Patients who had tested positive for SARS-CoV-2 infection either 7 days before or within 30 days after surgery during March-May 2020 were included in the study (n=52). Propensity score matched (1:6) patients who had been positive for SARS CoV-2 infection during this time-period but did not undergo surgery served as controls (n=314). The primary endpoint was 30-day mortality. Secondary endpoints included cardiac and pulmonary complications. Multivariable logistic regression analyses were utilized to account for baseline differences. RESULTS: The 30-day mortality (17.3% vs 13.1%, p=0.408) and cardiac (28.9% vs 19.1%, p=0.107) and pulmonary complication (55.8% vs 49.4%, p=0.392) rates were similar in the surgical and the non-surgical groups. Multivariable analyses confirmed that emergency surgical intervention was not associated with increased odds for any of the studied adverse events (p\u3e0.10 for all 3 endpoints). CONCLUSIONS: Our analysis of 366 novel coronavirus patients demonstrates that patients undergoing emergency surgery with SARS-CoV-2 infection do not have an increased risk for 30-day mortality and cardiopulmonary complications compared to their counterparts that do not require surgery. The importance of this study is that an emergency intervention does not portend a poorer prognosis among patients with a confirmed SARS-CoV-2 Infection

The cGMP-Dependent Protein Kinase II Is an Inhibitory Modulator of the Hyperpolarization-Activated HCN2 Channel

Opening of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated by direct binding of cyclic nucleotides to a cyclic nucleotide-binding domain (CNBD) in the C-terminus. Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation. Using coimmunoprecipitation and immunohistochemistry we demonstrate that cGKII and HCN2 interact and colocalize with each other upon heterologous expression as well as in native mouse brain. We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2–5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. The inhibitory cGMP effect can be either abolished by mutation of the phosphorylation site in HCN2 or by impairing the catalytic domain of cGKII. By contrast, the inhibitory effect is preserved in a HCN2 mutant carrying a CNBD deficient for cGMP binding. Our data suggest that bidirectional regulation of HCN2 gating by cGMP contributes to cellular fine-tuning of HCN channel activity

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Radiation Induces Acute Alterations in Neuronal Function

Every year, nearly 200,000 patients undergo radiation for brain tumors. For both patients and caregivers the most distressing adverse effect is impaired cognition. Efforts to protect against this debilitating effect have suffered from inadequate understanding of the cellular mechanisms of radiation damage. In the past it was accepted that radiation-induced normal tissue injury resulted from a progressive reduction in the survival of clonogenic cells. Moreover, because radiation-induced brain dysfunction is believed to evolve over months to years, most studies have focused on late changes in brain parenchyma. However, clinically, acute changes in cognition are also observed. Because neurons are fully differentiated post-mitotic cells, little information exists on the acute effects of radiation on synaptic function. The purpose of our study was to assess the potential acute effects of radiation on neuronal function utilizing ex vivo hippocampal brain slices. The cellular localization and functional status of excitatory and inhibitory neurotransmitter receptors was identified by immunoblotting. Electrophysiological recordings were obtained both for populations of neuronal cells and individual neurons. In the dentate gyrus region of isolated ex vivo slices, radiation led to early decreases in tyrosine phosphorylation and removal of excitatory N-methyl-D-aspartate receptors (NMDARs) from the cell surface while simultaneously increasing the surface expression of inhibitory gamma-aminobutyric acid receptors (GABAARs). These alterations in cellular localization corresponded with altered synaptic responses and inhibition of long-term potentiation. The non-competitive NMDAR antagonist memantine blocked these radiation-induced alterations in cellular distribution. These findings demonstrate acute effects of radiation on neuronal cells within isolated brain slices and open new avenues for study

Lineage-specific dynamic and pre-established enhancer–promoter contacts cooperate in terminal differentiation

Chromosome conformation is an important feature of metazoan gene regulation; however, enhancer–promoter contact remodeling during cellular differentiation remains poorly understood. To address this, genome-wide promoter capture Hi-C (CHi-C) was performed during epidermal differentiation. Two classes of enhancer–promoter contacts associated with differentiation-induced genes were identified. The first class ('gained') increased in contact strength during differentiation in concert with enhancer acquisition of the H3K27ac activation mark. The second class ('stable') were pre-established in undifferentiated cells, with enhancers constitutively marked by H3K27ac. The stable class was associated with the canonical conformation regulator cohesin, whereas the gained class was not, implying distinct mechanisms of contact formation and regulation. Analysis of stable enhancers identified a new, essential role for a constitutively expressed, lineage-restricted ETS-family transcription factor, EHF, in epidermal differentiation. Furthermore, neither class of contacts was observed in pluripotent cells, suggesting that lineage-specific chromatin structure is established in tissue progenitor cells and is further remodeled in terminal differentiation

Quality Measures for the Diagnosis and Non-Operative Management of Carpal Tunnel Syndrome in Occupational Settings

Introduction: Providing higher quality medical care to workers with occupationally associated carpal tunnel syndrome (CTS) may reduce disability, facilitate return to work, and lower the associated costs. Although many workers’ compensation systems have adopted treatment guidelines to reduce the overuse of unnecessary care, limited attention has been paid to ensuring that the care workers do receive is high quality. Further, guidelines are not designed to enable objective assessments of quality of care. This study sought to develop quality measures for the diagnostic evaluation and non-operative management of CTS, including managing occupational activities and functional limitations. Methods: Using a variation of the well-established RAND/UCLA Appropriateness Method, we developed draft quality measures using guidelines and literature reviews. Next, in a two-round modified-Delphi process, a multidisciplinary panel of 11 U.S. experts in CTS rated the measures on validity and feasibility. Results: Of 40 draft measures, experts rated 31 (78%) valid and feasible. Nine measures pertained to diagnostic evaluation, such as assessing symptoms, signs, and risk factors. Eleven pertain to non-operative treatments, such as the use of splints, steroid injections, and medications. Eleven others address assessing the association between symptoms and work, managing occupational activities, and accommodating functional limitations. Conclusions: These measures will complement existing treatment guidelines by enabling providers, payers, policymakers, and researchers to assess quality of care for CTS in an objective, structured manner. Given the characteristics of previous measures developed with these methods, greater adherence to these measures will probably lead to improved patient outcomes at a population level

Encoding of Temporal Information by Timing, Rate, and Place in Cat Auditory Cortex

A central goal in auditory neuroscience is to understand the neural coding of species-specific communication and human speech sounds. Low-rate repetitive sounds are elemental features of communication sounds, and core auditory cortical regions have been implicated in processing these information-bearing elements. Repetitive sounds could be encoded by at least three neural response properties: 1) the event-locked spike-timing precision, 2) the mean firing rate, and 3) the interspike interval (ISI). To determine how well these response aspects capture information about the repetition rate stimulus, we measured local group responses of cortical neurons in cat anterior auditory field (AAF) to click trains and calculated their mutual information based on these different codes. ISIs of the multiunit responses carried substantially higher information about low repetition rates than either spike-timing precision or firing rate. Combining firing rate and ISI codes was synergistic and captured modestly more repetition information. Spatial distribution analyses showed distinct local clustering properties for each encoding scheme for repetition information indicative of a place code. Diversity in local processing emphasis and distribution of different repetition rate codes across AAF may give rise to concurrent feed-forward processing streams that contribute differently to higher-order sound analysis