IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). The interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, and functional integrity of the IFNγ signaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB. Moreover, we discuss how to target IFNγ signaling to inform novel clinical trials to treat patients with colorectal cancer.     

The relationship between headache-attributed disability and lost productivity: 2. Empirical evidence from population-based studies in nine disparate countries

BackgroundHeadache disorders are disabling, with major consequences for productivity, yet the literature is silent on the relationship between headache-attributed disability and lost productivity, often erroneously regarding the two as synonymous. We evaluated the relationship empirically, having earlier found that investment in structured headache services would be cost saving, not merely cost-effective, if reductions in headache-attributed disability led to > 20% pro rata recovery of lost productivity.MethodsWe used individual participant data from Global Campaign population-based studies conducted in China, Ethiopia, India, Nepal, Pakistan and Russia, and from Eurolight in Lithuania, Luxembourg and Spain. We assessed relationships in migraine and probable medication-overuse headache (pMOH), the most disabling common headache disorders. Available symptom data included headache frequency, usual duration and usual intensity. We used frequency and duration to estimate proportion of time in ictal state (pTIS). Disability, in the sense used by the Global Burden of Disease study, was measured as the product of pTIS and disability weight for the ictal state. Impairment was measured as pTIS * intensity. Lost productivity was measured as lost days (absence or < 50% productivity) from paid work and corresponding losses from household work over the preceding 3 months. We used Spearman correlation and linear regression analyses.ResultsFor migraine, in a linear model, we found positive associations with lost paid worktime, significant (p < 0.05) in many countries and highly significant (p < 0.001) in some despite low values of R² (0–0.16) due to high variance. With lost household worktime and total lost productivity (paid + household), associations were highly significant in almost all countries, although still with low R² (0.04–0.22). Applying the regression equations for each country to the population mean migraine-attributed disability, we found pro rata recoveries of lost productivity in the range 16–56% (> 20% in all countries but Pakistan). Analysing impairment rather than disability increased variability. For pMOH, with smaller numbers, associations were generally weaker, occasionally negative and mostly not significant.ConclusionRelief of disability through effective treatment of migraine is expected, in most countries, to recover > 20% pro rata of lost productivity, above the threshold for investment in structured headache services to be cost saving.     

Examining the Dimensionality of Trust in the Inpatient Setting: Exploratory and Confirmatory Factor Analysis

BackgroundTrust in healthcare providers is associated with important outcomes, but has primarily been assessed in the outpatient setting. It is largely unknown how hospitalized patients conceptualize trust in their providers.ObjectiveTo examine the dimensionality of a measure of trust in the inpatient setting.DesignExploratory factor analysis (EFA) and confirmatory factor analysis (CFA).ParticipantsHospitalized patients (N = 1756; 76% response rate) across six hospitals in the midwestern USA. The sample was randomly split such that approximately one half was used in the EFA, and the other half in the CFA.Main MeasuresThe Trust in Physician Scale, adapted for inpatient care.Key ResultsBased on the Kaiser-Guttman criterion and parallel analysis, EFAs were inconclusive, indicating that trust may be comprised of either one or two factors in this sample. In follow-up CFAs, a 2-factor model fit best based on a chi-squared difference test (Δχ² = 151.48(1), p < .001) and a Comparative Fit Index (CFI) difference test (CFI difference = .03). The overall fit for the 2-factor CFA model was good (χ² = 293.56, df = 43, p < .01; CFI = .95; RMSEA = .081 [90% confidence interval = .072–.090]; TLI = .93; SRMR = .04). Items loaded onto two factors related to cognitive (i.e., whether patients view providers as competent) and affective (i.e., whether patients view that providers care for them) dimensions of trust.ConclusionsWhile measures of trust in the outpatient setting have been validated as unidimensional, in the inpatient setting, trust appears to be composed of two factors: cognitive and affective trust. This provides initial evidence that inpatient providers may need to work to ensure patients see them as both competent and caring in order to gain their trust.KEY WORDS: trust, trust in physician scale, psychometrics     

Trimerization and cyclization of reactive P-functionalities confined within OCO pincers

In order to stabilize a 10–P–3 species with C_2v symmetry and two lone pairs on the central phosphorus atom, a specialized ligand is required. Using an NCN pincer, previous efforts to enforce this planarized geometry at P resulted in the formation of a C_s-symmetric, 10π-electron benzazaphosphole that existed as a dynamic “bell-clapper” in solution. Here, OCO pincers 1 and 2 were synthesized, operating under the hypothesis that the more electron-withdrawing oxygen donors would better stabilize the 3-center, 4-electron O–P–O bond of the 10–P–3 target and the sp³-hybridized benzylic carbon atoms would prevent the formation of aromatic P-heterocycles. However, subjecting 1 to a metalation/phosphination/reduction sequence afforded cyclotriphosphane 3, resulting from trimerization of the P(i) center unbound by its oxygen donors. Pincer 2 featuring four benzylic CF₃ groups was expected to strengthen the O–P–O bond of the target, but after metal–halogen exchange and quenching with PCl₃, unexpected cyclization with loss of CH₃Cl was observed to give monochlorinated 5. Treatment of 5 with (p-CH₃)C₆H₄MgBr generated crystalline P-(p-Tol) derivative 6, which was characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography. The complex ¹⁹F NMR spectra of 5 and 6 observed experimentally, were reproduced by simulations with MestreNova.

Attempted synthesis of OCO-supported 10–P–3 species led to trimerization or cyclization.     

Actor–observer asymmetry in perceptions of parole board release decisions

In the current study, the actor–observer effect is tested with both mock parole board members and the public evaluating the responsibility of parole board members for a decision resulting in a parolee reoffending and committing a murder. Participants (two samples with a combined N = 1317) were randomly assigned to act as a mock parole board member and make a decision (which ended in the parolee reoffending) or as a member of the public who read a story about the same parole decision and outcome. Findings suggest that the traditional actor–observer asymmetry emerged across blame and responsibility concepts, emotion and moral judgments. Overall, the public held harsher judgments than the mock parole board members. Implications regarding self-enhancement, methodology and attribution theory are discussed.Key words: actor–observer, attributions, blame, decision-making, emotion, parole, responsibility

Parole has been a part of corrections reform since the early twentieth century, and it shares many goals with a more rehabilitative criminal justice approach seen gaining momentum recently (Cullen, 2017; Petersilia, 2000). Perceptions that prison sentences were too harsh and did not allow any room for rehabilitation spurred support for a more lenient approach to parole, and models of releasing less violent inmates that have shown good behavior were adopted (Clear & Cole, 1997). In general, there are two types of parole decisions; discretionary and mandatory parole (Maruschak & Bonczar, 2013). Discretionary parole involves a decision process through which parole board members review an inmate’s files and decide whether to grant or deny supervised release (parole). There is no required action given to the board, but the action is left up to the discretion of the board. In contrast, mandatory parole is a decision process by which inmates are released under specific circumstances after they have served a certain period of time in prison and do not have major violations or other factors barring their release (Hughes et al., 2001). Under mandatory release guidelines, the parole board is often obligated to release inmates to supervised release, usually based on determinate sentencing and good behavior, unless some major factor prevents such action (Abadinsky, 2012). Recently, discretionary parole has been used at a higher rate than mandatory parole, creating a trend over the past several years (Kaeble, 2018; Maruschak & Bonczar, 2013).In the United States, there are currently about 875,000 inmates on parole, with over 450,000 inmates being released on parole in 2016 (Kaeble, 2018). With an increase in discretionary parole decisions and a large parole population, the parole board likely faces scrutiny for the outcomes of its decisions and is held accountable by the public for ensuring safety and economy (e.g. Abadinsky, 2012; Mackenzie, 2001; National Parole Resource Center, 2012; Paparozzi & Guy, 2009). Parole board members’ perspectives and the public’s perspective might differ as they relate to how parole decisions are perceived and the accountability of the boards’ decisions. This divergence is important because legislation applicable to parole board decisions is intended to incorporate both perspectives, and any dialogue about parole should involve an attempt at mutual understanding. However, it is possible that the divergence in perspectives is due to experience and observational standpoint. The purpose of the current study is to apply an attribution framework to better understand the difference between perspectives of actors (parole board members) and observers (the public) by using a mock parole decision-making paradigm and comparing both parole board and public perspectives on the decision process and outcome with a focus on blame and responsibility for negative outcomes.     

Characteristics of Treatment Seeking Problem Gamblers with Adult ADHD

The present study investigates characteristics of treatment seeking problem gamblers with adult ADHD (n = 39) and those without ADHD (n = 87). Patients completed self-report questionnaires about gambling behaviors, impulsivity (UPPS-P), substance abuse (AUDIT/DAST), emotional dysregulation (PHQ-4), illegal activities, and gambling consequences. Each patient received a structured diagnostic interview (MINI) to assess for psychopathology, adult ADHD (ACDS), and gambling disorder (NODS). Results revealed that problem gamblers with adult ADHD encounter unique challenges above those common among problem gamblers including more problems with alcohol/drug abuse and higher levels of impulsivity. Earlier age for first gambling activities, onset of gambling problems, and higher severity of gambling problems was found among gamblers with ADHD. Gamblers with ADHD pawned more items to obtain money for gambling, were more likely to have debt, had significantly higher rates of bankruptcy and domestic violence arising from conflict with family members about their gambling. Interestingly, groups did not differ significantly on their time spent gambling prior to treatment, their win-to-loss ratio, and a number of other gambling-related consequences. These findings are discussed with their clinical ramifications for treatment.