Field interventions for climate change mitigation behaviors: A second-order meta-analysis.

Behavioral change is essential to mitigate climate change. To advance current knowledge, we synthesize research on interventions aiming to promote climate change mitigation behaviors in field settings. In a preregistered second-order meta-analysis, we assess the overall effect of 10 meta-analyses, incorporating a total of 430 primary studies. In addition, we assess subgroup analyses for six types of interventions, five behaviors, and three publication bias adjustments. Results showed that climate change mitigation interventions were generally effective (dunadjusted = 0.31, 95% CI [0.30, 0.32]). A follow-up analysis using only unique primary studies, adjusted for publication bias, provides a more conservative overall estimate (d = 0.18, 95% CI [0.13, 0.24]). This translates into a mean treatment effect of 7 percentage points. Furthermore, in a subsample of adequately powered large-scale interventions (n > 9,000, k = 32), the effect was adjusted downward to approximately 2 percentage points. This discrepancy might be because large-scale interventions often target nonvoluntary participants by less direct techniques (e.g., "home energy reports") while small-scale interventions often target voluntary participants by more direct techniques (e.g., face-to-face interactions). Subgroup analyses showed that interventions based on social comparisons or financial incentives were the most effective, while education or feedback was the least effective. These results provide a comprehensive state-of-the-art summary of climate change mitigation interventions, guiding both future research and practice.

Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the 40-gene expression profile.

Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART).Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event.Results: Random sampling of matched patient pairs (n = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1.Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).

Independent validation study: 40-GEP identifies patients with cutaneous squamous cell carcinoma who would be most likely to benefit from adjuvant radiation therapy.

Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Appropriate Statistical Methods to Assess Cross-study Diagnostic 23-Gene Expression Profile Test Performance for Cutaneous Melanocytic Neoplasms.

ABSTRACT: Comparing studies of molecular ancillary diagnostic tests for difficult-to-diagnose cutaneous melanocytic neoplasms presents a methodological challenge, given the disparate ways accuracy metrics are calculated. A recent report by Boothby-Shoemaker et al investigating the real-world accuracy of the 23-gene expression profile (23-GEP) test highlights this methodological difficulty, reporting lower accuracy than previously observed. However, their calculation method-with indeterminate test results defined as either false positive or false negative-was different than those used in previous studies. We corrected for these differences and recalculated their reported accuracy metrics in the same manner as the previous studies to enable appropriate comparison with previously published reports. This corrected analysis showed a sensitivity of 92.1% (95% confidence interval [CI], 82.1%-100%) and specificity of 94.4% (91.6%-96.9%). We then compared these results directly to previous studies with >25 benign and >25 malignant cases with outcomes and/or concordant histopathological diagnosis by ≥3 dermatopathologists. All studies assessed had enrollment imbalances of benign versus malignant patients (0.8-7.0 ratio), so balanced cohorts were resampled according to the lowest common denominator to calculate point estimates and CIs for accuracy metrics. Overall, we found no statistically significant differences in the ranges of 23-GEP sensitivity, 90.4%-96.3% (95% CI, 80.8%-100%), specificity, 87.3%-96.2% (78.2%-100%), positive predictive value, 88.5%-96.1% (81.5%-100%), or negative predictive value, 91.1%-96.3% (83.6%-100%) between previous studies and the cohort from Boothby-Shoemaker et al with this unified methodological approach. Rigorous standardization of calculation methods is necessary when the goal is direct cross-study comparability.

Oil and gas companies invest in legislators that vote against the environment.

Do campaign contributions from oil and gas companies influence legislators to vote against the environment, or do these companies invest in legislators that have a proven antienvironmental voting record? Using 28 y of campaign contribution data, we find that evidence consistently supports the investment hypothesis: The more a given member of Congress votes against environmental policies, the more contributions they receive from oil and gas companies supporting their reelection.

Real-World Evidence Shows Clinicians Appropriately Use the Prognostic 40-Gene Expression Profile (40-GEP) Test for High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients.

Treatment decisions for patients with cutaneous squamous cell carcinoma (cSCC) are traditionally based upon clinicopathologic risk factors and staging systems. Due to the accuracy limitations of these resources in predicting poor outcomes, there is a clinically significant need for more accurate methods of risk assessment. The 40-gene expression profile (40-GEP) test was developed to augment metastatic risk prediction of high-risk cSCC patients and has been validated in two independent, multi-center studies involving over 1,000 patients. This study substantiates that the 40-GEP is appropriately utilized by clinicians and that the personalized risk-stratification results are impactful in guiding risk-aligned patient management.

Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.

BACKGROUND: Many patients with low-stage cutaneous melanoma will experience tumor recurrence, metastasis, or death, and many higher staged patients will not. OBJECTIVE: To develop an algorithm by integrating the 31-gene expression profile test with clinicopathologic data for an optimized, personalized risk of recurrence (integrated 31 risk of recurrence [i31-ROR]) or death and use i31-ROR in conjunction with a previously validated algorithm for precise sentinel lymph node positivity risk estimates (i31-SLNB) for optimized treatment plan decisions. METHODS: Cox regression models for ROR were developed (n = 1581) and independently validated (n = 523) on a cohort with stage I-III melanoma. Using National Comprehensive Cancer Network cut points, i31-ROR performance was evaluated using the midpoint survival rates between patients with stage IIA and stage IIB disease as a risk threshold. RESULTS: Patients with a low-risk i31-ROR result had significantly higher 5-year recurrence-free survival (91% vs 45%, P < .001), distant metastasis-free survival (95% vs 53%, P < .001), and melanoma-specific survival (98% vs 73%, P < .001) than patients with a high-risk i31-ROR result. A combined i31-SLNB/ROR analysis identified 44% of patients who could forego sentinel lymph node biopsy while maintaining high survival rates (>98%) or were restratified as being at a higher or lower risk of recurrence or death. LIMITATIONS: Multicenter, retrospective study. CONCLUSION: Integrating clinicopathologic features with the 31-GEP optimizes patient risk stratification compared to clinicopathologic features alone.

Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test.

Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan-Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for class 1 and ≥50% for class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies.

Plain language summary Cutaneous squamous cell carcinoma is a common skin cancer, with approximately 2 million cases diagnosed each year in the USA. Because substantial numbers of patients experience metastasis, which can result in death, accurate metastatic risk assessment is important. Clinicians use clinicopathologic factors to determine risk for disease progression. However, traditional methods miss pinpointing many patients who experience metastasis and sometimes categorize patients as at risk who do not develop metastasis, indicating that additional tools are needed. A molecular test, the 40-gene expression profile (40-GEP), was developed to predict metastatic risk based on the biology of the tumor. This study demonstrates that the 40-GEP, either as an independent tool or together with traditional methods, accurately identifies patients' risk of metastasis. Using the 40-GEP could improve patient management to improve patient outcomes.

Discussing global warming leads to greater acceptance of climate science.

Climate change is an urgent global issue, with demands for personal, collective, and governmental action. Although a large body of research has investigated the influence of communication on public engagement with climate change, few studies have investigated the role of interpersonal discussion. Here we use panel data with 2 time points to investigate the role of climate conversations in shaping beliefs and feelings about global warming. We find evidence of reciprocal causality. That is, discussing global warming with friends and family leads people to learn influential facts, such as the scientific consensus that human-caused global warming is happening. In turn, stronger perceptions of scientific agreement increase beliefs that climate change is happening and human-caused, as well as worry about climate change. When assessing the reverse causal direction, we find that knowing the scientific consensus further leads to increases in global warming discussion. These findings suggest that climate conversations with friends and family enter people into a proclimate social feedback loop.

Systems thinking as a pathway to global warming beliefs and attitudes through an ecological worldview.

Prior research has found that systems thinking, the tendency to perceive phenomena as interconnected and dynamic, is associated with a general proenvironmental orientation. However, less is known about its relationship with public understanding of climate change and/or whether this relationship varies across people with different political views. Because climate change is a highly politicized issue, it is also important to understand the extent to which systems thinking can foster acceptance of climate science across political lines. Using an online sample of US adults (n = 1,058), we tested the degree to which systems thinking predicts global warming beliefs and attitudes (e.g., believing that global warming is happening, that it is human-caused, etc.), independent of an ecological worldview (i.e., the New Ecological Paradigm). We found that although systems thinking is positively related to global warming beliefs and attitudes, the relationships are almost fully explained by an ecological worldview. Indirect effects of systems thinking are consistently strong across political ideologies and party affiliations, although slightly stronger for conservatives and Republicans than for liberals and Democrats, respectively. We did not find evidence of the converse: Systems thinking does not seem to mediate the relationship between an ecological worldview and global warming beliefs and attitudes. Together, these findings suggest that systems thinking may support the adoption of global warming beliefs and attitudes indirectly by helping to develop an ecological ethic that people should take care of and not abuse the environment.

Increased glutamate transmission onto dorsal striatum spiny projection neurons in Pink1 knockout rats.

Loss-of-function PTEN Induced Kinase 1 (PINK1) mutations cause early-onset familial Parkinson's disease (PD) with similar clinical and neuropathological characteristics as idiopathic PD. While Pink1 knockout (KO) rats have mitochondrial dysfunction, locomotor deficits, and α-synuclein aggregates in several brain regions such as cerebral cortex, dorsal striatum, and substantia nigra, the functional ramifications on synaptic circuits are unknown. Using whole cell patch clamp recordings, we found a significant increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) onto striatal spiny projection neurons (SPNs) in Pink1 KO rats at ages 4 and 6 months compared to wild-type (WT) littermates, suggesting increased excitability of presynaptic neurons. While sEPSC amplitudes were also increased at 2 and 4 months, no changes were observed in AMPAR/NMDAR ratio or receptor expression. Further analysis revealed increased glutamate release probability and decreased recovery of the synaptic vesicle pool following a train of stimulation in Pink1 KO rats. Ultrastructural analysis revealed increased excitatory and inhibitory synapse number and increased levels of presynaptic α-synuclein, while the number and structure of striatal mitochondria appeared normal. Lastly, we found that Pink1 KO rats have altered striatal dopamine tone, which together with the abnormal α- synuclein distribution and dysfunctional mitochondria, could contribute to the increase in excitatory transmission. Together, these studies show that PINK1 is necessary for normal glutamatergic transmission onto striatal SPNs and reveal possible mechanisms underlying striatal circuit dysfunction in PD.

Precisely Control Mitochondria with Light to Manipulate Cell Fate Decision.

Mitochondrial dysfunction has been implicated in many pathological conditions and diseases. The normal functioning of mitochondria relies on maintaining the inner mitochondrial membrane potential (also known as ΔΨm) that is essential for ATP synthesis, Ca2+ homeostasis, redox balance, and regulation of other key signaling pathways such as mitophagy and apoptosis. However, the detailed mechanisms by which ΔΨm regulates cellular function remain incompletely understood, partially because of the difficulty of manipulating ΔΨm with spatiotemporal resolution, reversibility, or cell type specificity. To address this need, we have developed a next generation optogenetic-based technique for controllable mitochondrial depolarization with light. We demonstrate successful targeting of the heterologous channelrhodopsin-2 fusion protein to the inner mitochondrial membrane and formation of functional cationic channels capable of light-induced selective ΔΨm depolarization and mitochondrial autophagy. Importantly, we for the first time, to our knowledge, show that optogenetic-mediated mitochondrial depolarization can be well controlled to differentially influence the fate of cells expressing mitochondrial channelrhodopsin-2; whereas sustained moderate light illumination induces substantial apoptotic cell death, transient mild light illumination elicits cytoprotection via mitochondrial preconditioning. Finally, we show that Parkin overexpression exacerbates, instead of ameliorating, mitochondrial depolarization-mediated cell death in HeLa cells. In summary, we provide evidence that the described mitochondrial-targeted optogenetics may have a broad application for studying the role of mitochondria in regulating cell function and fate decision.

Predictors of PrEP Uptake Among Patients with Equivalent Access.

Increasing PrEP adoption for eligible individuals is critical, but limited research has examined individual-level factors that might be amenable to educational or behavioral intervention. Using data from a PrEP demonstration project conducted at a community health center, we examined differences in behavioral and psychosocial factors between patients offered PrEP who chose to accept it and those who declined. In a multivariable model, the odds of accepting PrEP were higher among those with an HIV-positive main partner, greater risk behavior in the past 3 months, and higher HIV risk perception. PrEP adoption was positively associated with PrEP adherence self-efficacy and negatively associated with perceived sensitivity to medicines. These psychological variables were associated with measures of PrEP- and HIV-related stigma. In the multivariable model, there were no differences in PrEP adoption by demographic factors or socioeconomic status. Data suggest that patients' decisions about PrEP uptake may be impacted not only by objective and subjective HIV risk, but also by psychological variables such as stigma beliefs, medication beliefs, and self-efficacy.

Observational Study Examining the Diagnostic Practice of Ki67 Staining for Melanocytic Lesions.

BACKGROUND: Dermatopathologists routinely use Ki67 immunostaining to assess atypical melanocytic lesions with a dermal component to determine whether an ambiguous tumor is melanoma. However, there is no universal standard of use for Ki67 in melanocytic neoplasms. We sought to observe the real-world use of Ki67 in the diagnosis of melanocytic lesions and establish a best practice recommendation. METHODS: We searched dermatopathology reports from 2 academic practices for melanocytic lesions in which Ki67 staining was used for diagnosis. The proliferation rate was compared between cases diagnosed as benign (not requiring re-excision), moderate to severely dysplastic or atypical Spitz nevi (requiring re-excision), and malignant melanoma. The use of other melanocytic markers and consensus review was also recorded and compared between institutions. RESULTS: Pathology reports for 106 cases were reviewed. A high Ki67 proliferation rate (n = 18) favored a diagnosis of melanoma or nevi requiring re-excision (15/18, 83.3%) versus a benign nevus (3/18, 16.67%). A high Ki67 rate was 71.4%-90.9% sensitive and 40%-56% specific for the diagnosis of nevus requiring re-excision or melanoma. Institutional practices differed in regard to reporting of Ki67 staining, the use of multiple markers in the workup of atypical melanocytic lesions (HMB45, Melan-A, Ki67 being most common), and consensus review. CONCLUSIONS: A negative or low Ki67 proliferation rate correlates well with rendering of a benign diagnosis. However, a low proliferation rate does not preclude the diagnosis of melanoma. Ki67 staining is most commonly used as an ancillary test to support a diagnosis after other factors have been considered, such as histopathologic morphology and results of additional concurrently used stains.

Treatment of Arsenic-Induced Bowen's Disease With Topical 5-Fluorouracil

Here, we present a case of arsenic-induced Bowen's disease treated with a regimen consisting of topical 5-fluouracil and oral nicotinamide. The use of this therapy modality resulted in near complete resolution of all of the patient's lesions except for those on her palms, soles, and scalp. Excellent wound care and treatment adherence were major factors contributing to the success of this treatment option. Our results ultimately provide an alternative approach to treating multiple arsenical keratoses in patients who are limited to a drug plan involving 5-FU and oral nicotinamide and who are able to be rigorously compliant with application of medication and wound care. J Drugs Dermatol. 2019;18(5):477-479.

New Developments in Genetic rat models of Parkinson's Disease.

Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.

Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity.

Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations. Here we identified a novel protein, F-box and leucine-rich repeat domain-containing protein 18 (Fbxl18) that physically associates with LRRK2. We demonstrated that Fbxl18 is a component of a Skp1-Cullin1-F-box ubiquitin ligase complex that regulates the abundance of LRRK2 by selectively targeting phosphorylated LRRK2 for ubiquitination and proteasomal degradation. Knockdown of endogenous Fbxl18 stabilized LRRK2 abundance while protein kinase C activation enhanced LRRK2 degradation by Fbxl18. Dephosphorylation of LRRK2 blocked Fbxl18 association with LRRK2. Taken together, we have identified potential mechanisms for LRRK2 regulation by kinase signaling pathways. Furthermore, Fbxl18 prevented caspase activation and cell death caused by LRRK2 and PD-linked mutant LRRK2. This reveals novel targets for developing potential therapies for familial and idiopathic PD.