Abstinence as Choice: Exploring Voluntary Abstinence from Alcohol Self-Administration Using the Resurgence-as-Choice Framework.

Resurgence is an increase in the rate of a previously suppressed behavior that occurs when an alternative source of reinforcement is made worse in some way. The Resurgence as Choice model offers a quantitative approach to understanding resurgence that may provide important insights into the variables that affect this form of relapse in the natural environment. Bringing this model to bear on relapse following reinforcement-based interventions for alcohol and other substance use disorders, however, may not be straightforward. Laboratory work on which the Resurgence as Choice model is based has almost exclusively focused on resurgence following extinction of target behavior, but abstinence from alcohol during intervention is often voluntary: Patients may drink alcohol and forfeit therapeutic reinforcers at any time. In this article, we first will review recent data from our group that demonstrate a method for studying resurgence following voluntary abstinence from alcohol seeking in rats. In a previous experiment, we reduced rats' alcohol-maintained lever pressing to low levels without placing it on extinction by arranging nondrug differential reinforcement of other behavior. Further, when we suspended nondrug reinforcement, resurgence of lever pressing occurred. Next, we will explore methods for modeling these outcomes using the Resurgence-as-Choice framework. We conclude that the data under consideration may not be sufficient to discriminate between candidate models of resurgence following voluntary abstinence and point to areas for future empirical and theoretical development. This work may provide a stronger bridge between preclinical and conceptual work on resurgence and clinical treatments for alcohol use disorder.

A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine.

Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Omadacycline is active in vitro and in vivo against ciprofloxacin-resistant Bacillus anthracis.

Bacillus anthracis, the causative agent of anthrax, is among the most likely bacterial pathogens to be used in a biological attack. Inhalation anthrax is a serious, life-threatening form of infection, and the mortality from acute inhaled anthrax can approach 100% if not treated early and aggressively. Food and Drug Administration-approved antibiotics indicated for post-exposure prophylaxis (PEP) or treatment of anthrax are limited. This study assessed the in vitro activity and in vivo efficacy of omadacycline and comparators against clinical isolates of B. anthracis, including a ciprofloxacin-resistant isolate. Minimum inhibitory concentrations (MICs) of omadacycline, ciprofloxacin, and doxycycline were determined against animal and human clinical isolates of B. anthracis, including the ciprofloxacin-resistant Ames strain BACr4-2. Mice were challenged with aerosolized BACr4-2 spores, and survival was monitored for 28 days post-challenge. Treatment was initiated 24 h after aerosol challenge and administered for 14 days. Omadacycline demonstrated in vitro activity against 53 B. anthracis isolates with an MIC range of ≤0.008-0.25 µg/mL, and an MIC50/MIC90 of 0.015/0.03 µg/mL. Consistent with this, omadacycline demonstrated in vivo efficacy in a PEP mouse model of inhalation anthrax caused by the Ames BACr4-2 ciprofloxacin-resistant B. anthracis isolate. Omadacycline treatment significantly increased survival compared with the vehicle control group and the ciprofloxacin treatment group. As antibiotic resistance rates continue to rise worldwide, omadacycline may offer an alternative PEP or treatment option against inhalation anthrax, including anthrax caused by antibiotic-resistant B. anthracis.

Synthesized alternative reinforcement and resurgence.

In treatments based on differential reinforcement of alternative behavior, applied researchers and clinicians often provide multiple, qualitatively different reinforcers (i.e., synthesized reinforcement) rather than a single reinforcer (i.e., isolated reinforcement) contingent on alternative behavior. Some research shows that providing synthesized reinforcement for alternative responses within such treatments produces more rapid and complete suppression of target behavior; however, there is limited research evaluating the durability of these effects during treatment disruptions. Conceptual explanations of resurgence (e.g., resurgence as choice, context theory) suggest that treatments that include synthesized alternative reinforcement may lead to more resurgence of target behavior when alternative reinforcement is disrupted relative to treatments using isolated reinforcement. We evaluated this hypothesis within a three-phase resurgence evaluation. We exposed rats to isolated or synthesized reinforcement for alternative responding in the second phase, and we exposed rats to extinction in the third phase. Synthesized alternative reinforcement produced more rapid and complete suppression of target behavior than did isolated reinforcement in the second phase; however, exposure to extinction following synthesized reinforcement produced more resurgence. We discuss these results in terms of their implications for applied research and their support for current conceptual explanations for resurgence.

Selective Detection of Paraquat in Adulterated and Complex Environmental Samples Using Raman Spectroelectrochemistry.

Growing demand for pesticides has created an environment prone to deceptive activities, where counterfeit or adulterated pesticide products infiltrate the market, often escaping rapid detection. This situation presents a significant challenge for sensor technology, crucial in identifying authentic pesticides and ensuring agricultural safety practices. Raman spectroscopy emerges as a powerful technique for detecting adulterants. Coupling the electrochemical techniques allows a more specific and selective detection and compound identification. In this study, we evaluate the efficacy of spectroelectrochemical measurements by coupling a potentiostat and Raman spectrograph to identify paraquat, a nonselective herbicide banned in several countries. Our findings demonstrate that applying -0.70 V during measurements yields highly selective Raman spectra, highlighting the primary vibrational bands of paraquat. Moreover, the selective Raman signal of paraquat was discernible in complex samples, including tap water, apple, and green cabbage, even in the presence of other pesticides such as diquat, acephate, and glyphosate. These results underscore the potential of this technique for reliable pesticide detection in diverse and complex matrices.

Investigating layer-by-layer films of carbon nanotubes and nickel phthalocyanine towards diquat detection.

The indiscriminate use of pesticides makes us susceptible to the toxicity of these chemical compounds, which may be present in high quantities in our food. It is crucial to develop inexpensive and rapid methods for determining these pesticides for government control or even for the general population. In this study, we investigated the fabrication of self-assembled LbL films using multi-walled carbon nanotubes (MWCNT) and nickel tetrasulphonated phthalocyanine (NiTsPc) as an electrochemical sensor for the herbicide Diquat (DQ). The Layer-by-Layer (LbL) assembly of the (MWCNT/NiTsPc) film was examined, along with its structural and morphological characteristics. The effect of the number of layers in DQ detection was evaluated by cyclic voltammetry, followed by the detection through differential pulse voltammetry. The achieved limit of detection was 9.62 × 10-7 mol L-1. A ~ 30% decrease in sensitivity was observed in the presence of Paraquat, a banned herbicide and electrochemical interferent due to the structural similarities, which is regularly neglected in the most published studies. The sensor was tested in real samples, demonstrating a recovery of 98.5% in organic apples.

Proton-Coupled Electron Transfer at the Pu5+/4+ Couple.

The synthesis and solution and solid-state characterization of [Pu4+(NPC)4], 1-Pu, (NPC = [NPtBu(pyrr)2]-; tBu = C(CH3)3; pyrr = pyrrolidinyl) and [Pu3+(NPC)4][K(2.2.2.-cryptand)], 2-Pu, is described. Cyclic voltammetry studies of 1-Pu reveal a quasi-reversible Pu4+/3+ couple, an irreversible Pu5+/4+ couple, and a third couple evincing a rapid proton-coupled electron transfer (PCET) reaction occurring after the electrochemical formation of Pu5+. The chemical identity of the product of the PCET reaction was confirmed by independent chemical synthesis to be [Pu4+(NPC)3(HNPC)][B(ArF5)4], 3-Pu, (B(ArF5)4 = tetrakis(2,3,4,5,6-pentafluourophenyl)borate) via two mechanistically distinct transformations of 1-Pu: protonation and oxidation. The kinetics and thermodynamics of this PCET reaction are determined via electrochemical analysis, simulation, and density functional theory. The computational studies demonstrate a direct correlation between the changing nature of 5f and 6d orbital participation in metal-ligand bonding and the electron density on the Nim atom with the thermodynamics of the PCET reaction from Np to Pu, and an indirect correlation with the roughly 5-orders of magnitude faster Pu PCET compared to Np for the An5+ species.

Genomic Landscape of Adenocarcinomas Across the Gastroesophageal Junction: Moving on from the Siewert Classification.

OBJECTIVE: To investigate how the Siewert classification of gastroesophageal junction adenocarcinomas correlates with genomic profiles. SUMMARY/BACKGROUND DATA: Current staging and treatment guidelines recommend that tumors with an epicenter less than 2 cm into the gastric cardia be treated as esophageal cancers, while tumors with epicenter greater than 2 cm into the cardia be staged and treated as gastric cancers. To date, however, few studies have compared the genomic profiles of the 3 Siewert classification groups to validate this distinction. METHODS: Using targeted tumor sequencing data on patients with adenocarcinoma of the gastroesophageal junction previously treated with surgery at our institution, we compared genomic features across Siewert classification groups. RESULTS: A total of 350 patients were included: 121 had Siewert type I, 170 type II, and 59 type III. Comparisons by Siewert location revealed that Siewert type I and II were primarily characterized as the chromosomal instability (CIN) molecular subtype and displayed Barrett's metaplasia and p53 and cell cycle pathway dysregulation. Siewert type III tumors, by contrast, were more heterogeneous, including higher proportions of microsatellite instability (MSI) and genomically stable (GS) tumors and more frequently displayed ARID1A and somatic CDH1 alterations, signet ring cell features, and poor differentiation. Overall, Siewert type I and II tumors demonstrated greater genomic overlap with lower esophageal tumors, while Siewert type III tumors shared genomic features with gastric tumors. CONCLUSIONS: Overall, our results support recent updates in treatment and staging guidelines. Ultimately, however, molecular rather than anatomic classification may prove more valuable in determining staging, treatment, and prognosis.

The Proposed 9th Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The 9th edition TNM classification of lung cancer, which is scheduled to take effect in January 2025, addresses this need. It is based on a large international database, multidisciplinary input, and extensive statistical analyses. Key features of the 9th edition include validation of the significant changes in the T component introduced in the 8th edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA, and IIIB. This article summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the 9th edition system.

Outbreak of Human Trichinellosis - Arizona, Minnesota, and South Dakota, 2022.

Trichinellosis is a parasitic zoonotic disease transmitted through the consumption of meat from animals infected with Trichinella spp. nematodes. In North America, human trichinellosis is rare and is most commonly acquired through consumption of wild game meat. In July 2022, a hospitalized patient with suspected trichinellosis was reported to the Minnesota Department of Health. One week before symptom onset, the patient and eight other persons shared a meal that included bear meat that had been frozen for 45 days before being grilled and served rare with vegetables that had been cooked with the meat. Investigation identified six trichinellosis cases, including two in persons who consumed only the vegetables. Motile Trichinella larvae were found in remaining bear meat that had been frozen for >15 weeks. Molecular testing identified larvae from the bear meat as Trichinella nativa, a freeze-resistant species. Persons who consume meat from wild game animals should be aware that that adequate cooking is the only reliable way to kill Trichinella parasites and that infected meat can cross-contaminate other foods.

De novo design of peptides that bind specific conformers of α-synuclein.

Insoluble amyloids rich in cross-ß fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloids in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aß40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

Radioresistant Pulmonary Oligometastatic and Oligoprogressive Lesions From Nonlung Primaries: Impact of Histology and Dose-Fractionation on Local Control After Radiation Therapy.

Purpose: We investigated whether pulmonary metastases from historically considered radioresistant primaries would have inferior local control after radiation therapy than those from nonradioresistant nonlung primaries, and whether higher biologically effective dose assuming alpha/beta=10 (BED10) would be associated with superior local control. Methods and Materials: We identified patients treated with radiation therapy for oligometastatic or oligoprogressive pulmonary disease to 1 to 5 lung metastases from nonlung primaries in 2013 to 2020 at a single health care system. Radioresistant primary cancers included colorectal carcinoma, endometrial carcinoma, renal cell carcinoma, melanoma, and sarcoma. Nonradioresistant primary cancers included breast, bladder, esophageal, pancreas, and head and neck carcinomas. The Kaplan-Meier estimator, log-rank test, and multivariable Cox proportional hazards regression were used to compare local recurrence-free survival (LRFS), new metastasis-free survival, progression-free survival, and overall survival. Results: Among 114 patients, 73 had radioresistant primary cancers. The median total dose was 50 Gy (IQR, 50-54 Gy) and the median number of fractions was 5 (IQR, 3-5). Median follow-up time was 59.6 months. One of 41 (2.4%) patients with a nonradioresistant metastasis experienced local failure compared with 18 of 73 (24.7%) patients with radioresistant metastasis (log-rank P = .004). Among radioresistant metastases, 12 of 41 (29.2%) patients with colorectal carcinoma experienced local failure compared with 6 of 32 (18.8%) with other primaries (log-rank P = .018). BED10 ≥100 Gy was associated with decreased risk of local recurrence. On univariable analysis, BED10 ≥100 Gy (hazard ratio [HR], 0.263; 95% CI, 0.105-0.656; P = .004) was associated with higher LRFS, and colorectal primary (HR, 3.060; 95% CI, 1.204-7.777; P = .019) was associated with lower LRFS, though these were not statistically significant on multivariable analysis. Among colorectal primary patients, BED10 ≥100 Gy was associated with higher LRFS (HR, 0.266; 95% CI, 0.072-0.985; P = .047) on multivariable analysis. Conclusions: Local control after radiation therapy was encouraging for pulmonary metastases from most nonlung primaries, even for many of those classically considered to be radioresistant. Those from colorectal primaries may benefit from testing additional strategies, such as resection or systemic treatment concurrent with radiation.

Investigation of the Electrocatalytic Reduction of Peroxydisulfate Using Scanning Electrochemical Microscopy.

The elementary steps of the electrocatalytic reduction of S2O82- using the Ru(NH3)63+/2+ redox couple were investigated using scanning electrochemical microscopy (SECM) and steady-state voltammetry (SSV). SECM investigations were carried out in a 0.1 M KCl solution using a 3.5 µm radius carbon ultramicroelectrode (UME) as the SECM tip and a 25 µm radius platinum UME as the substrate electrode. Approach curves were recorded in the positive feedback mode of SECM by reducing Ru(NH3)63+ at the tip electrode and oxidizing Ru(NH3)62+ at the substrate electrode, as a function of the tip-substrate separation and S2O82- concentration. The one-electron reaction between electrogenerated Ru(NH3)62+ and S2O82- yields the unstable S2O83•-, which rapidly dissociates to produce highly oxidizing SO4•-. Because SO4•- is such a strongly oxidizing species, it can be further reduced at both the tip and the substrate, or it can react with Ru(NH3)62+ to regenerate Ru(NH3)63+. SECM approach curves display a complex dependence on the tip-substrate distance, d, due to redox mediation reactions at both the tip and the substrate. Finite element method (FEM) simulations of both SECM approach curves and SSV confirm a previously proposed mechanism for the mediated reduction of S2O82- using the Ru(NH3)63+/2+ redox couple. Our results provide a lower limit for dissociation rate constant of S2O83•- (∼1 × 106 s-1), as well as the rate constants for electron transfer between SO4•- and Ru(NH3)62+ (∼1 × 109 M-1 s-1) and between S2O82- and Ru(NH3)62+ (∼7 × 105 M-1 s-1).

A tetrahedral neptunium(V) complex.

Neptunium is an actinide element sourced from anthropogenic production, and, unlike naturally abundant uranium, its coordination chemistry is not well developed in all accessible oxidation states. High-valent neptunium generally requires stabilization from at least one metal-ligand multiple bond, and departing from this structural motif poses a considerable challenge. Here we report a tetrahedral molecular neptunium(V) complex ([Np5+(NPC)4][B(ArF5)4], 1-Np) (NPC = [NPtBu(pyrr)2]-; tBu = C(CH3)3; pyrr = pyrrolidinyl (N(C2H4)2); B(ArF5)4 = tetrakis(2,3,4,5,6-pentafluourophenyl)borate). Single-crystal X-ray diffraction, solution-state spectroscopy and density functional theory studies of 1-Np and the product of its proton-coupled electron transfer (PCET) reaction, 2-Np, demonstrate the unique bonding that stabilizes this reactive ion and establishes the thermochemical and kinetic parameters of PCET in a condensed-phase transuranic complex. The isolation of this four-coordinate, neptunium(V) complex reveals a fundamental reaction pathway in transuranic chemistry.

Outbreak of Human Trichinellosis - Arizona, Minnesota, and South Dakota, 2022.

Trichinellosis is a parasitic zoonotic disease transmitted through the consumption of meat from animals infected with Trichinella spp. nematodes. In North America, human trichinellosis is rare and is most commonly acquired through consumption of wild game meat. In July 2022, a hospitalized patient with suspected trichinellosis was reported to the Minnesota Department of Health. One week before symptom onset, the patient and eight other persons shared a meal that included bear meat that had been frozen for 45 days before being grilled and served rare with vegetables that had been cooked with the meat. Investigation identified six trichinellosis cases, including two in persons who consumed only the vegetables. Motile Trichinella larvae were found in remaining bear meat that had been frozen for >15 weeks. Molecular testing identified larvae from the bear meat as Trichinella nativa, a freeze-resistant species. Persons who consume meat from wild game animals should be aware that that adequate cooking is the only reliable way to kill Trichinella parasites and that infected meat can cross-contaminate other foods.