Resurgence of ethanol seeking following voluntary abstinence produced by nondrug differential reinforcement of other behavior.

Resurgence refers to the relapse of a target behavior following the worsening of a source of alternative reinforcement that was made available during response elimination. Most laboratory analyses of resurgence have used a combination of extinction and alternative reinforcement to reduce target behavior. In contingency-management treatments for alcohol use disorder, however, alcohol use is not placed on extinction. Instead, participants voluntarily abstain from alcohol use to access nondrug alternative reinforcers. Inasmuch, additional laboratory research on resurgence following voluntary abstinence is warranted. The present experiment evaluated resurgence of rats' ethanol seeking following voluntary abstinence produced by differential reinforcement of other behavior (DRO). Lever pressing produced ethanol reinforcers during baseline phases. During DRO phases, lever pressing continued to produce ethanol and food reinforcers were delivered according to resetting DRO schedules. Ethanol and food reinforcers were suspended during resurgence test phases to evaluate resurgence following voluntary abstinence. Lever pressing was elevated during baseline phases and occurred at near-zero rates during DRO phases. During the resurgence test phases, lever pressing increased, despite that it no longer produced ethanol. The procedure introduced here may help researchers better understand the variables that affect voluntary abstinence from ethanol seeking and resurgence following voluntary abstinence.

Translational evaluation of on/off alternative reinforcement cycling.

Cycling between the availability and unavailability of reinforcement for alternative responding has successfully reduced resurgence in basic laboratory evaluations, but this approach represents a marked departure from current standards of care when treating problem behavior, warranting careful translation before its use clinically. Therefore, with extinction arranged for target responding across groups in Phase 2, we evaluated the effects of cycling between the availability and unavailability of differential reinforcement of alternative behavior (DRA) using a computer-based task with adult humans recruited through Amazon MTurk. Two control groups experienced constant DRA in Phase 2, with one group experiencing a dense DRA schedule and another group experiencing a lean DRA schedule. The cycling DRA group tended to show greater reductions in target responding and improved discrimination in Phase 2 and less target responding across Phases 2 and 3 than the lean DRA and dense DRA groups. These preliminary findings suggest that on/off DRA cycling procedures may produce more desirable treatment outcomes than constant DRA without producing negative side effects; however, further research is needed to confirm these possibilities.

Validating Human-Operant Software: A Case Example.

Human-operant experiments conducted with computer software facilitate translational research by assessing the generality of basic research findings and exploring previously untested predictions about behavior in a cost-effective and efficient manner. However, previous human-operant research with computer-based tasks has included little or no description of rigorous validation procedures for the experimental apparatus (i.e., the software used in the experiment). This omission, combined with a general lack of guidance regarding how to thoroughly validate experimental software, introduces the possibility that nascent researchers may insufficiently validate their computer-based apparatus. In this paper, we provide a case example to demonstrate the rigor required to validate experimental software by describing the procedures we used to validate the apparatus reported by Smith and Greer (2021) to assess relapse via a crowdsourcing platform. The validation procedures identified several issues with early iterations of the software, demonstrating how failing to validate human-operant software can introduce confounds into similar experiments. We describe our validation procedures in detail so that others exploring similar computer-based research may have an exemplar for the rigorous testing needed to validate computer software to ensure precision and reliability in computer-based, human-operant experiments.

Commentary on Slocum et al. (2022): Additional Considerations for Evaluating Experimental Control.

In the target article, Slocum et al. (2022) suggested that nonconcurrent multiple baseline designs can provide internal validity comparable to concurrent multiple baseline designs. We provide further support for this assertion; however, we highlight additional considerations for determining the relative strength of each design. We advocate for a more nuanced approach to evaluating design strength and less reliance on strict adherence to a specific set of rules because the details of the design only matter insofar as they help researchers convince others that the results are valid and accurate. We provide further support for Slocum et al.'s argument by emphasizing the relatively low probability that within-tier comparisons would fail to identify confounds. We also extend this logic to suggest that staggering implementation of the independent variable across tiers may be an unnecessary design feature in certain cases. In addition, we provide an argument that nonconcurrent multiple baseline designs may provide verification within baseline logic contrary to arguments made by previous researchers. Despite our general support for Slocum et al.'s assertions and our advocacy for more nuanced approaches to determining the strength of experimental designs, we urge experimenters to consider the perspectives of researchers from other fields who may favor concurrent multiple-baseline designs and suggest that using concurrent multiple-baseline designs when feasible may foster dissemination of behavior analytic research.

Spectral and polarization based imaging in deep-ultraviolet excited photoelectron microscopy.

Using photoelectron emission microscopy, nanoscale spectral imaging of atomically thin MoS2 buried between Al2O3 and SiO2 is achieved by monitoring the wavelength and polarization dependence of the photoelectron signal excited by deep-ultraviolet light. Although photons induce the photoemission, images can exhibit resolutions below the photon wavelength as electrons sense the response. To validate this concept, the dependence of photoemission yield on the wavelength and polarization of the exciting light was first measured and then compared to simulations of the optical response quantified with classical optical theory. A close correlation between experiment and theory indicates that photoemission probes the optical interaction of UV-light with the material stack directly. The utility of this probe is then demonstrated when both the spectral and polarization dependence of photoemission observe spatial variation consistent with grains and defects in buried MoS2. Taken together, these new modalities of photoelectron microscopy allow mapping of optical property variation at length scales unobtainable with conventional light-based microscopy.

Phase duration and resurgence.

Resurgence, the recurrence of responding due to a worsening of reinforcement conditions for current behavior, is a prevalent form of treatment relapse. Resurgence as Choice in Context predicts that increasing the duration of exposure to reinforcement for target responding during Phase 1 will increase resurgence magnitude, whereas increasing the duration of exposure to reinforcement for alternative responding and extinction for target responding during Phase 2 will decrease resurgence magnitude. We conducted an experiment evaluating these predictions with human participants recruited through Amazon's Mechanical Turk platform. We varied Phase 1 and Phase 2 durations across 4 experimental groups. Resurgence as Choice in Context successfully predicted the differences in resurgence magnitude across these groups, and fitting the quantitative model to the obtained data yielded an exceptional coefficient of determination. We discuss the implications of these results for using Resurgence as Choice in Context to inform experiments with human participants and the feasibility of using human-operant preparations to evaluate resurgence.

Sustaining behavior reduction by transitioning the topography of the functional communication response.

When a functional communication response (FCR) can be reliably occasioned, destructive behavior tends to be lower. However, the form of FCR may affect the durability of functional communication training, as missing FCR materials may promote resurgence. Experiment 1 demonstrated that resurgence of target responding was lower when a vocal FCR remained available but was placed on extinction compared to when a card-based FCR was unavailable. Experiment 2 replicated the finding that initiating treatment with a card FCR produced less target responding than when initiating treatment with a vocal FCR. We then evaluated a set of procedures for transitioning the card FCR to the previously unlearned vocal FCR. These findings suggest benefits of training different types of FCRs at different stages of treatment and provide a preliminary set of procedures for transitioning between FCR topographies while occasioning minimal target responding.

Determination of Hafnium Zirconium Oxide Interfacial Band Alignments Using Internal Photoemission Spectroscopy and X-ray Photoelectron Spectroscopy.

Doped ferroelectric HfO2 is highly promising for integration into complementary metal-oxide semiconductor (CMOS) technology for devices such as ferroelectric nonvolatile memory and low-power field-effect transistors (FETs). We report the direct measurement of the energy barriers between various metal electrodes (Pt, Au, Ta, TaN, Ti/Pt, Ni, Al) and hafnium zirconium oxide (Hf0.58Zr0.42O2, HZO) using internal photoemission (IPE) spectroscopy. Results are compared with valence band offsets determined using the three-sample X-ray photoelectron spectroscopy (XPS) as well as the two-sample hard X-ray photoelectron spectroscopy (HAXPES) techniques. Both XPS and IPE indicate roughly the same dependence of the HZO barrier on metal work function with a slope of 0.8 ± 0.5. XPS and HAXPES-derived barrier heights are on average about 1.1 eV smaller than barrier heights determined by IPE, suggesting the presence of negative charge in the HZO.

Empirically Deriving Omission and Commission Errors for Relapse Tests: A Demonstration of Reverse Translation.

Most studies examine treatment relapse by programming contextual changes with perfect treatment integrity or with omission errors in the absence of a context change (i.e., all alternative responses placed on extinction). Recently, Mitteer et al. (2018) examined caregiver behavior in response to a confederate playing the role of a child with destructive behavior, providing the opportunity for researchers to empirically derive reinforcement schedules and test caregiver error patterns within future relapse tests with children. The present study represents a pilot demonstration of methods for reverse translating findings from caregivers to relapse preparations with children. We used a human-operant arrangement with three children with autism spectrum disorder in which they (a) emitted a target response (i.e., pad touch) for a preferred item in a home-like context, (b) emitted an alternative response (e.g., card touch) for the item in a clinic context while the target response was extinguished, and (c) experienced a relapse test in which the experimenter programmed the same low-rate omission and commission errors that caregivers made in the prior study within the home-like context. During the relapse test, target responding approximated or exceeded baseline ranges for all cases, and alternative behavior extinguished for two of the three cases. We discuss how researchers might incorporate similar translation processes in future relapse research.

Phase-Exchange-Driven Wake-Up and Fatigue in Ferroelectric Hafnium Zirconium Oxide Films.

Ferroelectric hafnium zirconium oxide holds great promise for a broad spectrum of complementary metal-oxide-semiconductor (CMOS) compatible and scaled microelectronic applications, including memory, low-voltage transistors, and infrared sensors, among others. An outstanding challenge hindering the implementation of this material is polarization instability during field cycling. In this study, the nanoscale phenomena contributing to both polarization fatigue and wake-up are reported. Using synchrotron X-ray diffraction, the conversion of non-polar tetragonal and polar orthorhombic phases to a non-polar monoclinic phase while field cycling devices comprising noble metal contacts is observed. This phase exchange accompanies a diminishing ferroelectric remanent polarization and provides device-scale crystallographic evidence of phase exchange leading to ferroelectric fatigue in these structures. A reduction in the full width at half-maximum of the superimposed tetragonal (101) and orthorhombic (111) diffraction reflections is observed to accompany wake-up in structures comprising tantalum nitride and tungsten electrodes. Combined with polarization and relative permittivity measurements, the observed peak narrowing and a shift in position to lower angles is attributed, in part, to a phase exchange of the non-polar tetragonal to the polar orthorhombic phase during wake-up. These results provide insight into the role of electrodes in the performance of hafnium oxide-based ferroelectrics and mechanisms driving wake-up and fatigue, and demonstrate a non-destructive means to characterize the phase changes accompanying polarization instabilities.

Design and Synthesis of Isoquinolidinobenzodiazepine Dimers, a Novel Class of Antibody-Drug Conjugate Payload.

Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (S,S)-D211 isomer is functionally more active than (R,R)-D221 and (S,R)-D231 isomers by >50,000-fold and ∼200-fold, respectively. We also synthesized a linker-payload (D212) that uses (S,S)-D211 payload with a cathepsin cleavable linker, a hydrophilic PEG8 spacer, and a thiol reactive maleimide. In addition, homogeneous ADCs generated using D212 linker-payload exhibited ideal physicochemical properties, and anti-CD33 ADC displayed a robust target-specific potency on AML cell lines. These results demonstrate that D212 linker-payload described here can be utilized for developing novel ADC therapeutics for targeted cancer therapy.

Graphene-Insulator-Semiconductor Junction for Hybrid Photodetection Modalities.

A sensitive optical detector is presented based on a deeply depleted graphene-insulator-semiconducting (D2GIS) junction, which offers the possibility of simultaneously leveraging the advantages of both charge integration and localized amplification. Direct read-out and built-in amplification are accomplished via photogating of a graphene field-effect transistor (GFET) by carriers generated within a deeply depleted low-doped silicon substrate. Analogous to a depleted metal-oxide-semiconducting junction, photo-generated charge collects in the potential well that forms at the semiconductor/insulator interface and induces charges of opposite polarity within the graphene film modifying its conductivity. This device enables simultaneous photo-induced charge integration with continuous "on detector" readout through use of graphene. The resulting devices exhibit responsivities as high as 2,500 A/W (25,000 S/W) for visible wavelengths and a dynamic range of 30 dB. As both the graphene and device principles are transferrable to arbitrary semiconductor absorbers, D2GIS devices offer a high-performance paradigm for imaging across the electromagnetic spectrum.

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature.

Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.

The Microstructure of Cellulose Nanocrystal Aerogels as Revealed by Transmission Electron Microscope Tomography.

The microstructure of highly porous cellulose nanocrystal (CNC) aerogels is investigated via transmission electron microscope (TEM) tomography. The aerogels were fabricated by first supercritically drying a carboxylated CNC organogel and then coating via atomic layer deposition with a thin conformal layer of Al2O3 to protect the CNCs against prolonged electron beam exposure. A series of images was then acquired, reconstructed, and segmented in order to generate a three-dimensional (3D) model of the aerogel. The model agrees well with theory and macroscopic measurements, indicating that a thin conformal inorganic coating enables TEM tomography as an analysis tool for microstructure characterization of CNC aerogels. The 3D model also reveals that the aerogels consist of randomly orientated CNCs that attach to one another primarily in three ways: end to end contact, "T″ contact, and "X″ contact.

The critical shoulder angle is associated with rotator cuff tears and shoulder osteoarthritis and is better assessed with radiographs over MRI.

PURPOSE: The purpose of this study was to determine whether there is an association between the critical shoulder angle (CSA) and rotator cuff tears (RCT) as well as osteoarthritis (OA), and to compare the reproducibility and accuracy of CSA values as measured with radiograph and MRI. METHODS: Based on a pre hoc power analysis, three independent reviewers measured CSAs for three groups of 10 age-matched patients each (RCT group, OA group, and non-RCT/non-OA group) using radiographs and MRIs. Inter- and intra-observer agreements of CSAs were determined with intraclass correlation coefficients. ANOVA analysis was performed. RESULTS: Interobserver and intra-observer agreements on radiographs were 0.87 (95 % CI 0.78-0.93) and 0.91 (95 % CI 0.82-0.96), respectively. Significant differences in mean CSAs by radiographs were found between the groups (RCT 37.3° ± 2.6°; OA 28.7° ± 2.2°; non-RCT/non-OA 32.7° ± 2.5°; p < 0.001). CSAs obtained from MRI scans had interobserver agreement of 0.62 (95 % CI 0.43-0.78) and intra-observer agreement of 0.68 (95 % CI 0.50-0.80). There was a significant correlation between the patients' pathologies and CSAs measured by radiographs (r = 0.44; p = 0.02) and MRI (r = 0.50; p = 0.01). A significant difference in mean CSAs measured on radiograph versus MRI was seen in the OA group (28.7° ± 2.2° vs. 31.3° ± 4.4°; p = 0.01). CONCLUSION: CSA measurements obtained from radiographs demonstrated excellent interobserver agreement with less variability than CSAs from MRI, especially in OA patients. This study confirms an association between the CSA and RCTs as well as OA pathology. Assessing the CSA may be helpful during diagnostic evaluation of patients with shoulder pain and can help predict pathology. LEVEL OF EVIDENCE: Retrospective cohort study, Level IV.

Current ADC Linker Chemistry.

The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.

Association between scapula bony morphology and snapping scapula syndrome.

HYPOTHESIS AND BACKGROUND: Scapular incongruity has been described as a contributing factor to the development of snapping scapula syndrome (SSS). The purpose of this retrospective case-control study was to determine the association between scapula bony morphology on magnetic resonance imaging (MRI) and the diagnosis of SSS. METHODS: Bony morphologies of the scapula were evaluated on MRI scans of 26 patients with SSS and 19 patients with non-SSS pathologies. The medial scapula corpus angle (MSCA) was measured on axial MRI sequences. Scapulae were categorized as straight, S shaped, or concave. Two independent observers performed the measurements. Interobserver and intraobserver agreements of MSCA measurements were determined with intraclass correlation coefficients. RESULTS: Axial scapula bony morphology identified 28 scapulae of the straight type, 14 S-shaped scapulae, and 5 concave scapulae. All 5 concave scapulae had confirmed SSS. Measurement of the MSCA showed excellent interobserver agreement of 0.80 (95% confidence interval [CI], 0.67 to 0.89) and intraobserver agreement of 0.70 (95% CI, 0.52 to 0.82). There were significant differences in the mean MSCAs between shoulders with SSS (14.4° ± 19.3°) and non-SSS shoulders (-3.3° ± 15.3°, P = .001). The odds ratio was 8.4 (95% CI, 2.2 to 31.8) for positive MSCA and SSS. The scapulothoracic distance was significantly decreased in the SSS group (14.9 ± 5.8 mm) compared with the non-SSS patients (24.0 ± 6.7 mm, P < .001). DISCUSSION AND CONCLUSION: Anterior angulation of the medial scapula in the axial plane was associated with SSS. Patients with a concave-shaped scapula and a positive MSCA have a 12-fold increased risk of SSS. The MSCA may prove helpful in determining the location and amount of scapular resection needed for patients with SSS.

Healthcare information technology's relativity problems: a typology of how patients' physical reality, clinicians' mental models, and healthcare information technology differ.

OBJECTIVE: To model inconsistencies or distortions among three realities: patients' physical reality; clinicians' mental models of patients' conditions, laboratories, etc; representation of that reality in electronic health records (EHR). To serve as a potential tool for quality improvement of EHRs. METHODS: Using observations, literature, information technology (IT) logs, vendor and US Food and Drug Administration reports, we constructed scenarios/models of how patients' realities, clinicians' mental models, and EHRs can misalign to produce distortions in comprehension and treatment. We then categorized them according to an emergent typology derived from the cases themselves and refined the categories based on insights gained from the literature of interactive sociotechnical systems analysis, decision support science, and human computer interaction. Typical of grounded theory methods, the categories underwent repeated modifications. RESULTS: We constructed 45 scenarios of misalignment between patients' physical realities, clinicians' mental models, and EHRs. We then identified five general types of misrepresentation in these cases: IT data too narrowly focused; IT data too broadly focused; EHRs miss critical reality; data multiplicities-perhaps contradictory or confusing; distortions from data reflected back and forth across users, sensors, and others. The 45 scenarios are presented, organized by the five types. CONCLUSIONS: With humans, there is a physical reality and actors' mental models of that reality. In healthcare, there is another player: the EHR/healthcare IT, which implicitly and explicitly reflects many mental models, facets of reality, and measures thereof that vary in reliability and consistency. EHRs are both microcosms and shapers of medical care. Our typology and scenarios are intended to be useful to healthcare IT designers and implementers in improving EHR systems and reducing the unintended negative consequences of their use.

Securing Information Technology in Healthcare.

Dartmouth College's Institute for Security, Technology, and Society conducted three workshops on securing information technology in healthcare, attended by a diverse range of experts in the field. This article summarizes the three workshops.

Asymmetric carbon-carbon bond formation gamma to a carbonyl group: phosphine-catalyzed addition of nitromethane to allenes.

A chiral phosphine catalyzes the addition of a carbon nucleophile to the gamma position of an electron-poor allene (amide-, ester-, or phosphonate-substituted), in preference to isomerization to a 1,3-diene, in good ee and yield. This strategy provides an attractive method for the catalytic asymmetric gamma functionalization of carbonyl (and related) compounds.