Automating the analysis of facial emotion expression dynamics: A computational framework and application in psychotic disorders.

Facial emotion expressions play a central role in interpersonal interactions; these displays are used to predict and influence the behavior of others. Despite their importance, quantifying and analyzing the dynamics of brief facial emotion expressions remains an understudied methodological challenge. Here, we present a method that leverages machine learning and network modeling to assess the dynamics of facial expressions. Using video recordings of clinical interviews, we demonstrate the utility of this approach in a sample of 96 people diagnosed with psychotic disorders and 116 never-psychotic adults. Participants diagnosed with schizophrenia tended to move from neutral expressions to uncommon expressions (e.g., fear, surprise), whereas participants diagnosed with other psychoses (e.g., mood disorders with psychosis) moved toward expressions of sadness. This method has broad applications to the study of normal and altered expressions of emotion and can be integrated with telemedicine to improve psychiatric assessment and treatment.

Psychosis superspectrum II: neurobiology, treatment, and implications.

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care.

Non-mutagenic impurities - Recent industry experience of using dose durational limits in drug development.

Absence of clear guidance on the qualification threshold for non-mutagenic impurities during clinical development is a source of inconsistency in both sponsor qualification approaches and health authority requests. A survey was conducted in March 2020 with 6 member companies of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Thirteen examples were gathered of where non-International Council for Harmonisation (ICH) limits have been used in regulatory submissions for various indications and stages of development, together with the regulatory outcomes. As expected, few challenges were faced in early clinical development, with health authorities generally commenting that sponsors should work towards ICH Q3A and Q3B guideline specification limits as development progresses. However, inconsistent health authority requests were noted even for early phase clinical trials in late-stage oncology patients. For an optimised use of resources, consistent approaches would have the benefit of supporting faster access of safe medicines to patients while including Replacement, Reduction and Refinement (the 3Rs) considerations with respect to animal testing.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

Scope of the Problem: Ankle Arthroscopy.

Ankle arthroscopy has seen increased utilization and application in recent years. Through the advent of improved instrumentation and techniques, indications have been expanded to include the management of traumatic, degenerative, inflammatory, and neoplastic conditions. It is important to review anterior and posterior ankle arthroscopies along with the history, pertinent anatomy, techniques, indications, and complications as well as gain insight into the future of ankle arthroscopy.

Scope of the Problem: Tendoscopy and Small Joint Arthroscopy of the Foot and Ankle.

It is important to identify and describe practical applications of arthroscopy in the management of foot and ankle pathology. Utilization of the arthroscope provides a minimally invasive means of evaluating and addressing pathology. It obviates the need for a large open approach, which has additional value in the setting of a multiprocedure surgery. In addition to reducing surgical time, arthroscopy provides a potentially enhanced field of view and an adequate working space to address injury. As interest in minimally invasive options grows, the need for safe, effective tendoscopic and arthroscopic options in the foot and ankle increases. A clear and high-yield reference is needed with which to approach these procedures.

The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork.

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by ß-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

Framework for sensitization assessment of extractables and leachables in pharmaceuticals.

During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety.

Calculating qualified non-mutagenic impurity levels: Harmonization of approaches.

The presence of impurities in drugs is unavoidable. As impurities offer no direct benefit to the patient, it is critical that impurities do not compromise patient safety. Current guidelines on the derivation of acceptable impurity levels leave aspects of calculations open for interpretation, resulting in inconsistencies across industry and regulators. To understand current impurity qualification practices from a safety standpoint, regulatory expectations and the safety risk that impurities pose, the IQ DruSafe Impurities Working Group (WG) conducted a pharmaceutical industry-wide survey. Survey results highlighted areas that could benefit from harmonization, including nonclinical species/sex selection and the application of adjustment factors (i.e., body surface area). Recommendations for alignment on these topics is included in this publication. Additionally, the WG collated repeat-dose toxicity information for 181 starting materials and intermediates, reflective of pharmaceutical impurities, to understand the toxicological risks they generally pose in relation to the drug substance (DS) and the assumptions surrounding the calculation of qualified impurity levels. An evaluation of this dataset and the survey were used to harmonize how to calculate a safe limit for an impurity based on toxicology testing of the impurity when present within the DS.

Emotional context effects on memory accuracy for neutral information.

Despite decades of study, it remains unclear how emotional contexts influence memory for non-emotional information. In two studies, we previously found memory accuracy for neutral information encoded in an emotional context differed by valence. Specifically, neutral images encoded in a negative context were remembered with similar accuracy as those encoded in a non-emotional context, and neutral images encoded in a positive context were remembered with less accuracy than a non-emotional context. This Registered Report contains a third study to replicate our original results and allow for direct comparison between the negative and positive encoding conditions. People in the positive condition showed decreased memory accuracy, but this effect was very small in size and only significant when compared to the neutral condition. Given the lack of difference between negative and neutral conditions, effects of emotion on memory are not only a function of emotional arousal. At the same time, given the nonsignificant, small difference between positive and negative conditions, effects of emotion on memory are also not solely attributable to valence. This series of studies represents a step towards re-examining the tenet that emotion enhances memory unless the experience elicits sufficiently high arousal levels such that memory is impaired.

What you want may not be what you like: A test of the aberrant salience hypothesis in schizophrenia risk.

Motivational abnormalities represent a key area of dysfunction in individuals with, or at risk for, schizophrenia and severely limit broad domains of functioning in these populations. The aberrant salience hypothesis posits that motivational abnormalities are the result of an over-attribution of salience to nonpleasurable stimuli but an under-attribution of salience to pleasurable ones. Consequently, people "want" what they do not "like" but do not "want" what they "like." However, it is unclear how this hypothesis manifests in schizophrenia risk beyond monetary rewards. The current research provided a multimodal investigation of the aberrant salience hypothesis in people with elevated psychotic-like experiences (PLEs) who are at risk for developing psychosis. Study 1 examined the link between liking and incentive salience using a neurobiological indicator of incentive salience (contingent negative variation/CNV) in 23 PLEs and 21 Control participants. The PLEs group showed diminished CNV reactivity to pleasant (vs. neutral) social images, which was driven by an augmented response to neutral stimuli. Study 2 examined liking, incentive salience, and conscious wanting experience using a psychological indicator of incentive salience (positive spontaneous thoughts/PSTs) in 38 PLEs and 246 Control participants. The PLEs group showed diminished correspondence between liking, PSTs, and conscious wanting across diverse reward contexts. Collectively, individuals with PLEs over-attribute salience to neutral stimuli and, to a lesser degree, under-attribute salience to rewards. Findings of the current research support abnormal salience attribution as a trait-like feature implicated in the pathophysiology and development of schizophrenia and provide valuable insights on research and treatment of this illness.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.

Background: Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods: DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results: Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). Conclusions: In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration: NCT02403674.

Affective forecasting and accuracy in social anhedonia: Predicted and experienced emotion for a social interaction.

OBJECTIVE: Previous research suggests people with social anhedonia (SocAnh) exhibit deficits in anticipated pleasure for social stimuli relative to controls. However, previous research has relied on hypothetical social stimuli and has focused on anticipated pleasure without examining negative affect. METHOD: Participants were informed that they would complete an "enjoyable" sharing task with a peer and were asked to forecast positive and negative affect during the interaction. After the interaction, participants reported their experienced emotions. RESULTS: We found SocAnh and controls anticipated and experienced similar levels of positive affect and that both groups underpredicted positive affect. The SocAnh group anticipated and experienced more negative affect than controls and was more accurate in forecasting negative affect. CONCLUSION: This is the first study to show that SocAnh is associated with the heightened anticipation of negative affect and that experiencing heightened negative affect during social interactions could drive reduced motivation and desire to engage in future social interaction.

Decreased Self-Concept Clarity in People with Schizophrenia.

Disturbances in the perception of self are thought to be central to the development of psychosis. Self-concept clarity (SCC) is the extent to which one's beliefs about oneself are internally consistent, stable, and clear. Participants with schizophrenia (N = 54) and healthy controls (N = 32) completed the Me Not-Me Decision Task (MNMDT), in which they decided whether 60 adjectives (30 pairs of antonyms) did or did not describe themselves. SCC is conceptualized as the number of consistent responses. Participants also completed the Self-Concept Clarity Scale (SCCS). Compared to healthy controls, participants with schizophrenia scored lower on the MNMDT and SCCS, and scores were negatively correlated with positive and negative symptoms. In a simultaneous regression, SCCS scores were uniquely associated with positive symptoms, whereas MNMDT scores were uniquely associated with negative symptoms. This suggests that people with schizophrenia have decreased self-concept clarity that is related to positive and negative symptoms.

Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."

Social functioning and age across affective and nonaffective psychoses.

Both nonaffective and affective psychoses are associated with deficits in social functioning across the course of the illness. However, it is not clear how social functioning varies among diagnostic groups as a function of age. The current study examined the relationship between social functioning and age in schizophrenia (SZ), schizoaffective disorder (SZA), and psychotic bipolar disorder (PBD). We found that individuals with PBD had the highest functioning, whereas individuals with SZ had the poorest. The functioning of individuals with SZA fell in between those of other groups. We also found that older ages were associated with poorer functioning. Although there was not a significant diagnostic group by age interaction, visual inspection of our data suggests a subtly steeper trajectory of decline in PBD. Overall, these results indicate that early interventions targeting social functioning may benefit individuals with either non-affective or affective psychoses to slow a projected decline.

An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride.

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB1 and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB1 and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.

Carbon Footprint of Minor Foot and Ankle Surgery: A Randomized Controlled Trial.

Background: Climate change poses a substantial threat to human health, and operating rooms (ORs) have an outsized environmental impact. The Program for Research in Sustainable Medicine (PRiSM) designed a protocol for minor foot and ankle surgery intended to reduce waste, streamline instrument trays, and minimize laundry. We conducted a randomized controlled trial to compare the carbon footprint of procedures performed using the PRiSM protocol vs a traditional protocol. Methods: Forty adult patients undergoing foreign body removal, hammertoe correction, toe amputation, hardware removal, mass excision, or gastrocnemius recession were randomized to the PRiSM or our "Traditional" protocol. The PRiSM protocol used a smaller instrument tray, fewer drapes and towels, and minimal positioning blankets. No changes were made to surgical site preparation or operative techniques. Environmental impact was estimated using the carbon footprint, measured in kilograms of carbon dioxide equivalents (CO2e). Emissions associated with OR waste, instrument processing, and laundry were calculated. Results: On average, PRiSM cases had a smaller carbon footprint than Traditional cases (17.3 kg CO2e [SD = 3.2] vs 20.6 kg CO2e [SD = 2.0], P < .001). Waste-associated emissions from PRiSM cases were reduced (16.0 kg CO2e [SD = 2.7] vs 18.4 kg CO2e [SD = 1.8], P = .002), as were modeled instrument processing-related emissions (0.34 vs 0.91 kg CO2e). One superficial surgical site infection occurred in each group. Conclusion: We found a small but statistically significant reduction in the environmental impact of minor foot and ankle surgery when using the PRiSM vs Traditional protocol. The environmental impact of these cases was dominated by plastic waste-related emissions. Orthopaedic surgeons should think critically about what components of their surgical setup are truly necessary for patient care, as minor changes in product utilization can have significant impacts on waste and greenhouse gas emissions. Level of Evidence: Level I, randomized controlled trial.