The role of retinal irradiance estimates in melanopsin-driven retinal responsivity: A reanalysis of the post-illumination pupil response (PIPR) in seasonal affective disorder.

To isolate melanopsin contributions to retinal sensitivity measured by the post-illumination pupil response (PIPR), controlling for individual differences in non-melanopsin contributions including retinal irradiance is required. When methodologies to negate such differences present barriers, statistical controls have included age, baseline diameter, iris pigmentation, and circadian time of testing. Alternatively, the pupil light reflex (PLR) and calculations estimating retinal irradiance both reflect retinal irradiance, while the PLR also reflects downstream pathways. We reanalyzed data from an observational, correlational study comparing the PIPR across seasons in seasonal affective disorder (SAD) and controls. The PIPR was measured in 47 adults in Pittsburgh, Pennsylvania (25 SAD) over 50 s after 1 s red and blue stimuli of 15.3 log photons/cm2/s. The PLR was within 1 s while PIPR was averaged over 10-40 seconds post-stimulus. Two raters ranked iris pigmentation using a published scale. We evaluated model fit using Akaike's Information Criterion (AIC) across different covariate sets. The best fitting models included either estimated retinal irradiance or PLR, and circadian time of testing. The PLR is collected contemporaneously in PIPR studies and is an individually specific measure of nonspecific effects, while being minimally burdensome. This work extends the prior publication by introducing theoretically grounded covariates that improved analytic model fits based on AIC specific to the present methods and sample. Such quantitative methods could be helpful in studies which must balance participant and researcher burden against tighter methodological controls of individual differences in retinal irradiance.

Circadian photoentrainment varies by season and depressed state: associations between light sensitivity and sleep and circadian timing.

STUDY OBJECTIVES: Altered light sensitivity may be an underlying vulnerability for disrupted circadian photoentrainment. The photic information necessary for circadian photoentrainment is sent to the circadian clock from melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The current study tested whether the responsivity of ipRGCs measured using the post-illumination pupil response (PIPR) was associated with circadian phase, sleep timing, and circadian alignment, and if these relationships varied by season or depression severity. METHODS: Adult participants (N = 323, agem = 40.5, agesd = 13.5) with varying depression severity were recruited during the summer (n = 154) and winter (n = 169) months. Light sensitivity was measured using the PIPR. Circadian phase was assessed using Dim Light Melatonin Onset (DLMO) on Friday evenings. Midsleep was measured using actigraphy. Circadian alignment was calculated as the DLMO-midsleep phase angle. Multilevel regression models covaried for age, gender, and time since wake of PIPR assessment. RESULTS: Greater light sensitivity was associated with later circadian phase in summer but not in winter (ß = 0.23; p = 0.03). Greater light sensitivity was associated with shorter DLMO-midsleep phase angles (ß = 0.20; p = 0.03) in minimal depression but not in moderate depression (SIGHSAD < 6.6; Johnson-Neyman region of significance). CONCLUSIONS: Light sensitivity measured by the PIPR was associated with circadian phase during the summer but not in winter, suggesting ipRGC functioning in humans may affect circadian entrainment when external zeitgebers are robust. Light sensitivity was associated with circadian alignment only in participants with minimal depression, suggesting circadian photoentrainment, a possible driver of mood, may be decreased in depression year-round, similar to decreased photoentrainment in winter.

Social functioning mediates the relationship between psychiatric symptoms and recovery among veteran and community service users with serious mental illness.

OBJECTIVE: Previous research has established the impact of psychiatric symptoms on social functioning, while there is a paucity of research examining how social functioning relates to personal recovery, an individual's self-assessment of their mental health recovery. This study examined the mediating effect of social engagement, interpersonal communication, and satisfaction with support in the relationship between distinct psychiatric symptom clusters and perceived mental health recovery. METHODS: In a cross-sectional study, both patient self-report and provider assessment data were collected for 250 patients with serious mental illness (SMI) across four mental health service sites. Parallel mediation analytic models were used. RESULTS: Interpersonal communication partially mediated the relationship between positive and negative symptom clusters and personal recovery. Satisfaction with social supports partially mediated the relationship between excited symptoms and personal recovery. Both interpersonal communication and satisfaction with social supports partially mediated the relationship between general psychological distress and depressive symptoms and personal recovery. Collectively, social functioning mediators explained nearly half of the relationship between general psychological distress and excited symptoms and personal recovery and nearly all of the relationship between positive symptoms and personal recovery. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Clinical providers working with persons with SMI should regularly assess social functioning in addition to assessing psychiatric symptoms and personal recovery factors and should incorporate social skills education into SMI group and individual treatments. Social functioning as a target of treatment may be especially beneficial for patients who are dissatisfied with other interventions or feel they have experienced the maximum benefit from treatment and are seeking additional methods to support personal recovery. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Probe metal binding mode of imine covalent organic frameworks: cycloiridation for (photo)catalytic hydrogen evolution from formate.

Metalation of covalent organic frameworks (COFs) is a critical strategy to functionalize COFs for advanced applications yet largely relies on the pre-installed specific metal docking sites in the network, such as porphyrin, salen, 2,2'-bipyridine, etc. We show in this study that the imine linkage of simple imine-based COFs, one of the most popular COFs, readily chelate transition metal (Ir in this work) via cyclometalation, which has not been explored before. The iridacycle decorated COF exhibited more than 10-fold efficiency enhancement in (photo)catalytic hydrogen evolution from aqueous formate solution than its molecular counterpart under mild conditions. This work will inspire more functional cyclometallated COFs to be explored beyond catalysis considering the large imine COF library and the rich metallacycle chemistry.

Reward Devaluation in Autistic Children and Adolescents with Complex Needs: A Feasibility Study.

Rewards act as a motivator for positive behavior and learning. Although compounding evidence indicates that reward processing operates differently in autistic individuals who do not have co-occurring learning disabilities, little is known about individuals who have such difficulties or other complex needs. This study aimed first to assess the feasibility of using an adapted reward devaluation paradigm to examine basic reward processes in this underrepresented population, and second to investigate whether autistic children and adolescents with complex needs would show dynamic behavioral changes in response to changes in the motivational value of a reward. Twenty-seven autistic children and adolescents with complex needs and 20 typically developing 5-year-old children took part in the study. Participants were presented with two visual cues on a touchscreen laptop, which triggered the delivery of a video, music, or physical reward. One of the rewards was then presented in abundance to decrease its motivational value. Participants showed decreased interest in the video and music rewards after devaluation. The experimental setup was found to be suitable to test individuals with complex needs, although recommendations are made for the use of physical rewards. The results suggest that autistic participants with complex needs demonstrate goal-directed behavior and that it is feasible to develop experimental paradigms that can shed important light on learning processes that are fundamental to many education and intervention strategies for this population. Autism Res 2020, 13: 1915-1928. © 2020 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC. LAY SUMMARY: We adapted an experimental task to conduct research with autistic children and adolescents with complex needs, who remain grossly underrepresented in autism research. We found that once a reward was presented in great quantity, participants were less motivated to obtain it, showing that they adapted their behavior to changes in the value of that reward. This is an important finding to help promote learning and design better interventions for this population.

Proteomic Analysis of Resistance of Gram-Negative Bacteria to Chlorhexidine and Impacts on Susceptibility to Colistin, Antimicrobial Peptides, and Ceragenins.

Use of chlorhexidine in clinical settings has led to concerns that repeated exposure of bacteria to sub-lethal doses of chlorhexidine might result in chlorhexidine resistance and cross resistance with other cationic antimicrobials including colistin, endogenous antimicrobial peptides (AMPs) and their mimics, ceragenins. We have previously shown that colistin-resistant Gram-negative bacteria remain susceptible to AMPs and ceragenins. Here, we investigated the potential for cross resistance between chlorhexidine, colistin, AMPs and ceragenins by serial exposure of standard strains of Gram-negative bacteria to chlorhexidine to generate resistant populations of organisms. Furthermore, we performed a proteomics study on the chlorhexidine-resistant strains and compared them to the wild-type strains to find the pathways by which bacteria develop resistance to chlorhexidine. Serial exposure of Gram-negative bacteria to chlorhexidine resulted in four- to eight-fold increases in minimum inhibitory concentrations (MICs). Chlorhexidine-resistant organisms showed decreased susceptibility to colistin (8- to 32-fold increases in MICs) despite not being exposed to colistin. In contrast, chlorhexidine-resistant organisms had the same MICs as the original strains when tested with representative AMPs (LL-37 and magainin I) and ceragenins (CSA-44 and CSA-131). These results imply that there may be a connection between the emergence of highly colistin-resistant Gram-negative pathogens and the prevalence of chlorhexidine usage. Yet, use of chlorhexidine may not impact innate immune defenses (e.g., AMPs) and their mimics (e.g., ceragenins). Here, we also show that chlorhexidine resistance is associated with upregulation of proteins involved in the assembly of LPS for outer membrane biogenesis and virulence factors in Pseudomonas aeruginosa. Additionally, resistance to chlorhexidine resulted in elevated expression levels of proteins associated with chaperones, efflux pumps, flagella and cell metabolism. This study provides a comprehensive overview of the evolutionary proteomic changes in P. aeruginosa following exposure to chlorhexidine and colistin. These results have important clinical implications considering the continuous application of chlorhexidine in hospitals that could influence the emergence of colistin-resistant strains.

Susceptibility of Multidrug-Resistant Bacteria, Isolated from Water and Plants in Nigeria, to Ceragenins.

The continuous emergence of multidrug resistant pathogens is a major global health concern. Although antimicrobial peptides (AMPs) have shown promise as a possible means of combatting multidrug resistant strains without readily engendering resistance, costs of production and targeting by proteases limit their utility. Ceragenins are non-peptide AMP mimics that overcome these shortcomings while retaining broad-spectrum antimicrobial activity. To further characterize the antibacterial activities of ceragenins, their activities against a collection of environmental isolates of bacteria were determined. These isolates were isolated in Nigeria from plants and water. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of selected ceragenins and currently available antimicrobials against these isolates were measured to determine resistance patterns. Using scanning electron microscopy (SEM), we examined the morphological changes in bacterial membranes following treatment with ceragenins. Finally, we investigated the effectiveness of ceragenins in inhibiting biofilm formation and destroying established biofilms. We found that, despite high resistance to many currently available antimicrobials, including colistin, environmental isolates in planktonic and biofilm forms remain susceptible to ceragenins. Additionally, SEM and confocal images of ceragenin-treated cells confirmed the effective antibacterial and antibiofilm activity of ceragenins.

Validation of the Sleep-Wake Scoring of a New Wrist-Worn Sleep Monitoring Device.

STUDY OBJECTIVES: To test the sleep-wake scoring reliability of a new wrist-worn sleep monitoring device. METHODS: Twenty-seven adult good sleepers underwent 1 night of polysomnography (PSG) while wearing both the new device (myCadian [MC]; CurAegis Technologies, Rochester, New York, United States) and commercially available actigraphy (Actiwatch 2 [AW]; Philips Respironics, Murrysville, Pennsylvania, United States) on their nondominant wrist. PSG tests were manually stage scored. After excluding missing data, 20 participants had full-night data on all three devices with 17,734 total 30-second epochs. Using PSG as the gold standard, pooled epoch-by-epoch agreement for sleep and wake was calculated for each device using percent agreement and Cohen kappa statistic. Positive predictive values for both sleep and wake epochs, as well as sleep continuity statistics, were calculated. RESULTS: Percent agreement with PSG-scored wake and sleep was 91.3% for MC (kappa = 0.67) and 87.7% for AW (kappa = 0.50). Positive predictive values for sleep epochs were 94.4% and 90.8% for MC and AW, respectively, and 74.5% and 65.6% for wake. Both devices underestimated wake and overestimated sleep compared to PSG. Descriptively, compared to PSG, sleep latency was higher with MC and wake after sleep onset higher with AW. Total sleep time and sleep efficiency were more similar across devices. CONCLUSIONS: The kappa statistic for MC is consistent with a high level of agreement with PSG. Overall, the reliability of MC compared to PSG scoring was slightly more favorable than that of AW. Findings suggest that MC provides reliable sleep-wake scoring during a nocturnal sleep period for good sleepers.

Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms.

Background: Candida auris has emerged as a serious threat to human health. Of particular concern are the resistance profiles of many clinical isolates, with some being resistant to multiple classes of antifungals. Objectives: Measure susceptibilities of C. auris isolates, in planktonic and biofilm forms, to ceragenins (CSAs). Determine the effectiveness of selected ceragenins in gel and cream formulations in eradicating fungal infections in tissue explants. Materials and methods: A collection of 100 C. auris isolates available at CDC was screened for susceptibility to a lead ceragenin. A smaller collection was used to characterize antifungal activities of other ceragenins against organisms in planktonic and biofilm forms. Effects of ceragenins on fungal cells and biofilms were observed via microscopy. An ex vivo model of mucosal fungal infection was used to evaluate formulated forms of lead ceragenins. Results: Lead ceragenins displayed activities comparable to those of known antifungal agents against C. auris isolates with MICs of 0.5-8 mg/L and minimum fungicidal concentrations (MFCs) of 2-64 mg/L. No cross-resistance with other antifungals was observed. Fungal cell morphology was altered in response to ceragenin treatment. Ceragenins exhibited activity against sessile organisms in biofilms. Gel and cream formulations including 2% CSA-44 or CSA-131 resulted in reductions of over 4 logs against established fungal infections in ex vivo mucosal tissues. Conclusions: Ceragenins demonstrated activity against C. auris, suggesting that these compounds warrant further study to determine whether they can be used for topical applications to skin and mucosal tissues for treatment of infections with C. auris and other fungi.

Antibacterial and Antifungal Activities of Poloxamer Micelles Containing Ceragenin CSA-131 on Ciliated Tissues.

Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated with cystic fibrosis. A characteristic of an optimal therapeutic for use in the lungs and trachea is the exertion of potent antimicrobial activities without damaging the cilia that play a critical role in these tissues. In previous work, potent antimicrobial activities of ceragenin CSA-131 have been reported; however, we found in ex vivo studies that this ceragenin, at concentrations necessary to eradicate established biofilms, also causes loss of cilia function. By formulating CSA-131 in poloxamer micelles, cilia damage was eliminated and antimicrobial activity was unaffected. The ability of CSA-131, formulated with a poloxamer, to reduce the populations of fungal pathogens in tracheal and lung tissue was also observed in ex vivo studies. These findings suggest that CSA-131, formulated in micelles, may act as a potential therapeutic for polymicrobial and biofilm-related infections in the lung and trachea.