Effects of neural oscillation power and phase on discrimination performance in a visual tilt illusion.

Neural oscillations reflect fluctuations in the relative excitation/inhibition of neural systems1,2,3,4,5 and are theorized to play a critical role in canonical neural computations6,7,8,9 and cognitive processes.10,11,12,13,14 These theories have been supported by findings that detection of visual stimuli fluctuates with the phase of oscillations prior to stimulus onset.15,16,17,18,19,20,21,22,23 However, null results have emerged in studies seeking to demonstrate these effects in visual discrimination tasks,24,25,26,27 raising questions about the generalizability of these phenomena to wider neural processes. Recently, we suggested that methodological limitations may mask effects of phase in higher-level sensory processing.28 To test the generality of phasic influences on perception requires a task that involves stimulus discrimination while also depending on early sensory processing. Here, we examined the influence of oscillation phase on the visual tilt illusion, in which a center grating has its perceived orientation biased away from the orientation of a surround grating29 due to lateral inhibitory interactions in early visual processing.30,31,32 We presented center gratings at participants' subjective vertical angle and had participants report whether the grating appeared tilted clockwise or counterclockwise from vertical on each trial while measuring their brain activity with electroencephalography (EEG). In addition to effects of alpha power and aperiodic slope, we observed robust associations between orientation perception and alpha and theta phase, consistent with fluctuating illusion magnitude across the oscillatory cycle. These results confirm that oscillation phase affects the complex processing involved in stimulus discrimination, consistent with its purported role in canonical computations that underpin cognition.

Modulation of endogenous opioid signaling by inhibitors of puromycin sensitive aminopeptidase.

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

Feeding Management and Palate Repair Timing in Infants with Cleft Palate with and without Pierre Robin Sequence: A Multisite Study.

OBJECTIVES: Compare the feeding management practices in infants with cleft palate with and without Pierre Robin sequence (PRS) and determine if specific feeding difficulties or interventions predict delayed palate repair. DESIGN: Retrospective cross-sectional study. SETTING: Seventeen cleft palate teams contributed data. PATIENTS: 414 infants were included in this study: 268 infants with cleft palate only and 146 infants with cleft palate and PRS. PROCEDURES: Data were collected via parent interview and electronic health records. MAIN OUTCOME MEASURES: Outcomes for the primary objective included categorical data for: history of poor growth, feeding therapy, milk fortification, use of enteral feeding, and feeding difficulties. The outcome for the secondary objective was age in months at primary palate repair. RESULTS: Infants with PRS had a significantly higher prevalence of feeding difficulties (81% versus 61%) and poor growth (29% versus 15%) compared to infants with cleft palate only. Infants with PRS received all feeding interventions-including feeding therapy, milk fortification, and enteral feeding-at a significantly higher frequency. Infants with PRS underwent primary palate repair at a mean age of 13.55 months (SD = 3.29) which was significantly (P < .00001) later than infants with cleft palate only who underwent palate repair at a mean age of 12.05 months (SD = 2.36). Predictors of delayed palate repair included diagnosis of PRS as well as Hispanic ethnicity and a history of poor growth. CONCLUSIONS: These findings can be used to establish clinical directives focused on providing early, multimodal feeding interventions to promote optimal growth and timely palate repair for infants with PRS.

Can MRI Replace Nasopharyngoscopy in the Evaluation of Velopharyngeal Insufficiency?

OBJECTIVE: To investigate whether flexible nasopharyngoscopy, when performed in addition to magnetic resonance imaging (MRI), influences the type of surgery selected or success of surgery in patients with velopharyngeal insufficiency (VPI). DESIGN: Cohort study. SETTING: A metropolitan children's hospital. PATIENTS: Patients with non-syndromic, repaired cleft palate presenting for management of VPI. INTERVENTIONS: MRI and nasopharyngoscopy or MRI alone for preoperative imaging of the velopharyngeal mechanism. MAIN OUTCOME MEASURES: (1) Surgical selection and (2) resolution of hypernasality. All speech, MRI, and nasopharyngoscopy measurements were performed by raters blinded to patients' medical and surgical history. RESULTS: Of the 25 patients referred for nasopharyngoscopy, 76% completed the exam. Of the 41 patients referred for MRI, the scan was successfully completed by 98% of patients. Completion of nasopharyngoscopy was significantly (p=0.01) lower than MRI. Surgical selection did not significantly differ (p=0.73) between the group receiving MRI and nasopharyngoscopy and the group receiving MRI alone, nor was there a significant difference between these groups in the proportion of patients achieving resolution of hypernasality postoperatively (p=0.63). Percent total velopharyngeal closure assessments on nasopharyngoscopy and MRI were strongly correlated (r=0.73). CONCLUSIONS: In patients receiving MRI as part of their preoperative VPI evaluation, the addition of nasopharyngoscopy did not result in a difference in surgical selection or resolution of hypernasality. Routine inclusion of nasopharyngoscopy may not be necessary for the evaluation of velopharyngeal anatomy when MRI is available.

A novel PSMB8 isoform associated with multiple sclerosis lesions induces P-body formation.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Current therapies primarily target the inflammatory component of the disease and are highly effective in early stages of MS while limited therapies have an effect in the more chronic progressive stages of MS where resident glia have a larger role. MS lesions tend to be inflammatory even after the initial peripheral immune cell invasion has subsided and this inflammation is known to cause alternative splicing events. We used qPCR of normal-appearing white matter and white matter lesions from postmortem MS tissue, in vitro studies, and immunostaining in MS tissue to investigate the alternative splicing of one gene known to be important during recovery in an animal model of MS, PSMB8. We found a novel, intron-retained isoform which has not been annotated, upregulated specifically in MS patient white matter lesions. We found that this novel isoform activates the nonsense-mediated decay pathway in primary human astrocytes, the most populous glial cell in the CNS, and is then degraded. Overexpression of this isoform in astrocytes leads to an increased number of processing bodies in vitro, the primary site of mRNA decay. Finally, we demonstrated that MS white matter lesions have a higher burden of processing bodies compared to normal-appearing white matter, predominantly in GFAP-positive astrocytes. The increase in alternative splicing of the PSMB8 gene, the stress that this alternative splicing causes, and the observation that processing bodies are increased in white matter lesions suggests that the lesion microenvironment may lead to increased alternative splicing of many genes. This alternative splicing may blunt the protective or reparative responses of resident glia in and around white matter lesions in MS patients.

Support Needs of Labor and Delivery Nurses After Traumatic Experiences.

OBJECTIVE: To examine the effect of psychological distress, overall distress, and institutional support following a traumatic workplace event on absenteeism, turnover intention, and resilience among labor and delivery nurses. DESIGN: A quantitative cross-sectional survey. SETTING: Online distribution from January 13, 2021, to February 2, 2021. PARTICIPANTS: A nationwide convenience sample of labor and delivery nurses recruited from the Association of Women's Health, Obstetric and Neonatal Nurses (N = 171). METHODS: Participants completed a survey that included the Second Victim Experience and Support Tool-Revised and the Second Victim Support Desirability survey. We compared available versus desired support options using descriptive analyses. We examined levels of psychological distress and lack of institutional support in relation to turnover intention, absenteeism, and resilience using multiple regression analyses. RESULTS: Participants identified and described various traumatic experiences in the workplace, including neonatal and maternal death, complicated births, and workplace violence. Participants indicated that the available support services did not meet their needs. Psychological distress, overall distress, and lack of institutional support were associated with absenteeism and turnover, whereas only institutional support was associated with resilience. CONCLUSION: Labor and delivery nurses encounter various traumatic events in the workplace, and the support services provided after an event do not meet their needs. Additional research is needed to understand the scope of the problem and investigate best practices to assist labor and delivery nurses following traumatic events.

Cooperation between Nodal and FGF signals regulates zebrafish cardiac cell migration and heart morphogenesis.

Asymmetric vertebrate heart development is driven by an intricate sequence of morphogenetic cell movements, the coordination of which requires precise interpretation of signaling cues by heart primordia. Here we show that Nodal functions cooperatively with FGF during heart tube formation and asymmetric placement. Both pathways act as migratory stimuli for cardiac progenitor cells (CPCs), but FGF is dispensable for directing heart tube asymmetry, which is governed by Nodal. We further find that Nodal controls CPC migration by inducing left-right asymmetries in the formation of actin-based protrusions in CPCs. Additionally, we define a developmental window in which FGF signals are required for proper heart looping and show cooperativity between FGF and Nodal in this process. We present evidence FGF may promote heart looping through addition of the secondary heart field. Finally, we demonstrate that loss of FGF signaling affects proper development of the atrioventricular canal (AVC), which likely contributes to abnormal chamber morphologies in FGF-deficient hearts. Together, our data shed insight into how the spatiotemporal dynamics of signaling cues regulate the cellular behaviors underlying organ morphogenesis.

A simple, fast, and cost-effective smartphone-based digital imaging method for quantification of lidocaine hydrochloride in pharmaceutical formulations.

OBJECTIVE: A simple, highly specific, accurate and fast method by smartphone-based digital imaging was developed for estimating lidocaine hydrochloride in pharmaceutical formulations. MATERIAL AND METHODS: To obtain the images, a Galaxy A03 Core smartphone and an image acquisition device developed in the laboratory were used to control the incident factors in reproducibility of the measurements. The processing of the images was carried out with the Color Grab application. Finally, the absorbance values were calculated using the RGB intensity values of blank, standard, and sample solutions. The proposed method was compared with spectroscopic and chromatographic methods. RESULTS: The reaction between copper and lidocaine hydrochloride was characterized, showing better results in an equimolar ratio and maintaining the pH of the solution above 11.5. The use of the device for the capture of digital images allowed to control those sensitive parameters for reproducibility so that the analytical measurements showed adequate precision and accuracy. Validation of the main parameters of the method showed compliance with acceptance criteria. The application of the method for the analysis of injectable samples achieved reliable results, which were statistically similar to other reference instrumental methods. CONCLUSION: The proposed method presented figures of merit in relation to linearity, precision, selectivity, accuracy, and robustness; it was carried out by designing and manufacturing a device for capturing digital images on a smartphone, which were analyzed to obtain RGB intensity values. These data are finally used to calculate absorbance values of solutions. All these elements provide this work with innovative characteristics in the field of analysis for control of pharmaceutical formulations.

Can Better Leadership Reduce Nursing Home Staff Turnover?

OBJECTIVES: To assess whether a measure of leadership support for worker safety, health, and well-being predicts staff turnover in nursing homes after controlling for other factors. DESIGN: This paper uses administrative payroll data to measure facility-level turnover and uses a survey measure of nursing home leadership commitment to workers. In addition, we use data from Medicare to measure various nursing home characteristics. SETTING AND PARTICIPANTS: Nursing homes with at least 30 beds serving adults in California, Ohio, and Massachusetts were invited to participate in the survey. The analysis sample included 495 nursing homes. METHODS: We used a multivariable ordinary least squares model with turnover rate as the dependent variable. We used an indicator for nursing homes who scored above the median on the measure of leadership that supports worker safety, health, and well-being. Control variables include bed count (deciles), ownership (corporate/noncorporate × for-profit/not-for-profit), percent of residents on Medicaid, state, being in a nonmetropolitan county, and total nurse staffing per patient day in the 2 quarters before the survey. RESULTS: The unadjusted turnover rate was lower for those nursing homes that scored higher on leadership commitment to worker safety, health, and well-being. After controlling for additional variables, greater leadership commitment was still associated with lower turnover but with some attenuation. CONCLUSIONS AND IMPLICATIONS: We find that nursing homes with leadership that communicated and demonstrated commitment to worker safety, health, and well-being had relatively fewer nurses leave during the study period, with turnover rates approximately 10% lower than homes without. These findings suggest that leadership may be a valuable tool for reducing staff turnover.

The Use of Medical Crowdfunding to Mitigate the Personal Costs of Serious Chronic Illness: Scoping Review.

BACKGROUND: Persons diagnosed with serious chronic illnesses and their caretakers experience multiple types of financial costs that strain their income and generate financial distress. Many turn to medical crowdfunding (MCF) to mitigate the harms of these costs on their health and quality of life. OBJECTIVE: This scoping review aims to summarize the research on MCF for persons diagnosed with serious chronic illness regarding study designs and methods; the responsible conduct of research practices; and study foci as they relate to stress, stress appraisals, and the coping processes. METHODS: This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. Eligible studies were conducted in countries designated as high income by the World Bank and focused on beneficiaries diagnosed with serious chronic illness. The findings of the included studies were summarized as they related to the key concepts in a conceptual framework derived from an established stress, appraisal, and coping framework and a conceptual model of financial toxicity in pediatric oncology. RESULTS: Overall, 26 studies were eligible for inclusion in the review. The main findings included a lack of integration of qualitative and quantitative approaches and the inconsistent reporting of the responsible conduct of research practices. The included studies focused on financial stressors that contributed to financial burden, such as out-of-pocket payments of medical bills, basic living expenses, medical travel expenses, and lost income owing to illness-related work disruptions. Few studies addressed stress appraisals as threatening or the adequacy of available financial resources. When mentioned, appraisals related to the global financial struggle during the COVID-19 pandemic or the capacity of social network members to donate funds. The consequences of MCF included the receipt of 3 forms of social support (tangible, informational, and emotional), privacy loss, embarrassment, and the propagation of scientifically unsupported information. Studies found that friends and family tended to manage MCF campaigns. Although most of the studies (21/26, 81%) focused on monetary outcomes, a few (5/26, 19%) concentrated on peoples' experiences with MCF. CONCLUSIONS: The identified methodological gaps highlight the need for more robust and reproducible approaches to using the copious data available on public MCF platforms. The integration of quantitative and qualitative methods will allow for nuanced explorations of the MCF experience. A more consistent elaboration of strategies to promote the responsible conduct of research is warranted to minimize risk to populations that are vulnerable and express concerns regarding the loss of privacy. Finally, an examination of the unanticipated consequences of MCF is critical for the development of future interventions to optimize existing supports while providing needed supports, financial and nonfinancial, that are lacking.

Injury-related emergency department use among people with intellectual and developmental disabilities insured by Medicaid from 2010 to 2016.

OBJECTIVES: Data on non-fatal injuries and visits to the emergency department (ED) for injuries are not readily available. The objective of this paper is to describe injury-related ED visits for people with intellectual and developmental disabilities who are covered by the Medicaid insurance programme. METHODS: We aggregated 2010-2016 Medicaid claims data from eight states. Using these data, we identified individuals with intellectual and developmental disabilities and then determined an all-cause ED visit rate, ED visit due to injury rate and admission from ED due to injury rate. Data were stratified by sex and age group. Results were compared with national rates. RESULTS: Medicaid members with intellectual and developmental disabilities visited EDs at approximately 1.8 times the rate of the general population. The ED visit rate due to injury was approximately 1.5 times that observed in the population overall. When ED visits due to injury data were stratified by age and sex, the largest discrepancy was observed in women ages 45-64, who visited EDs due to injury at a rate 2.1 times that of women of the same age in the general population. The admission rate from ED due to injury increased over the study period most notably in the older age groups. CONCLUSIONS: While rates and patterns of ED utilisation among Medicaid members with intellectual and developmental disabilities vary by age and gender, our findings suggest this group visits the ED due to injury at rates well above the general population.

Predictors of Cannabis Use Among Canadian University Students.

Objective: To examine the correlates between cannabis use, motives to use, related psychosocial outcomes and academic behaviours among a sample of Canadian university students. Methods: A random sample of 6,000 students who were enrolled in at least one class and were 18 years or over were asked to complete a cross-sectional online survey. Of the 920 students that responded, 478 (ages 18-55; mean age = 25.02, SD = 5.95) identified as having used cannabis within the past six months and thus were included as participants in the current study. Participants completed a battery of measures designed to examine cannabis use and associated constructs (i.e., substance use risk, personal well-being, non-specific psychological distress, academic behaviours, and motivations for use). Results: Among the participants, 31% (n = 148) were found to be frequent (i.e., hazardous) users. Using cannabis for enhancement, coping, expansion, sleep difficulties, and conformity purposes, as well as impulsive personality traits were found to be predictors of cannabis use severity, with the enhancement motive identified as the strongest predictor for the total sample, males, and hazardous users. The coping motive was the strongest predictor for females, and impulsivity was the strongest predictor for non-hazardous users. Conclusion: Findings will help inform the development of campus guidelines for lower risk cannabis use. Information gleaned from this study will also provide important information for those that use cannabis, policymakers, and health care providers in considering optimal personal use, prevention, and intervention plans.

Comparative Effectiveness of Secondary Furlow and Buccal Myomucosal Flap Lengthening to Treat Velopharyngeal Insufficiency.

Background: Secondary Furlow (Furlow) and buccal myomucosal flaps (BMMF) treat velopharyngeal insufficiency by lengthening the palate and retropositioning the levator veli palatini muscles. The criteria for choosing one operation over the other remain unclear. Methods: A single-center retrospective cohort study was conducted. Thirty-two patients with nonsyndromic, repaired cleft palate were included. All patients underwent a Furlow or BMMF. Outcome measures included (1) resolution of hypernasality 12 months postoperatively, (2) degree of improvement of hypernasality severity; and (3) change in velar length, as measured on magnetic resonance imaging scans obtained preoperatively and 12 months postoperatively. All measures were performed by raters blinded to participants' medical and surgical history. Results: Hypernasality was corrected to normal in 80% of the Furlow group and in 56% of the BMMF group. Patients receiving BMMF had more severe hypernasality during preoperative speech evaluation. Both groups had a median decrease of two scalar rating points for severity of hypernasality (P = 0.58). On postoperative magnetic resonance imaging, patients who underwent Furlow had a median increased velar length of 6.9 mm. Patients who received BMMF had a median increased velar length of 7.5 mm. There was no statistically significant difference between groups regarding increase in velar length (P = 0.95). Conclusions: Furlow and BMMF procedures increase velar length with favorable speech outcomes. The same degree of improvement for hypernasality was observed across groups, likely explained by the similar increase in velar length achieved. Anatomic changes in palate length and levator veli palatini retropositioning persist 1 year after surgery.

Immunity impacts cognitive deficits across neurological disorders.

Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated with multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) and autoimmune disorders such as multiple sclerosis (MS), in which over half of all patients experience some form of cognitive deficits. Other degenerative diseases of the central nervous system (CNS) including frontotemporal lobe dementia (FTLD), and Parkinson's disease (PD) as well as traumatic brain injury (TBI) and psychological disorders like major depressive disorder (MDD), and even normal aging all have cytokine-associated reductions in cognitive function. Thus, there is likely commonality between these secondary cognitive deficits and inflammation. Neurological disorders are increasingly associated with substantial neuroinflammation, in which CNS-resident cells secrete cytokines and chemokines such as tumor necrosis factor (TNF)α and interleukins (ILs) including IL-1ß and IL-6. CNS-resident cells also respond to a wide variety of cytokines and chemokines, which can have both direct effects on neurons by changing the expression of ion channels and perturbing electrical properties, as well as indirect effects through glia-glia and immune-glia cross-talk. There is significant overlap in these cytokine and chemokine expression profiles across diseases, with TNFα and IL-6 strongly associated with cognitive deficits in multiple disorders. Here, we review the involvement of various cytokines and chemokines in AD, MS, FTLD, PD, TBI, MDD, and normal aging in the absence of dementia. We propose that the neuropsychiatric phenotypes observed in these disorders may be at least partially attributable to a dysregulation of immunity resulting in pathological cytokine and chemokine expression from both CNS-resident and non-resident cells.

IV BCG Vaccination and Aerosol BCG Revaccination Induce Mycobacteria-Responsive γδ T Cells Associated with Protective Efficacy against M. tb Challenge.

Intravenously (IV) delivered BCG provides superior tuberculosis (TB) protection compared with the intradermal (ID) route in non-human primates (NHPs). We examined how γδ T cell responses changed in vivo after IV BCG vaccination of NHPs, and whether these correlated with protection against aerosol M. tuberculosis challenge. In the circulation, Vδ2 T cell populations expanded after IV BCG vaccination, from a median of 1.5% (range: 0.8-2.3) of the CD3+ population at baseline, to 5.3% (range: 1.4-29.5) 4 weeks after M. tb, and were associated with TB protection. This protection was related to effector and central memory profiles; homing markers; and production of IFN-γ, TNF-α and granulysin. In comparison, Vδ2 cells did not expand after ID BCG, but underwent phenotypic and functional changes. When Vδ2 responses in bronchoalveolar lavage (BAL) samples were compared between routes, IV BCG vaccination resulted in highly functional mucosal Vδ2 cells, whereas ID BCG did not. We sought to explore whether an aerosol BCG boost following ID BCG vaccination could induce a γδ profile comparable to that induced with IV BCG. We found evidence that the aerosol BCG boost induced significant changes in the Vδ2 phenotype and function in cells isolated from the BAL. These results indicate that Vδ2 population frequency, activation and function are characteristic features of responses induced with IV BCG, and the translation of responses from the circulation to the site of infection could be a limiting factor in the response induced following ID BCG. An aerosol boost was able to localise activated Vδ2 populations at the mucosal surfaces of the lung. This vaccine strategy warrants further investigation to boost the waning human ID BCG response.

Current Postoperative Feeding Practices Following Surgical Repairs for Infants With Cleft Palate.

BACKGROUND: Nearly all surgeons have restrictive postoperative feeding protocols in place after primary cleft lip and cleft palate repairs. There are no standardized recommendations, potentially resulting in widely variable practices among cleft surgeons and teams. The purpose of this study was to examine current postoperative feeding practices for infants with cleft palate after lip and palate repairs. METHODS: A survey of 50 questions was sent to members of the American Cleft Palate-Craniofacial Association (ACPA). Inclusion criteria included providers from North America that have either currently or previously served on a cleft palate team and reached the surgical question set within the survey. RESULTS: Sixty-four respondents met inclusion criteria. The majority were in speech-language pathology (47%) or nursing (41%) disciplines, involved in feeding consultations frequently (84%), and working in an outpatient setting (69%). After lip surgery, respondents recommended cleft-adapted bottle feeding (88%), spoon feeding (9%), cup feeding (13%), and syringe/squeeze bottle feeding (23%). The majority of respondents (69%) indicated infants could return to their preoperative feeding modality immediately after lip surgery. After palate surgery, respondents recommended cleft-adapted bottle feeding (55%), typical bottle feeding (3%), spoon feeding (36%), cup feeding (64%), and syringe/squeeze bottle feeding (30%). Infants could use a feeding system that required suction at an average of 20 days postoperatively and return to an age-appropriate diet at an average of 15 days postoperatively. CONCLUSIONS: The present study describes the wide variation of postoperative feeding guidelines used by cleft teams after lip and palate repairs.

Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.

Limited evidence for quantitative contribution of rare and endangered species to agricultural production.

Biodiversity underpins ecosystem functions that provide benefits to people, yet the role of rare and endangered species (RES) in supporting ecosystem services is unclear. Thus, it remains controversial whether arguments for conservation that focus on ecosystem services align with the protection of RES. We designed a systematic review protocol to critically assess the evidence for quantitative contributions of RES to terrestrial agricultural production, which is a key driver of biodiversity change and, simultaneously, could suffer from the loss of ecosystem services provided by biodiversity. Our review search criteria required that studies: 1) provide information on RES, 2) focus on an ecosystem service relevant for agriculture; and 3) include a quantitative measure of agricultural production. Surprisingly, we found only four studies that fulfilled these criteria, which was insufficient to perform a meta-analysis of results. Thus, we highlight here the gap in quantitative research, discuss the implications of this knowledge gap for the conservation of RES, and suggest future research directions. We conclude that further quantitative research is urgently needed to better inform conservation and agricultural policies, including research that focuses specifically on RES, incorporates more ecosystem services, and covers a wider range of climatic and socioeconomic contexts.

A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by stem cell transplant, targeted approaches such as the BTK inhibitor ibrutinib, and CD19 chimeric antigen receptor (CAR) T cells. CD74 is a nonpolymorphic type II integral membrane glycoprotein identified as an MHC class II chaperone and a receptor for macrophage migration inhibitory factor. Our group previously reported on CD74's abundant expression in MCL and its ability to increase via pharmacological inhibition of autophagosomal degradation. Milatuzumab, a fully humanized anti-CD74 monoclonal antibody, demonstrated significant activity in preclinical lymphoma models but failed to provide meaningful benefits in clinical trials mainly due to its short half-life. We hypothesized that targeting CD74 using a CAR-T cell would provide potent and durable anti-MCL activity. METHODS: We engineered a second generation anti-CD74 CAR with 4-1BB and CD3ζ signaling domains (74bbz). Through in silico and rational mutagenesis on the scFV domain, the 74bbz CAR was functionally optimized for superior antigen binding affinity, proliferative signaling, and cytotoxic activity against MCL cells in vitro and in vivo. RESULTS: Functionally optimized 74bbz CAR-T cells (clone 42105) induced significant killing of MCL cell lines, and primary MCL patient samples including one relapse after commercial CD19 CAR-T cell therapy with direct correlation between antigen density and cytotoxicity. It significantly prolonged the survival of an animal model established in NOD-SCIDγc-/- (NSG) mice engrafted with a human MCL cell line Mino subcutaneously compared to controls. Finally, while CD74 is also expressed on normal immune cell subsets, treatment with 74bbz CAR-T cells resulted in minimal cytotoxicity against these cells both in vitro and in vivo. CONCLUSIONS: Targeting CD74 with 74bbz CAR-T cells represents a new cell therapy to provide a potent and durable and anti-MCL activity.

Cutaneous Sarcoidosis in Skin of Color.

Cutaneous sarcoidosis presents in 25% of all sarcoidosis cases. African American populations, particularly African American women, are more likely to develop the dermatologic manifestations of the disease. There are several types of skin manifestations of sarcoidosis, which can make it more difficult to diagnose it clinically. Given the higher incidence of sarcoidosis and the poorer outcomes in these populations, it is essential to understand and recognize the variety of dermatologic symptoms associated with sarcoidosis. By doing so, patients can be diagnosed and treated earlier in their disease progression. Williams JR, Frey C, Cohen GF. Cutaneous sarcoidosis in skin of color. J Drugs Dermatol. 2023;22(7):695-697. doi:10.36849/JDD.7008.