Discovery of Crystallizable Organic Semiconductors with Machine Learning.

Crystalline organic semiconductors are known to have improved charge carrier mobility and exciton diffusion length in comparison to their amorphous counterparts. Certain organic molecular thin films can be transitioned from initially prepared amorphous layers to large-scale crystalline films via abrupt thermal annealing. Ideally, these films crystallize as platelets with long-range-ordered domains on the scale of tens to hundreds of microns. However, other organic molecular thin films may instead crystallize as spherulites or resist crystallization entirely. Organic molecules that have the capability of transforming into a platelet morphology feature both high melting point (Tm) and crystallization driving force (ΔGc). In this work, we employed machine learning (ML) to identify candidate organic materials with the potential to crystallize into platelets by estimating the aforementioned thermal properties. Six organic molecules identified by the ML algorithm were experimentally evaluated; three crystallized as platelets, one crystallized as a spherulite, and two resisted thin film crystallization. These results demonstrate a successful application of ML in the scope of predicting thermal properties of organic molecules and reinforce the principles of Tm and ΔGc as metrics that aid in predicting the crystallization behavior of organic thin films.

Percutaneous distal bicortical proximal phalanx osteotomy for second toe deformities - A two-year prospective cohort study.

PURPOSE: The main purpose of our study was to evaluate satisfaction, recurrence, bone union and other complications after a minimum of two years follow-up in patients who had percutaneous claw and hammer (CHT) second toe correction utilizing a novel distal and bicortical proximal phalanx osteotomy (DBPPO). METHODS: A minimum two-year follow-up prospective cohort study was conducted on consecutive patients with symptomatic CHT deformities of the second toe corrected with percutaneous surgery. Primary outcomes included satisfaction, recurrence, bony union, and other complication rates specific to the second toe deformity correction. Secondary outcomes included Metatarsophalangeal-Interphalangeal AOFAS scale and Visual Analogue Scale (VAS). RESULTS: Between January and October 2020, 34 patients (43 feet) were clinically and radiologically evaluated pre and postoperatively at a mean of 26.6 months. Thirty-eight feet (88.4 %) were satisfied or very satisfied with their second toe deformity correction and 41 feet (95.3 %) would undergo surgery on this toe again. No deformity recurrence requiring revision was found. There were two complications (4.7 %): one toe (2.3 %) with persistent numbness and one (2.3 %) had a simple infection that resolved with oral antibiotics. All 43 s toe osteotomies demonstrated bony consolidation. Stiffness was reported in nine second toes (20.9 %), seven of them (77.8 %) having a rigid pre-operative deformity. Secondary outcomes demonstrated significant improvement in the mean ( ± standard deviation) AOFAS score which increased from 47.5 ± 17.9 preoperatively to 95.7 ± 7.7 postoperatively (p < .001). Mean VAS significantly improved from 4.9 ± 2.5 preoperatively to 0.3 ± 1.3 postoperatively (p < .001). CONCLUSION: Percutaneous treatment of claw and hammer second toe deformities utilizing a DBPPO resulted in high levels of satisfaction with bony consolidation, no recurrence and low complication rates at two years follow-up. LEVEL OF EVIDENCE: Level II - Prospective cohort study.

Pharmacogenomic Profiling of Pediatric Patients on Psychotropic Medications in an Emergency Department.

OBJECTIVE: The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population. METHODS: This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered "incongruent," and medications without a GDI were considered "congruent." Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement. RESULTS: Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications ( P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01). CONCLUSIONS: Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.

Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

Coaching paraeducators to implement functional communication training involving augmentative and alternative communication for students with autism spectrum disorder.

Paraeducators play an important role in assisting teachers and other professionals to support students with autism spectrum disorder (ASD), including delivering positive behavioral supports to those students who engage in persistent challenging behavior. The purpose of this multiple baseline design across participants study was to support paraeducators to implement functional communication training (FCT) to address challenging behavior among three students with ASD who used augmentative and alternative communication (AAC). Paraeducators implemented FCT with high levels of fidelity after participating in an initial training session and follow-up coaching and generally found the initial training and coaching strategies to be effective and feasible. Reductions in challenging behavior were variable across student participants. Implications for practice and future research directions are discussed in relation to FCT for students with ASD who use AAC and paraeducator training.

Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes.

There is an active and growing interest in cannabis female inflorescence (Cannabis sativa) for medical purposes. Therefore, a definition of its quality attributes can help mitigate public health risks associated with contaminated, substandard, or adulterated products and support sound and reproducible basic and clinical research. As cannabis is a heterogeneous matrix that can contain a complex secondary metabolome with an uneven distribution of constituents, ensuring its quality requires appropriate sampling procedures and a suite of tests, analytical procedures, and acceptance criteria to define the identity, content of constituents (e.g., cannabinoids), and limits on contaminants. As an independent science-based public health organization, United States Pharmacopeia (USP) has formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes. The consensus within the expert panel was that these specifications should differentiate between cannabis chemotypes. Based on the secondary metabolite profiles, the expert panel has suggested adoption of three broad categories of cannabis. These three main chemotypes have been identified as useful for labeling based on the following cannabinoid constituents: (1) tetrahydrocannabinol (THC)-dominant chemotype; (2) intermediate chemotype with both THC and cannabidiol (CBD); and (3) CBD-dominant chemotype. Cannabis plants in each of these chemotypes may be further subcategorized based on the content of other cannabinoids and/or mono- and sesquiterpene profiles. Morphological and chromatographic tests are presented for the identification and quantitative determination of critical constituents. Limits for contaminants including pesticide residues, microbial levels, mycotoxins, and elemental contaminants are presented based on toxicological considerations and aligned with the existing USP procedures for general tests and assays. The principles outlined in this review should be able to be used as the basis of public quality specifications for cannabis inflorescence, which are needed for public health protection and to facilitate scientific research on cannabis safety and therapeutic potential.

Increasing standing tolerance in office workers with standing-induced back pain.

Sit-stand desks are popular however many people have standing-induced low back pain (LBP). People with LBP have fewer standing weight shifts compared with back-healthy people. Participants were classified as standing-tolerant or intolerant. Participants were provided sit-stand desks for 12 weeks. Participants were assigned to intervention (graded standing exposure and exercise) or control (no instruction) conditions. Participants reported weekly sitting time and average/worst LBP. Standing weight shifts and LBP were re-assessed post-intervention. All groups decreased sitting time (range: 30-50%) over 12 weeks. Sitting time and average LBP were correlated in all standing-intolerant individuals, worst LBP and sitting time were correlated for intervention group only. All standing-intolerant individuals increased standing weight shifts and decreased LBP after 12-weeks. Standing-intolerant individuals benefitted from 12-weeks of sit-stand desk use regardless of intervention. Motivated individuals with standing-induced LBP may increase standing tolerance with sit-stand desk use. Additional benefits may exist when structured guidance is provided. Practitioner summary: Many people are standing-intolerant due to low back pain (LBP). This lab and field-based study showed some benefits from structured approaches to gradually progress standing time when transitioning to standing work. Using a sit-stand desk for 12 weeks resulted in decreased LBP and sitting time in standing-intolerant people. Abbreviations: LBP: low back pain; OSPAQ: Occupational Sitting and Physical Activity Questionnaire; VAS: visual analog scale; GRF: ground reaction force; WeekVASMAX: worst low back pain reported on visual analog scale for prior week; WeekVASAVE: average low back pain reported on visual analog scale for prior week; ICC: intraclass correlation coefficient; LabVASMAX: worst low back pain reported on visual analog scale during lab-based standing; LabVASAVE: average low back pain reported on visual analog scale during lab-based standing; FvR,L: vertical ground reaction force for right and left force plate; BWSSMALL: small (10-29% body weight) body weight shift; BWSLARGE: large (> 30% body weight) body weight shift; ActivPALSED: ActivePAL data for sedentary time; ActivPALSTND: ActivePAL data for standing time; ANOVA: analysis of variance; Standing Intolerant-INT: standing intolerant participants assigned to intervention condition; Standing Intolerant-CON: standing intolerant participants assigned to control condition; Standing Tolerant-INT: standing tolerant participants assigned to intervention condition; Standing Tolerant-CON: standing tolerant participants assigned to control condition; SI: standing intolerant; ST: standing tolerant; INT: intervention; CON: control.

Exploring job satisfaction and workplace engagement in millennial nurses.

AIM: To examine job satisfaction and workplace engagement of millennial nurses. BACKGROUND: Millennial nurses are a rapidly growing segment of the workforce. They are significantly less satisfied in their jobs compared with nurses of other generations and are more likely to have perceptions that may negatively impact job satisfaction and engagement. It is important for nurse leaders to understand and value the perspective of these nurses to improve job satisfaction and engagement. METHOD: Exploratory-descriptive qualitative approach with 33 millennial nurses interviewed in nine focus groups. RESULTS: Five themes revealed areas that both enhance and hinder job satisfaction and engagement. Themes include the following: (1) professional relationships; (2) rewards; (3) communication; (4) professional development; and (5) workload/staffing. CONCLUSION: Concerns identified by millennial nurses provide direction for nurse leaders who are charged with fostering a workplace setting that nurtures empathy and respect for nurses of all generations. IMPLICATIONS FOR NURSING MANAGEMENT: Strategies to address preferences of millennials include employee rounding to ask about their needs, offer assistance and provide positive feedback. Ongoing mentoring regarding opportunities to support millennials' professional development includes offering participation in activities to advance evidence-based practice, preceptor training, financial assistance with national certification examinations and tuition reimbursement.

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development.

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria.

Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.

Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation.

G protein pathway suppressor 2 (GPS2) is a multifunctional protein involved in the regulation of a number of metabolic organs. First identified as part of the NCoR-SMRT corepressor complex, GPS2 is known to play an important role in the nucleus in the regulation of gene transcription and meiotic recombination. In addition, we recently reported a non-transcriptional role of GPS2 as an inhibitor of the proinflammatory TNFα pathway in the cytosol. Although this suggests that the control of GPS2 localization may be an important determinant of its molecular functions, a clear understanding of GPS2 differential targeting to specific cellular locations is still lacking. Here we show that a fine balance between protein stabilization and degradation tightly regulates GPS2 nuclear function. Our findings indicate that GPS2 is degraded upon polyubiquitination by the E3 ubiquitin ligase Siah2. Unexpectedly, interaction with the exchange factor TBL1 is required to protect GPS2 from degradation, with methylation of GPS2 by arginine methyltransferase PRMT6 regulating the interaction with TBL1 and inhibiting proteasome-dependent degradation. Overall, our findings indicate that regulation of GPS2 by posttranslational modifications provides an effective strategy for modulating its molecular function within the nuclear compartment.

Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption.

Theiler's murine encephalomyelitis virus is a widely used model to study the initiation and progression of multiple sclerosis. Many researchers have used this model to investigate how the immune system and genetic factors contribute to the disease process. Current research has highlighted the importance of cytotoxic CD8 T cells and specific major histocompatibility complex (MHC) class I alleles. Our lab has adopted this concept to create a novel mouse model to study the mechanism of blood-brain barrier (BBB) disruption, an integral feature of numerous neurological disorders. We have demonstrated that epitope-specific CD8 T cells cause disruption of the tight junction architecture and ensuing CNS vascular permeability in the absence of neutrophil support. This CD8 T cell-initiated BBB disruption is dependent on perforin expression. We have also elucidated a potential role for hematopoietic factors in this process. Despite having identical MHC class I molecules, similar inflammation in the CNS, and equivalent ability to utilize perforin, C57BL/6 mice are highly susceptible to this condition, while 129 SvIm mice are resistant. This susceptibility is transferable with the bone marrow compartment. These findings led us to conduct a comprehensive genetic analysis which has revealed a list of candidate genes implicated in regulating traits associated with BBB disruption. Future studies will continue to define the underlying molecular mechanism of CD8 T cell-initiated BBB disruption and may assist in the development of potential therapeutic approaches to ameliorate pathology associated with BBB disruption in neurological disorders.

CD8 T cell-initiated blood-brain barrier disruption is independent of neutrophil support.

Blood-brain barrier (BBB) disruption is a common feature of numerous neurologic disorders. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. We have previously shown that CD8 T cells play a critical role in initiating BBB disruption in the peptide-induced fatal syndrome model developed by our laboratory. However, myelomonocytic cells such as neutrophils have also been implicated in promoting CNS vascular permeability and functional deficit in murine models of neuroinflammatory disease. For this reason, we evaluated neutrophil depletion in a murine model of CD8 T cell-initiated BBB disruption by employing traditionally used anti-granulocyte receptor-1 mAb RB6-8C5 and Ly-6G-specific mAb 1A8. We report that CNS-infiltrating antiviral CD8 T cells express high levels of granulocyte receptor-1 protein and are depleted by treatment with RB6-8C5. Mice treated with RB6-8C5, but not 1A8, display: 1) intact BBB tight junction proteins; 2) reduced CNS vascular permeability visible by gadolinium-enhanced T1-weighted magnetic resonance imaging; and 3) preservation of motor function. These studies demonstrate that traditional methods of neutrophil depletion with RB6-8C5 are broadly immune ablating. Our data also provide evidence that CD8 T cells initiate disruption of BBB tight junction proteins and CNS vascular permeability in the absence of neutrophil support.

A Novel Technique for Intraoperative Mapping of the Somatosensory Cortex.

OBJECTIVE: Intraoperative mapping of the nervous system is used to identify "eloquent" cortical areas. In this technical report, we describe a novel way of mapping the somatosensory cortex so that injury to those critical pathways can be avoided. METHODS: An 8-year-old female with drug resistant epilepsy presented for resection of a right posterior parietal focal cortical dysplasia. Left median nerve stimulation was used to record somatosensory evoked potentials (SEPs) directly from the somatosensory cortex with a strip electrode. A handheld monopolar electrode was also used to record both the median and tibial SEP. Total intravenous anesthesia with propofol and remifentanil was used. RESULTS: SEP recordings were obtained from a 4-contact strip electrode placed across the central sulcus. A phase reversal was identified and the most likely post central gyrus was noted. With the strip electrode left in place, a monopolar handheld electrode was used to record the median nerve SEPs from different locations on the postcentral gyrus. The tibial nerve was also stimulated to record where the highest amplitude tibial nerve SEP was present. This map was used delineate functionally "eloquent" areas to avoid during surgery. During resection, the median nerve SEP was recorded from the strip electrode continuously. No significant change in the SEP was noted, and the patient awoke without any sensory deficits. CONCLUSIONS: Sensory mapping of the cortex is possible with a handheld monopolar electrode. This technique is easy to perform and can help reduce neurological morbidity.

Facilitation of motor evoked potentials after tetanic peripheral nerve stimulation.

OBJECTIVE: Tetanic stimulation of a peripheral nerve prior to transcranial electrical stimulation (TES) may enhance motor evoked potential (MEP) amplitudes. The purpose of this study was to investigate the post-tetanic MEP (p-MEP) technique in improving MEP amplitudes. METHODS: Conventional TES MEPs (c-MEP) and p-MEPs with left upper limb stimulation (p-MEPUL) or left lower limb stimulation (p-MEPLL) were performed in 26 patients. Bilateral hand and foot MEP amplitudes obtained with each protocol were compared. Subgroup comparisons were performed for myelopathy and peripheral neuropathy patients. Within-subject amplitude differences between c-MEP and each p-MEP technique were compared using a Wilcoxon test. RESULTS: The mean age of the patients was 52.7 years (range, 12-79 years). Overall, p-MEPUL resulted in MEP improvement in 25 of 26 (96%) patients, and p-MEPLL improved MEPs in 19 of 26 (73%) patients. The increase in MEP amplitudes were statistically significant in all muscle groups except left foot. Similar improvements were seen in the myelopathy group; in the neuropathy group, p-MEPUL produced similar results, but p-MEPLL did not. CONCLUSIONS: The p-MEP technique can improve MEP amplitudes, including in patients with myelopathy. In patients with peripheral neuropathy, the results were mixed. SIGNIFICANCE: Tetanic stimulation can enhance intraoperative MEP amplitudes.

Advancing botanical safety: A strategy for selecting, sourcing, and characterizing botanicals for developing toxicological tools.

Increases in botanical use, encompassing herbal medicines and dietary supplements, have underlined a critical need for an advancement in safety assessment methodologies. However, botanicals present unique challenges for safety assessment due to their complex and variable composition arising from diverse growing conditions, processing methods, and plant varieties. Historically, botanicals have been largely evaluated based on their history of use information, based primarily on traditional use or dietary history. However, this presumption lacks comprehensive toxicological evaluation, demanding innovative and consistent assessment strategies. To address these challenges, the Botanical Safety Consortium (BSC) was formed as an international, cross-sector forum of experts to identify fit-for purpose assays that can be used to evaluate botanical safety. This global effort aims to assess botanical safety assessment methodologies, merging traditional knowledge with modern in vitro and in silico assays. The ultimate goal is to champion the development of toxicity tools for botanicals. This manuscript highlights: 1) BSC's strategy for botanical selection, sourcing, and preparation of extracts to be used in in vitro assays, and 2) the approach utilized to characterize botanical extracts, using green tea and Asian ginseng as examples, to build confidence for use in biological assays.

Sublimed C60 for efficient and repeatable perovskite-based solar cells.

Thermally evaporated C60 is a near-ubiquitous electron transport layer in state-of-the-art p-i-n perovskite-based solar cells. As perovskite photovoltaic technologies are moving toward industrialization, batch-to-batch reproducibility of device performances becomes crucial. Here, we show that commercial as-received (99.75% pure) C60 source materials may coalesce during repeated thermal evaporation processes, jeopardizing such reproducibility. We find that the coalescence is due to oxygen present in the initial source powder and leads to the formation of deep states within the perovskite bandgap, resulting in a systematic decrease in solar cell performance. However, further purification (through sublimation) of the C60 to 99.95% before evaporation is found to hinder coalescence, with the associated solar cell performances being fully reproducible after repeated processing. We verify the universality of this behavior on perovskite/silicon tandem solar cells by demonstrating their open-circuit voltages and fill factors to remain at 1950 mV and 81% respectively, over eight repeated processes using the same sublimed C60 source material. Notably, one of these cells achieved a certified power conversion efficiency of 30.9%. These findings provide insights crucial for the advancement of perovskite photovoltaic technologies towards scaled production with high process yield.

Quantitative trait loci analysis reveals candidate genes implicated in regulating functional deficit and CNS vascular permeability in CD8 T cell-initiated blood-brain barrier disruption.

BACKGROUND: Blood-brain barrier (BBB) disruption is an integral feature of numerous neurological disorders. However, there is a relative lack of knowledge regarding the underlying molecular mechanisms of immune-mediated BBB disruption. We have previously shown that CD8 T cells and perforin play critical roles in initiating altered permeability of the BBB in the peptide-induced fatal syndrome (PIFS) model developed by our laboratory. Additionally, despite having indistinguishable CD8 T cell responses, C57BL/6J (B6) mice are highly susceptible to PIFS, exhibiting functional motor deficits, increased astrocyte activation, and severe CNS vascular permeability, while 129S1/SvImJ (129S1) mice remain resistant. Therefore, to investigate the potential role of genetic factors, we performed a comprehensive genetic analysis of (B6 x 129S1) F2 progeny to define quantitative trait loci (QTL) linked to the phenotypic characteristics stated above that mediate CD8 T cell-initiated BBB disruption. RESULTS: Using single nucleotide polymorphism (SNP) markers and a 95% confidence interval, we identified one QTL (PIFS1) on chromosome 12 linked to deficits in motor function (SNP markers rs6292954, rs13481303, rs3655057, and rs13481324, LOD score = 3.3). In addition we identified a second QTL (PIFS2) on chromosome 17 linked to changes in CNS vascular permeability (SNP markers rs6196216 and rs3672065, LOD score = 3.7). CONCLUSIONS: The QTL critical intervals discovered have allowed for compilation of a list of candidate genes implicated in regulating functional deficit and CNS vascular permeability. These genes encode for factors that may be potential targets for therapeutic approaches to treat disorders characterized by CD8 T cell-mediated BBB disruption.

School-wide positive behavioral interventions and supports and students with extensive support needs: a scoping review.

School-wide Positive Behavioral Interventions and Supports (SWPBIS) is an inclusive multi-tiered system of behavioral supports that has been widely adopted by K-12 schools in the United States. SWPBIS focuses on creating safe, equitable, and inclusive school environments and has been linked to both positive behavioral and academic outcomes for students and improved perceptions of efficacy and job satisfaction for school personnel. However, there remain concerns about the involvement of students with extensive support needs (ESN) in SWPBIS despite calls to action in 2006 and 2016 for research in this area. Addressing these concerns, we conducted a scoping review to examine the current research literature on SWPBIS and students with ESN. We found that only 10 studies have been conducted since the 2006 call to action. Studies primarily focused on stakeholder perspectives regarding the importance or availability of SWPBIS for students with ESN. Although few studies examined SWPBIS effectiveness, findings from these studies lend support to the effectiveness of Tier 1 SWPBIS for students with ESN. We describe several key implications for supporting the inclusion of students with ESN in SWPBIS and future research initiatives.