Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation.

Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson's Disease (PD) is unknown. Here, we investigated the impact of the most common PD-linked mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (G2019S) on the synaptic functions of astrocytes. We found that both in human and mouse cortex, the LRRK2 G2019S mutation causes astrocyte morphology deficits and enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), which are important components of perisynaptic astrocyte processes. Reducing ERM phosphorylation in LRRK2 G2019S mouse astrocytes restored astrocyte morphology and corrected excitatory synaptic deficits. Using an in vivo BioID proteomic approach, we found Ezrin, the most abundant astrocytic ERM protein, interacts with the Autophagy-Related 7 (Atg7), a master regulator of catabolic processes. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in the LRRK2 G2019S astrocytes. Importantly, Atg7 function is required to maintain proper astrocyte morphology. These studies reveal an astrocytic molecular mechanism that could serve as a therapeutic target in PD.

Diagnosis and Treatment of Presumed Naltrexone-XR-precipitated Opioid Withdrawal in a Patient Chronically Treated With Buprenorphine-XR: A Case Report.

ABSTRACT: Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment.

When Being Bad Feels Good: A Systematic Review of the Relationship Between Positive Emotion and Antisocial Behavior in Children and Adolescents.

Antisocial behavior in childhood and adolescence is associated with poor family and peer relationships, and a higher risk of mental and physical health problems in adulthood, as well as criminality. Emotions play a central role in children's moral development, but most research has focused on negative emotions (e.g., shame and guilt), in relation to childhood antisocial behavior. Research in adult populations indicates that positive emotions experienced in anticipation of, during, and after antisocial acts may play an important role in the development and maintenance of antisocial behavior. Consequently, this systematic review aimed to investigate the relationship between positive emotion and antisocial behavior in children and adolescents. A systematic search in five databases was conducted, yielding 52 studies that used different methodological approaches, samples, designs and methods to examine this association. Results provide support for a positive relationship between positive emotion and antisocial behavior across community, forensic and clinical samples. This link appeared to be stronger for younger children, boys, and for children high in social dominance, callous-unemotional or sensation-seeking traits. Results suggested that positive affect may act in concert with negative emotion, cognitive, personality and motivational processes, as well as peer influences to determine the initiation and maintenance of antisocial behavior. This review presents directions for future research and discusses the implications of findings for prevention and intervention programs for youth with antisocial behavior.

In Situ Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System.

Long-acting drug delivery systems are promising platforms to improve patient adherence to medication by delivering drugs over sustained periods and removing the need for patients to comply with oral regimens. This research paper provides a proof-of-concept for the development of a new optimized in situ forming injectable depot based on a tetrabenzylamine-tetraglycine-d-lysine-O-phospho-d-tyrosine peptoid-D-peptide formulation ((NPhe)4GGGGk(AZT)y(p)-OH). The chemical versatility of the peptoid-peptide motif allows low-molecular-weight drugs to be precisely and covalently conjugated. After subcutaneous injection, a hydrogel depot forms from the solubilized peptoid-peptide-drug formulation in response to phosphatase enzymes present within the skin space. This system is able to deliver clinically relevant concentrations of a model drug, the antiretroviral zidovudine (AZT), for 35 days in Sprague-Dawley rats. Oscillatory rheology demonstrated that hydrogel formation began within ∼30 s, an important characteristic of in situ systems for reducing initial drug bursts. Gel formation continued for up to ∼90 min. Small-angle neutron scattering data reveal narrow-radius fibers (∼0.78-1.8 nm) that closely fit formation via a flexible cylinder elliptical model. The inclusion of non-native peptoid monomers and D-variant amino acids confers protease resistance, enabling enhanced biostability to be demonstrated in vitro. Drug release proceeds via hydrolysis of an ester linkage under physiological conditions, releasing the drug in an unmodified form and further reducing the initial drug burst. Subcutaneous administration of (NPhe)4GGGGk(AZT)y(p)-OH to Sprague-Dawley rats resulted in zidovudine blood plasma concentrations within the 90% maximal inhibitory concentration (IC90) range (30-130 ng mL-1) for 35 days.

Multimodal MALDI imaging mass spectrometry for improved diagnosis of melanoma.

Imaging mass spectrometry (IMS) provides promising avenues to augment histopathological investigation with rich spatio-molecular information. We have previously developed a classification model to differentiate melanoma from nevi lesions based on IMS protein data, a task that is challenging solely by histopathologic evaluation. Most IMS-focused studies collect microscopy in tandem with IMS data, but this microscopy data is generally omitted in downstream data analysis. Microscopy, nevertheless, forms the basis for traditional histopathology and thus contains invaluable morphological information. In this work, we developed a multimodal classification pipeline that uses deep learning, in the form of a pre-trained artificial neural network, to extract the meaningful morphological features from histopathological images, and combine it with the IMS data. To test whether this deep learning-based classification strategy can improve on our previous results in classification of melanocytic neoplasia, we utilized MALDI IMS data with collected serial H&E stained sections for 331 patients, and compared this multimodal classification pipeline to classifiers using either exclusively microscopy or IMS data. The multimodal pipeline achieved the best performance, with ROC-AUCs of 0.968 vs. 0.938 vs. 0.931 for the multimodal, unimodal microscopy and unimodal IMS pipelines respectively. Due to the use of a pre-trained network to perform the morphological feature extraction, this pipeline does not require any training on large amounts of microscopy data. As such, this framework can be readily applied to improve classification performance in other experimental settings where microscopy data is acquired in tandem with IMS experiments.

Automated vs. manual coding of neuroimaging reports via natural language processing, using the international classification of diseases, tenth revision.

Objective: Natural language processing (NLP) can generate diagnoses codes from imaging reports. Meanwhile, the International Classification of Diseases (ICD-10) codes are the United States' standard for billing/coding, which enable tracking disease burden and outcomes. This cross-sectional study aimed to test feasibility of an NLP algorithm's performance and comparison to radiologists' and physicians' manual coding. Methods: Three neuroradiologists and one non-radiologist physician reviewers manually coded a randomly-selected pool of 200 craniospinal CT and MRI reports from a pool of >10,000. The NLP algorithm (Radnosis, VEEV, Inc., Minneapolis, MN) subdivided each report's Impression into "phrases", with multiple ICD-10 matches for each phrase. Only viewing the Impression, the physician reviewers selected the single best ICD-10 code for each phrase. Codes selected by the physicians and algorithm were compared for agreement. Results: The algorithm extracted the reports' Impressions into 645 phrases, each having ranked ICD-10 matches. Regarding the reviewers' selected codes, pairwise agreement was unreliable (Krippendorff α = 0.39-0.63). Using unanimous reviewer agreement as "ground truth", the algorithm's sensitivity/specificity/F2 for top 5 codes was 0.88/0.80/0.83, and for the single best code was 0.67/0.82/0.67. The engine tabulated "pertinent negatives" as negative codes for stated findings (e.g. "no intracranial hemorrhage"). The engine's matching was more specific for shorter than full-length ICD-10 codes (p = 0.00582x10-3). Conclusions: Manual coding by physician reviewers has significant variability and is time-consuming, while the NLP algorithm's top 5 diagnosis codes are relatively accurate. This preliminary work demonstrates the feasibility and potential for generating codes with reliability and consistency. Future works may include correlating diagnosis codes with clinical encounter codes to evaluate imaging's impact on, and relevance to care.

Responses of vascular plant fine roots and associated microbial communities to whole-ecosystem warming and elevated CO2 in northern peatlands.

Warming and elevated CO2 (eCO2) are expected to facilitate vascular plant encroachment in peatlands. The rhizosphere, where microbial activity is fueled by root turnover and exudates, plays a crucial role in biogeochemical cycling, and will likely at least partially dictate the response of the belowground carbon cycle to climate changes. We leveraged the Spruce and Peatland Responses Under Changing Environments (SPRUCE) experiment, to explore the effects of a whole-ecosystem warming gradient (+0°C to 9°C) and eCO2 on vascular plant fine roots and their associated microbes. We combined trait-based approaches with the profiling of fungal and prokaryote communities in plant roots and rhizospheres, through amplicon sequencing. Warming promoted self-reliance for resource uptake in trees and shrubs, while saprophytic fungi and putative chemoorganoheterotrophic bacteria utilizing plant-derived carbon substrates were favored in the root zone. Conversely, eCO2 promoted associations between trees and ectomycorrhizal fungi. Trees mostly associated with short-distance exploration-type fungi that preferentially use labile soil N. Additionally, eCO2 decreased the relative abundance of saprotrophs in tree roots. Our results indicate that plant fine-root trait variation is a crucial mechanism through which vascular plants in peatlands respond to climate change via their influence on microbial communities that regulate biogeochemical cycles.

An Unusual Presentation of Syphilis in the Context of Child Sexual Abuse.

A 13-year-old presented with a genital lesion, which helped in guiding a diagnosis of child sexual abuse. The patient disclosed unprotected penile-vaginal penetration by a 20-year-old male neighbor. On exam, her left labia minora had a single 2-cm hypopigmented fleshy non-tender mass, and laboratory studies revealed positive Treponemal IgG IgM antibody (>8) and rapid plasma reagin titer of 1:128, indicating syphilis infection. Given the resolution of the labial mass with treatment of syphilis, this lesion was most consistent with condyloma lata. Genital exams are an important component of pediatric evaluations. Condyloma lata can vary in appearance (papules, nodules, or wart-like lesions) and color and may present as a single lesion or multiple lesions. Our patient had one 2-cm lesion, and therefore, clinicians should assume that an anogenital lesion is condyloma lata in the setting of positive syphilis testing.

Efficacy of Child Abuse Evaluations for Infants With Possible Subdural Hemorrhage Identified on Cranial Ultrasound Completed for Macrocephaly.

Abusive head trauma (AHT) is a significant cause of morbidity and mortality for infants. Determining when to pursue a complete physical abuse evaluation can be difficult, especially for nonspecific findings or when a child appears clinically well. This retrospective study of 7 cases sought to describe the presentation, evaluation, and diagnoses for infants with abnormal subdural collections identified on cranial ultrasound for macrocephaly, and to determine how frequently AHT is diagnosed. The results of this study showed that while each patient presented due to asymptomatic macrocephaly, the extent of the workup varied greatly. In addition, no infants had suspicious injuries for abuse during the initial evaluation or the year following. In summary, among the 7 patients seen for asymptomatic macrocephaly with possible subdural hemorrhage, there were very inconsistent child abuse workups. There needs to be a standardized clinical guideline for this specific patient population involving a child abuse pediatric evaluation.

Dual stimuli-responsive delivery system for self-regulated colon-targeted delivery of poorly water-soluble drugs.

Inflammatory bowel disease (IBD) are chronic inflammatory conditions which cause significant patient morbidity. Local drug delivery to the colon can improve treatment efficacy and reduce side effects associated with IBD treatment. Smart drug delivery systems are designed to regulate the release of therapeutic agents at the desired site of action. pH-responsive drug carriers have been previously utilised for improved oral drug delivery beyond stomach harsh conditions. Additionally, the colon possesses a diverse microbiome secreting bioactive molecules e.g., enzymes, that can be exploited for targeted drug delivery. We herein synthesised and characterised a 2-hydroxyethyl methacrylate and methacrylic acid copolymer, crosslinked with an azobenzyl crosslinker, that displayed pH- and enzyme-responsive properties. The swelling and drug release from hydrogel were analysed in pH 1.2, 6.5 and 7.4 buffers, and in the presence of rat caecal matter using metronidazole and mesalamine as model BCS Class I and IV drugs, respectively. Swelling studies displayed pH-responsive swelling behaviour, where swelling was maximum at pH 7.4 and minimum at pH 1.2 (69 % versus 32 %). Consequently, drug release was limited in gastric and small intestinal conditions but increased significantly when exposed to colonic conditions containing caecal matter. This system displays promising capacity for achieving colon-targeted drug delivery with enhanced dissolution of poorly water-soluble drugs for local treatment of IBD and other colon-targeted therapies.

Caring for Domestic Minor Sex Trafficking Patients: Recommendations for Identification, Interventions, and Resources.

Domestic minor sex trafficking has increasingly gained awareness as a social phenomenon that affects adolescent health and safety. Healthcare providers are uniquely positioned to identify and facilitate supportive interventions for adolescents at high risk or involved in trafficking. A growing literature base and clinical experience provide recommendations on how to identify, engage trafficked youth, and provide beneficial linkages with community resources. A coordinated, multidisciplinary, and trauma-informed response that fosters therapeutic alliances promoting agency, safety, and trust are key components of successful care for this vulnerable adolescent population.

Female Caregivers' Perception of their Child's Sexualized Behaviors: A Pilot Study at a Child Protection Clinic.

This pilot study explored female caregiver's perception of their child's behaviors during sexual abuse evaluations. We compared reports by caregivers with histories of their own child sexual abuse (PCSA) to caregivers with no prior history of child sexual abuse (NPCSA) regarding their 1) child's sexualized behaviors and (2) perceptions of whether their child had been sexually abused. Forty-four caregivers met inclusion criteria. Ninety-five percent of PCSA caregivers versus 21% of NPCSA caregivers reported at least one behavior from the Child Sexual Behavior Inventory. Our findings identified that PCSA caregivers reported more sexualized behaviors for their children overall, potentially contributing to their perception that their child had been sexually abused. This pilot study demonstrated that caregivers were able to tolerate answering questions about their own history of child abuse. Parents should be asked these questions as this may influence perceptions of their child's behaviors and possible sexual abuse.

A Unique Canine Comfort Therapy Program for Child Maltreatment Cases.

Research has shown that programs utilizing comfort therapy canines in cases of child maltreatment have been successful in providing valuable support to children and their families. To date these programs have made canine comfort therapy dogs available solely within one of the involved disciplines. Therefore, a unique canine comfort therapy program was established specifically to support this pediatric population by implementing a collaborative canine comfort therapy program within two separate disciplines. CALI (Cranston Police, Aubin Center, Leadership in Innovation) was the first official K-9 comfort therapy dog in a police department in Rhode Island (RI), and the first employed dog within the state's only children's hospital. This program provides a longitudinal experience that supports children and their families by fostering a sense of familiarity and trust throughout all the difficult components of a child maltreatment case (e.g., evaluation, treatment, investigation and prosecution).

A Guide to MALDI Imaging Mass Spectrometry for Tissues.

Imaging mass spectrometry is a well-established technology that can easily and succinctly communicate the spatial localization of molecules within samples. This review communicates the recent advances in the field, with a specific focus on matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) applied on tissues. The general sample preparation strategies for different analyte classes are explored, including special considerations for sample types (fresh frozen or formalin-fixed,) strategies for various analytes (lipids, metabolites, proteins, peptides, and glycans) and how multimodal imaging strategies can leverage the strengths of each approach is mentioned. This work explores appropriate experimental design approaches and standardization of processes needed for successful studies, as well as the various data analysis platforms available to analyze data and their strengths. The review concludes with applications of imaging mass spectrometry in various fields, with a focus on medical research, and some examples from plant biology and microbe metabolism are mentioned, to illustrate the breadth and depth of MALDI IMS.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Feasibility and Acceptability of LNG 1.5 mg as an On-Demand Pericoital Contraceptive in Ghana.

Globally, there is a need for more family planning method options as currently, available options do not adequately meet the needs of women, specifically those who have infrequent sex. Levonorgestrel (LNG) 1.5 mg is widely available as emergency contraception pills (ECP), and recent research has shown that certain women take it as their main form of contraception. Furthermore, limited studies have found repeat, on-demand use safe and efficacious. This 12-month prospective, single-arm, interventional study in Ghana tested whether a single LNG 1.5 mg on-demand or pericoital ("around the time of sex") dose contraceptive was acceptable to women who have infrequent sex and if pharmacy provision was feasible. The study sample (1,890) comprised women of reproductive age recruited from urban areas, having infrequent sex (i.e., coital frequency ≤ 6× per month), and not using any other modern methods except condoms or ECP at the time of study inclusion. Results indicated that there is demand and acceptability for a pericoital pill and that pharmacy provision is feasible. Furthermore, precoital use of the pill had high levels of satisfaction and was popular with new users. Adding LNG 1.5 mg for pericoital use to the family planning method mix has the potential to address an important segment of the population currently underserved, decrease unwanted pregnancies, and increase modern contraceptive prevalence rates.

Guillain-Barre Syndrome With Concomitant Severe Preeclampsia: A Case Report.

With an estimated 100,000 new cases yearly worldwide, Guillain-Barre syndrome (GBS) is the most common cause of flaccid paralysis. GBS is exceedingly rare in pregnancy and carries high maternal and fetal risk. We report a case of a 38-year-old essential primigravida who presented at 38 weeks six days gestational age with ascending paraplegia progressing to dysarthria, dysphagia, and facial weakness. A clinical diagnosis of GBS was made in an outside institution, supported by elevated protein on lumbar puncture. During the antepartum period, a diagnosis of gestational hypertension progressed to preeclampsia with severe features when a sudden rise in liver function tests occurred. The patient underwent an uneventful planned cesarean delivery but could not be extubated due to respiratory failure. After a 20-day critical care admission, she was extubated and had an improvement in neurologic status to near her baseline.