Tackling unmanaged oropharyngeal dysphagia in primary care: a behavioural science realist review of interventions.

INTRODUCTION: Oropharyngeal dysphagia (OD) is difficulty manipulating a food bolus from the mouth to the throat. Up to 70% of older adults develop OD; however, it is unmanaged in primary care, leading to avoidable hospitalisation. OBJECTIVE: This behavioural science realist review aimed to develop programme theories to describe how interventions facilitate primary care healthcare professionals (HCPs) to proactively manage OD. METHODS: We developed initial programme theories (IPTs) inductively using the expertise of stakeholders and deductively using the theoretical domains framework (TDF). Databases were searched to identify evidence regarding contexts, behavioural mechanisms and outcomes related to proactive management of OD and comparative behaviours which offer transferrable learning. IPTs were tested with the evidence to confirm, refine or refute, to produce final programme theories. RESULTS: 36 sources of evidence were included. Five final programme theories were generated explaining how primary care HCPs can be facilitated to proactively manage OD: (1) OD education and training, (2) checklists with OD signs and symptoms, (3) incorporating OD identification into existing workflow, (4) making HCPs aware that older adults and carers expect them to manage OD and (5) raising awareness of the adverse outcomes of OD. CONCLUSION: The five programme theories provide the behavioural mechanisms by which an intervention may facilitate primary care HCPs to proactively manage OD. Through the programme theories' linkage to the TDF, behaviour change techniques (BCTs) mapped to the relevant TDF domain can be selected for an intervention. Operationalisation of selected BCTs into a coherent intervention package should be undertaken using codesign methodology. PROSPERO REGISTRATION NUMBER: CRD42022320327.

Development of the Guide to Disseminating Research (GuiDiR): A consolidated framework.

BACKGROUND: Less than one third of research evidence is translated into policy or practice. Knowledge translation requires effective dissemination, adoption and finally implementation. These three stages are equally important, however, existing knowledge translation models and frameworks provide little and disparate information about the steps and activities required for effective dissemination. OBJECTIVE: This study aimed to empirically develop a consolidated framework of evidence-based steps and activities for disseminating research evidence. METHODS: We identified models and frameworks from a scoping review and dissemination and implementation webtool. We synthesised them into a prototype dissemination framework. Models and frameworks were eligible to inform steps in our framework if they fulfilled at least one of three elements of dissemination: intending to generate awareness of a message, incorporates targeting an audience: tailoring communication. An initial coding framework was created to organise data into dissemination steps. Drawing on 'co-approach' principles, authors of the included models and frameworks (dissemination experts) and health service researchers (end users) were invited to test and refine the prototype framework at a workshop. RESULTS: From 48 models and frameworks reviewed, only 32 fulfilled one or more of the three dissemination elements. The initial coding framework, upon refinement, yielded the Guide to Disseminating Research (GuiDiR) comprising five steps. 1) Identify target audiences and dissemination partners. 2) Engage with dissemination partners. 3) Identify barriers and enablers to dissemination. 4) Create dissemination messages. 5) Disseminate and evaluate. Multiple activities were identified for each step and no single model or framework represents all steps and activities in GuiDiR. CONCLUSIONS: GuiDiR unifies dissemination components from knowledge translation models and frameworks and harmonises language into a format accessible to non-experts. It outlines for researchers, funders and practitioners the expected structure of dissemination and details the activities for executing an evidence-based dissemination strategy.

An optical photothermal infrared investigation of lymph nodal metastases of oral squamous cell carcinoma.

In this study, optical photothermal infrared (O-PTIR) spectroscopy combined with machine learning algorithms were used to evaluate 46 tissue cores of surgically resected cervical lymph nodes, some of which harboured oral squamous cell carcinoma nodal metastasis. The ratios obtained between O-PTIR chemical images at 1252 cm-1 and 1285 cm-1 were able to reveal morphological details from tissue samples that are comparable to the information achieved by a pathologist's interpretation of optical microscopy of haematoxylin and eosin (H&E) stained samples. Additionally, when used as input data for a hybrid convolutional neural network (CNN) and random forest (RF) analyses, these yielded sensitivities, specificities and precision of 98.6 ± 0.3%, 92 ± 4% and 94 ± 5%, respectively, and an area under receiver operator characteristic (AUC) of 94 ± 2%. Our findings show the potential of O-PTIR technology as a tool to study cancer on tissue samples.

Postoperative Revision, Complication and Economic Outcomes of Patients with Reverse or Anatomic Total Shoulder Arthroplasty at One Year: A Retrospective, United States Hospital Billing Database Analysis.

BACKGROUND: Data on the one-year postoperative revision, complication, and economic outcomes in a hospital setting after total shoulder arthroplasty (TSA) are sparse. METHODS: A retrospective cohort study using the Premier Healthcare Database, a hospital-billing data source, evaluated one-year postoperative revision, complication, and economic outcomes of reverse (RTSA) and anatomic (ATSA) TSA for patients who underwent the procedure from 2015 until 2021. All-cause revisits, including revision-related events (categorized as either irrigation and débridement or revision procedures and device removals) and shoulder/non-shoulder complications were collected. The incidences and costs of these revisits were evaluated. Generalized linear models were used to evaluate the associations between patient characteristics and revision and complication occurrences and costs. RESULTS: Among 51,478 RTSA and 34,623 ATSA patients (mean [standard deviation (SD)] ages RTSA 71.5 [8.1] years, ATSA 66.8 [9.0] years), one-year adjusted incidences of all-cause revisits, irrigation/débridement, revision procedures/device removals, and shoulder/non-shoulder complications were RTSA: 45.0% (95% confidence interval (CI): 44.6%-45.5%), 0.1% (95% CI: 0.1%-0.2%), 2.1% (95% CI: 2.0%-2.2%), and 17.8% (95% CI: 17.5%-18.1%) and ATSA: 42.3% (95% CI: 41.8%-42.9%), 0.2% (95% CI: 0.1%-0.2%), 1.9% (95% CI: 1.8%-2.1%), and 14.4% (95% CI: 14.0%-14.8%), respectively; shoulder-related complications were RTSA: 12.4% (95% CI: 12.1%-12.7%) and ATSA: 9.9% (95% CI: 9.6%-10.3%). Significant factors associated with a high risk of revisions and complications included, but were not limited to, chronic comorbidities and noncommercial insurance. Per patient, the mean (SD) total one-year hospital cost was $25,225 ($15,911) and $21,520 ($13,531) for RTSA and ATSA, respectively. Revision procedures and device removals were most costly, averaging $22,920 ($18,652) and $26,911 ($18,619) per procedure for RTSA and ATSA, respectively. Patients with revision-related events with infections had higher total hospital costs than patients without this event (RTSA: $60,887 (95% CI: $56,951-$64,823) and ATSA: $59,478 (95% CI: $52,312-$66,644)), equating to a mean difference of $36,148 with RTSA and $38,426 with ATSA. Significant factors associated with higher costs of revision-related events and complications included age, race, chronic comorbidities, and noncommercial insurance. CONCLUSIONS: Nearly 45% RTSA and 42% ATSA patients returned to the hospital, most often for shoulder/non-shoulder complications (overall 17.8% RTSA and 14.4% ATSA, and shoulder-related 12.4% RTSA and 9.9% ATSA). Revisions and device removals were most expensive ($22,920 RTSA and $26,911 ATSA). Infection complications requiring revision had the highest one-year hospital costs (∼$60,000). This study highlights the need for technologies and surgical techniques that may help reduce TSA healthcare utilization and economic burden.

Human Milk Cannabinoid Concentrations and Associations with Maternal Factors: The Lactation and Cannabis (LAC) Study.

Background and Objectives: As cannabis use increases among reproductive-aged women, there is a growing need to better understand the presence of cannabinoids in milk produced by women using cannabis. It is unclear how concentrations of cannabinoids such as delta-9-tetrahydrocannabinol (Δ9-THC) persist in milk after cannabis use and what factors contribute to variation in milk Δ9-THC concentrations. Our objectives were to measure cannabinoids in human milk following cannabis abstention, after single and repeated instances of cannabis use, and identify factors contributing to concentration variation. Methods: The Lactation and Cannabis (LAC) Study prospectively observed 20 breastfeeding participants who frequently used cannabis (≥1/week), had enrolled <6 months postpartum, were feeding their infant their milk ≥5 times/day, and were not using any illicit drugs. Participants collected a baseline milk sample after ≥12 hours of abstaining from cannabis and five milk samples at set intervals over 8-12 hours after initial cannabis use. Participants completed surveys and recorded self-directed cannabis use during the study period. Results: Δ9-THC peaked 120 minutes after a single instance of cannabis use (median, n = 9). More instances of cannabis use during the study period were associated with greater Δ9-THC area-under-the-curve concentrations (ρ = 0.65, p = 0.002), indicating Δ9-THC bioaccumulation in most participants. Baseline Δ9-THC logged concentration was positively associated with self-reported frequency of cannabis use (b = 0.57, p = 0.01). Conclusions: Cannabinoids are measurable in human milk following cannabis use, and concentrations remain elevated with repeated cannabis use over a day. Substantial variation in Δ9-THC milk concentrations reflects individual differences in characteristics and behavior, including average postpartum frequency of cannabis use.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial ß-glucuronidase targeting compound Inh 1.

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial ß-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively.The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat.Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

The peptidase DA1 cleaves and destabilizes WUSCHEL to control shoot apical meristem size.

Stem cells in plants and animals are the source of new tissues and organs. In plants, stem cells are maintained in the central zone (CZ) of multicellular meristems, and large shoot meristems with an increased stem cell population hold promise for enhancing yield. The mobile homeodomain transcription factor WUSCHEL (WUS) is a central regulator of stem cell function in plant shoot meristems. Despite its central importance, the factors that directly modulate WUS protein stability have been a long-standing question. Here, we show that the peptidase DA1 physically interacts with and cleaves the WUS protein, leading to its destabilization. Furthermore, our results reveal that cytokinin signaling represses the level of DA1 protein in the shoot apical meristem, thereby increasing the accumulation of WUS protein. Consistent with these observations, loss of DA1 function results in larger shoot apical meristems with an increased stem cell population and also influences cytokinin-induced enlargement of shoot apical meristem. Collectively, our findings uncover a previously unrecognized mechanism by which the repression of DA1 by cytokinin signaling stabilizes WUS, resulting in the enlarged shoot apical meristems with the increased stem cell number during plant growth and development.

Prevalence and duration of SARS-CoV-2 fecal shedding in breastfeeding dyads following maternal COVID-19 diagnosis.

Background: There is a paucity of data on the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in feces of lactating women with coronavirus disease 2019 (COVID-19) and their breastfed infants as well as associations between fecal shedding and symptomatology. Objective: We examined whether and to what extent SARS-CoV-2 is detectable in the feces of lactating women and their breastfed infants following maternal COVID-19 diagnosis. Methods: This was a longitudinal study carried out from April 2020 to December 2021 involving 57 breastfeeding maternal-infant dyads: 33 dyads were enrolled within 7 d of maternal COVID-19 diagnosis, and 24 healthy dyads served as controls. Maternal/infant fecal samples were collected by participants, and surveys were administered via telephone over an 8-wk period. Feces were analyzed for SARS-CoV-2 RNA. Results: Signs/symptoms related to ears, eyes, nose, and throat (EENT); general fatigue/malaise; and cardiopulmonary signs/symptoms were commonly reported among mothers with COVID-19. In infants of mothers with COVID-19, EENT, immunologic, and cardiopulmonary signs/symptoms were most common, but prevalence did not differ from that of infants of control mothers. SARS-CoV-2 RNA was detected in feces of 7 (25%) women with COVID-19 and 10 (30%) of their infants. Duration of fecal shedding ranged from 1-4 wk for both mothers and infants. SARS-CoV-2 RNA was sparsely detected in feces of healthy dyads, with only one mother's and two infants' fecal samples testing positive. There was no relationship between frequencies of maternal and infant SARS-CoV-2 fecal shedding (P=0.36), although presence of maternal or infant fever was related to increased likelihood (7-9 times greater, P≤0.04) of fecal shedding in infants of mothers with COVID-19.

Prediction of prognosis in oral squamous cell carcinoma using infrared microspectroscopy.

BACKGROUND: Estimation of prognosis of oral squamous cell carcinoma (OSCC) is inaccurate prior to surgery, only being effected following subsequent pathological analysis of the primary tumour and excised lymph nodes. Consequently, a proportion of patients are overtreated, with an increase in morbidity, or undertreated, with inadequate margins and risk of recurrence. We hypothesise that it is possible to accurately characterise clinical outcomes from infrared spectra arising from diagnostic biopsies. In this first step, we correlate survival with IR spectra derived from the primary tumour. METHODS: Infrared spectra were collected from tumour tissue from 29 patients with OSCC and subject to classification modelling. RESULTS: The model had a median AUROC of 0.89 with regard to prognosis, a median specificity of 0.83, and a hazard ratio of 6.29 in univariate Cox proportional hazard modelling. CONCLUSION: The data suggest that FTIR spectra may be a useful early biomarker of prognosis in OSCC.

Evaluating clinical reasoning in first year DPT students using a script concordance test.

BACKGROUND: A script concordance test (SCT) provides a series of clinical vignettes to assess clinical reasoning in uncertainty. Appraised throughout health education literature, SCTs are cognitive assessments of clinical reasoning, though their use in Doctor of Physical Therapy (DPT) entry-level education has not been investigated. The purpose of this study was to develop and explore the reliability and validity of a SCT for first year DPT students. METHODS: The SCT was developed and implemented over four phases. During phases one and two, DPT program faculty consulted on course content from the first-year curriculum. Thirty clinical vignettes with three follow-up questions each were constructed. The SCT was pilot tested with five clinicians in phase three to assess question clarity. During phase four, the SCT was administered to students and a reference panel via Qualtrics. First year DPT students (n = 44) and reference panel physical therapists with at least two years of experience and advanced certification (n = 15) completed the SCT. Internal consistency was analyzed using Cronbach's Alpha. Differences between student and reference panel percent-correct scores were analyzed with a t-test. Relationships between student SCT scores and academic records were explored with Spearman's Rho. RESULTS: The SCT had an internal consistency of 0.74. A significant difference in scores was found between the students [mean 58.5 (+/-5.31)] and reference panel [65.8 (+/-4.88), p < .01]. No significant correlations between student SCT scores and academic records were found. CONCLUSIONS: The developed SCT was reliable and demonstrated satisfactory internal consistency among test items. The SCT successfully differentiated between groups, with the reference panel demonstrating statistically significant higher percent-correct scores compared to students. SCTs may provide means to measure clinical reasoning in DPT students and lead to novel pedagogical approaches to enhance clinical reasoning.

Cannabis use, decision making, and perceptions of risk among breastfeeding individuals: the Lactation and Cannabis (LAC) Study.

OBJECTIVE: Our primary objective was to understand breastfeeding individuals' decisions to use cannabis. Specifically, we investigated reasons for cannabis use, experiences with healthcare providers regarding use, and potential concerns about cannabis use. METHODS: We collected survey data from twenty breastfeeding participants from Washington and Oregon who used cannabis at least once weekly. We documented individuals' cannabis use and analyzed factors associated with their decisions to use cannabis during lactation. Qualitative description was used to assess responses to an open-ended question about potential concerns. RESULTS: Fifty-five percent of participants (n = 11) reported using cannabis to treat or manage health conditions, mostly related to mental health. Eighty percent of participants (n = 16) reported very few or no concerns about using cannabis while breastfeeding, although participants who used cannabis for medical purposes had significantly more concerns. Most participants (n = 18, 90%) reported receiving either no or unhelpful advice from healthcare providers. Four themes arose through qualitative analysis, indicating that breastfeeding individuals are: 1) identifying research gaps and collecting evidence; 2) monitoring their child's health and development; 3) monitoring and titrating their cannabis use; and 4) comparing risks between cannabis and other controlled substances. CONCLUSIONS: Breastfeeding individuals reported cannabis for medical and non-medical reasons and few had concerns about cannabis use during breastfeeding. Breastfeeding individuals reported using a variety of strategies and resources in their assessment of risk or lack thereof when deciding to use cannabis. Most participants reported receiving no helpful guidance from healthcare providers.

How do patient reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients.

OBJECTIVES: The ASSIST study investigated prescribing in routine psoriatic arthritis (PsA) care and whether the patient reported outcome: PsA Impact of Disease questionnaire (PsAID-12), impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. METHODS: Patients with PsA were selected across the UK and Europe between July 2021-March 2022. Patients completed the PsAID questionnaire, with the results shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. RESULTS: 503 patients recruited. 36.2% had changes made to treatment, 88.8% of this had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; the PsAID-12 score was associated with odds of treatment escalation (OR: 1.58; p< 0.0001). However, most clinicians reported PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician's assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation, (OR = 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. CONCLUSION: This study highlights multiple factors impacting treatment decision making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported the PsAID-12 did not influence treatment escalation decisions. PsAID scoring could be used to increase confidence in treatment de-escalation.

Investigation of Hypothalamic Pituitary Adrenal Axis and Oxytocinergic System Changes in a Pragmatic Randomized Controlled Feasibility Trial of Acupuncture for Antenatal Depression.

Background: Antenatal depression is common and associated with detrimental impacts on women and their families. Disrupted neuroendocrine functioning is reported in women experiencing perinatal mental health disturbances. Preliminary randomized controlled trial (RCT) evidence suggests acupuncture may provide a safe and effective adjunct treatment; however, underlying mechanisms of effect are unclear. We conducted an RCT examination of acupuncture for the management of antenatal depressive symptomologies, which included oxytocinergic and hypothalamic pituitary adrenal (HPA) axis system evaluations. This article reports postintervention changes to cortisol: dehydroepiandrosterone (DHEA) ratios, and oxytocin (OT) hormone concentrations. Methods: Fifty-seven women with Edinburgh Postnatal Depression Scale (EPDS) scores ≥13 were randomized to receive individually tailored depressed specific acupuncture, progressive muscle relaxation (PMR) attention comparator, or treatment as usual (TAU). Weekly 1-h sessions were conducted for 8 weeks (24-31 of pregnancy). Preintervention and postintervention saliva samples were collected. Results: Postintervention mean cortisol: DHEA ratio differences were not significantly predicted by group allocation (n = 46, p = 0.065). Two-group comparisons demonstrated cortisol: DHEA ratios were significantly increased and predicted by group allocation when acupuncture was compared to TAU (p = 0.039); however, not between acupuncture and PMR (p = 0.179), or PMR and TAU (p = 0.421). Postintervention OT concentrations were not significantly predicted by group allocation. Limitations: Small sample size and posthoc analysis Conclusion: Findings suggest positive regulation of the HPA axis may be an underlying mechanism by which acupuncture provided the significant improvements to antenatal depression, stress, and distress observed in this cohort. Trial Registration: Registered on March 19, 2015, with the Australian New Zealand Clinical Trials Registry (ACTRN12615000250538).

LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development.

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers.

Beyond the binary: Characterizing the relationships between sex and neuropeptide receptor binding density measures in the rat brain.

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints.

Examining Phosphatases Through Immunofluorescent Microscopy.

Immunofluorescent microscopy enables the examination of cellular expression and localization of proteins. Cellular localization can often impact protein function, as certain molecular interactions occur in specific cellular compartments. Here we describe in detail the processes necessary for identifying phosphatases in the cell through immunofluorescent microscopy. Identification of phosphatase expression and localization could lead to the discovery of protein function in disease states along with potential substrates and binding partners.

Cytoglobin regulates NO-dependent cilia motility and organ laterality during development.

Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer's vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase-soluble guanylate cyclase-cyclic GMP that is necessary for normal cilia motility and left-right patterning.

Cerebellar Compression by Giant Extracanalicular Osteoma with Central Cholesterol Granuloma.

Temporal bone osteomas comprise 0.1-1% of benign tumors involving the skull, the majority of which arise in the external auditory canal. More rarely, they can arise from the mastoid portion of the temporal bone. These generally present as a slow growing skull base lesion that can cause cosmetic deformity, headache, and/or hearing loss. Here, we report a case of extracanalicular mastoid osteoma uniquely presenting with posterior fossa and cerebellar compression with associated dizziness and imbalance.