Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson's disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8-35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5-3 Hz) power was reduced (p = 0.038) whereas beta (8-35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = -0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD.

Short chain fatty acids inhibit corneal inflammatory responses to TLR ligands via the ocular G-protein coupled receptor 43.

PURPOSE: Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye. METHODS: Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount. RESULTS: GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells. CONCLUSIONS: This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43.

A Photoresponsive Homing Endonuclease for Programmed DNA Cleavage.

Homing endonucleases are used in a wide range of biotechnological applications including gene editing, in gene drive systems, and for the modification of DNA structures, arrays, and prodrugs. However, controlling nuclease activity and sequence specificity remain key challenges when developing new tools. Here a photoresponsive homing endonuclease was engineered for optical control of DNA cleavage by partitioning DNA binding and nuclease domains of the monomeric homing endonuclease I-TevI into independent polypeptide chains. Use of the Aureochrome1a light-oxygen-voltage domain delivered control of dimerization with light. Illumination reduced the concentration needed to achieve 50% cleavage of the homing target site by 6-fold when compared to the dark state, resulting in an up to 9-fold difference in final yields between cleavage products. I-TevI nucleases with and without a native I-TevI zinc finger motif displayed different nuclease activity and sequence preference impacting the promiscuity of the nuclease domain. By harnessing an alternative DNA binding domain, target preference was reprogrammed only when the nuclease lacked the I-TevI zinc finger motif. This work establishes a first-generation photoresponsive platform for spatiotemporal activation of DNA cleavage.

Paradoxical Modulation of STN ß-Band Activity with Medication Compared to Deep Brain Stimulation.

BACKGROUND: Excessive subthalamic nucleus (STN) ß-band (13-35 Hz) synchronized oscillations has garnered interest as a biomarker for characterizing disease state and developing adaptive stimulation systems for Parkinson's disease (PD). OBJECTIVES: To report on a patient with abnormal treatment-responsive modulation in the ß-band. METHODS: We examined STN local field potentials from an externalized deep brain stimulation (DBS) lead while assessing PD motor signs in four conditions (OFF, MEDS, DBS, and MEDS+DBS). RESULTS: The patient presented here exhibited a paradoxical increase in ß power following administration of levodopa and pramipexole (MEDS), but an attenuation in ß power during DBS and MEDS+DBS despite clinical improvement of 50% or greater under all three therapeutic conditions. CONCLUSIONS: This case highlights the need for further study on the role of ß oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of ß or other biomarker-based DBS closed loop algorithms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism.

Increasing evidence associates slow-wave sleep (SWS) dysfunction with neurodegeneration. Using a within-subject design in the nonhuman primate model of Parkinson's disease (PD), we found that reduced SWS quantity in mild parkinsonism was accompanied by elevated beta and reduced delta power during SWS in the motor cortex. Our findings support excessive beta oscillations as a mechanism for SWS dysfunction and will inform development of neuromodulation therapies for enhancing SWS in PD.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Effect of subthalamic coordinated reset deep brain stimulation on Parkinsonian gait.

Introduction: Coordinated Reset Deep Brain Stimulation (CR DBS) is a novel DBS approach for treating Parkinson's disease (PD) that uses lower levels of burst stimulation through multiple contacts of the DBS lead. Though CR DBS has been demonstrated to have sustained therapeutic effects on rigidity, tremor, bradykinesia, and akinesia following cessation of stimulation, i.e., carryover effect, its effect on Parkinsonian gait has not been well studied. Impaired gait is a disabling symptom of PD, often associated with a higher risk of falling and a reduced quality of life. The goal of this study was to explore the carryover effect of subthalamic CR DBS on Parkinsonian gait. Methods: Three non-human primates (NHPs) were rendered Parkinsonian and implanted with a DBS lead in the subthalamic nucleus (STN). For each animal, STN CR DBS was delivered for several hours per day across five consecutive days. A clinical rating scale modified for NHP use (mUPDRS) was administered every morning to monitor the carryover effect of CR DBS on rigidity, tremor, akinesia, and bradykinesia. Gait was assessed quantitatively before and after STN CR DBS. The stride length and swing speed were calculated and compared to the baseline, pre-stimulation condition. Results: In all three animals, carryover improvements in rigidity, bradykinesia, and akinesia were observed after CR DBS. Increased swing speed was observed in all the animals; however, improvement in stride length was only observed in NHP B2. In addition, STN CR DBS using two different burst frequencies was evaluated in NHP B2, and differential effects on the mUPDRS score and gait were observed. Discussion: Although preliminary, our results indicate that STN CR DBS can improve Parkinsonian gait together with other motor signs when stimulation parameters are properly selected. This study further supports the continued development of CR DBS as a novel therapy for PD and highlights the importance of parameter selection in its clinical application.

clifford B.4.1 , an allele of CG1603 , causes tissue overgrowth in the Drosophila melanogaster eye.

Mutant B.4.1 , generated via EMS mutagenesis in Drosophila melanogaster , was studied by undergraduate students participating in the Fly-CURE. After inducing genetically mosaic tissue in the adult eye, B.4.1 mutant tissue displays a robust increase in cell division and a rough appearance. Complementation mapping and sequence analysis identified a nonsense mutation in the gene CG1603 , which we named clifford ( cliff ) due to observed increases in red-pigmented mutant tissue compared to controls. cliff encodes a zinc finger-containing protein implicated in transcriptional control. RNAi knockdown of cliff similarly results in rough eyes, confirming a role for Cliff in eye development.

A general health economics review of the hidden costs involved in discharging coeliac patients from hospital-based specialty clinics to community-based management.

Aim: The aim of this work was to highlight the impact and hidden costs incurred by the NHS in supporting this management process. Background: Coeliac disease (CD) is a common auto-immune condition which affects around 1% of the general population. In 2005 there was a drive by the government to discharge patients with CD from specialist hospital follow up to community-based management to improve cost efficiency. Methods: A retrospective analysis of 1317 CD patients collected from a local coeliac database created between 2005 and 2016. Results: During these 12 years, CD patients accounted for 1965 hospital admissions with a total 5716 days spent within the hospital setting. There were 33150 adult and paediatric OPAs attended equating to 25.17 per coeliac patient, or 2.29 per person per year. The cost to the CCG totalled £5,167,396. A total of 527 lower GI procedures were undertaken with findings of microscopic colitis, melanosis coli, inflammatory bowel disease and colon cancer. 420 (29%) of the coeliac cohort were found to have IDA with just 4% (17/420) receiving an intravenous (IV) iron infusion. Conclusion: It would appear that the government's attempts to reduce the cost of CD care within the NHS was not particularly effective, from a financial, or patient care perspective. A hospital-based, specialist nurse led, virtual management system (with consultant over-view) may prove to be a more efficient compromise, to help reduce down waiting times and costs, whilst still providing coeliac patients with the specialist and holistic input they require and deserve.

Forensic Nurses' Understanding of Emergency Contraception Mechanisms: Implications for Access to Emergency Contraception.

BACKGROUND: An estimated 25,000 pregnancies result from sexual assault in the United States annually. Numerous professional healthcare organizations endorse offering emergency contraception (EC) as an integrated aspect of post-sexual-assault care. Lack of knowledge surrounding EC's mechanism of action, including misinterpreting ECs as abortifacients, might restrict patient access to this important healthcare option. PURPOSE: We evaluated sexual assault nurse examiners' understanding of the mechanism of action of oral ECs levonorgestrel (LNG) and ulipristal acetate (UPA). METHODS: A cross-sectional survey of practicing sexual assault nurse examiners was conducted through the International Association of Forensic Nurses. RESULTS: Among 173 respondents, 96.53% reported they prescribed/dispensed EC at the time of medical forensic examinations. LNG was prescribed more frequently than UPA (57.80% vs. 38.2%, respectively). When asked if they agreed or disagreed if LNG and UPA can disrupt an established pregnancy, 83.2% selected disagree/strongly disagree for LNG versus 78.6% for UPA, which were not significantly different. When asked whether the Supreme Court ruling overturning Roe v. Wade would change their EC prescribing, 79.77% reported it will have no change, 6.94% said it would increase, and 12.72% reported they were unsure. Several commented they were concerned whether state laws would prohibit EC and at least one program stopped prescribing EC because of their state laws. IMPLICATIONS: Addressing misinformation regarding EC's mechanism of action and increasing access to oral EC options after sexual assault have the potential to reduce the incidence of rape-related pregnancy.

From inequity to access: Evidence-based institutional practices to enhance care for individuals with disabilities.

People with disabilities experience barriers to care in all facets of health care, from engaging with the provider in a clinical setting (attitudinal and communication barriers) to navigating a large institution in a complex health care environment (organizational and environmental barriers), culminating in significant health care disparities. Institutional policy, culture, and physical layout may be inadvertently fostering ableism, which can perpetuate health care inaccessibility and health disparities in the disability community. Here, we present evidence-based interventions at the provider and institutional levels to accommodate patients with hearing, vision, and intellectual disabilities. Institutional barriers can be met with strategies of universal design (i.e., accessible exam rooms and emergency alerts), maximizing electronic medical record accessibility/visibility, and institutional policy development to recognize and reduce discrimination. Barriers at the provider level can be met with dedicated training on care of patients with disabilities and implicit bias training specific to the surrounding patient demographics. Such efforts are crucial to ensuring equitable access to quality care for these patients.

3D printed guide tube system for acute Neuropixels probe recordings in non-human primates.

Objective.Neuropixels (NP) probes are a significant advance in electrophysiological recording technology that enable monitoring of hundreds of neurons in the brain simultaneously at different depths. Application of this technology has been predominately in rodents, however widespread use in non-human primates (NHPs) such as rhesus macaques has been limited. In this study we sought to overcome two overarching challenges that impede acute NP implantation in NHPs: (1) traditional microdrive systems that mount to cephalic chambers are commonly used to access cortical areas for microelectrode recordings but are not designed to accommodate NP probes, and (2) NHPs have thick dura mater and tissue growth within the cephalic chambers which poses a challenge for insertion of the extremely fragile NP probe.Approach.In this study we present a novel NP guide tube system that can be adapted to commercial microdrive systems and demonstrate an implant method using the NP guide tube system. This system was developed using a combination of CAD design, 3D printing, and small part machining. Software programs, 3D Slicer and SolidWorks were used to target cortical areas, approximate recording depths and locations, and for in-silico implant testing.Main results.We performedin vivotesting to validate our methodology, successfully implanting, explanting, and reimplanting NP probes. We collected stable neurophysiological recordings in the premotor cortex of a rhesus macaque at rest and during performance of a reaching task.Significance.In this study we demonstrate a robust Neuropixels implant system that allows multiple penetrations with the same NP probe and share design files that will facilitate the adoption of this powerful recording technology for NHP studies.

The mental wellbeing of prison staff in England during the COVID-19 pandemic: A cross-sectional study.

Background: COVID-19 is likely to have had an impact on the mental wellbeing of prison staff because of the high risk for infectious disease outbreaks in prisons and the pre-existing high burden of mental health issues among staff. Methods: A cross-sectional study of staff within 26 prisons in England was carried out between 20th July 2020 and 2nd October 2020. Mental wellbeing was measured using the Short-version of Warwick-Edinburgh Wellbeing Scale (SWEMWBS). Staff wellbeing was compared to that of the English population using indirectly standardised data from the Health Survey for England 2010-13 and a one-sample t-test. Multivariate linear regression modelling explored associations with mental wellbeing score. Results: Two thousand five hundred and thirty-four individuals were included (response rate 22.2%). The mean age was 44 years, 53% were female, and 93% were white. The sample mean SWEMWBS score was 23.84 and the standardised population mean score was 23.57. The difference in means was statistically significant (95% CI 0.09-0.46), but not of a clinically meaningful level. The multivariate linear regression model was adjusted for age category, sex, ethnicity, smoking status, occupation, and prison service region. Higher wellbeing was significantly associated with older age, male sex, Black/Black British ethnicity, never having smoked, working within the health staff team, and working in certain prison regions. Interpretation: Unexpectedly, prison staff wellbeing as measured by SWEMWBS was similar to that of the general population. Reasons for this are unclear but could include the reduction in violence within prisons since the start of the pandemic. Qualitative research across a diverse sample of prison settings would enrich understanding of staff wellbeing within the pandemic.

Examining agreement between finite element modelling methodologies in predicting pathological fracture risk in proximal femurs with bone metastases.

BACKGROUND: Finite element modelling methodologies available for assessing femurs with metastases accurately predict strength and pathological fracture risk which has led them to being considered for implementation into the clinic. However, the models available use varying material models, loading conditions, and critical thresholds. The aim of this study was to determine the agreement between finite element modelling methodologies in assessing fracture risk in proximal femurs with metastases. METHODS: CT images of the proximal femur were obtained of 7 patients who presented with a pathologic femoral fracture (fracture group) and the contralateral femur of 11 patients scheduled for prophylactic surgery (non-fracture group). Fracture risk was predicted for each patient following three established finite modelling methodologies which have previously shown to accurately predict strength and determine fracture risk: non-linear isotropic -based model, strain fold ratio -based model, Hoffman failure criteria -based model. FINDINGS: The methodologies demonstrated good diagnostic accuracy in assessing fracture risk (AUC = 0.77, 0.73, and 0.67). There was a stronger monotonic association between the non-linear isotropic and Hoffman -based models (τ = 0.74) than with the strain fold ratio model (τ = -0.24 and - 0.37). There was moderate or low agreement between methodologies in discriminating between individuals at high or low risk of fracture (κ = 0.20, 0.39, and 0.62). INTERPRETATION: The present results suggest there may be a lack of consistency in the management of pathological fractures in the proximal femur based on the finite element modelling methodologies.

Classification of electrically-evoked potentials in the parkinsonian subthalamic nucleus region.

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinson's disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n = 3) or non-directional (n = 1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6 and 7.4 ms after a stimulus pulse). Using these features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinson's disease with DBS therapy.

Compromised T Cell Immunity Links Increased Cutaneous Papillomavirus Activity to Squamous Cell Carcinoma Risk.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer, with increased incidence in immunosuppressed patients. ß-Human papillomavirus has been proposed as a contributor to cSCC risk partly on the basis of increased ß-human papillomavirus viral load and seropositivity observed among patients with cSCC. Experimental data in mice colonized with mouse papillomavirus type 1 suggest that T cell immunity against ß-human papillomavirus suppresses skin cancer in immunocompetent hosts, and the loss of this immunity leads to the increased risk of cSCC. In this study, we show that CD8+ T cell depletion in mouse papillomavirus type 1‒colonized mice that underwent skin carcinogenesis protocol led to increased viral load in the skin and seropositivity for anti‒mouse papillomavirus type 1 antibodies. These findings provide evidence that compromised T cell immunity can be the link that connects increased ß-human papillomavirus detection to cSCC risk.

Application of statistical shape modeling to the human hip joint: a scoping review.

OBJECTIVE: The objective of this scoping review was to identify all examples of the application of statistical shape models to the human hip joint, with a focus on applications, population, methodology, and validation. INTRODUCTION: Clinical radiographs are the most common imaging tool for management of hip conditions, but it is unclear whether radiographs can adequately diagnose or predict outcomes of 3D deformity. Statistical shape modeling, a method of describing the variation of a population of shapes using a small number of variables, has been identified as a useful tool to associate 2D images with 3D anatomy. This could allow clinicians and researchers to validate clinical radiographic measures of hip deformity, develop new ones, or predict 3D morphology directly from radiographs. In identifying all previous examples of statistical shape modeling applied to the human hip joint, this review determined the prevalence, strengths, and weaknesses, and identified gaps in the literature. INCLUSION CRITERIA: Participants included any human population. The concept included development or application of statistical shape models based on discrete landmarks and principal component analysis. The context included sources that exclusively modeled the hip joint. Only peer-reviewed original research journal articles were eligible for inclusion. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, IEEE Xplore, Web of Science Core Collection, OCLC PapersFirst, OCLC Proceedings, Networked Digital Library of Theses and Dissertations, ProQuest Dissertations and Theses Global, and Google Scholar for sources published in English between 1992 and 2021. Two reviewers screened sources against the inclusion criteria independently and in duplicate. Data were extracted by 2 reviewers using a REDCap form designed to answer the review study questions, and are presented in narrative, tabular, and graphical form. RESULTS: A total of 104 sources were considered eligible based on the inclusion criteria. From these, 122 unique statistical shape models of the human hip were identified based on 86 unique training populations. Models were most often applied as one-off research tools to describe shape in certain populations or to predict outcomes. The demographics of training populations were skewed toward older patients in high-income countries. A mean age between 60 and 79 years was reported in 29 training populations (34%), more than reported in all other age groups combined, and 73 training populations (85%) were reported or inferred to be from Europe and the Americas. Only 4 studies created models in a pediatric population, although 15 articles considered shape variation over time in some way. There were approximately equal numbers of 2D and 3D models. A variety of methods for labeling the training set was observed. Most articles presented some form of validation such as reporting a model's compactness (n = 71), but in-depth validation was rare. CONCLUSIONS: Despite the high volume of literature concerning statistical shape models of the human hip, there remains a need for further research in key areas. We identified the lack of models in pediatric populations and low- and middle-income countries as a notable limitation to be addressed in future research.