Ambulatory intracranial pressure in humans: ICP increases during movement between body positions.

Introduction: Positional changes in intracranial pressure (ICP) have been described in humans when measured over minutes or hours in a static posture, with ICP higher when lying supine than when sitting or standing upright. However, humans are often ambulant with frequent changes in position self-generated by active movement. Research question: We explored how ICP changes during movement between body positions. Material and methods: Sixty-two patients undergoing clinical ICP monitoring were recruited. Patients were relatively well, ambulatory and of mixed age, body habitus and pathology. We instructed patients to move back and forth between sitting and standing or lying and sitting positions at 20 s intervals after an initial 60s at rest. We simultaneously measured body position kinematics from inertial measurement units and ICP from an intraparenchymal probe at 100 Hz. Results: ICP increased transiently during movements beyond the level expected by body position alone. The amplitude of the increase varied between participants but was on average ∼5 mmHg during sit-to-stand, stand-to-sit and sit-to-lie movements and 10.8 mmHg [95%CI: 9.3,12.4] during lie-to-sit movements. The amplitude increased slightly with age, was greater in males, and increased with median 24-h ICP. For lie-to-sit and sit-to-lie movements, higher BMI was associated with greater mid-movement increase (ß = 0.99 [0.78,1.20]; ß = 0.49 [0.34,0.64], respectively). Discussion and conclusion: ICP increases during movement between body positions. The amplitude of the increase in ICP varies with type of movement, age, sex, and BMI. This could be a marker of disturbed ICP dynamics and may be particularly relevant for patients with CSF-diverting shunts in situ.

The Impact of Intracranial Pressure Telesensors: An Observational Propensity-Matched Control Analysis of Service Demand and Costs.

BACKGROUND AND OBJECTIVES: Implantable telemetric intracranial pressure (ICP) sensors (telesensors) enable routine, noninvasive ICP feedback, aiding clinical decision-making and attribution of pressure-related symptoms in patients with cerebrospinal fluid shunt systems. Here, we aim to explore the impact of these devices on service demand and costs in patients with adult hydrocephalus. METHODS: We performed an observational propensity-matched control study, comparing patients who had an MScio/Sensor Reservoir (Christoph Miethke, GmbH & Co) against those with a nontelemetric reservoir inserted between March 2016 and March 2018. Patients were matched on demographics, diagnosis, shunt-type, and revision status. Service usage was recorded with frequencies of neurosurgical admissions, outpatient clinics, scans, and further surgical procedures in the 2 years before and after shunt insertion. RESULTS: In total, 136 patients, 73 telesensors, and 63 controls were included in this study (48 matched pairs). Telesensor use led to a significant decrease in neurosurgical inpatient admissions, radiographic encounters, and procedures including ICP monitoring. After multivariate adjustment, the mean cumulative saving after 2 years was £5236 ($6338) in telesensor patients (£5498 on matched pair analysis). On break-even analysis, cost-savings were likely to be achieved within 8 months of clinical use, postimplantation. Telesensor patients also experienced a significant reduction in imaging-associated radiation (4 mSv) over 2 years. CONCLUSION: The findings of this exploratory study reveal that telesensor implantation is associated with reduced service demand and provides net financial savings from an institutional perspective. Moreover, telesensor patients required fewer appointments, invasive procedures, and had less radiation exposure, indicating an improvement in both their experience and safety.

The Montana Interfacility Blood Network: A Novel Lifesaving "Hand-off" for the Optimal Care of Rural Patients.

Purpose: The state of Montana encompasses and defines rural health care as it is known in the United States (US) today. This vast area is punctuated by pockets of health care availability with varying access to blood products for transfusion. Furthermore, timely transport is frequently challenged by weather that may limit air transportation options, resulting in multiple hours in ground transport to definitive care. Patients and Methods: The Montana State Trauma Care Committee (MT-STCC) developed the Montana Interfacility Blood Network (MT-IBN) to ensure blood availability in geographically distanced cases where patients may otherwise not survive. The index case that led to the formal development of the MT-IBN is described, followed by a second case illustrating the IBN process. Results: This process and development manuscript details the innovative efforts of MT-STCC to develop this fledgling idea unique to rural US health care. We review guidelines that have been developed to define broad aspects of the MT-IBN including the reason to share resources, proper packaging, paperwork necessary for transfer, and how to provide resources directly to the patient. Finally, we describe implementation within the state. Conclusion: The MT-IBN was developed by MT-STCC to facilitate the hand-off of lifesaving blood to patients being transported by ground to definitive care in Montana without having to stop at an intermediary facility. This has already led to lives saved in areas that are limited in blood availability due to rurality.

"Until death do us part". A multidisciplinary study on human- Animal co- burials from the Late Iron Age necropolis of Seminario Vescovile in Verona (Northern Italy, 3rd-1st c. BCE).

Animal remains are a common find in prehistoric and protohistoric funerary contexts. While taphonomic and osteological data provide insights about the proximate (depositional) factors responsible for these findings, the ultimate cultural causes leading to this observed mortuary behavior are obscured by the opacity of the archaeological record and the lack of written sources. Here, we apply an interdisciplinary suite of analytical approaches (zooarchaeological, anthropological, archaeological, paleogenetic, and isotopic) to explore the funerary deposition of animal remains and the nature of joint human-animal burials at Seminario Vescovile (Verona, Northern Italy 3rd-1st c. BCE). This context, culturally attributed to the Cenomane culture, features 161 inhumations, of which only 16 included animal remains in the form of full skeletons, isolated skeletal parts, or food offerings. Of these, four are of particular interest as they contain either horses (Equus caballus) or dogs (Canis lupus familiaris)-animals that did not play a dietary role. Analyses show no demographic, dietary, funerary similarities, or genetic relatedness between individuals buried with animals. Isotopic data from two analyzed dogs suggest differing management strategies for these animals, possibly linked to economic and/or ritual factors. Overall, our results point to the unsuitability of simple, straightforward explanations for the observed funerary variability. At the same time, they connect the evidence from Seminario Vescovile with documented Transalpine cultural traditions possibly influenced by local and Roman customs.

Reference intervals for deconjugated urine metanephrines by Bhattacharya analysis.

BACKGROUND: Urine metanephrines are used to screen for phaeochromocytoma or paraganglioma (PPGL). Current reference intervals (RI) derived in healthy individuals are not age or sex-stratified, and lower than in hypertensive patients, leading to high false positive rates. This study aims to determine age and sex-stratified RI from a contingent screening population. METHODS: Patients with 24-h deconjugated urine metanephrines from 3/6/2010 to 27/8/2022 were included (2936 males, 5285 females), initially by liquid chromatography-electrochemical detection (LC-ECD) then liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bhattacharya analysis was used after log transformation to determine age and sex-stratified RI for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. RESULTS: Normetanephrine excretion increases with age (RI: males: 18-<30 years: <3.4 µmol/24 h, 30-<40 years: <3.7 µmol/24 h, 40+ years: <5.3 µmol/24 h; females: 18-<30 years: <2.7 µmol/24 h, 30-<40 years: <3.1 µmol/24 h, 40+ years: <3.7 µmol/24 h), while metanephrine excretion was consistent across adulthood (RI: males: 18+ years: <1.8 µmol/24 h; females: 18+ years: <1.2 µmol/24 h). However, normetanephrine/creatinine and metanephrine/creatinine increase steadily with age after early adulthood, likely due to a decrease in muscle mass, with females having higher normetanephrine/creatinine and metanephrine/creatinine ratios. CONCLUSIONS: Age and sex-stratified RI were derived for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. This is expected to reduce false positives while flagging most PPGL.

Outcomes in necrotizing soft tissue infections are worse in rural versus urban Montana: a 10-year single center retrospective review.

Time to definitive surgical debridement has been recognized as a predictor for morbidity and mortality in necrotizing soft-tissue infections (NSTI). Rural patients are at particular risk due to limited local resources, decreased access to care, and prolonged transport times. The aim of the current study was to examine the outcomes of NSTI requiring surgical treatment in a previously non-described setting. This retrospective study (2010-2020) from a single tertiary care center in Montana reviewed patients ≥18 years old with a NSTI via ICD9/10 codes. Rural-Urban Continuum Codes (RUCC; characterizing counties by population size) were used to distinguish urban versus rural counties. Race (White and American Indian/Alaskan Native (AI/AN)) was self-described. Qualitative and quantitative comparisons between groups were determined using the appropriate two-tailed statistical tests. An aggregate of 177 patients was identified. Mean age in AI/AN was significantly lower (P<0.0001) compared to White patients with no preexisting condition delineation. NSTI demonstrated an elevated incidence in both rural areas and AI/AN patients. Diabetes was also significantly higher (P=0.0073) in rural versus urban patients. Both rural and AI/AN patients faced extended travel distance for treatment. AI/AN patients had a significantly different infection location than White. Furthermore, polymicrobial species were significantly more prevalent in AI/AN patients. Morbidities (defined as septic shock and/or amputation) were significantly higher in AI/AN patients and rural environments (P<0.01). There was no significant difference in all-cause mortality between respective groups. The state of Montana presents unique challenges to optimizing NSTI treatment due to excessive distances to regional tertiary care facilities. This delay in treatment can lead to increased morbidity.

Genetic influences on epilepsy outcomes: A whole-exome sequencing and health care records data linkage study.

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.

A retrospective comparison of the emergent use of fixed-dose four-factor prothrombin complex versus weight-based dosing for intracranial hemorrhage assessing medication delivery time and cost.

OBJECTIVES: The goal of this study was to evaluate a low fixed-dose versus weight-based dosing strategy for four-factor prothrombin complex (4F-PCC) time to administration in intracranial hemorrhage (ICH) patients. METHODS: A retrospective analysis was conducted at a single rural Tertiary referral center in patients ≥18 years old on warfarin with ICH who received 4F-PCC. Continuous variables were summarized using mean (±95% CI) and compared using two-tailed tests; p values ≤0.05 were considered statistically significant. RESULTS: A total of 46 ICH patients were reversed using 4F-PCC (Fixed, n = 27 and Weight, n = 19). Baseline characteristics were equivalent. Total units of 4F-PCC (mean dose units 2525.1 versus 1623.3) and dose per kg were significantly reduced in the fixed-dose group. Total time from order to delivery was significantly reduced with the fixed-dose strategy (mean time 43.0 versus 29.0 minutes). Hospital length of stay (LOS), intensive care unit LOS, and mortality were equivalent with a similar mechanism. International Normalized Ratio (INR) reversal success (≤1.5) and total INR change was comparable with no difference in adverse thromboses between groups. CONCLUSIONS: A fixed-dosed strategy reduced time to 4F-PCC administration for warfarin reversal in ICH, as compared to a weight-based strategy; with no increase in LOS, mortality, or need for additional dosing. This also resulted in significant cost savings.

Artefactually low creatinine by Beckman Coulter enzymatic method due to immunoglobulin M paraprotein interference.

An 81-year-old man was admitted to hospital with symptomatic coronavirus disease (COVID-19) infection. He had a background of progressive chronic inflammatory demyelinating polyneuropathy associated with Waldenstrom's macroglobulinaemia. His plasma creatinine on four separate samples was inconceivably low (all ≤13 µmol/L), as measured by a Beckman Coulter enzymatic assay) after being 72 µmol/L 3 months earlier. On further investigation, his serum immunoglobulin M (IgM) was 15.4 g/L and his plasma creatinine measured by Roche enzymatic and Roche Jaffe methods was 62 µmol/L and 64 µmol/L, respectively. This was consistent with results post dilution studies and polyethylene glycol (PEG) precipitation on the Beckman Coulter assay. There was no evidence of similar interference when reviewing creatinine results from 10 other patients with IgM paraproteinaemia who had been tested in our laboratory. Clinicians and laboratorians are reminded that enzymatic creatinine is not free from interferences. IgM paraprotein negative interference of enzymatic creatinine is rare and specific to a patient's IgM and assay combination, but should be considered in patients with an unexplained low enzymatic creatinine result. Useful investigations to identify an interference include dilution studies, PEG precipitation and measuring creatinine on an alternative method such as Jaffe, mass spectrometry or an enzymatic method from a different platform.

Bringing Trauma Education to the Frontier: Overcoming Distance Barriers Utilizing a Virtual Platform.

BACKGROUND: The American College of Surgeons and state regulations mandate that trauma facilities offer trauma-specific continuing education throughout the region they serve. These requirements come with unique challenges when serving a rural and sparsely populated state. A novel approach to providing education was necessitated by the coronavirus disease 2019 pandemic, travel distance, and limited local specialists. OBJECTIVE: The purpose of this article is to describe the development of a virtual educational program used to improve access to quality trauma education and decrease barriers to obtaining continuing education hours inherent in the region. METHODS: This article describes the development and implementation of the Virtual Trauma Education program, which provided one free continuing education hour per month from October 2020 to October 2021. The program reached more than 2,000 viewers and established a method to provide continuous monthly educational offerings throughout the region. RESULTS: After the Virtual Trauma Education program implementation, monthly educational attendance increased from an average of 55 to 190. Viewership data indicate that trauma education across our region is far more robust, available, and accessible using a virtual platform. With more than 2,000 views from October 2020 to October 2021, Virtual Trauma Education offerings have spread far beyond regional borders, reaching 25 states and 169 communities. CONCLUSION: Virtual Trauma Education delivers easily accessible trauma education and is a program that has proven its sustainability.

The pursuit of approaches to federate data to accelerate Alzheimer's disease and related dementia research: GAAIN, DPUK, and ADDI.

There is common consensus that data sharing accelerates science. Data sharing enhances the utility of data and promotes the creation and competition of scientific ideas. Within the Alzheimer's disease and related dementias (ADRD) community, data types and modalities are spread across many organizations, geographies, and governance structures. The ADRD community is not alone in facing these challenges, however, the problem is even more difficult because of the need to share complex biomarker data from centers around the world. Heavy-handed data sharing mandates have, to date, been met with limited success and often outright resistance. Interest in making data Findable, Accessible, Interoperable, and Reusable (FAIR) has often resulted in centralized platforms. However, when data governance and sovereignty structures do not allow the movement of data, other methods, such as federation, must be pursued. Implementation of fully federated data approaches are not without their challenges. The user experience may become more complicated, and federated analysis of unstructured data types remains challenging. Advancement in federated data sharing should be accompanied by improvement in federated learning methodologies so that federated data sharing becomes functionally equivalent to direct access to record level data. In this article, we discuss federated data sharing approaches implemented by three data platforms in the ADRD field: Dementia's Platform UK (DPUK) in 2014, the Global Alzheimer's Association Interactive Network (GAAIN) in 2012, and the Alzheimer's Disease Data Initiative (ADDI) in 2020. We conclude by addressing open questions that the research community needs to solve together.

Biodegradable temporising matrix: use of negative pressure wound therapy shows a significantly higher success rate.

OBJECTIVE: The purpose of this case series was to evaluate the efficacy of a synthetic biodegradable temporising matrix (BTM; PolyNovo Biomaterials Pty Ltd, Australia) and compare the outcome of BTM patients with and without negative pressure wound therapy (NPWT). METHOD: A retrospective chart review was conducted on patients admitted with deep full-thickness burns, traumatic or complex wound injuries treated with BTM. Electronic medical records and images were evaluated by a team of clinical professionals. Endpoints included: the measure of successful BTM integration; and comparison between patients treated with and without NPWT. Additional measures were BTM total surface area, BTM sites, timeliness of BTM application and any complications. RESULTS: A total of 28 patients were evaluated and 23 (82.1%) demonstrated overall successful BTM integration. Patients treated with BTM in conjunction with NPWT (n=16) demonstrated a significantly higher (p=0.046) integration rate compared to patients treated without NPWT (n=12) (93.8% versus 58.3%, respectively). Patients treated with BTM with NPWT continued to successfully integrate and sustain favourable outcomes despite the presence of severe infection or the development of haematomas. CONCLUSION: A significantly higher integration rate was demonstrated when BTM was used in conjunction with NPWT. The results of this study further support the efficacy of successful integration of BTM as a replacement for tissue loss in the treatment of deep, full-thickness burns, traumatic and complex wound injuries, and particularly favourable outcomes with the use of NPWT. To the best of our knowledge, this is the first reported case series comparing the clinical outcomes of BTM with and without the use of NPWT.

ATTAC! Development of a Novel Advanced Trauma Team Application Course.

BACKGROUND: Although existing trauma nurse courses provide basic education, advanced courses with simulation experiences that enhance team leadership, communication, and workflows are lacking. OBJECTIVE: To design and implement the Advanced Trauma Team Application Course (ATTAC) to promote advanced skills for nurses and respiratory therapists with varied experience and skill levels. METHODS: Trauma nurses and respiratory therapists were selected to participate based on years of experience and the novice to expert nurse model. Two nurses from each level (excluding novice) participated, ensuring a diverse cohort to promote development and mentorship. The 11-module course was presented over 12 months. A five-question survey was employed at the end of each module to self-evaluate assessment skills, communication skills, and comfort for trauma patient care. Participants rated skills and comfort on a "0-10" scale, with 0 being "not at all" to 10 being "extensively." RESULTS: The pilot course was conducted from May 2019 to May 2020 at a Level II trauma center in the Northwest United States. Nurses reported ATTAC improved assessment skills, team communication, and comfort in caring for trauma patients (mean = 9.4; 95% CI [9.0, 9.8]; scale of 0-10). Participants indicated scenarios closely mimicked real-world situations; concept application commenced directly following each session. CONCLUSION: This novel approach to advanced trauma education promotes development of advanced skills that enable nurses to anticipate needs rather than being reactive, engage in critical thinking, and adapt to rapidly changing patient conditions.

Research-ready data: the C-Surv data model.

Research-ready data (data curated to a defined standard) increase scientific opportunity and rigour by integrating the data environment. The development of research platforms has highlighted the value of research-ready data, particularly for multi-cohort analyses. Following stakeholder consultation, a standard data model (C-Surv) optimised for data discovery, was developed using data from 5 population and clinical cohort studies. The model uses a four-tier nested structure based on 18 data themes selected according to user behaviour or technology. Standard variable naming conventions are applied to uniquely identify variables within the context of longitudinal studies. The data model was used to develop a harmonised dataset for 11 cohorts. This dataset populated the Cohort Explorer data discovery tool for assessing the feasibility of an analysis prior to making a data access request. Data preparation times were compared between cohort specific data models and C-Surv.It was concluded that adopting a common data model as a data standard for the discovery and analysis of research cohort data offers multiple benefits.

Common governance model: a way to avoid data segregation between existing trusted research environment.

Background: Trusted Research Environments provide a legitimate basis for data access along with a set of technologies to support implementation of the "five-safes" framework for privacy protection. Lack of standard approaches in achieving compliance with the "five-safes" framework results in a diversity of approaches across different TREs. Data access and analysis across multiple TREs has a range of benefits including improved precision of analysis due to larger sample sizes and broader availability of out-of-sample records, particularly in the study of rare conditions. Knowledge of governance approaches used across UK-TREs is limited. Objective: To document key governance features in major UK-TRE contributing to UK wide analysis and to identify elements that would directly facilitate multi TRE collaborations and federated analysis in future. Method: We summarised three main characteristics across 15 major UK-based TREs: 1) data access environment; 2) data access requests and disclosure control procedures; and 3) governance models. We undertook case studies of collaborative analyses conducted in more than one TRE. We identified an array of TREs operating on an equivalent level of governance. We further identify commonly governed TREs with architectural considerations for achieving an equivalent level of information security management system standards to facilitate multi TRE functionality and federated analytics. Results: All 15 UK-TREs allow pooling and analysis of aggregated research outputs only when they have passed human-operated disclosure control checks. Data access requests procedures are unique to each TRE. We also observed a variability in disclosure control procedures across various TREs with no or minimal researcher guidance on best practices for file out request procedures. In 2023, six TREs (40.0%) held ISO 20071 accreditation, while 9 TREs (56.2%) participated in four-nation analyses. Conclusion: Secure analysis of individual-level data from multiple TREs is possible through existing technical solutions but requires development of a well-established governance framework meeting all stakeholder requirements and addressing public and patient concerns. Formation of a standard model could act as the catalyst for evolution of current TREs governance models to a multi TRE ecosystem within the UK and beyond.

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.