Definitive Assessment Research Articles

Evaluating the connection between mean platelet volume (MPV) and peripheral arterial disease risk: a meta-analysis

Background: Numerous studies have been conducted to evaluate the role of Mean Platelet Volume (MPV) in relation to Peripheral Artery Disease (PAD). However, the results of these studies have been inconsistent regarding the significance of MPV as an indicator for PAD. Objective: This meta-analysis aimed to clarify the role of MPV in PAD by collecting and analyzing data from various studies. The goal was to provide a more definitive assessment of whether MPV levels could serve as a reliable indicator for PAD Methods: We conducted a meta-analysis from July to August 2024, utilizing data from three major databases: Scopus, Embase, and PubMed. We gathered data on MPV levels from studies comparing PAD patients with control groups. The meta-analysis included cumulative effect estimates, with analysis performed using the inverse variance method to synthesize data and evaluate the overall effect of MPV on PAD. Results: Nine studies were included in this meta-analysis, comprising 1,214 PAD cases and 6,568 controls. Our analysis demonstrated that MPV was a significant marker in PAD, with PAD patients having higher MPV levels compared to controls (MD: 0.46; 95%CI: 0.25, 0.66; p Egger: 0.0911; p Heterogeneity <0.0001; p <0.0001). Conclusion: Our findings support that MPV is an important indicator in the context of PAD. Further study is needed to explore the clinical applications of MPV in PAD and to establish standardized thresholds for its use in clinical practice. Keyword: diagnosis, mean platelet volume, peripheral disease, predictor

Assessment of Different Castration Resistance Definitions and Staging Modalities in Metastatic Castration-Resistant Prostate Cancer.

Background/Objectives: Progression to metastatic castration-resistant prostate cancer (mCRPC) is defined either biochemically, radiographically or both. Moreover, staging for mCRPC can be performed either conventionally or with molecular imaging such as prostate-specific membrane antigen computer tomography (PSMA-PET/CT). Methods: We relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to compare progression-free (PFS) and overall survival (OS) outcomes regarding the cause of castration resistance and the staging modality used. Results: Overall, 35% progressed to mCRPC biochemically vs. 23% radiographically vs. 42% biochemically + radiographically. The PSA nadir in mHSPC (1.4 vs. 0.4 vs. 0.8 ng/mL) and PSA level at mCRPC progression (15 vs. 2 vs. 21 ng/mL, both p ≤ 0.01) were significantly higher for biochemical vs. radiographic vs. both progressed patients. In PFS and OS analyses, no significant differences were observed among all three compared groups. In the comparison of the staging used for progression to mCRPC, 67% received conventional vs. 33% PSMA-PET/CT, with higher metastatic burden in mHSPC and osseous lesions in mCRPC for conventionally staged patients (both p < 0.01). In PFS (15.3 vs. 10.1 months, hazard ratio [HR]: 0.75) and OS analyses (52.6 vs. 34.3 months, HR: 0.61, both p < 0.05), PSMA-PET/CT harbored better prognosis; however, this did not hold after multivariable adjustment. Similar results were observed for further analyses in second- and third-line mCRPC or patients with a PSA level of ≥2 ng/mL. Conclusions: The cause of progression to mCRPC seems not to influence cancer-control outcomes, despite important baseline tumor characteristic differences. The PSMA-PET/CT staging modality might be associated with better PFS and OS outcomes, possibly due to its more sensitive detection of progression or new metastatic lesions.

Effect of endoscopic ultrasound guided celiac plexus block on the palliation of pain in chronic pancreatitis (EPOCH Trial): study protocol for a randomized multicenter sham-controlled trial {1}

BackgroundCeliac plexus block has been commonly utilized for the treatment of chronic pancreatitis-associated abdominal pain. Prospective studies suggest efficacy in 30 to 50% of patients, although no randomized sham-controlled trials have been performed. The objective of this study is to assess the effect of endoscopic ultrasound (EUS)-guided celiac plexus block on abdominal pain in patients with documented chronic pancreatitis. MethodsThis is a two-arm randomized sham-controlled trial with blinded evaluators. The study will be conducted at multiple academic sites in the United States who are members of the United States Pancreatic Disease Study Group (USPG). Patients referred for EUS to exclude chronic pancreatitis as a cause of abdominal pain as well as those with established painful chronic pancreatitis undergoing EUS for another indication will be eligible. At the time of EUS with confirmation of chronic pancreatitis by standard EUS diagnostic criteria, patients will be randomized to either celiac plexus block or sham whereby an anesthetic and steroid combination will be injected into the celiac plexus or saline will be injected into the gastric lumen with the same type of needle as used for celiac plexus block, respectively. The main outcome measure will be a 50% reduction in abdominal pain using the Brief Pain Inventory Short Form (BPI-SF) at 1 month post-intervention. A number of secondary outcomes will be measured including visual analog scale (VAS), Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) pain scores, and quality of life using a pancreas-specific validated measure (PANQOLI).DiscussionIn this study, the effect of celiac plexus block on abdominal pain in patients with chronic pancreatitis will be compared to a sham intervention. This randomized trial will offer a definitive assessment of the role of celiac plexus block for the treatment of abdominal pain in this setting.Trial registration {2}ClinicalTrials.gov NCT 06178315. Registered on December 21, 2023

Bifurcated Endografts for the Treatment of Aortoiliac Disease a Systematic Review and Individual Patient Data (IPD) Meta-Analysis.

This review aimed to assess the efficacy and safety of bifurcated endografts in the treatment of aortoiliac disease (AOID). A systematic search on PubMed, Scopus, and Web of Science was performed. The primary endpoint was primary patency, whereas secondary endpoints included reintervention, technical, clinical success, and overall postoperative complications. Ten studies with a total of 365 patients were included in this review. Most included studies used the AFX unibody endograft, one study the Excluder endograft, and one the Powerlink endograft. The majority of included patients displayed TransAtlantic InterSociety Consensus (TASC) D aortoiliac lesions (56.1% 205/365). The pooled primary patency estimates at 12, 24, and 36 months were 93.93% (95% confidence interval [CI]: 87.7-100), 91.46% (95% CI: 84.6-98.8), and 90.25% (95% CI: 82.6-98.6), respectively. The mean primary patency time was 85.74 months (95% CI: 71.99-86.88). The pooled freedom from reintervention estimates at 12, 24, and 36 months were 91.94% (95% CI: 81.4-100), 91.03% (95% CI: 79.8-100), and 91.03% (95% CI: 79.8-100), respectively. The pooled estimates of major complications (rupture, graft thrombosis, amputation) were 11.12% (95% CI, 0.05%-3.03%), 3.76% (0.32%-9.45%), and 0.38% (0%-2.59%), whereas the pooled estimates for minor complications (hematoma, groin infection, dissection) and overall mortality were 5.27% (95% CI, 1.11%-11.38%), 6.93% (95% CI, 2.94%-12.16%), 2.19% (95% CI, 0.06%-6.14%), and1.57% (95% CI, 0.13-3.97), respectively. Technical and clinical success estimates were 99.92% (95% CI: 98.86%-100%) and 99.47% (95% CI: 94.92%-100%), respectively. The application of bifurcated endografts may present a safe and viable option in the treatment of AOID, with preliminary results indicating promising primary patency outcomes. However, the definitive assessment of their efficacy and safety will be better determined through long-term follow-up studies and high-quality randomized controlled trials, which are essential to substantiate these initial findings. Bifurcated endograft application may be a safe and viable alternative for high-risk patients with complex AOID TASC C and D lesions with encouraging primary patency outcomes potentially comparable to those of open surgery. Non-negligible postoperative complication rates were also noted. High-quality randomized controlled trials and studies comparing CERAB, kissing stenting, and the use bifurcated endografts for the treatment of AOID is necessary to draw more definite conclusions.

Spin-orbit alignment in very low mass tight binaries: results for the 2MASS J0746425+200032AB and 2MASS J1314203+132001AB systems using spectroscopic and optically derived rotational estimates

Context. Constraining the coplanarity status of very low mass (VLM) tight binary systems provides valuable information towards understanding the dominant mechanisms in star and planetary formation at the lower end of the initial mass function. Aims. We sought to constrain the v sin i degeneracies of two nearby tight VLM binary systems, 2MASS J0746+20AB and 2MASS J1314+13AB, by independently determining each companion’s rotational period and so characterize each system’s spin-orbit alignment. Methods. Long observational baseline high cadence I band photometry data were obtained for both systems using the Galway Ultra Fast Imager (GUFI) on the Mount Graham International Observatory’s Vatican Advanced Technology Telescope. Previously known rotational periods determined in other passbands were used as a basis for recovering additional periodic modulations in the time-series data. Results. Using the known rotational period of 3.32 hours for 2MASS J0746425+200032A, we recovered an underlying periodic modulation of 2.14 ± 0.11 hours, which we associate with 2MASS J0746425+200032B. Breaking each components’ v sin i corresponds to equatorial inclination angles of 32 ± 4 degrees and 37 ± 4 degrees for components A &amp; B respectively. We recover a weaker 2.06 ± 0.05 hours modulation separate from the known 3.79 hour signature for J1314203+132001B, which we associate with J1314203+132001A. We place a lower limit on J1314203+132001A’s equatorial inclination angle to be in the range of 24.5−3+3.5 degrees, which deviates from the system’s orbital plane previously determined to be 49.34−0.23+0.28 degrees. Conclusions. We confirm long term, consistent periodic modulations from both binary systems and report the first definitive rotational period for J1314203+132001A of 2.06 ± 0.05 hours, in addition to coplanarity to within 10 degrees in the spin-orbit alignment of the 2MASS J0746425+200032AB system. The lack of separate v sin i values for the 2MASS J1314203+132001AB system limits a definitive assessment but best estimates suggest coplanarity to be unlikely.

The Role of Helmet Therapy in Craniosynostosis: A Systematic Review

AbstractThe aim of this study was to determine the impact of helmet therapy (HT) as a treatment for craniosynostosis, with a focus on the outcomes of skull morphology, reoperation rate, complications of HT, and quality of life of patients who receive it. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review utilized the PICO format: Does HT following strip craniectomy (SC) improve outcomes (outcome) compared to SC alone (comparison) in patients undergoing craniosynostosis correction (intervention)? Searches were performed from January 1, 2000 to December 31, 2022, using PubMed, Cochrane Library, and Ovid Medline databases. Study quality was evaluated using the National Heart, Lung, and Blood Institute (NHLBI) quality assessment scale. Fourteen studies meeting the inclusion criteria were identified. Among these, 438 patients underwent SC-HT, while 104 patients underwent SC without HT. The preoperative cephalic indices for sagittal craniosynostosis in the HT and non-HT groups were 66.8 and 67.8, respectively, which improved postoperatively to 75 and 76.2, respectively. Limited long-term follow-up hindered a definitive assessment of reoperation rates. Complication rates related to HT were low at approximately 2.9%, primarily consisting of skin irritation. Parental satisfaction was high, correlating with a strong compliance rate. Existing literature does not demonstrate a clear superiority between SC with or without HT for treating nonsyndromic sagittal craniosynostosis. Outcomes appear comparable, but evidence is constrained by the predominance of single-center retrospective studies with limited methodological rigor. There is a pressing need for international multicenter trials to furnish more robust and generalizable findings.

Validating, Implementing, and Monitoring Machine Learning Solutions in the Clinical Laboratory Safely and Effectively.

Machine learning solutions offer tremendous promise for improving clinical and laboratory operations in pathology. Proof-of-concept descriptions of these approaches have become commonplace in laboratory medicine literature, but only a scant few of these have been implemented within clinical laboratories, owing to the often substantial barriers in validating, implementing, and monitoring these applications in practice. This mini-review aims to highlight the key considerations in each of these steps. Effective and responsible applications of machine learning in clinical laboratories require robust validation prior to implementation. A comprehensive validation study involves a critical evaluation of study design, data engineering and interoperability, target label definition, metric selection, generalizability and applicability assessment, algorithmic fairness, and explainability. While the main text highlights these concepts in broad strokes, a supplementary code walk-through is also provided to facilitate a more practical understanding of these topics using a real-world classification task example, the detection of saline-contaminated chemistry panels.Following validation, the laboratorian's role is far from over. Implementing machine learning solutions requires an interdisciplinary effort across several roles in an organization. We highlight the key roles, responsibilities, and terminologies for successfully deploying a validated solution into a live production environment. Finally, the implemented solution must be routinely monitored for signs of performance degradation and updated if necessary. This mini-review aims to bridge the gap between theory and practice by highlighting key concepts in validation, implementation, and monitoring machine learning solutions effectively and responsibly in the clinical laboratory.

A single center experience on PI3K/AKT/MTOR signaling defects: Towards pathogenicity assessment for four novel defects.

Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia. To characterize the PI3K/AKT/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity. We included 12 patients (heterozygous PIK3CD (n = 9) and PIK3R1 (n = 1) (activated PI3K delta syndrome (APDS) with gain-of-function mutations) and homozygous PIK3R1 variant (n = 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5-37) in APDS. Median diagnostic delay was 12.9 years (1.6-27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non-Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late-onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss-of function mutations. Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.

Benchmarking the effective temperature scale of red giant branch stellar models: The case of the metal-poor halo giant HD 122563

Context. There is plenty of evidence in the literature of significant discrepancies between the observations and models of metal-poor red giant branch stars, in particular regarding the effective temperature Teff scale. Aims. We revisit the benchmark star HD 122563 using the most recent observations from Gaia Data Release 3, to investigate if these new constraints may help in resolving this discrepancy. Methods. We review the most recent spectroscopic determinations of the metallicity [Fe/H] of HD 122563, and provide a new assessment of its fundamental parameters, specifically, bolometric luminosity, Teff, surface gravity, plus a photometric determination of its metal content. Using these constraints, we compare the position of the star in the Hertzsprung-Russell (H–R) diagram with various recent sets of stellar evolution tracks. Results. The H-R diagram analysis reveals a significant disagreement between observed and theoretical Teff values, when adopting the most recent spectroscopic estimate of [Fe/H]. On the other hand, by using the photometric determination of [Fe/H], some of the selected sets of stellar tracks appear in fair agreement with observations. The sets with discrepant Teff can be made to agree with observations either by modifying the prescription adopted to calculate the models’ outer boundary conditions, and/or by reducing the adopted value of the mixing length parameter with respect to the solar-calibration. Conclusions. A definitive assessment of whether the Teff scale of metal-poor stellar red giant branch models is consistent with observations requires a more robust determination of the fundamental parameters of HD 122563 and also a larger sample of calibrators. From the theoretical side, it is crucial to minimise the current uncertainties in the treatment (boundary conditions, temperature gradient) of the outer layers of stellar models with convective envelopes.

Assessment of scope definition for building projects in Saudi Arabia

ABSTRACT Effective project management is crucial for the successful delivery of construction projects, ensuring they are completed on time, within budget, and to the desired quality standards. Project scope definition is at the heart of project management, which forms the basis for project planning, execution, and control. However, despite its importance, there is a lack of comprehensive investigation into project scope definition compared to other areas of management knowledge. This research paper identifies the key enablers and elements of project scope definition, as well as their relative importance. Moreover, this study develops an assessment model using the Analytic Hierarchy Process (AHP) to evaluate the completeness of the project scope definition. Data was gathered through a questionnaire survey deployed to subject matter experts specialized in building projects in Saudi Arabia. The results highlight the significance of understanding the direct impact of scope definition on project success, which emerged as the most influential enabler in facilitating scope definition. Among the top ten elements of scope definition are project financial requirements, regulatory requirements, and building site location and geotechnical data. The findings and AHP assessment model can assist project stakeholders and managers in effectively defining project scope, potentially leading to efficient management of building projects.

Monitoring Overall Survival in Pivotal Trials in Indolent Cancers

Indolent cancers are characterized by lengthy overall survival (OS) times. Therefore, powering a clinical trial to provide definitive assessment of the effects of an experimental intervention on OS in a reasonable timeframe is generally infeasible. Instead, the primary outcome in many pivotal trials is an intermediate clinical response such as progression-free survival. In several recently reported pivotal trials of interventions for indolent cancers that yielded promising results on an intermediate outcome, however, more mature data or post-approval trials showed concerning OS trends. These problematic results have prompted a keen interest in quantitative approaches for monitoring OS that can support regulatory decision-making related to the risk of an unacceptably large detrimental effect on OS. The US Food and Drug Administration, the American Association for Cancer Research, and the American Statistical Association recently organized a one-day multi-stakeholder workshop entitled “Overall Survival in Oncology Clinical Trials.” In this article, we propose OS monitoring guidelines tailored for the setting of indolent cancers. Our pragmatic approach is modeled, in part, on the monitoring guidelines the FDA has used in cardiovascular safety trials conducted in Type 2 Diabetes Mellitus. We illustrate proposals through application to several examples informed by actual case studies.

In-situ monitoring of the CSC gas gain at CMS

The Cathode Strip Chambers (CSCs) are multiwire proportional chambers with cathode strip readout, and they constitute the primary muon tracking device in the endcaps of the CMS (Compact Muon Solenoid) experiment at the Large Hadron Collider (LHC). The CSCs have accumulated a significant radiation dose since the beginning of LHC operations, and it is important to monitor any possible signs of aging and confirm that the detector can sustain the full integrated luminosity expected at the HL-LHC ( 3000 fb−1). Aging effects are assessed by performing in-situ measurements of the gas gain in CSCs as a function of the integrated luminosity. CSC gas gain is studied using muon-induced charge on cathodes using data collected during 2022, corresponding to an integrated luminosity of 39.4 fb−1. The impact of atmospheric pressure and changes in detector settings (HV, gas mixture, etc.) are also taken into account. Based on these CSC gas gain measurements, chamber aging will not be a problem for Run 3. To ensure a definitive assessment for the HL-LHC, an improved control over systematic effects is needed.

P-338 Redefining elective co-parenting: a systematic assessment of concepts and definitions found in the literature and a recommendation for new terminology

Abstract Study question What concepts and concept definitions (including normative meanings) are found in the literature for forms of ‘elective co-parenting’ and which can be recommended? Summary answer Current terminology lacks comprehensiveness and often contains additional (hidden) meanings, thereby jeopardizing its usability for research on contemporary family formation. We suggest a new nomenclature. What is known already There is an increase in the variation of family forms, types of parenthood roles and methods for family formation. One such way of family building has most recently been referred to as “elective co-parenting”. Not to be confused with parenting after separation, elective co-parenting typically alludes to the intentional undertaking of a shared parental project by persons who are primarily in a reproductive (and not a ‘romantic’) relationship with each other. However, many other terms and somewhat diverging concept definitions have been put forward. It seems that a fundamental conceptual framework has not yet been established. Study design, size, duration We will adhere to a tailored set of guidelines for conceptual engineering organized in five stages: (i) Identify potential attributes by collecting a representative set of definitions, (ii) Organize the potential attributes by theme and identify any necessary &amp; sufficient or shared ones, (iii) Develop a preliminary definition of the concept, (iv) Determine what functions our concepts should serve going forward, (v) Refine the conceptual definition and improve or replace the concept. Participants/materials, setting, methods A scoping review was performed by implementing a wide-ranging search string in ProQuest. We used the following selection criteria: the article is (a) a peer-reviewed journal article, book chapter, conference paper, or report, (b) published in the last ten years, (c) written in English, that (d) proposes an explicit concept definition (also including normative meanings). Papers cited in the retrieved publications were also included if they satisfied (a), (b), (c) and (d). Main results and the role of chance After screening the available literature for academic articles that contained one or several explicit definition(s) of ‘elective co-parenting’, and that met the other selection criteria; (a), (b) and (c), key attributes mentioned in these definitions were organized in themes, i.e. necessary and/or sufficient conditions; e.g. (a) ‘Pre-conception temporality’, (b) ‘Collaborative nature’, etc. Data analysis is currently ongoing. Our aim is to put forward a new and comprehensive concept definition. In this, we will provide more clarity by making explicit all the necessary conditions (and not merely one or two as is the case in many current definitions). Furthermore, prompted by ethical considerations (e.g. ‘elective’ puts notable emphasis on free choice), we will also propose a new term for the concept of ‘elective co-parenting’; one that is more neutral and therefore more appropriate to describe the particular family building practice. The study will be completed in the forthcoming months. Limitations, reasons for caution The main challenge of this study was the construction of a suitable search strategy to find papers on a topic for which a wide range of (often contested) concepts and terminology was used. For this, several, but certainly not all (e.g. empirical research), possible strategies and data sources were explored. Wider implications of the findings This study highlights the importance of establishing clear concepts and concept definitions in the pursuit of high quality research. Providing a more appropriate concept and concept definition for what is now known as “elective co-parenting” renders further inquiry into the topic more intellectually and ethically sound. Trial registration number N/A

Chest X-Ray-Based Telemedicine Platform for Pediatric Tuberculosis Diagnosis in Low-Resource Settings: Development and Validation Study.

Tuberculosis (TB) remains a major cause of morbidity and death worldwide, with a significant impact on children, especially those under the age of 5 years. The complex diagnosis of pediatric TB, compounded by limited access to more accurate diagnostic tests, underscores the need for improved tools to enhance diagnosis and care in resource-limited settings. This study aims to present a telemedicine web platform, BITScreen PTB (Biomedical Image Technologies Screen for Pediatric Tuberculosis), aimed at improving the evaluation of pulmonary TB in children based on digital chest x-ray (CXR) imaging and clinical information in resource-limited settings. The platform was evaluated by 3 independent expert readers through a retrospective assessment of a data set with 218 imaging examinations of children under 3 years of age, selected from a previous study performed in Mozambique. The key aspects assessed were the usability through a standardized questionnaire, the time needed to complete the assessment through the platform, the performance of the readers to identify TB cases based on the CXR, the association between the TB features identified in the CXRs and the initial diagnostic classification, and the interreader agreement of the global assessment and the radiological findings. The platform's usability and user satisfaction were evaluated using a questionnaire, which received an average rating of 4.4 (SD 0.59) out of 5. The average examination completion time ranged from 35 to 110 seconds. In addition, the study on CXR showed low sensitivity (16.3%-28.2%) but high specificity (91.1%-98.2%) in the assessment of the consensus case definition of pediatric TB using the platform. The CXR finding having a stronger association with the initial diagnostic classification was air space opacification (χ21>20.38, P<.001). The study found varying levels of interreader agreement, with moderate/substantial agreement for air space opacification (κ=0.54-0.67) and pleural effusion (κ=0.43-0.72). Our findings support the promising role of telemedicine platforms such as BITScreen PTB in enhancing pediatric TB diagnosis access, particularly in resource-limited settings. Additionally, these platforms could facilitate the multireader and systematic assessment of CXR in pediatric TB clinical studies.

Monitoring Probe Deployment Patterns for Cloud-Native Applications: Definition and Empirical Assessment

Monitoring Probe Deployment Patterns for Cloud-Native Applications: Definition and Empirical Assessment

Redesigned Electrodes for Improved Intraoperative Nerve Conduction Studies during the Treatment of Peripheral Nerve Injuries.

Traumatic peripheral nerve injuries (PNI), present with symptoms ranging from pain to loss of motor and sensory function. Difficulties in intraoperative visual assessment of nerve functional status necessitate intraoperative nerve conduction studies (INCSs) by neurosurgeons and neurologists to determine the presence of functioning axons in the zone of a PNI. This process, also referred to as nerve "inching", uses a set of stimulating and recording electrode hooks to lift the injured nerve from the surrounding surgical field and to determine whether an electrical stimulus can travel through the zone of injury. However, confounding electrical signal artifacts can arise from the current workflow and electrode design, particularly from the mandatory lifting of the nerve, complicating the definitive assessment of nerve function and neurosurgical treatment decision-making. The objective of this study is to describe the design process and verification testing of our group's newly designed stimulating and recording electrodes that do not require the lifting or displacement of the injured nerve during INCSs. Ergonomic in vivo analysis of the device within a porcine model demonstrated successful intraoperative manipulation of the device, while quantitative nerve action potential (NAP) signal analysis with an ex vivo simulated "inching" procedure on healthy non-human primate nerve tissue demonstrated excellent reproducible recorded NAP fidelity and the absence of NAP signal artifacts at all points of recording. Lastly, electrode pullout force testing determined maximum forces of 0.43 N, 1.57 N, and 3.61 N required to remove the device from 2 mm, 5 mm, and 1 cm nerve models, respectively, which are well within established thresholds for nerve safety. These results suggest that these new electrodes can safely and successfully perform accurate PNI assessment without the presence of artifacts, with the potential to improve the INCS standard of care while remaining compatible with currently used neurosurgical technology, infrastructure, and clinical workflows.

Preimplementation of Critical Care Early Mobility Clinical Decision Support: A Content Validation Study.

Early mobility is a form of critical care rehabilitation ranging from in-bed exercise to ambulation and is known to limit post-intensive-care functional decline. Multiple barriers prevent widespread early mobility implementation. Clinical decision support systems can optimize the decision-making process and overcome barriers to care. However, critical care early mobility clinical decision support does not exist. Our objective was to develop and establish the content validation of the operational definitions for a novel critical care early mobility assessment instrument. Content validation was conducted in two steps: (1) development of operational definitions by the research team and (2) content validation with 10 nurse experts. Quality assessment and suitability of the operational definitions for 30 items, across four safety domains, were assessed using a 7 point-Likert scale. Item content validity index scores ranged from 0.6 to 0.1 after the first validation round. Domains containing items with item content validity index scores less than the lower limit of 0.78 were modified for clarity of language. Item content validity index scores ranged from 0.8 to 1.0, and the scale-level content validity index was 0.93 after the second content validation round. Excellent content validity of the operational definitions was achieved. This is the first methodological step in a larger project to develop clinical decision support for critical care early mobility.

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

Background Choroideremia is an X-linked inherited retinal degeneration that begins in childhood with nyctalopia and loss of peripheral vision, and gradually progresses to blindness in adulthood. Choroideremia is caused by null mutations in the CHM gene, which encodes Rab escort protein 1. Objective Assessment of the efficacy and safety of a single subretinal injection of an adeno-associated virus serotype 2 vector encoding Rab escort protein 1 in patients with choroideremia. Design Multicentre open-label clinical trial of a gene therapy for choroideremia using an adeno-associated virus serotype 2-Rab escort protein 1 vector. Setting This study (NCT02407678) was conducted at two NHS eye hospitals in the UK. Participants Males aged 18 years or above, having a clinical diagnosis of choroideremia with genetic confirmation of CHM gene mutation or molecular confirmation of Rab escort protein 1 protein deficiency and having best corrected visual acuity better than or equal to 6/60 (20/200; LogMAR 1.0). Intervention Adeno-associated virus serotype 2-Rab escort protein 1 vector suspension (1 × 1012 vector particles per ml) was supplied by Nightstar Therapeutics (London, UK), now part of Biogen Inc. (Cambridge, MA, USA). Up to 0.1 ml of adeno-associated virus serotype 2-Rab escort protein 1 vector suspension, corresponding to a dose of up to 1 × 1011 vector particles, was administered to the treated eye by subretinal injection. Selection of treated eyes was randomised in participants having relatively symmetrical retinal degeneration. Main outcome measures The primary safety-related outcome was change from baseline in best corrected visual acuity in treated eyes at 24 months post treatment, with prospective efficacy evaluated by comparative change from baseline in best corrected visual acuity in treated and untreated contralateral (control) eyes. Secondary outcomes included comparative change from baseline in mean retinal sensitivity (microperimetry) and retinal anatomy (area of autofluorescence) in treated and control eyes. Visual assessments were conducted by masked assessors. Results The primary efficacy-related outcome (comparative change from baseline in best corrected visual acuity in treated and control eyes at 24 months post treatment) was not statistically different between treated eyes (−2.63 letters, standard error of the mean 2.76) and control eyes (+2.67 letters, standard error of the mean 0.768) in all 30 participants (p = 0.08). Greater loss of visual fields, possibly surgery-induced, was observed in treated eyes. Six serious adverse events were reported in the treated eyes of four participants: one surgery-related and two inflammation-related serious adverse events involving clinically significant decreases in best corrected visual acuity, and three serious adverse events in one participant involving reduction in central retinal sensitivity, but with best corrected visual acuity remaining stable. Limitations No evidence of possible efficacy of the intervention was observed, as a meaningful difference in comparative change from baseline in best corrected visual acuity in treated and control eyes was not discernible at 24 months post treatment. As choroideremia is a very slow degeneration, best corrected visual acuity in control eyes did not decline significantly during the assessment period. Conclusion Although this study has not presented evidence that reduction in visual fields caused by the intervention would be justified by the possible rescue of best corrected visual acuity, a more definitive assessment may be provided by long-term monitoring of trial participants in an observational study (NCT03584165). Trial registration This study is registered as ISRCTN15602229 (www.isrctn.com/) and NCT02407678 (https://clinicaltrials.gov/). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/66/35) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 9. See the NIHR Funding and Awards website for further award information.

A new approach for the assessment of coastal flooding risk. Application in Rhodes island, Greece

A directional, copula-based, Monte Carlo approach is proposed for the quantitative assessment of a new definition of coastal flooding risk, namely a probability-based index due to extreme combinations of wave conditions and sea levels, which could be a key element for coastal zone planning and management. This approach differs from the standard practice, which focuses on the extreme events and studies either their specific return values or their worst-case scenarios. The adopted approach incorporates mean wave direction as a covariate into the probabilistic representation of sea states, and via the use of a variety of probabilistic and statistical tools, represents a total of five stochastic variables, namely the significant wave height, the peak wave period, the mean wave direction, the storm surge, and tide. Two directional, alternative methods have been developed; a trivariate copula- and a bivariate copula-based method, that seemed to produce quite similar results. Four types of copulas have been examined for their goodness-of-fit, i.e., three Archimedean copulas, namely, the Clayton, the Gumbel, and the Frank copulas, as well as the elliptical Gaussian copula. A comparative analysis of the two methods is performed aiming to point out their pros, as well as their accuracy and complexity issues. The application of the proposed method to the natural beaches of the Rhodes Island in Greece, in combination with a recently developed formula for wave run-up, highlighted the most crucial parameters affecting the coastal flooding risk in the study area.

How has research on the effectiveness and safety of COVID-19 vaccination been evaluated: a scope review with emphasis on CoronaVac.

The control of the COVID-19 epidemic has been focused on the development of vaccines against SARS-CoV-2. All developed vaccines have reported safety and efficacy results in preventing infection and its consequences, although the quality of evidence varies depending on the vaccine considered. Different methodological designs have been used for their evaluation, which can influence our understanding of the effects of these interventions. CoronaVac is an inactivated vaccine, and it has been assessed in various studies, including clinical trials and observational studies. Given these differences, our objective was to explore the published information to answer the question: how has the efficacy/effectiveness and safety of CoronaVac been evaluated in different studies? This is to identify potential gaps and challenges to be addressed in understanding its effect. A scoping review was carried out following the methodology proposed by the Joanna Briggs Institute, which included studies carried out in humans as of 2020, corresponding to systematic reviews, clinical trials, analytical or descriptive observational studies, in which the effectiveness and/or safety of vaccines for COVID19 were evaluated or described. There were no age restrictions for the study participants. The efficacy/effectiveness and safety of this vaccine was assessed through 113 studies. Nineteen corresponded to experimental studies, 7 of Phase II, 5 of Phase IV, and 4 were clinical trials with random assignment. Although some clinical trials with random assignment have been carried out, these have limitations in terms of feasibility, follow-up times, and with this, the possibility of evaluating safety outcomes that occur with low frequencies. Not all studies have used homogeneous methods of analysis. Both the prevention of infection, and the prevention of outcomes such as hospitalization or death, have been valued through similar outcomes, but some through multivariate analysis of dependencies, and others through analysis that try to infer causally through different control methods of confounding. Published information on the evaluation of the efficacy/effectiveness and safety of the CoronaVac is abundant. However, there are differences in terms of vaccine application schedules, population definition, outcomes evaluated, follow-up times, and safety assessment, as well as non-standardization in the reporting of results, which may hinder the generalizability of the findings. It is important to generate meetings and consensus strategies for the methods and reporting of this type of studies, which will allow to reduce the heterogeneity in their presentation and a better understanding of the effect of these vaccines.