Clinical Relevance Research Articles

Imaging Recommendations for Diagnosis and Management of Primary Parathyroid Pathologies: A Comprehensive Review.

Parathyroid pathologies are suspected based on the biochemical alterations and clinical manifestations, and the predominant roles of imaging in primary hyperparathyroidism are localisation of tumour within parathyroid glands, surgical planning, and to look for any ectopic parathyroid tissue in the setting of recurrent disease. This article provides a comprehensive review of embryology and anatomical variations of parathyroid glands and their clinical relevance, surgical anatomy of parathyroid glands, differentiation between multiglandular parathyroid disease, solitary adenoma, atypical parathyroid tumour, and parathyroid carcinoma. The roles, advantages and limitations of ultrasound, four-dimensional computed tomography (4DCT), radiolabelled technetium-99 (99mTc) sestamibi or dual tracer 99mTc pertechnetate and 99mTc-sestamibi with or without single photon emission computed tomography (SPECT) or SPECT/CT, dynamic enhanced magnetic resonance imaging (4DMRI), and fluoro-choline positron emission tomography (18F-FCH PET) or [11C] Methionine (11C -MET) PET in the management of parathyroid lesions have been extensively discussed in this article. The role of fluorodeoxyglucose PET (FDG-PET) has also been elucidated in this article. Management guidelines for parathyroid carcinoma proposed by the American Society of Clinical Oncology (ASCO) have also been described. An algorithm for management of parathyroid lesions has been provided at the end to serve as a quick reference guide for radiologists, clinicians and surgeons.

The genomic and immunogenomic landscape of mechanics pathway informs clinical prognosis and response to mechanotherapy.

Mechanics shape cell and tissue plasticity and maintain their homeostasis. In cancers, mechanical signals regulate cancer hallmarks via mechanotransduction pathways, such as proliferation, metastasis and metabolic reprogramming. However, comprehensive characterization of mechanotransduction pathway genes and their clinical relevance across different cancer types remains untouched. Herein, we systematically portrayed the alterations of mechanotransduction pathway genes across 31 cancer types using The Cancer Genome Atlas (TCGA) databases. All the cancer types could be categorized into 6 subtypes based upon the transcriptional pattern of mechanics pathway genes. Each subtype has its own unique molecular expression pattern, mutation landscapes, immune infiltrates, and patient clinical outcome. We further found that the responses of two subtypes of cancers, one with the optimal outcome and the other with the worst prognosis, to a classical mechanotherapeutic agent (Fasudil, RhoA/ROCK inhibitor) were totally different, indicating that our cancer stratification system based upon mechanotransduction pathway genes could inform clinical responses of patients to mechanotherapeutic agents. Collectively, our study provides a novel pan-cancer landscape of the mechanotransduction pathways and underscores its potential clinical significance in the prediction of clinical prognosis and therapeutic responses to mechanotherapy among cancer patients.

Age- and sex-dependent cardiovascular impact of maternal perinatal stress and altered dopaminergic metabolism in the medulla oblongata of the offspring.

M Maternal Major Depressive Disorder with Peripartum Onset presents health risks to the mother and the developing fetus. Using a rat model of chronic mild stress, we previously reported on the neurodevelopmental impact of maternal perinatal stress on their offspring; the present study examined the cardiovascular impact of maternal perinatal stress on their offspring. The cardiovascular impact was assessed in terms of blood pressure and echocardiographic parameters. The results examined by a three-way ANOVA showed a significant association of cardiovascular parameters with maternal perinatal stress, and offspring sex and age. Increased blood pressure was observed in adolescent female and adult male offspring of stress-exposed dams. Echocardiography showed an increase in left atrial dimension and a reduction in left ventricular systolic function in adolescent stress-exposed female offspring. Increased interventricular septum thickness at end-diastole and left ventricular diastolic dysfunction were observed in adult stress-exposed male offspring. The underlying mechanisms of cardiovascular impact were examined in stress-exposed adult offspring by assessing the levels of neurotransmitters and their metabolites in the medulla oblongata using high-performance liquid chromatography. A significant decrease in homovanillic acid, a dopamine metabolite and indicator of dopaminergic activity, was observed in adult stress-exposed female offspring. These results suggest a significant sex- and age-dependent impact of maternal stress during the peripartum period on the cardiovascular system in the offspring that extends to adulthood and suggests a multigenerational effect. The presented data urgently need a follow-up to confirm its potential clinical and public health relevance.

Evaluation of the Bio-Speedy Meningitis/Encephalitis Panel in the Diagnosis of Central Nervous System Infections

Infections of the central nervous system (CNS) can lead to severe outcomes if not accurately diagnosed and treated. The broad spectrum of pathogens involved in CNS infections can make diagnosis challenging. Polymerase chain reaction (PCR) -based multiplex molecular diagnostic panels can rapidly and simultaneously detect multiple neuropathogens in cerebrospinal fluid (CSF). This study was aimed to assess the Bio-Speedy Meningitis/Encephalitis RT-PCR MX-17 panel (Bioeksen, İstanbul, Türkiye), a novel multiplex PCR test, in diagnosing CNS infections. The panel can detect a range of pathogens, including Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae, enterovirus (EV), herpes simplex virus (HSV) 1 and 2, HHV-6, HHV-7, HHV-8, human parechovirus (HPeV), varicella zoster virus (VZV), cytomegalovirus (CMV) and Cryptococcus gatti/neoformans in CSF samples. This retrospective study included 128 CSF samples from 128 patients sent to Bursa Uludağ University Health Application and Research Center Microbiology Laboratory between June 2022 and July 2023 to search for CNS infectious agents. Patient clinical, radiological and laboratory data were collected from the Hospital Information Record System (HIRS). Bacterial pathogens were identified through culture, while viral pathogens were detected in CSF samples using the Fast Track Diagnostics (FTD) multiplex RT-PCR panel (Fast Track Diagnostics Ltd., Luxembourg) for HSV-1, HSV-2, VZV, EV, mumps virus and HPeV. The stored CSF samples were then tested using the BioSpeedy panel and the results were compared with those of the culture and the FTD panel. Pathogens that were detected were considered positive if they were consistent with the patient's symptoms and CSF characteristics according to infectious disease and pediatric infectious disease specialists. Pathogens detected but not supported by the patient's symptoms and CSF characteristics were classified as uncertain clinical relevance (UCR). Out of the 128 patients tested for CNS infectious agents, 44 (34.4%) were diagnosed with a CNS infection. The overall pathogen detection rate with all methods was 43.2% (19/44). The Bio-Speedy panel identified pathogens in 29.5% (13/44) of the patients, followed by the FTD panel (20.5%, 9/44) and culture (9.1%, 4/44). Four bacteria were identified with culture, three of which were also detected by the Bio-Speedy panel. Additionally, six bacteria were identified with Bio-Speedy panel, that were not identified by culture. The FTD panel identified nine viruses, four of which were also identified by Bio-Speedy. In total, the Bio-Speedy panel detected 13 of the 19 positive pathogens (nine bacteria and four viruses: [S.pneumoniae (n= 3), VZV (n= 3), N.meningitidis (n= 2), H.influenzae (n= 2), L.monocytogenes (n= 1), E.coli (n= 1) ve EV (n= 1)]. However, the Bio-Speedy panel identified 15 pathogens [S.pneumoniae (n= 1), E.coli (n= 1), C.gatti/neoformans (n= 1), CMV (n= 8), HHV-6 (n= 3) ve HHV-7 (n= 1)] considered as UCR. The Bio-Speedy identified the causative pathogens in the highest percentage (29.5%) of patients with confirmed CNS infections. Nevertheless, test results should be interpreted based on patient characteristics to ensure appropriate patient management. Using multiple methods and multiplex tests may improve diagnostic accuracy for CNS infections.

Heterogeneity in the Definitions of Proximal Junctional Kyphosis and Failure in Spinal Deformity Literature: A Tower of Babel.

Systematic review. To describe the various definitions of PJK and PJF used in spinal deformity literature and their utility over time. Proximal junctional kyphosis or failure (PJK/PJF) is among the most common complication after long-segment fusions, but there is no consensus on their definitions. This presents challenges in understanding risk factors, management, and prevention strategies. A systematic literature review was performed on studies specifying a definition of PJK and/or PJF. PJK definitions were categorized as radiographic vs non-radiographic and data was collected on PJK criteria including threshold for proximal junctional angle (PJA), change in PJA, vertebra selection for PJA measurement, and follow-up timepoints. PJF definitions were categorized as structural failure, need for revision, symptomatic failure, and radiographic (angular). 359 studies defining PJK and/or PJF were identified. While 56% of studies used the definition PJA>10° and PJA change from baseline>10°, the remainder expressed significant heterogeneity with respect to criteria for magnitude of PJA and degree of PJA change. The most common vertebrae assessed were UIV/UIV+2 (74%) and most common minimum follow-up (mFU) listed was 2 years (60%). Mean FUs for studies varied considerably even in studies with the same mFU, from 2.1-8.9 years (2-year mFU) and 1.1-4.0 years (1-year mFU). PJF definitions were most commonly structural (58%) or defined as a need for revision (48%), with a much less common use of PJA thresholds (23%). The challenges faced in preventing proximal junctional complications are mired in the heterogenous groundwork by which PJK and PJF are defined. Most definitions of PJK use radiographic thresholds without consideration of clinical relevance and variations in individual alignment. Conversely, definitions of PJF are based on clinical criteria, which are often subjective. Future research should focus on understanding the mechanisms of PJK/PJF, as only then will we be able to accurately define and prevent these complications.

Association of CD8+TILs co-expressing granzyme A and interferon-γ with colon cancer cells in the tumor microenvironment

CD8+T cells secreting granzyme A (GZMA) can induce pyroptosis in tumor cells by effectively cleaving gasdermin B (GSDMB), which is stimulated by interferon-γ (IFN-γ). However, the interaction between GZMA-expressing CD8+T cells and GSDMB-expressing tumor cells in colon cancer remains poorly understood. Our research employed multi-color immunohistochemistry (mIHC) staining and integrated clinical data to explore the spatial distribution and clinical relevance of GZMA- and IFN-γ-expressing CD8+ tumor-infiltrating lymphocytes (TILs), as well as GSDMB-expressing CK+ cells, within the tumor microenvironment (TME) of human colon cancer samples. Additionally, we utilizing single-cell RNA sequencing (scRNA-seq) data to examine the functional dynamics and interactions among these cell populations. scRNA-seq analysis of colorectal cancer (CRC) tissues revealed that CD8+TILs co-expressed GZMA and IFN-γ, but not other cell types. Our mIHC staining results indicated that a significant reduction in the infiltration of GZMA+IFN-γ+CD8+TILs in colon cancer patients (P < 0.01). Functional analysis results indicated that GZMA+IFN-γ+CD8+TILs demonstrated enhanced activation and effector functions compared to other CD8+TIL subsets. Furthermore, GSDMB-expressing CK+ cells exhibited augmented immunogenicity. Correlation analysis highlighted a positive association between GSDMB+CK+ cells and GZMA+IFN-γ+CD8+TILs (r = 0.221, P = 0.033). Analysis of cell-cell interactions further showed that these interactions were mediated by IFN-γ and transforming growth factor-β (TGF-β), the co-stimulatory molecule ICOS, and immune checkpoint molecules TIGIT and TIM-3. These findings suggested that GZMA+IFN-γ+CD8+TILs modulating GSDMB-expressing tumor cells, significantly impacted the immune microenvironment and patients’ prognosis in colon cancer. By elucidating these mechanisms, our present study aims to provide novel insights for the advancement of immunotherapeutic strategies in colon cancer.

Values of peripapillary retinal nerve fibre layer thickness are different in children and adults

ABSTRACT Clinical relevance The detection of abnormal values of peripapillary nerve fibre layer (pRNFL) thickness measured with optical coherence tomography (OCT) is important for detecting optic nerve disease in children. Background To evaluate the level of agreement between the adult reference database supplied with an OCT device and the present paediatric study database for the measurement of pRNFL thickness in children. This study also aimed to provide reference values for pRNFL thickness according to the spherical equivalent in the paediatric population. Methods This was a cross-sectional study. One hundred and twenty-six healthy children were included, who had undergone a full ophthalmological examination including cycloplegic refraction and examination of pRNFL thickness using the Topcon 3D OCT 2000 device (Topcon Corporation, Tokyo, Japan). Values equal to or below the fifth percentile (≤p5) and above the 95th percentile (>p95) were considered abnormal. Observed agreement and specific agreement were investigated between OCT measurements classified with paediatric and adult reference values for normality. Results Values ≤ p5 in the adult database were recorded for 2 of the 30 values (6.6%) of the pRNFL values by quadrants ≤p5 in the paediatric database and 17 of the 88 (19.3%) values by sectors ≤p5. For values >p95 in the adult database, 88% by quadrants and 72% by sectors would have been classified as being within the normal range using the paediatric database. Conclusion The use of adult reference values currently available in OCT devices can lead to classification errors concerning the normal range of pRNFL thickness in a large proportion of paediatric patients. The use of normative paediatric databases, such as the one discussed in this study, should be taken into consideration.

CFD simulation of arterial hypotension in a left anterior coronary artery section with potential clinical relevance

ABSTRACT Atherosclerosis is a complex cardiovascular condition characterised by the buildup of fatty deposits, known as plaques, on the inner walls of arteries. Stenosis occurs when the narrowing of an artery becomes particularly pronounced due to the accumulation of plaque. This narrowed lumen leads to significant pressure drops during blood flow, which may lead to decreased blood flow to the target tissues. The current study focuses on conducting computational fluid dynamic (CFD) simulations of blood flow within a linear segment of the LAD (Left anterior descending) coronary artery, subject to differing degrees of atherosclerotic stenosis. The simulations are performed using COMSOL Multiphysics 5.6®. The study has computed pressure drops by considering the laminar flow of blood as a two-phase non-Newtonian fluid. The rheological characteristics have been modelled using the Carreau Yasuda model. It considers varying stenosis severities ranging from 10% to 90%, coupled with blood velocities spanning from 0.07 m/s to 0.2 m/s. Additionally, the findings have been compared to results generated using the Power Law model and Casson-Papanastasiou model for blood rheology. The pressure drop within the stenosed section has been correlated with stenosis percentages through power law models.

A multi-task generative model for simultaneous post-contrast MR image synthesis and brainstem glioma segmentation

ObjectivesThis study aims to generate post-contrast MR images reducing the exposure of gadolinium-based contrast agents (GBCAs) for brainstem glioma (BSG) detection, simultaneously delineating the BSG lesion, and providing high-resolution contrast information. MethodsA retrospective cohort of 30 patients diagnosed with brainstem glioma was included. Multi-contrast images, including pre-contrast T1 weighted (pre-T1w), T2 weighted (T2w), arterial spin labeling (ASL) and post-contrast T1w images, were collected. A multi-task generative model was developed to synthesize post-contrast T1w images and simultaneously segment BSG masks from the multi-contrast inputs. Performance evaluation was conducted using peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean absolute error (MAE) metrics. A perceptual study was also undertaken to assess diagnostic quality. ResultsThe proposed model achieved SSIM of 0.86 ± 0.04, PSNR of 26.33 ± 0.05 and MAE of 57.20 ± 20.50 for post-contrast T1w image synthesis. Automated delineation of the BSG lesions achieved Dice similarity coefficient (DSC) score of 0.88 ± 0.27. ConclusionsThe proposed model can synthesize high-quality post-contrast T1w images and accurately segment the BSG region, yielding satisfactory DSC scores. Clinical relevance statementThe synthesized post-contrast MR image presented in this study has the potential to reduce the usage of gadolinium-based contrast agents, which may pose risks to patients. Moreover, the automated segmentation method proposed in this paper aids radiologists in accurately identifying the brainstem glioma lesion, facilitating the diagnostic process.

A microdiscectomy surgical video annotation framework for supervised machine learning applications.

Lumbar discectomy is among the most common spine procedures in the US, with 300,000 procedures performed each year. Like other surgical procedures, this procedure is not excluded from potential complications. This paper presents a video annotation methodology for microdiscectomy including the development of a surgical workflow. In future work, this methodology could be combined with computer vision and machine learning models to predict potential adverse events. These systems would monitor the intraoperative activities and possibly anticipate the outcomes. A necessary step in supervised machine learning methods is video annotation, which involves labeling objects frame-by-frame to make them recognizable for machine learning applications. Microdiscectomy video recordings of spine surgeries were collected from a multi-center research collaborative. These videos were anonymized and stored in a cloud-based platform. Videos were uploaded to an online annotation platform. An annotation framework was developed based on literature review and surgical observations to ensure proper understanding of the instruments, anatomy, and steps. An annotated video of microdiscectomy was produced by a single surgeon. Multiple iterations allowed for the creation of an annotated video complete with labeled surgical tools, anatomy, and phases. In addition, a workflow was developed for the training of novice annotators, which provides information about the annotation software to assist in the production of standardized annotations. A standardized workflow for managing surgical video data is essential for surgical video annotation and machine learning applications. We developed a standard workflow for annotating surgical videos for microdiscectomy that may facilitate the quantitative analysis of videos using supervised machine learning applications. Future work will demonstrate the clinical relevance and impact of this workflow by developing process modeling and outcome predictors.

Professional perspective of vision therapy worldwide among optometrists and ophthalmologists

ABSTRACT Clinical relevance Perception of optometrists and ophthalmologists of vision therapy (VT) as well as their methods for performing the sessions is of great importance for understanding the problems that professionals face and what should be improved in their clinical practice. Background The objective of this study was to determine the perception of VT and protocols used by eye care professionals globally. Methods A cross-sectional study was performed among eye care professionals internationally. The participants completed via online (Google Forms) a questionnaire of 40 questions on their perception and clinical practice of VT. The survey only permitted one answer per email address and was only collected if professionals gave their consent to participate. Results A total of 205 professionals from 43 countries answered the questionnaire (171 optometrists and 34 ophthalmologists). Accommodation and convergence problems were the main indication reported for VT (47.8%), followed by amblyopia (26.3%). The principal negative factor associated to VT was the limited number of professionals dedicated to this field (55.6%). The most common program of VT was the combination of VT sessions at home and at office (85.5%), with a great variability in terms of duration. Few professionals made use of the new technologies when programming VT, such as eye trackers (2.7%) or virtual reality (6.4%). European professionals surveyed had a more negative perception of VT (p < 0.031). Conclusions Eye care professionals globally perceive VT as a scientifically based procedure. Overall, they believe that it has low recognition and prestige, especially ophthalmologists. A great variability in the programming of VT sessions was found, which highlights the need for standardised protocols that professionals could follow in their clinical practice.

Response of the human choroid to short-term changes in eyelid and periocular temperature

ABSTRACT Clinical relevance Choroidal thickness measurement is gaining popularity in clinical practice and research as an early indicator of myopia progression. Understanding the influence of temperature on choroidal thickness changes will improve the reliability of the measures. Background It has been suggested that environmental temperature may affect choroidal thickness and blood flow, with potential implications for ocular disease and refractive development. This study investigates the effect of changes in eyelid/ocular adnexa temperature on choroidal thickness. Methods In a paired-eye study, 20 young, healthy subjects received a warm stimulus (heat pack) over one closed eye and simultaneously a cold stimulus (ice pack) over the other for 10 min. Eyelid temperatures were monitored with thermal probes, and optical coherence tomography scans of the retina and choroid were taken before and after heating and cooling, and then every 5 min during a 15-min recovery period. Retinal and choroidal thicknesses were measured across the macular region (6 mm), including the subfoveal (1 mm), parafoveal (1–3 mm), and perifoveal (3–5 mm) regions, and compared between the cooled and warmed eyes. Results When the thermal stimuli were applied, eyelid surface temperatures changed predictably and remained significantly different (by approximately 10–15°C) between the eyes after 2 min (p < .001). Relative to the warmed eye, macular choroidal thickness in the cooled eye increased significantly after 10 min of treatment (p = .004). This choroidal thickening response occurred in the subfoveal, parafoveal, and perifoveal regions (all p < .05). Upon removal of the thermal stimuli, choroidal thickness rapidly returned to the baseline and was no longer different between the cooled and warmed eye (p = .641). Conclusion Cooling the anterior eye by application of a cold stimulus directly onto the closed eyelid caused a small but significant increase in choroidal thickness relative to warming the anterior eye, demonstrating that the choroid can modulate its thickness rapidly and transiently in response to local temperature changes.

Assessment of cardiovascular risk and physical activity: the role of cardiac-specific biomarkers in the general population and athletes.

The first part of this Inter-Society Document describes the mechanisms involved in the development of cardiovascular diseases, particularly arterial hypertension, in adults and the elderly. It will also examine how consistent physical exercise during adolescence and adulthood can help maintain blood pressure levels and prevent progression to symptomatic heart failure. The discussion will include experimental and clinical evidence on the use of specific exercise programs for preventing and controlling cardiovascular diseases in adults and the elderly. In the second part, the clinical relevance of cardiac-specific biomarkers in assessing cardiovascular risk in the general adult population will be examined, with a focus on individuals engaged in sports activities. This section will review recent studies that suggest a significant role of biomarkers in assessing cardiovascular risk, particularly the presence of cardiac damage, in athletes who participate in high-intensity sports. Finally, the document will discuss the potential of using cardiac-specific biomarkers to monitor the effectiveness of personalized physical activity programs (Adapted Physical Activity, APA). These programs are prescribed for specific situations, such as chronic diseases or physical disabilities, including cardiovascular diseases. The purposes of this Inter-Society Document are the following: 1) to discuss the close pathophysiological relationship between physical activity levels (ranging from sedentary behavior to competitive sports), age categories (from adolescence to elderly age), and the development of cardiovascular diseases; 2) to review in detail the experimental and clinical evidences supporting the role of cardiac biomarkers in identifying athletes and individuals of general population at higher cardiovascular risk; 3) to stimulate scientific societies and organizations to develop specific multicenter studies that may take into account the role of cardiac biomarkers in subjects who follow specific exercise programs in order to monitor their cardiovascular risk.

Anticancer activity of new water-soluble sulfonated thiosemicarbazone copper(II) complexes targeting disulfide isomerase

Copper complexes have shown promising anticancer properties, but they are often poorly soluble in aqueous solutions, thus limiting their possible medical developments and applications. We have recently isolated some copper(II) complexes with salicylaldehyde thiosemicarbazone ligands exhibiting remarkable nanomolar cytotoxic activity, but in vivo tests evidenced several difficulties related to their poor solubility. To overcome these limitations and increase solubility in aqueous solution, herein we report the synthetic strategy that led to the introduction of the sulfonic group on the ligands, then separated as salts (NaH2L1 - NaH2L5), as well as the synthesis and characterization of the related copper(II) complexes. The characterization of the complexes is completed by the analysis of the structures obtained by X-rays diffraction on single crystals on the species [Cu(HL5)(H2O)]2.2H2O, [Cu(HL2)(H2O)2].2H2O, and [Cu(HL1)(H2O]2.2H2O. While the uncoordinated ligands do not affect cancer cell viability, copper(II) complexes exhibit low to sub-micromolar cytotoxic activity, which is maintained in 3D (HCT-15 and 2008) spheroidal models of cancer cell. Notably, copper(II) complexes were selective towards cancer cells, showing high selectivity indexes. Investigations focused on elucidating the mechanism of action evidenced the protein disulfide-isomerase as an innovative molecular target for this class of water-soluble copper(II) complexes. Finally, preliminary in vivo experiments performed with the most representative derivative in the murine Lewis Lung Carcinoma, highlight its significant antitumor efficacy and better tolerability profile with respect to the reference metallodrug, suggesting for this sulfonated Cu(II) complex a potential clinical relevance.

Effectiveness of Custom-Made Designed and 3D-Printed Wrist-Driven Orthoses on Grasp Strength of Lost Hand Function

ABSTRACT Introduction Wrist-driven orthoses can be used in people who have lost their hand functions to a certain extent. The orthoses are designed to harness residual wrist power and convert it with a mechanism to move the fingers. We developed 3D-printed wrist-driven orthoses for spastic hands and improved three-point grasp between thumb and index-middle fingers’ function. Methods Three orthoses were designed and manufactured for two participants with and without extension assists according to children’s needs. This study presents 3D designing and printing of three orthoses and investigates the effectiveness on the pinch force and daily living activities for participants with loss of hand function. Results Custom-made 3D-printed wrist-driven orthoses that provide hand function and are functional, lightweight, and aesthetically pleasing were manufactured in a shorter duration than conventional orthoses. Discussion This technique is acceptable and improves function of spastic and different traumatically injured hands. A wrist-driven orthosis was used in the treatment of 2 patients. It was found that the pinch force and the performance in daily living activities had increased. Complete joint alignment was guaranteed, and the orthoses were aesthetically pleasing and light. Clinical Relevance This study is clinically relevant since it gives a suitable, easy to produce, modifiable, economic orthosis design while continuing to provide comfortable, durable, and lightweight design.

Abnormal thyroid markers in critically ill patients-harmless irritation or areal problem?

Abnormal thyroid markers are a frequent occurrence in emergency and intensive care medicine. Correct interpretation of their clinical relevance and distinction from a primary thyroid disease, particularly prior to potential administration of iodine-containing antiarrhythmic drugs such as amiodaron or radiocontrast agents, are both essential and challenging. This article aims to present the pathophysiology of abnormal thyroid markers in acute or protracted critical disease. Their relevance for administration of amiodaron or iodine-containing radiocontrast agents is discussed, and concrete practical recommendations are presented. The current work comprises a discussion of expert recommendations, guidelines, and basic research. Approximately one third of intensive care patients develop non-thyroidal illness syndrome (NTIS) during the course of their critical disease. NTIS is characterized by a reduction in the serum concentration of fT3 and, during the course, also in those of thyroid-stimulating hormone (TSH) and fT4, despite an organically intact thyroid gland. A greater extent of the deviations correlates with a worse overall prognosis. The mechanisms involved are manifold and influence different levels of hormonal signaling axes. They are mediated by interaction with acute stress signals such as inflammatory factors and elevated cortisol levels and are influenced by medication. The components vary depending on disease severity and the protracted course. NTIS does not require any specific treatment; the focus is on treating the underlying disease. Latent hyperthyroidism in particular must be distinguished from NTIS. In unclear situations and high-risk constellations, perchlorate is indicated before (and after) iodine exposure.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes

BackgroundSepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches.MethodsWe performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme.ResultsAmong 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes.ConclusionsOur research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.Graphical abstract

Effects of antiseptic irrigation solutions on osseointegration in a cementless tibial implantation mouse model.

Despite the success of standard antiseptic irrigation solutions in reducing periprosthetic joint infection (PJI) rates, there is still a need for more effective solutions. Synergistic use of povidone-iodine (PI) and hydrogen peroxide (H2O2) has shown promising results; however, the optimal solution concentration balancing bactericidal activity and osseointegration remains unknown. This study aims to evaluate the impact of these antiseptic irrigation solutions on osseointegration and the bone-implant interface strength in vivo. Forty C57BL/6 mice underwent bilateral tibial implantation surgery and were randomly allocated into three groups receiving 0.3% PI, 10% PI mixed with 3% H2O2, or saline as irrigation solutions intraoperatively. Assessments were performed on postoperative Days 1 and 28, including plain radiographs, microcomputed tomography (microCT) evaluation, histological analysis, immunohistochemistry, and biomechanical pull-out testing. No wound complications were observed. MicroCT scans revealed no differences in peri-implant trabecular bone parameters. Biomechanical pull-out testing showed no differences in the bone-implant interface strength across groups. Histological analysis indicated no differences in bone and bone marrow percentage areas among treatment groups. Immunohistochemical analysis demonstrated no differences among groups in peri-implant osteocalcin, osterix, or endomucin-positive cells. In conclusion, using either antiseptic irrigation solution showed no differences in osseointegration parameters compared to the control group, demonstrating safety and the absence of toxicity. CLINICAL RELEVANCE: Dilute 0.3% povidone-iodine and a 1:1 combination of 10% povidone-iodine mixed with 3% hydrogen peroxide can be safely used during primary and revision total joint arthroplasty without compromising osseointegration or causing wound complications.

An externally validated resting-state brain connectivity signature of pain-related learning

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.