Normal Profile Research Articles

Normal tissue transcriptional signatures for tumor-type-agnostic phenotype prediction

Cancer transcriptional patterns reflect both unique features and shared hallmarks across diverse cancer types, but whether differences in these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that these shared transcriptomic signatures reflect repurposed versions of functional tasks performed by normal tissues. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies. We show that differential enrichment of these signatures correlates with key tumor characteristics, including overall patient survival and drug sensitivity, independent of clinically actionable DNA alterations. Additionally, we show that in HR+/HER2- breast cancers, metastatic tumors adopt transcriptomic signatures consistent with the invaded tissue. Broadly, our findings suggest that cancer often arrogates normal tissue transcriptomic characteristics as a component of both malignant progression and drug response. This quantitative framework provides a strategy for connecting the diversity of cancer phenotypes and could potentially help manage individual patients.

A rare genetic association of one silent (ADGRV1) and other unquiet (MED13L) mutation: A case report

Two genes likely to cause epilepsy, one silent and the other manifesting in a patient with drug-resistant epilepsy, can be quite unusual. Herein, we described the case of a 2-year-old girl who presented with predominant language development delay, facial dysmorphism, and refractory epilepsy with normal neuroimaging and metabolic profiles, which prompted us to consider genetic etiology. Her genetic test revealed two novel likely pathogenic mutations, in Mediator complex subunit 13-like (MED13L) and adhesion G protein-coupled receptor V1 (ADGRV1). Sanger sequencing of her parents revealed an ADGRV1 variant in her unaffected mother. The child had a phenotypic match with the MED13L genotype. However, only a few cases of MED13L have reported refractory epilepsy and the corresponding mutation was missense. To the best of our knowledge, this is the first case of frameshift mutation in MED13L presenting with refractory epilepsy. Although the child harbored two likely pathogenic mutations, the one inherited from her mother in ADGRV1 did not manifest, whereas the frameshift mutation in MED13L had expressed as refractory epilepsy, which has not been described hitherto.

Assessment of gamified mixed reality environments for upper limb robotic rehabilitation: pilot study on healthy adults

Exoskeletons for rehabilitation have the potential to aid movement and promote intensive, task-oriented, and personalized motor training. However, robotic-assisted training and user experience could be further improve by including Mixed Reality Environments (MREs) and using a gamification approach. This paper presents the design and evaluation of a MR solution based on Microsoft Hololens 2 for robot-assisted bilateral shoulder training. It is based on gamified MREs designed to guide and encourage bilateral synchronous and asynchronous movements of the upper extremities while a 6 Degrees of Freedom (DOF) exoskeleton (FLOAT) provides motor assistance only to the impared limb. The robotic-assisted bimanual tasks involve the use of rehabilitative tools (such as a dowel rod), as a means to interact with the virtual world and to enable the intact limb guide and control the motions of the disable limb. The gamified MR training solution generates meaningful performance metrics from the kinematic analysis of hands movement, captured by Hololens. The subjective evaluation of the gamified MR solution focused on usability, cognitive load, and user experience. Meanwhile, the objective evaluation encompassed the analysis of the robot-assisted movements with and without gamified MREs, a comparative analysis between metrics obtained from Hololens and Vicon data, and the collection of reference data and trajectories. There were twenty-one healthy adults involved in the evaluation of the system. The results with the gamified MREs highlight excellent system usability, low cognitive load, and high user experience. Additionally, integrating gamified MREs into robot-assisted movements enhances shoulder movements. Data collection with Hololens demonstrated to be reliable and consistent. Furthermore, the normal reference values, paths, and velocity profiles obtained from healthy individuals offer a foundation for assessing the performance of individuals with disabilities. In summary, the introduction of gamified MREs for robot-assisted bilateral shoulder movements marks a significant and promising advancement in rehabilitation technology.

Signal-morphology impedance cardiography is a non-invasive tool to predict responses to exercise based cardiac rehabilitation in chronic heart failure patients

Abstract Background All the studies and meta-analyses showed beneficial effects of the exercise based cardiac rehabilitation (ExBCR) on peak value of oxygen uptake (VO2peak) in patient with chronic heart failure (CHF). It is widely recognized that changes in VO2peak induced by training (ΔVO2peak) have a prognostic value. A 5.0% increase in ΔVO2peak has been associated with a significant clinical improvement1. However, 20 to 30 % of CHF are non-responders to ExBCR. The Signal-Morphology Impedance Cardiography (SM-ICGTM) technology has allowed previous researchers to show the role of cardiac output (CO) on DVO2peak2. CO responses may be partly attributed to the peak ejection flow velocity that can explain the impaired response to ExBCR. Purpose The study aimed to establish whether SM-ICGTM is an appropriate technology to predict responses to ExBCR in CHF patients. Methods A retrospective study was conducted on 65 CHF patients (LVEF: 29.0±8.3%). All patients performed a cardiopulmonary exercise test (CPET) on bicycle to determine ventilation (VE) and VO2peak before and after 20 ExBCR sessions. In addition, stroke volume (SV), heart rate (HR), and CO were continuously monitored by SM-ICGTM (PhysioFlow® Lab1). The value of peak ejection flow velocity, so called CTi by the manufacturer, was calculated as the peak of the first mathematical derivative over the time of the impedance waveform during the systole and measured by PhysioFlow® throughout the test. For the analysis of training response patients were divided in two groups: the normal CTi profile which was characterized by an initial increase followed by a plateau until CPET exhaustion, and the abnormal CTi response if CTi decreased at the onset of CPET or increased then decreased before exhaustion. Statistical analyses were performed with JASP. The significant level was set at p value < 0.05 for 95% confidence interval. Results Our study population consisted in 32 patients who presented a normal CTi profile and 33 with an abnormal CTi profile. As shown in Table 1, no significant difference was found at baseline between both groups. ExBCR induced significant changes in VO2peak even if 29 % patients were non-responders. Patients with normal CTi profile presented a greater DVO2peak compared to patients with abnormal CTi profile (28 ± 30 vs. 14 ± 19 %, p<0.01). 78% of patients with normal CTi profile versus only 64% of patients with abnormal CTi profile were ExBCR responders. The logistic regression showed that patient with normal CTi profile were 3.3 time more likely to present a ΔVO2peak ≥ 5%. Conclusion Exercise CTi profiles determined by SM-ICGTM prove to be an interesting tool to help predicting ExBCR responses in CHF patients and maybe highlighting the hemodynamic determinants of VO2 responses to exercise training.

Metabolically healthy obesity and cardiovascular outcomes

Abstract Obesity increases cardiovascular risk through a deterioration of the metabolic profile. However, obesity is not always accompanied by a worsening metabolic profile. This longitudinal study aimed to determine whether obesity with a normal metabolic profile, i.e. metabolically healthy obesity, increases the risk of cardiovascular disease. We analyzed a health insurance data of Shizuoka prefecture resident. This data includes data from annual health check-ups performed for insured persons. This study analyzed data from 168,699 individuals aged <65 years. Obesity was defined as ≥ 25 kg/m2 body mass index. Metabolically healthy was defined as ≤ 1 metabolic risk factors (high blood pressure, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, or high hemoglobin A1c). Incidence rate of cardiovascular diseases (stroke and myocardial infarction), and all-cause mortality identified from the insurance data were compared between clinical profile-matched metabolically healthy obesity and non-obesity groups (n = 8,644 each). Clinical parameters, namely systolic blood pressure (standard mean difference = 0.03), HDL cholesterol (0.01), LDL cholesterol (0.01), and hemoglobin A1c (0.01) did not differ among the metabolically healthy obesity and non-obesity groups. The incident rate of stroke (obesity: 9.2 per 10,000 person-years; non-obesity: 10.5; log-rank test P = 0.595), myocardial infarction (obesity: 3.7; non-obesity: 3.1; P = 0.613), and all-cause mortality (obesity: 26.6; nonobesity: 23.2; P = 0.304) also did not differ significantly among the groups even when abdominal obesity was considered in the analysis, though the population with metabolically healthy obesity reported negligibly worse metabolic profiles than the population with nonobese at the 5.6-year follow-up. Obesity, when accompanied by a healthy metabolic profile, did not increase the risk of cardiovascular outcomes and all-cause mortality. Key messages • Metabolically healthy obesity did not increase cardiovascular disease risks. • Metabolically healthy obesity was associated with worse metabolic profiles after a few years later.

Influence of manufacturing errors on the aerodynamic working stability of axial flow compressors

In turbomachinery, manufacturing errors in blades have been found to impact aerodynamic performance. This paper aims to investigate the effect of manufacturing errors on the stability of compressor operation. To this end, a geometric uncertainty reduced-order model is developed to generate the normal profile error of rotor blades based on specific tolerances, considering the simultaneous variation of blade parameters during manufacturing. The stability margin improvement of the compressor is then calculated using computational fluid dynamics (CFD), and a neural network is employed to predict the relationship between the uncertainty input variables and the stability margin improvement. Finally, a large number of samples are generated using the Quasi-Monte Carlo method, and Sobol sensitivity analysis is performed. According to the results, manufacturing errors can reduce the stability margin by an average of 0.9% and up to 3% in the limiting case. The parameters that have the greatest impact on the stability of the compressor are the blade chord length of the hub section and the maximum thickness of the tip section. These two parameters affect blade tip blockage by influencing spanwise secondary flow on the suction surface. Additionally, the decrease in maximum thickness at the tip section affects the separation of the boundary layers on the suction surface, resulting in additional effects.

Metabolic disorders in patients with chronic thromboembolic pulmonary hypertension

To analyze the relationship between metabolic disorders and obesity with hemodynamic parameters and the severity of the condition of patients with chronic thromboembolic pulmonary hypertension (CTEPH) based on the POLET register. The study included patients with CTEPH from the POLET register. Data from medical history, lipid profile, glycemia, uric acid level, weight, height, functional class (FC), distance in the 6-minute walk test (6MWT), echocardiography, and right heart catheterization were used for analysis. The study included 84 patients 60±14 years old, including 45 men. The majority of patients had FC III - 51 (65%), which corresponded to 6MWT - 338±113 m. Nineteen (23%) people had experience in taking PAH specific therapy, 37 (46%) had cardiovascular comorbidity. In the general group, the body mass index (BMI) was 25.7±4.5 kg/m2, and normal glycemia, lipid profile, and uric acid levels were also determined. mPAP was 51±12 mmHg, RA area was 25.5 (20; 30) cm2. Correlations were identified between: RA area and the level of total cholesterol (r=0.60; p<0.01), triglycerides (r=-0.24; p<0.001), LDL cholesterol (r=0.75; p=0.04), uric acid (r=0.75; p=0.03); total cholesterol and 6MWT (r=0.44; p=0.04). Analysis of metabolic disorders, FC and comorbidity revealed differences between FC III and IV groups in the level of HDL cholesterol (p=0.02) and triglycerides (p<0.01). The POLET registry includes mainly older patients. Severe FC (87% - III and IV) may be a result of the older age and the presence of concomitant pathology in almost half of the patients. The discovered relationships between the area of RA and FC with lipid and purine metabolism were discovered for the first time, however, they correspond to the direction of the world scientific researches, are important due to the use of these indicators in the scale for calculating the risk of death in patients with PAH and require further development.

Significance of mixed convection and heat transfer flow past a vertical Riga plate in the presence of alumina nanoparticles: Analysis of streamlines for oblique stagnation point

AbstractThe aim of the current study to inspect the magnetic flow properties and heat transport features near an oblique stagnation point of a nanofluid with mixed convection through a vertical Riga plate are examined. The Riga plate is a familiar actuator made out of permanently fixed electrodes and magnets that moved away from the plate due to an exponential decline in the Lorentz force. Nanofluid is taken into consideration due to its peculiar properties, such as remarkable thermal conductivity is the significance of the study. These properties are important in heat exchangers, electronics, advanced nanotechnology, and material sciences. Using usual similarity transformations, the group of leading partial differential equations is distorted into a group of nonlinear ordinary differential equations. Then, a very proficient procedure namely bvp4c is utilized to discover the solution. For particular values of the different influential fluid parameters, the characteristics of the dimensionless temperature and velocity along with drag force and heat transfer are investigated graphically. In addition, the symmetrical results were initiated for both cases of the slip and without slip parameters. It is demonstrated that for greater influence of the volume fraction of nanoparticles, the normal and tangential velocity profile drops down for the instances of aiding and opposing flows due to fluctuations in the presence of slip factor, and absence of slip factor. In contrast, the temperature profile intensifies in both the cases of slip parameters and without the slip parameter owing to the phenomenon of assisting flow and opposing flow subject to superior impressions of the nanoparticle volume fractions. It is also observed that depending on the equilibrium between buoyancy effects, obliqueness, velocity slip parameters, and straining motion, the location of the point of zero shear stress (friction factor on the surface of the wall) is displaced to the right or the left of the origin.

Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature

Recurrent rhabdomyolysis, marked by skeletal muscle breakdown, can stem from various causes, including genetic disorders. We detail a patient of a 22-year-old male with carnitine palmitoyltransferase II (CPT-2) deficiency manifesting recurrent rhabdomyolysis despite normal acylcarnitine profiles. Whole-genome sequencing identified two CPT2 gene variants: c.338C > T and c.482G > A, confirming the diagnosis. We conducted a case report and a comprehensive literature review encompassing 262 articles related to CPT-2 deficiency available on PubMed. The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms. The study highlighted the variability and complexity of CPT-2 deficiency phenotypes, emphasizing correlations between variants and phenotypes as well as gender distribution. Although the CPT-2 deficiency genotype does not entirely predict phenotype severity, it remains informative for most patients, assisting in assessing the severity linked to each genetic variant. The results of our study offer crucial insights into evaluating the severity associated with individual genetic variants. Notably, our patient displayed normal acylcarnitine profiles between illness episodes, indicating possible profile abnormalities only during active disease states.We propose the collection of additional blood samples for acylcarnitine analysis during episodes of rhabdomyolysis without delay in all patients presenting with rhabdomyolysis of unknown cause as a crucial diagnostic strategy. This approach may unveil unexpected underlying diseases, enabling early and accurate diagnoses.

6448 Metabolic Profile and Adipose Tissue Distribution of Young Individuals with Turner Syndrome

Abstract Disclosure: V.M. Thomas: None. P.F. Backeljauw: Consulting Fee; Self; Novo Nordisk, Ascendis, Biomarin, Cavalry Biosciences, Upsher-Smith Laboratories, Tolmar. Speaker; Self; BioMarin, Ascendis.. A. Shah: None. I. Gutmark-Little: Research Investigator; Self; Novo Nordisk, Ascendis, OPKO. Introduction: Turner syndrome (TS) is the most common sex chromosome abnormality in females. Incidence of type 2 diabetes mellitus, hypertension, and dyslipidemia is high in TS. Current practice is to employ BMI as a proxy for adiposity. However, BMI is not an optimal tool due to the short stature observed in TS. Alternate methods such as the dual-energy x-ray absorptiometry (DXA) scan and bioelectrical impedance (BI) may provide more information about body composition. Objectives: The objective of this study is to assess alternative outpatient methods for body composition assessment, including adiposity in pediatric patients with TS. The secondary goal is to characterize the metabolic profile of pediatric subjects with TS compared to obese (BMI ≥95 th%ile) and lean controls (BMI: 5-85th%ile). Methods: This is a cross-sectional study. TS patients are on ≥50mcg transdermal estradiol equivalent replacement OR are self-menstruating. BI, DXA, metabolic markers, interleukin-6 (IL-6) &amp; C-reactive protein (CRP) were obtained in all 3 groups. Statistical analysis was conducted using SPSS software. Results: We present preliminary data on 15 TS, 12 obese, and 15 lean youth, aged 13-19 years. TS youth averages: Age 16.5±1.3 years; BMI 29.3±8.5 kg/m2 (z-score: 1.21±1.27). DXA visceral adiposity (DXA VA): 392±257 g; BI visceral fat (BI VF): 1300±750 cm². Elevated LDL-C&amp;gt;100 mg/dL was noted in n=5 (102-166). Elevated AST &amp;/or ALT &amp;gt;40 unit/L were found in 6 TS. 6 TS had elevated BI VF and DXA VA (&amp;gt;250g) with BMI z-score &amp;lt;2.0. Increased CRP &amp;/or IL-6 levels were noted in 4 TS (BMI z-score: 1.29-2.54), all of whom had primary ovarian failure. These 4 also had increased DXA VA (358-887 g), and BI VF (1500-2500 cm²) compared to the rest of the group. Obese youth averages: Age 16.7±1.83 years; BMI 38 kg/m2 (z-score: 2.26±0.3); DXA VA 674±226 g; BI VF 2300±390 cm². LDL-C&amp;gt;100 mg/dL noted in n=5 (102-121). AST&amp;ALT&amp;lt;35 units/L for all. Increased CRP &amp;/or IL-6 were noted in 4 study subjects (DXA VA: 474-718 g). All 4 had normal A1c, lipid, and liver profiles. Lean youth averages: Age 16.4±2.4 years, BMI 21.6 kg/m2 (z-score: 0.32±0.7); DXA VA 162±68 g; BI VF: 580±370 cm². LDL-C &amp;gt;100 mg/dL noted in n=3 (106-120); 1 subject had increased AST&amp;ALT &amp;gt;40 unit/L. All others had AST &amp; ALT&amp;lt;26 units/L. Elevated CRP/IL-6 was noted in 4 subjects, 1 of whom had increased DXA VA (367g). All subjects had normal HgA1c (≤5.6). Total mass, lean mass, and fat % from DXA and BI were compared (correlation analysis) for each subject and showed agreement throughout. Conclusion: Based on these preliminary data, BI may be a convenient and noninvasive tool to assess adiposity in the outpatient setting in TS. BI and DXA both detected increased visceral fat in TS subjects with normal BMI. BI could potentially identify TS individuals at risk for metabolic dysfunction. Further studies on larger patient numbers will be needed to confirm these preliminary findings. Presentation: 6/2/2024

A-066 Does essential fatty acid deficiency alter ethanolamine plasmalogen concentrations in red blood cells? Implications for clinical testing

Abstract Background Plasmalogens are glycerophospholipids characterized by a fatty alcohol at the sn-1 position, a polyunsaturated fatty acid at the sn-2 position, most commonly docosahexaenoic acid (DHA) or arachidonic acid, and a polar head group at the sn-3 position, mainly phosphoethanolamine. Markedly reduced plasmalogens are seen in peroxisome biogenesis defects, including Zellweger spectrum disorders (ZSD), since the first two steps of plasmalogen synthesis occur in peroxisomes. Disruption of the peroxisomal β-oxidation pathway also causes DHA deficiency in ZSD patients. Since plasmalogens are composed of fatty acids, the deficiency of DHA or other essential fatty acids could further decrease the plasmalogen level in ZSD patients and lower the results of plasmalogen testing in patients without ZSD. To test this hypothesis, we evaluated the impact of essential fatty acid (EFA) deficiency on plasmalogens in patients with ZSD and individuals with EFA deficiency due to unrelated causes. Methods Red blood cell (RBC) samples were obtained from individuals without ZSD referred to ARUP laboratories for clinical EFA testing (n = 80; age range: birth - 89 years), and from patients with ZSD (n = 7; age range birth - 9 years). Three ZSD patients were older and with a less severe phenotype. A total of 18 intact ethanolamine plasmalogen species were extracted from packed RBCs and quantified using a XEVO TQ-XS Mass Spectrometer in conjunction with Ultra-High Performance Liquid Chromatography (Waters). Total plasmalogen values were also calculated; plasmalogen deficiency was defined as ≤60% of age-matched control median. Fatty acids (FAs) were quantified by gas chromatography negative chemical ionization-mass spectrometry (GC-NCI-MS). EFA deficiency was diagnosed by increased Triene/Tetraene ratio (Mead acid/Arachidonic acid). Data was analyzed using Prism v.8.3.0 software (La Jolla, CA). The study was approved by the Institutional Review Board of the University of Utah. Results Out of the 80 samples from individuals without ZSD referred for EFA testing, 18% had normal fatty acid profile, 57% were receiving dietary supplements and 25% had elevated Triene/Tetraene ratio suggesting EFA deficiency. EFA deficiency was accompanied by low DHA only in two individuals without ZSD, whereas it was present in most of the samples from ZSD patients evaluated (5/7). None of the individuals without ZSD were deficient in plasmalogens. Moreover, when compared to individuals without ZSD with a normal FA profile, there was no significant difference observed with EFA deficiency or FA supplementation. Although our ZSD cohort is small, no correlation between EFA deficiency and plasmalogen levels was also seen in ZSD: 2 patients with milder phenotype had EFA deficiency but normal plasmalogens, 2 patients had EFA deficiency and low plasmalogens, 2 patients with low plasmalogens had low DHA without EFA deficiency, and 1 patient had low plasmalogens but normal EFA. Conclusions Plasmalogen quantitation in RBCs by LC-MS/MS is not significantly affected by EFA deficiency. Although more data is warranted to elucidate the correlation between plasmalogen levels and ZSD phenotype, plasmalogens can be within normal reference intervals in ZSD regardless of EFA status.

Identification of an osteopontin structural element for the restoration of a normal endometrial epidermal growth factor (EGF) profile determined by the EGF concentration on day 3 of estrous cycle and pregnancy outcome in repeat breeder dairy cows

The loss of a cyclic change with two peaks of increased endometrial epidermal growth factor (EGF) concentration on days 2−4 and 13−14 during the estrous cycle has been linked to low fertility in repeat breeder (RB) cows. We have shown that an intravaginal infusion of osteopontin (OPN) restored the EGF profile in RB cows. The present study aimed to determine a structural element of OPN to restore the normal EGF profile and fertility. Holstein RB cows were diagnosed the EGF profile by a single examination of the endometrial EGF concentration on day 3 of the estrous cycle. Those with an altered EGF profile were intravaginally infused with OPN and its fragments on the day of insemination (day 0); the concentration of endometrial EGF was measured on day 3, and pregnancy was diagnosed on days 30−35. In Study 1, recombinant OPN (rOPN) (16 nmol), thrombin-cleaved N- and C-terminal fragments of rOPN (N-rOPN and C-rOPN, respectively), and a combination of these fragments (Th-rOPN) were infused (n = 13−20). The restoration rate of the normal EGF profile of the N-rOPN group (25.0%) was a level in between the C-rOPN group (7.7%) and both the rOPN (55.6%) and Th-rOPN (64.3%) groups. In Study 2, PBS (n = 47), rOPN (9.5 nmol, n = 83), and peptides of integrin binding motifs, GRGDSVAYGLK (peptide 1; 32, 320, and 1,600 nmol), GRGDS (peptide 2; 320 and 1,600 nmol), and SVAYGLK (peptide 3; 320 and 1,600 nmol), were infused (n = 20−25). Restoration rates of the normal EGF profile of peptide 1 (320 and 1,600 nmol) and peptide 3 (1,600 nmol) groups (44.0−56.3%) were comparable with those of the rOPN group (63.9%) and higher than those of the PBS group (15.6%). Restoration rates of the other groups were similar to those of the PBS group. Additional cows received infusions to determine the effect on fertility. Conception rates of the peptide 1 (320 and 1,600 nmol; n = 50 each), peptide 3 (1,600 nmol; n = 55), and rOPN (n = 111) groups (41.8−50.0%) were comparable and higher than that of the PBS group (21.6%, n = 75). In Study 3, PBS (n = 24), peptide 1 (320 nmol; n = 78), and GRGESVAYGLK peptide (peptide 4; 320 and 1,600 nmol; n = 50 and 26, respectively) were infused. Restoration rates of the normal EGF profile of peptide 4 and PBS groups (16.0−19.2%) were comparable and lower than those of the peptide 1 group (44.9%). Thus, the SVAYGLK motif may be an OPN structural element to restore the normal EGF profile and fertility in RB cows, and the RGD motif may enhance its effect.

Ventilator performances for non-invasive ventilation: a bench study

IntroductionA wide range of recent ventilators, dedicated or not, is available for non-invasive ventilation (NIV) in respiratory or intensive care units (ICU). We conducted a bench study to compare their...

Enhanced spinal cord repair using bioengineered induced pluripotent stem cell-derived exosomes loaded with miRNA

BackgroundA spinal cord injury (SCI) can result in severe impairment and fatality as well as significant motor and sensory abnormalities. Exosomes produced from IPSCs have demonstrated therapeutic promise for accelerating spinal cord injury recovery, according to a recent study.ObjectiveThis study aims to develop engineered IPSCs-derived exosomes (iPSCs-Exo) capable of targeting and supporting neurons, and to assess their therapeutic potential in accelerating recovery from spinal cord injury (SCI).MethodsiPSCs-Exo were characterized using Transmission Electron Microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and western blot. To enhance neuronal targeting, iPSCs-Exo were bioengineered, and their uptake by neurons was visualized using PKH26 labeling and fluorescence microscopy. In vitro, the anti-inflammatory effects of miRNA-loaded engineered iPSCs-Exo were evaluated by exposing neurons to LPS and IFN-γ. In vivo, biodistribution of engineered iPSC-Exo was monitored using a vivo imaging system. The therapeutic efficacy of miRNA-loaded engineered iPSC-Exo in a SCI mouse model was assessed by Basso Mouse Scale (BMS) scores, H&E, and Luxol Fast Blue (LFB) staining.ResultsThe results showed that engineered iPSC-Exo loaded with miRNA promoted the spinal cord injure recovery. Thorough safety assessments using H&E staining on major organs revealed no evidence of systemic toxicity, with normal organ histology and biochemistry profiles following engineered iPSC-Exo administration.ConclusionThese results suggest that modified iPSC-derived exosomes loaded with miRNA have great potential as a cutting-edge therapeutic approach to improve spinal cord injury recovery. The observed negligible systemic toxicity further underscores their potential safety and efficacy in clinical applications.

Meta-Analytical and Meta-Regression Evaluation of Subclinical Hyperthyroidism's Effect on Male Reproductive Health: Hormonal and Seminal Perspectives.

Subclinical hyperthyroidism (SCH) is a subtle thyroid dysfunction marked by decreased serum thyroid-stimulating hormone (TSH) levels while maintaining a normal thyroid hormone profile. Despite its mild nature, SCH can significantly impact various physiological functions, including male reproductive health. However, the effects of SCH on reproductive hormones and semen quality are less understood compared to overt thyroid disorders. This study employed extensive search methods across various databases from January 2000 to February 2024 to explore the relationship between SCH and Hormonal and Seminal Perspectives. Effect sizes, estimated using the standardized mean difference (SMD) and pooled with a Random-effect model, provided significant insights from 748 participants. Included studies adhered to the following criteria: Patients (male individuals with SCH), Intervention (assessment of reproductive hormones and semen quality), Comparison (SCH patients versus healthy controls), and Outcome (changes in reproductive factors). Significant alterations in reproductive hormones were observed in SCH patients, including reduced LH levels (SMD = - 0.20; p = 0.007), elevated FSH levels (SMD = 0.25; p = 0.002), and stable testosterone levels (SMD = - 0.05; p = 0.50). Regarding thyroid profile, SCH was associated with increased FT3 (SMD = 0.15; p < 0.001) and FT4 (SMD = 0.08; p = 0.002) levels, along with decreased TSH levels (SMD = - 2.00; p < 0.001). Adverse effects on semen quality were also observed. These findings underscore the need to incorporate thyroid health assessments in the evaluation of male infertility, recognizing the impact of minor thyroid hormone deviations on reproductive outcomes.

Unravelling a hidden pathology of a vertebral fracture in a teenage girl

BackgroundAlthough the skeleton remains a common target of primary hyperparathyroidism, the classic bone disease “osteitis fibrosa cystica” is currently rare due to early diagnosis. This case represents severe classic bone manifestations of primary hyperparathyroidism due to delayed diagnosis and delayed medical attention.Case presentationA 19-year-old young female was symptomatically managed for chronic back pain and nonspecific bone pain in the small joints of both hands over 2 months by a general practitioner. The patient had delayed seeking for treatment for 3 months. Later, she was evaluated for tuberculosis, hematological malignancies and rheumatic disorders following a fractured T12 vertebra and underwent pedicle screw fixation. However, clinical examination and investigations, including biochemistry, imaging and histology, ruled out the above conditions. Unfortunately, serum calcium level was not performed at the initial presentation. Later, primary hyperparathyroidism was diagnosed on the basis of moderate hypercalcaemia and elevated intact PTH levels (2064 pg/ml). She had sufficient vitamin D levels and normal kidney function. Her DXA scan revealed severe secondary osteoporosis with the lowest Z score of -8 at the total lumbar spine. Ultrasonography of the thyroid revealed a hypo echoic mass in the left lower neck, and localization studies with technetium-99 m sestamibi and 4D-CT revealed a left inferior parathyroid adenoma (1.6 × 1.5 × 1.6 cm). CT scan also revealed brown tumors in the mandible and vertebrae and diffuse bony changes in the skull, sternum, humerus and vertebrae. Her radiographs revealed subperiosteal bone resorption on the radial aspects of the middle and distal phalanges and brown tumors in both the ulna and fibula. We excluded MEN and other hereditary syndromes in our patient with a personal and family history and with a normal pituitary hormone profile because of poor resources for genetic testing. She underwent parathyroid adenoma excision, and the postoperative period was complicated with hungry bone syndrome, requiring high doses of calcium and active vitamin D supplements. These supplements were gradually weaned off over 6 months, and she recovered with normal biochemical investigations. Histology revealed parathyroid adenoma without malignant features.ConclusionIn developing countries where routine calcium screening is not available, clinicians should be aware of various manifestations of primary hyperparathyroidism to allow diagnosis as soon as possible without delay to prevent further progression, as it is a treatable condition.

Comparison of simplex and duplex drum brakes linings with transverse slots in vehicles

In this paper, experimental comparison between Simplex and Duplex drum brake units performance for three different drum lining profile designs is carried out. The three linings profiles are normal (no slot), with one slot and with three slots. In this study, brake test rig has been designed to represent the actual braking process environment. Brake oil pressure and drum speed are the operational parameters that are varied during the experimental work. From the experimental work and mathematical models for brake force, brake factor, and final friction temperature, the comparisons were carried out. The final conclusions indicate that lining with one slot profile is the most suitable, since the percentage improvement of mean brake force and brake factor of duplex drum brake (D) linings versus simplex drum brake (S) linings reaching 84.09% and 82.73% higher than three slots lining profile but lower than lining with normal profile at low pressure 5 bar and low speed 50 rpm. Also, the percentage improvement of mean primary shoe final friction temperature reduction for the one slot profile reaches 30.00% higher than normal lining profile but lower than lining with three slots profile at high pressure 20 bar and drum speed 50 rpm.

Understanding the variability in red cell and plasma volume combinations can help guide management in heart failure.

Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles across heart failure (HF) phenotypes. These profiles extend from hypovolaemia to normal BV and to variable degrees of BV hypervolaemia, frequently with similar clinical presentations. However, a comprehensive survey of BV profiles providing practical clinical guidance for the interpretation and management of quantitative plasma volume (PV) and red blood cell (RBC) mass findings has not been reported. The intent of this study is to advance this concept through a multicentre analysis. A retrospective analysis of clinical and BV data was undertaken in stable NYHA class II-III HF patients (N=546). BV was quantitated using established nuclear medicine indicator-dilution methodology. Differing combinations of PV and RBC mass were identified contributing to marked heterogeneity in overall BV profiles. A quantitatively normal BV was identified in 32% of the cohort but of these only ~1/3 demonstrated a true normal BV (i.e., normal PV+normal RBC mass). The remaining portion of normal BV profiles reflected balanced combinations of compensatory PV expansion with RBC mass deficit (anaemia) (14% of cohort) and PV contraction with RBC mass excess (erythrocythemia) (6% of cohort). Main contributors to BV hypervolaemia were PV excess with a normal RBC mass (21% of cohort; 23% female) and PV excess with erythrocythemia (24% of cohort; 26% female). Hypovolaemia was predominately defined by RBC mass deficit with a normal PV (6% of cohort; 57% female) or RBC mass deficit with PV contraction (5% of cohort; 48% female). Findings support the clinical relevance of identifying and accurately interpreting the varying combinations of PV and RBC mass in patients with chronic HF. This in turn helps guide appropriate individualized patient management strategies. A practical volume-based guideline is provided in an effort to aid clinician interpretation.

Selection of number of clusters and warping penalty in clustering functional electrocardiogram.

Clustering functional data aims to identify unique functional patterns in the entire domain, but this can be challenging due to phase variability that distorts the observed patterns. Curve registration can be used to remove this variability, but determining the appropriate level of warping flexibility can be complicated. Curve registration also requires a target to which a functional object is aligned, typically the cross-sectional mean of functional objects within the same cluster. However, this mean is unknown prior to clustering. Furthermore, there is a trade-off between flexible warping and the number of resulting clusters. Removing more phase variability through curve registration can lead to fewer remaining variations in the functional data, resulting in a smaller number of clusters. Thus, the optimal number of clusters and warping flexibility cannot be uniquely identified. We propose to use external information to solve the identification issue. We define a cross validated Kullback-Leibler information criterion to select the number of clusters and the warping penalty. The criterion is derived from the predictive classification likelihood considering the joint distribution of both the functional data and external variable and penalizes the uncertainty in the cluster membership. We evaluate our method through simulation and apply it to electrocardiographic data collected in the Chronic Renal Insufficiency Cohort study. We identify two distinct clusters of electrocardiogram (ECG) profiles, with the second cluster exhibiting ST segment depression, an indication of cardiac ischemia, compared to the normal ECG profiles in the first cluster.

P061 AMBULATORY BLOOD PRESSURE MONITORING (ABPM) CHARACTERIZATION IN PATIENTS CONSULTING A CARE CENTER IN THE CITY OF POPAYÁN, COLOMBIA BETWEEN JANUARY 2019 AND JUNE 2021

Background: Ambulatory blood pressure monitoring (ABPM) provides important information on the circadian behavior of this variable. This measure provides different phenotypes that can be analyzed in more depth than office blood pressure measurement. Several associations have been identified between altered circadian phenotypes, such as non dipper, and adverse cardiovascular outcomes, such as cardiovascular mortality, coronary heart disease, cerebrovascular disease, chronic kidney disease, and hospitalization for heart failure. To date, the behavior of blood pressure according to the MAPA is unknown in the population of the department of Cauca, Colombia. Therefore, our objective was to characterize the arterial hypertension profiles in a sample of this population. Materials and methods: A cross-sectional descriptive study was conducted in patients over 18 years of age, undergoing ambulatory BP monitoring from 2019 to 2021; data were recorded in an instrument containing sociodemographic, clinical, and therapeutic characteristics. The data were analyzed with the SPSS 25 program. Results: A total of 440 blood pressure monitoring (ABPM) records were obtained, of which, 80.4% of the records were found to be compatible with a diagnosis of arterial hypertension. The distribution of the profiles included: normal dipper (55.2%), attenuated dipper (non-dipper) (23.6%), inverted dipper (13.6%) and extreme dipping (1.4%). Most of the overweight and obese patients presented arterial hypertension in the ABPM records, with 41.1% being overweight patients and 25.2% obese. Regarding the arterial hypertension profiles, there were no statistically significant differences in relation to overweight and obesity. Conclusions: Among the BP profiles measured by ABPM in the population studied, the most prevalent was the normal dipper profile, followed by non-dipper, inverted dipper, and extreme dipper. There was a tendency for the overweight and obese population to present abnormal circadian BP profiles more frequently; however, in our study these results were not statistically significant.