Clinical Testing Research Articles

Analysis of potential microRNA biomarkers for multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating autoimmune neurodegenerative disorder for which no specific blood biomarker is available. MicroRNAs (miRNAs) have been investigated for their diagnostic potential in MS. However, MS-associated miRNAs are rarely replicated in different MS populations, thus impeding their use in clinical testing. Here, we evaluated the fold expression of seven reported MS miRNAs associated with MS incidence and clinical characteristics in 76 MS patients and 75 healthy control plasma samples. We found miR-23a-3p to be upregulated in relapsing-remitting MS (RRMS), while miR-326 was downregulated. MiR-150-5p and -320a-3p were significantly downregulated in secondary progressive MS (SPMS) patients compared to RRMS. High disability was associated with low miR-320a-3p, whereas low BDNF levels were associated with upregulation of miR-150-5p and downregulation of miR-326 expression in the total cohort. MiR-23a-3p and miR-326 showed significant diagnostic sensitivity, specificity, and accuracy for RRMS diagnosis. In addition, miR-150-5p and miR-320a-3p had comparable significant diagnostic test performance metrics distinguishing SPMS from RRMS. Therefore, there is potential for including miR-23a-3p and miR-326 in an RRMS diagnostic miRNA panel. Moreover, we have shown that miR-150-5p and miR-320a-3p could be novel RRMS conversion to SPMS biomarkers. The use of these miRNAs in MS diagnosis and prognosis warrants further investigation.

Endolysins: a new antimicrobial agent against antimicrobial resistance. Strategies and opportunities in overcoming the challenges of endolysins against Gram-negative bacteria

Antibiotic-resistant bacteria are rapidly emerging, and the increasing prevalence of multidrug-resistant (MDR) Acinetobacter baumannii poses a severe threat to humans and healthcare organizations, due to the lack of innovative antibacterial drugs. Endolysins, which are peptidoglycan hydrolases encoded by a bacteriophage, are a promising new family of antimicrobials. Endolysins have been demonstrated as an effective therapeutic agent against bacterial infections of A. baumannii and many other Gram-positive and Gram-negative bacteria. Endolysin research has progressed from basic in vitro characterization to sophisticated protein engineering methodologies, including advanced preclinical and clinical testing. Endolysin are therapeutic agent that shows antimicrobial properties against bacterial infections caused by drug-resistant Gram-negative bacteria, there are still barriers to their implementation in clinical settings, such as safety concerns with outer membrane permeabilizers (OMP) use, low efficiency against stationary phase bacteria, and stability issues. The application of protein engineering and formulation techniques to improve enzyme stability, as well as combination therapy with other types of antibacterial drugs to optimize their medicinal value, have been reviewed as well. In this review, we summarize the clinical development of endolysin and its challenges and approaches for bringing endolysin therapies to the clinic. This review also discusses the different applications of endolysins.

Evaluating User Experience and DNA Yield from Self-Collection Devices.

The COVID-19 pandemic emphasized an urgent need for devices used in the self-collection of biospecimens in an evolving patient care system. The mailing of biospecimen self-collection kits to patients, with samples returned via mail, provides a more convenient testing regimen, but could also impart patient sampling variabilities. User compliance with device directions is central to downstream testing of collected biospecimens and clear instructions are central to this goal. Here, we performed an evaluation of 10 oral DNA collection devices involving either swab or saliva self-collection and analyzed ease of use and comfort level with a device, as well as DNA recovery quantity/quality and sample stability. We show that while these DNA quality/quantity metrics are comparable between devices, users prefer direct saliva collection over swab-based devices. This information is useful in guiding future experiments including their use in human RNA, microbial, or viral sample collection/recovery and their use in clinical testing.

Towards proactive palliative care in oncology: developing an explainable EHR-based machine learning model for mortality risk prediction

BackgroundEx-ante identification of the last year in life facilitates a proactive palliative approach. Machine learning models trained on electronic health records (EHR) demonstrate promising performance in cancer prognostication. However, gaps in literature include incomplete reporting of model performance, inadequate alignment of model formulation with implementation use-case, and insufficient explainability hindering trust and adoption in clinical settings. Hence, we aim to develop an explainable machine learning EHR-based model that prompts palliative care processes by predicting for 365-day mortality risk among patients with advanced cancer within an outpatient setting.MethodsOur cohort consisted of 5,926 adults diagnosed with Stage 3 or 4 solid organ cancer between July 1, 2017, and June 30, 2020 and receiving ambulatory cancer care within a tertiary center. The classification problem was modelled using Extreme Gradient Boosting (XGBoost) and aligned to our envisioned use-case: “Given a prediction point that corresponds to an outpatient cancer encounter, predict for mortality within 365-days from prediction point, using EHR data up to 365-days prior.” The model was trained with 75% of the dataset (n = 39,416 outpatient encounters) and validated on a 25% hold-out dataset (n = 13,122 outpatient encounters). To explain model outputs, we used Shapley Additive Explanations (SHAP) values. Clinical characteristics, laboratory tests and treatment data were used to train the model. Performance was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC), while model calibration was assessed using the Brier score.ResultsIn total, 17,149 of the 52,538 prediction points (32.6%) had a mortality event within the 365-day prediction window. The model demonstrated an AUROC of 0.861 (95% CI 0.856–0.867) and AUPRC of 0.771. The Brier score was 0.147, indicating slight overestimations of mortality risk. Explanatory diagrams utilizing SHAP values allowed visualization of feature impacts on predictions at both the global and individual levels.ConclusionOur machine learning model demonstrated good discrimination and precision-recall in predicting 365-day mortality risk among individuals with advanced cancer. It has the potential to provide personalized mortality predictions and facilitate earlier integration of palliative care.

NEUROFILAMENTS AS A POTENTIAL BIOMARKER IN PATIENTS WITH MULTIPLE SCLEROSIS: A REVIEW OF LITERATURE

Background: Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage and loss of neurons. Its growing incidence has determined the need for more intensive research towards effective models for managing disease progression and evaluation of treatment response. Finding clinically relevant biomarkers has been a significant challenge. Purpose: This review aims to summarize the findings from current relevant literature sources on neurofilaments as a potential biomarker of diagnostic and prognostic value in patients with MS. Results: Recently, neurofilaments have been identified as the most promising and informative biomarkers of axonal damage and loss. Neurofilament concentration demonstrates a strong association with the disease course, activity and progression, disability accumulation and response to disease-modifying treatment. A significant correlation with future relapse rates, symptom worsening and risk of conversion from clinically isolated syndrome (CIS) to definite MS has also been established. Several MS therapies have demonstrated a substantial reduction in neurofilament levels upon treatment initiation. Conclusion: The results available from real-world studies and clinical trials regarding neurofilaments as a reliable predictor and indicator of MS disease course are encouraging. They have consistently proven to be of utility if integrated into the diagnostic and therapeutic algorithm of MS patients. This review encompasses undeniable data confirming the considerable potential of neurofilaments for becoming the first globally verified biomarker for MS. The accessibility, safety, low cost and possibility for serial evaluation make the neurofilaments the perfect component to be implemented in routine clinical tests for MS.

Comparative studies between humans and golden Syrian hamsters via thromboelastography.

Thromboelastography (TEG) is a widely utilized clinical testing method for real-time monitoring of platelet function and the thrombosis process. Lipid metabolism disorders are crucial risk factors for thrombosis. The lipid metabolism characteristics of hamsters resemble those of humans more closely than mice and rats, and their relatively large blood volume makes them suitable for studying the mechanisms of thrombosis related to plasma lipid mechanisms. Whole blood samples from golden Syrian hamsters and healthy humans were obtained following standard clinical procedures. TEG was employed to evaluate coagulation factor function, fibrinogen (Fib) function, platelet function, and the fibrinolytic system. The whole blood from hamster or healthy human was isolated following the clinical procedure, and TEG was employed to evaluate the coagulation factor function, Fib function, platelet function, and fibrinolytic system. Coagulation analysis used ACLTOP750 automatic coagulation analysis pipeline. Blood routine testing used XN-2000 automatic blood analyzer. TEG parameters revealed that hamsters exhibited stronger coagulation factor function than humans (reaction time [R], p = 0.0117), with stronger Fib function (alpha angle, p < 0.0001; K-time [K], p < 0.0001). Platelet function did not differ significantly (maximum amplitude [MA], p = 0.077). Hamsters displayed higher coagulation status than humans (coagulation index [CI], p = 0.0023), and the rate of blood clot dissolution in hamsters differed from that in humans (percentage lysis 30 min after MA, p = 0.02). Coagulation analysis parameters indicated that prothrombin time (PT) and activated partial thromboplastin time (APTT) were faster in hamsters than in humans (PT, p = 0.0014; APTT, p = 0.03), whereas the Fib content was significantly lower in hamsters than in humans (p < 0.0001). No significant difference was observed in thrombin time (p = 0.1949). In summary, TEG could be used to evaluate thrombosis and bleeding parameters in whole blood samples from hamsters. The platelet function of hamsters closely resembled that of humans, whereas their coagulation function was significantly stronger.

An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Abstract A004: Clinical test design affects tumor tissue and ctDNA FGFR gene status in metastatic urothelial cancer: a prospective study

Abstract Fibroblast growth factor receptor (FGFR) gene alterations are common in urothelial cancer (UC) and targetable with erdafitinib. The co-approved companion diagnostic is an amplicon-based tumor tissue test that detects a limited number of recurrent FGFR alterations. However, FGFR status may change during disease progression, and rare FGFR alterations not typically covered by existing tests may be of clinical importance. Therefore, in a prospective pan-Canadian study (NCT06129084), we compared standard archival tissue testing to broad targeted sequencing of cell-free circulating tumor DNA (ctDNA) to detect FGFR alterations in UC. Eligible patients had progressing metastatic UC and were undergoing tissue FGFR testing. Blood was drawn at study enrollment and plasma cell-free DNA and matched white blood cell DNA underwent deep-targeted sequencing with a hybridization capture panel including the introns and exons of FGFR1-4 and the common breakpoint region of TACC3. Archival tissue selection and testing was initiated by the treating physician and typically used the Oncomine Focus assay. 210 patients were enrolled across 12 sites, and 140 patients have tissue and ctDNA results available for concordance assessment. 43/140 (31%) of cell-free DNA samples had low tumor fraction (&amp;lt;0.5%) and were considered inconclusive. For the remaining 97 same-patient tissue and ctDNA pairs, FGFR status was identical in 88 (91%). In 7 of 9 discordant cases, the tissue was negative, but ctDNA was positive for FGFR alterations: these were enriched for FGFR3-TACC3 fusions (4/7). Two discordant fusions had canonical breakpoints that can be identified by current amplicon-based companion diagnostics, indicating potential spatiotemporal heterogeneity in somatic FGFR status. The other two discordant (ctDNA-only) fusions had non-canonical breakpoints that are not amenable to detection by current amplicon-based companion diagnostics. In two mutation discordant cases (S249C positive in ctDNA only), lack of signal in tumor tissue could be explained by the presence of additional FGFR3 variants within 25bp of S249 and in cis - disrupting primer binding sites. There were only two cases of tissue-only FGFR alterations among the 97 evaluable pairs (FGFR3-TACC3 fusion, S249C). ctDNA testing of metastatic UC with a broad capture-based approach covering all exons and introns of FGFR genes can identify additional alterations not detected with current amplicon-based companion diagnostics applied to archival tissue. Our results support ctDNA testing as a valuable adjunct to tissue testing, but not as a replacement due to the high frequency of inconclusive ctDNA results, secondary to tumor fraction below the threshold. Assay design, including target enrichment technique, is a significant source of variability in tissue and ctDNA FGFR status and should be carefully considered in future clinical biomarker testing strategies. Citation Format: David C. Müller, Gillian Vandekerkhove, Andrew J. Murtha, Jack V.W. Bacon, Carlos Vasquez-Rios, Maria Stephenson, Kimia Rostin, Elena Schönlau, Connor Wells, Sunil Parimi, Krista Noonan, Naveen S. Basappa, Jenny J. Ko, Daygen Finch, Nimira Alimohamed, Tarek A. Bismar, Gang Wang, Andreas Papadakis, Lucia Nappi, Matti Annala, Cecily Q. Bernales, Alan Spatz, Kim N. Chi, Alexander W. Wyatt, Bernhard J. Eigl. Clinical test design affects tumor tissue and ctDNA FGFR gene status in metastatic urothelial cancer: a prospective study [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A004.

P25 Identification of early changes in extracellular microRNA biomarkers of scleroderma for point-of-care diagnosis

Abstract Introduction and aims Scleroderma is a rare autoimmune disease, characterized by excessive extracellular matrix deposition leading to chronic inflammation and fibrosis. As a progressive disease initially affecting the skin, it presents similarly to Raynaud phenomenon, which delays diagnosis and treatment. Clinical diagnostic tests lack sensitivity, therefore novel Methods of detection and sensitive biomarkers are required to improve diagnosis rates. MicroRNAs are short, stable, noncoding RNAs, often present in the extracellular space, and can be sampled from interstitial skin fluid (ISF) through the employment of hydrogel microneedles. We aim to use this technique to improve upon current clinical gold standards of diagnosing scleroderma, at earlier stages of the disease. Methods In this study, we performed next-generation small-RNA sequencing on ISF from healthy individuals, patients prior to a clinical diagnosis of scleroderma [termed very early detection of systemic sclerosis (VEDOSS)], and patients with scleroderma classified as low and high skin score, identifying a panel of microRNA biomarkers for scleroderma diagnosis. Swellable hydrogel microneedles were manufactured in house, applied to excised human tissue and preclinical mouse models to demonstrate the ability to access and quantify extracellular microRNAs in ISF. Results Patients who received a VEDOSS diagnosis have increased ISF abundance of miR-379-5p and miR-125a-5p and decreased miR-30e-3p compared with healthy patients. miR-379-5p, miR-363-3p and miR-221-3p are sensitive to the progression of scleroderma and could be used to track the disease with improved sensitivity to autoantibodies in blood or where clinical practices usually require a skin biopsy. Using preclinical models of skin disease, we could differentiate between conditions, with higher sensitivity than blood sampling using our microneedle technology. Conclusions By identifying extracellular mircoRNAs, we have shown the potential use of these sensitive biomarkers in a liquid biopsy that can be applied at point-of-care. Peptide nucleic acids complementary to our microRNA biomarkers, will be used to provide real-time on-the-chip readouts of these ­biomarkers.

Performance on clinical outcomes, activities of daily living anduser experience on head-mounted displays for people withvision impairment.

To compare the objective performance, acceptance and usability of head-mounted displays (HMDs) to provide evidence-based data that could be used to increase the efficiency of device referrals based upon a person's vision loss and functional needs. A cross-sectional, counterbalanced, individually controlled crossover study was performed on 15 adults with various eye conditions. Performance was measured when using four HMDs: eSight4, Eyedaptic EYE3, Eyedaptic EYE4 and IrisVision Inspire. Performance on clinical visual acuity tests and contrast were assessed, as well as vision-related activities of daily living (ADL) which were divided into three categories: Reading, Searching & Identifying and Eye-hand Coordination. User-experience was also assessed. Logistic regression analyses, Friedman one-way repeated measure analyses of variance by ranks and multivariate permutation testing were used for analysis. There was a significant improvement in visual acuity when using all devices. For contrast tasks, only the eSight4 and Eyedaptic EYE3 improved performance relative to baseline. For most Reading and Searching & Identifying tasks, the odds of being able to perform the tasks were significantly higher while using the devices. However, the actual performance with most devices (e.g., number of words read or reading speed) did not improve significantly over baseline for most tasks. For the Eye-hand Coordination tasks, participants performed equivalent to or significantly poorer than baseline when using the devices. No demographic or clinical predictors of outcomes were identified. Participants expressed dissatisfaction with the devices' effectiveness, acceptability and usability. While performance on clinical tests was better when using the devices, performance on most real-world ADLs was equal to or worse than baseline. No single device improved performance on all tasks, and performance on any one task was not improved with all the devices. The overall dissatisfaction with the devices paralleled the lack of objective improvement in the performance of real-world tasks.

The Development of a New Vagus Nerve Simulation Electroceutical to Improve the Signal Attenuation in a Living Implant Environment

An electroceutical is a medical device that uses electrical signals to control biological functions. It can be inserted into the human body as an implant and has several crucial advantages over conventional medicines for certain diseases. This research develops a new vagus nerve simulation (VNS) electroceutical through an innovative approach to overcome the communication limitations of existing devices. A phased array antenna with a better communication performance was developed and applied to the electroceutical prototype. In order to effectively respond to changes in communication signals, we developed the steering algorithm and firmware, and designed the smart communication protocol that operates at a low power that is safe for the patients. This protocol is intended to improve a communication sensitivity related to the transmission and reception distance. Based on this technical approach, the heightened effectiveness and safety of the prototype have been ascertained, with the actual clinical tests using live animals. We confirmed the signal attenuation performance to be excellent, and a smooth communication was achieved even at a distance of 7 m. The prototype showed a much wider communication range than any other existing products. Through this, it is conceivable that various problems due to space constraints can be resolved, hence presenting many benefits to the patients whose last resort to the disease is the VNS electroceutical.

Chylomicron retention disease caused by SAR1B gene variations in 2 cases and literatures review

Objective: To summarize the genotype and clinical characteristics of chylomicron retention disease (CMRD) caused by secretion associated Ras related GTPase 1B (SAR1B) gene variations. Methods: Clinical data and genetic testing results of 2 children with CMRD treated at Children's Hospital of Fudan University and Jiangxi Provincial Children's Hospital from May 2022 to July 2023 were summarized. To provide an overview of the clinical and genetic characteristics of CMRD caused by SAR1B gene variations, all of the literature was searched and reviewed from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to January 2024) with "chylomicron retention disease" "Anderson disease" or "Anderson syndrome" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of CMRD caused by SAR1B gene variations. Results: One 11-year-old boy and one 4-month-old girl with CMRD. Both patients had lipid malabsorption, failure to thrive, decreased cholesterol, elevated transaminase and creatine kinase, and vitamin E deficiency, with homozygous variations (c.224A>G) and compound heterozygous variations (c.224A>G and c.554G>T) in SAR1B gene, respectively. Case 1 was followed up for over a month, and he still occasionally experienced lower limb muscle pain. Case 2 was followed up for more than a year, and her had caught up to normal levels. Both patients had no other significant discomfort. Literature search retrieved 0 Chinese literature and 22 English literatures. In addition to the 2 cases reported in this study, a total of 51 patients were identified as CMRD caused by SAR1B gene variations. Twenty-one types of SAR1B variants 10 missense, 4 nonsense, 3 frameshift, 1 in-frame deletion, 1 splice, 1 gross deletion, and 1 gross insertion-deletion were found among the 51 CMRD cases. Among all the patients, 49 cases had lipid malabsorption (43 cases had diarrhea or fatty diarrhea, 17 cases had vomiting, and 12 cases had abdominal distension), 45 cases had lipid soluble Vitamin deficiency (43 cases had Vitamin E deficiency, 10 cases had Vitamin A deficiency, 9 case had Vitamin D deficiency, and 5 cases had Vitamin K deficiency), 35 cases had failure to thrive, 32 cases had liver involvement (32 cases had elevated transaminases, 5 cases had fatty liver, and 3 cases had hepatomegaly), 29 cases had white small intestinal mucosa under endoscopy, and 17 cases had elevated creatine kinase, 14 cases had neuropathy, 5 cases had ocular lesions, 2 cases had acanthocytosis, 1 case had decreased cardiac ejection fraction, and 1 case was symptom-free. Conclusions: Early infancy failure to thrive and lipid malabsorption are common issues for CMRD patients. The Laboratory tests are characterized by hypocholesterolemia with or without fat-soluble vitamin deficiency, elevated liver enzymes and (or) creatine kinase. Currently, missense variations are frequent among the primarily homozygous SAR1B genotypes that have been described.

AGE, DISEASE DURATION AND MULTIMORBIDITY AS PREDICTORS OF HYPOGLYCEMIA IN ELDERLY AND SENILE WOMEN WITH TYPE 2 DIABETES MELLITUS

AbstractAim – to study the relationship between age, duration of the disease and concomitant chronic non-infectious pathology with the risk of developing hypoglycemia in patients with type 2 diabetes mellitus (T2DM).Material and methods. The study involved 90 elderly and senile women (mean age 70.5 ± 6.2 years) with T2DM. A detailed history of the disease was collected from all study participants, and medical documentation was studied. The indicators of clinical blood test and biochemical blood test were studied, and the Charlson comorbidity index was calculated.Results. The prevalence of hypoglycemia among patients with T2DM was: 47% in the elderly and 75% in senile patients. The correlation index between the indicators “Patient’s age” and “Presence of hypoglycemia” was r = 0.2489 (p = 0.018), which indicates a statistical dependence of these values. When calculating χ2 (chi-square), the value obtained was χ2 = 5.513 (p = 0.018). One-way analysis of variance on these values shows a result of F-ratio = 5.811 at the significance level (p = 0.018), which confirms a significant relationship between the two variables. The correlation index was calculated for the indicators “Presence of cases of hypoglycemia” and “Existence of diabetes mellitus” (r = 0.3512 with a significance level of p = 0.0007). The data allows us to draw a conclusion about the statistical dependence of these values. The result of the χ2 test for trend was the value χ2 (trend) = 10.982, (p = 0.0009). The data presented indicate the relationship between these variables. The correlation between the indicators “Presence of cases of hypoglycemia” and “Charlson Comorbidity Index (scores)” is confirmed by the value r = 0.4020 (p = 0.0001). The relationship between these variables was revealed by calculating χ2 = 16.336, (p = 0.0059). Based on the χ2 test for trend, the value χ2 (trend) = 14.544, (p = 0.0001) was obtained. One-way analysis of variance for these indicators shows the result of F-ratio = 3.734 (p = 0.004).Conclusion. The patient's age, duration of T2DM and multimorbidity are significantly associated with the risk of hypoglycemia in patients with T2DM.

Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers

BackgroundChimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If...

A machine learning approach to evaluate the impact of virtual balance/cognitive training on fall risk in older women

A machine learning approach to evaluate the impact of virtual balance/cognitive training on fall risk in older women

Unilateral gamma knife thalamotomy for tremor safety and efficacy in multimodal assessment: a prospective case-control study with two-year follow-up.

Unilateral gamma knife thalamotomy (GKT) is a treatment option for pharmacoresistant tremor of various aetiologies. There have been to date no randomised controlled trials performed to assess its safety and efficacy. Our aim was to summarise a two-year multimodal observation of patients with tremor caused by Parkinson's Disease (PD) or essential tremor (ET). 23 patients with PD (n = 12) or ET (n = 11) were included. They underwent assessments before, V0 (n = 23), and 12 months, V12 (n = 23), and 24 months, V24 (n = 15), after unilateral GKT. Patients were assessed with psychological tests and acoustic voice analysis. Tremor assessment was performed with a digitising table using the Fahn-Tolosa-Marin rating scale (FTMRS). The Unified Parkinson's Disease rating scale part III (UPDRS-III) was also used in the PD group. Gait and balance was assessed using clinical tests, stabilometric platform, and treadmill. No side effects were observed in a two-year follow-up. There was no notable deterioration observed in the patients' psychological evaluation, speech, or assessment of gait and balance. The scores were significantly lower (p = 0.01) in parts A and B of FTMRS one year after GKT. In post hoc analysis, the scores did not differ significantly between V0 and V24. In FTMRS part C (activities of daily living), no significant change was observed. There was no significant difference in total UPDRS part III score or in score of UPDRS part III domains 3 and 4 ('tremor at rest' and 'action and postural tremor of hands') between measurements. UGKT may be a safe treatment modality if performed in an experienced centre. Tremor reduction may diminish over time, and UGKT did not lead to cognitive, gait or speech deterioration in a long-term observation.

Lowering the Acquisition of Multi-drug Resistant Organism (MDROs) with Pulsed-xenon (LAMP) Study: a cluster randomized controlled, double-blinded, interventional crossover trial.

Environmental disinfection is essential for reducing spread of healthcare associated infections (HAIs). Previous studies report conflicting results regarding the effects of ultraviolet light (UV) in reducing infections. This trial evaluated the impact of adding pulsed xenon UV (PX-UV) to standard terminal cleaning in reducing environmentally-implicated HAIs (eiHAIs). The LAMP trial was conducted in 2 hospitals (15 inpatient wards) utilizing a cluster randomized controlled, double-blinded, interventional crossover trial comparing standard terminal cleaning followed by either pulsed xenon ultraviolet (PX-UV) disinfection (intervention arm) or sham disinfection (control arm). The primary outcome was incidence of eiHAIs from clinical microbiology tests on the 4th day of stay or later or within 3 days after discharge from the study unit. EiHAIs included clinical cultures positive for vancomycin-resistant enterococci (VRE), extended spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumonia, methicillin-resistant Staphylococcus aureus (MRSA), and Acinetobacter baumannii, and stool PCR positive for Clostridiodes difficile. Between May 18, 2017 to Jan 7, 2020, 25,732 patients were included, with an incidence of 601 eiHAI and 180,954 patient days. There was no difference in the rate of eiHAIs in the intervention and sham arms (3.49 vs 3.17 infections/1000 patient days respectively, RR 1.10 CI (0.94, 1.29, p= 0.23)). Study results were similar when stratified by eiHAI type, hospital, and unit type. The LAMP study failed to demonstrate an effect of the addition of UV light disinfection following terminal cleaning on reductions in rates of eiHAIs. Further investigations targeting hospital environmental surfaces and the role of no touch technology to reduce HAIs are needed.

Integrated proteogenomic analysis for inherited bone marrow failure syndrome.

Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.

Point-of-care testing: a critical analysis of the market and future trends

Point-of-care testing (POCT) involves conducting diagnostic tests outside the laboratory. These tests are utilized for their quick and reliable results in detecting chronic diseases and acute infections. We examined the historical market value trends of the POCT industry and projected its future growth. POCT devices offer several advantages, such as portability, no specific storage requirements, and simplicity of use. However, issues such as inaccurate results can reduce demand for POCT compared to traditional laboratory testing alternatives. While the benefits of POCT are clear, it’s important to acknowledge the challenges. The accuracy of POCT devices can be compromised due to factors such as user error, environmental conditions, and limitations in technology. Furthermore, the cost-effectiveness of these devices is often a concern, particularly in resource-limited settings. The regulatory landscape for POCT is also complex and varies by region, which can pose challenges for manufacturers and end-users. Improvements in POCT devices’ sensitivity, specificity, cost, and turnaround time for test results could enhance their utility. Enhancements to a POCT device should be considered if they are economically viable and lead to a significant increase in demand. Our financial analysis of the POCT market revealed a positive growth trend. We identified potential areas for growth that could help the industry progress and expand in line with its projected growth in the coming years. The industry could focus on integrating intelligent technologies into POCT devices and collaborating with the innovative technology sector to increase revenue. It could also develop more sensitive and accurate POCT devices for non-communicable diseases. Another potential area of growth is in diseases that require continuous patient monitoring but where conventional clinical testing is time-consuming. Enhancing the POCT devices used in these areas could revolutionize medical diagnosis and potentially save many lives, provided they meet clinical standards.

Nanoformulation of dasatinib cannot overcome therapy resistance of pancreatic cancer cells with low LYN kinase expression.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult to treat tumors. The Src (sarcoma) inhibitor dasatinib (DASA) has shown promising efficacy in preclinical studies of PDAC. However, clinical confirmation could not be achieved. Overall, our aim was to deliver arguments for the possible reinitiating clinical testing of this compound in a biomarker-stratifying therapy trial for PDAC patients. We tested if the nanofunctionalization of DASA can increase the drug efficacy and whether certain Src members can function as clinical predictive biomarkers. Methods include manufacturing of poly(vinyl alcohol) stabilized gold nanoparticles and their drug loading, dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, Zeta potential measurement, sterile human cell culture, cell growth quantification, accessing and evaluating transcriptome and clinical data from molecular tumor dataset TCGA, as well as various statistical analyses. We generated homo-dispersed nanofunctionalized DASA as an AuNP@PVA-DASA conjugate. The composite did not enhance the anti-growth effect of DASA on PDAC cell lines. The cell model with high LYN expression showed the strongest response to the therapy. We confirm deregulated Src kinetome activity as a prevalent feature of PDAC by revealing mRNA levels associated with higher malignancy grade of tumors. BLK (B lymphocyte kinase) expression predicts shorter overall survival of diabetic PDAC patients. Nanofunctionalization of DASA needs further improvement to overcome the therapy resistance of PDAC. LYN mRNA is augmented in tumors with higher malignancy and can serve as a predictive biomarker for the therapy resistance of PDAC cells against DASA. Studying the biological roles of BLK might help to identify underlying molecular mechanisms associated with PDAC in diabetic patients.