Current Clinical Protocols Research Articles

CD36 cell surface expression as a surrogate marker to identify ABL/JAK-class kinase fusions in pediatric BCP-ALL.

Genetic alterations are the cornerstone of risk stratification in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and their accurate identification is critical for optimal treatment. Most cases with ABL-class fusion are classified as high-risk yet display good responses to tyrosine kinase inhibitors (TKIs). Current clinical protocols recommend adding a TKI to chemotherapy as soon as possible, making it mandatory to rapidly identify these alterations. We investigated here whether the identification of immunophenotypic features associated with these molecular alterations could be a valuable screening tool. CD36 expression was shown to be a characteristic feature of ABL- or JAK-class kinase fusions. The main genetic subgroups clustering in the subset with Philadelphia (Ph)-like features were also found to display specific immunophenotypic characteristics. A predictive multiparameter scoring system was generated, segregating genetic subtypes with aberrant kinase activation (PAX5/CRLF2alt, BCR::ABL1, ABL/JAK-class). The most robust markers identified were the TSLPR with CD19/22/9/38/81/304 and CD49f. As TKI adjunction is currently limited to the ABL-class kinase fusions, immunophenotypes distinguishing ABL from JAK-class were also investigated. The flow cytometry method reported here, accessible to most hematology departments, is thus a new useful tool to quickly screen for Ph-like kinase fusion with a good sensitivity (95%) and specificity (96%).

American presidential campaign and ageism.

Ageism is still acceptable in our society, as age-focused criticism during the last American presidential campaign shows. Media and social media discourse on ageism, sexism, and racism shows the need of raising the awareness of ageism. We present Eugene Braunwald as an example of excellence at an advanced age. Dr. Braunwald, aged 95, has just published his article number 1,618. Preventing and counteracting ageism should be an objective of health-care workers, journalists, governments, companies, and civil society organizations. Some of our current clinical guidelines and medical care protocols might discriminate the elderly. To overcome age bias we must educate politicians, physicians, and the public. We propose some measures to fight against this type of discrimination, as asking politicians about age/aging/ ageism, promoting clinical trials in older patients, and avoiding the use of age alone in the decision-making processes.

Lung Involvement in Systemic Sclerosis—From Pathogenesis to Prediction

Systemic sclerosis (SSc) is a rare, multifactorial autoimmune disease characterized by widespread vascular damage and fibrosis. Pulmonary involvement is a significant manifestation of SSc, contributing to considerable morbidity and mortality. Therefore, identifying reliable biomarkers is of the utmost importance. This review explores emerging biomarkers to enhance diagnostic accuracy, prognostic assessment, and disease monitoring in SSc lung involvement. We discuss recent findings in immunological biomarkers, inflammatory indicators, and other parameters that can function as potential diagnostic and prognostic tools. A comprehensive understanding of these biomarkers could result in earlier and more accurate detection of pulmonary complications in SSc, aiding in timely intervention. Furthermore, we explore the advances in disease monitoring through innovative biomarkers, focusing on their roles in disease activity and treatment response. Integrating these novel biomarkers into current clinical practice and therapeutic protocols through clinical trials can revolutionize the management of SSc-related lung disease, ultimately improving patient outcomes and quality of life.

Comparison of data fusion strategies for automated prostate lesion detection using mpMRI correlated with whole mount histology

BackgroundIn this work, we compare input level, feature level and decision level data fusion techniques for automatic detection of clinically significant prostate lesions (csPCa).MethodsMultiple deep learning CNN architectures were developed using the Unet as the baseline. The CNNs use both multiparametric MRI images (T2W, ADC, and High b-value) and quantitative clinical data (prostate specific antigen (PSA), PSA density (PSAD), prostate gland volume & gross tumor volume (GTV)), and only mp-MRI images (n = 118), as input. In addition, co-registered ground truth data from whole mount histopathology images (n = 22) were used as a test set for evaluation.ResultsThe CNNs achieved for early/intermediate / late level fusion a precision of 0.41/0.51/0.61, recall value of 0.18/0.22/0.25, an average precision of 0.13 / 0.19 / 0.27, and F scores of 0.55/0.67/ 0.76. Dice Sorensen Coefficient (DSC) was used to evaluate the influence of combining mpMRI with parametric clinical data for the detection of csPCa. We compared the DSC between the predictions of CNN’s trained with mpMRI and parametric clinical and the CNN’s trained with only mpMRI images as input with the ground truth. We obtained a DSC of data 0.30/0.34/0.36 and 0.26/0.33/0.34 respectively. Additionally, we evaluated the influence of each mpMRI input channel for the task of csPCa detection and obtained a DSC of 0.14 / 0.25 / 0.28.ConclusionThe results show that the decision level fusion network performs better for the task of prostate lesion detection. Combining mpMRI data with quantitative clinical data does not show significant differences between these networks (p = 0.26/0.62/0.85). The results show that CNNs trained with all mpMRI data outperform CNNs with less input channels which is consistent with current clinical protocols where the same input is used for PI-RADS lesion scoring.Trial registrationThe trial was registered retrospectively at the German Register for Clinical Studies (DRKS) under proposal number Nr. 476/14 & 476/19.

The use of Bacillus subtilis as a cost-effective expression system for production of Cholera Toxin B fused factor VIII epitope regions applicable for inducing oral immune tolerance.

Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance.

AcquisitionFocus: Joint Optimization of Acquisition Orientation and Cardiac Volume Reconstruction Using Deep Learning.

In cardiac cine imaging, acquiring high-quality data is challenging and time-consuming due to the artifacts generated by the heart's continuous movement. Volumetric, fully isotropic data acquisition with high temporal resolution is, to date, intractable due to MR physics constraints. To assess whole-heart movement under minimal acquisition time, we propose a deep learning model that reconstructs the volumetric shape of multiple cardiac chambers from a limited number of input slices while simultaneously optimizing the slice acquisition orientation for this task. We mimic the current clinical protocols for cardiac imaging and compare the shape reconstruction quality of standard clinical views and optimized views. In our experiments, we show that the jointly trained model achieves accurate high-resolution multi-chamber shape reconstruction with errors of <13 mm HD95 and Dice scores of >80%, indicating its effectiveness in both simulated cardiac cine MRI and clinical cardiac MRI with a wide range of pathological shape variations.

Altered PBP4 and GdpP functions synergistically mediate MRSA-like high-level, broad-spectrum β-lactam resistance in Staphylococcus aureus.

In Staphylococcus aureus, high-level, broad-spectrum resistance to β-lactams such as methicillin, also referred to as methicillin resistance, is largely attributed to mecA. This study demonstrates that S. aureus strains that lack mecA but contain mutations that functionally alter PBP4 and GdpP can also mediate high-level, broad-spectrum resistance to β-lactams. Resistance brought about by the synergistic action of functionally altered PBP4 and GdpP was phenotypically comparable to that displayed by mecA, as seen by increased bacterial survival in the presence of β-lactams. An analysis of mutations detected in naturally isolated strains of S. aureus revealed that a significant proportion of them had similar pbp4 and GGDEF domain protein containing phosphodiesterase (gdpP) mutations, making this study clinically significant. This study not only identifies important players of non-classical mechanisms of β-lactam resistance but also indicates reconsideration of current clinical diagnosis and treatment protocols of S. aureus infections.

Abstract 7181: Low dose interleukin-6 (SON-080) for neuropathies: Toxicology and clinical plans

Abstract Neuropathies are conditions in which peripheral nerves degenerate, resulting in sensory and motor symptoms that can profoundly affect the patients’ quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is induced by most antineoplastic agents, affecting cancer patients during or following completion of treatment. Neuropathy-specific pain medication is most often inefficient against pain, can cause major side effects that limit their use, do not address non-pain related symptoms, and do not stop CIPN progression. Most evidence suggests that physical exercise is the most efficient approach to reduce neuropathy symptoms and potentially, progression. Other publications have causally linked exercise, through the ability of contracting muscles to release low levels of interleukin-6 into the bloodstream thereby activating several metabolic and physiological pathways that help regenerate muscle and nerve tissue, affect glucose homeostasis, increase lipolysis, improve microvascular blood flow and reduce inflammation. Preclinical disease models of CIPN and diabetic peripheral neuropathy (DPN) have confirmed that IL-6 administered at low doses is capable of stimulating peripheral nerve growth, thereby ameliorating motor and sensory functions and normalizing the associated pain or sensation disturbance of neuropathy. The maximum tolerated (MTD) dose of recombinant human IL-6 (rhIL-6) has been established as a treatment for thrombocytopenia in hundreds of cancer patients using the drug product that was produced in the 1990’s (Process A) dosed intravenously (IV) or subcutaneously (SC). We have developed a cGMP compliant version of rhIL-6 (SON-080) using a state-of-the-art process (Process B) that meets current regulatory guidelines for cell lines and processes. An analytical comparison of SON-080 with Process A rhIL-6 concluded that both drugs are highly comparable for at least 14 different key physicochemical characteristics. Therefore, we expect similar in vivo behavior with Process B material as compared with the Process A molecule. In order to support clinical plans for the safety and toxicity of rhIL-6, a dose range and schedule of administration that matches the current clinical protocol was performed in a cynomolgus monkey primate toxicology model. Under these conditions, SON-080 was found safe and well tolerated with a No Adverse Effect Levels (NOAEL) of 30µg/kg, the highest dose tested. On this basis, a fully controlled Phase 1b/2a clinical study, SB211, is ongoing to evaluate safety, tolerability, and efficacy of subcutaneous SON-080 dosage and administration schedule that targets an exposure mirroring the endogenous release levels elicited by moderate to heavy exercise. Confirmation of safety in the first portion of the trial will pave the way for efficacy evaluation with the objective to provide CIPN patients with a novel, safe, and effective treatment for painful neuropathies. Citation Format: Susan Dexter, Gael Hedou, Richard T. Kenney, Darrel J. Rezac, Pankaj Mohan. Low dose interleukin-6 (SON-080) for neuropathies: Toxicology and clinical plans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7181.

Analysis of Loudness Discomfort Level Tests in Tinnitus Patients

Introduction: We aimed to investigate the clinical significance of the loudness discomfort level (LDL) test in tinnitus patients and its relationship with pure-tone audiometry, tinnitogram, and questionnaires. Methods: We retrospectively reviewed the medical records of 320 tinnitus patients who visited a tertiary university hospital’s tinnitus clinic and completed LDL tests between March 2020 and December 2022. Epidemiological data and psychoacoustic test results were collected. Results: The LDL showed no significant differences between frequencies for both ears. The mean LDL did not correlate with mean pure-tone average or hearing thresholds at each frequency. The hearing loss group had a higher LDL at 8 kHz compared to the normal hearing group (p < 0.01). Objective sound intolerance was found in a quarter, correlating with subjective hyperacusis, anxiety, and depression. Weak negative correlations were found between most of questionnaire’s scores and LDL on the left side. Tinnitus loudness weak negatively correlated with LDL at most frequencies, except 8 kHz. Discussion/Conclusion: Our findings suggest a notable association between LDL levels and emotional factors in tinnitus patients, rather than with auditory thresholds. While lateralized differences in LDL responses were observed, specifically on the left side, these preliminary results do not confirm a causal link and thus do not warrant changes to current clinical testing protocols without further research.

Carbon dot dressing as a treatment of alkali-induced skin burns

Background. Chemical burns, comprising 5–10 % of total burns but causing 30 % of burn-related deaths, are now a notable concern in Ukraine. Current clinical protocols lack specific approaches for chemical burns, and research on this type of burn is limited. Carbon-based nanoparticles show promise for wound healing because of anti-inflammatory, antioxidant, and antibacterial activities. So, the ability of carbon dots obtained from citric acid and urea (further called CD) to improve the healing of alkali-induced skin burn was aimed to be discovered. Materials and Methods. The study was conducted on male Wistar rats. Burn was modeled by application of gauze disc soaked with 3 M NaOH solution on shaved skin of anesthetized rats for 10 min. A CD dressing, consisting of a CD solution (1 mg/mL) mixed with cellulose-based hydrogel that served as a vehicle, was applied to burned skin daily during a 7-day period. There were following groups: control (healthy rats), a burn-only group (rats that received no dressing), a burn + vehicle group (rats that received vehicle dressing), and a burn + CD group (rats that received CD dressing). The study involved monitoring of burn areas, conducting skin histopathology, and perfor­ming blood biochemical analyses. Results. The daily CD dressing significantly decreased alkali-induced burn area (by 76 % compared to 40 % in burn-only group) after seven daily dressings. The level of inflammation in the burn site was also less expressed in CD-treated animals, compared to respective controls (non-treated animals and animals treated with Vehicle). There was no substantial systemic toxicity of the burn (of such area) and its healing, manifested by absence of body weight loss, and absence of dramatical changes in serum biochemical parameters (indicators of liver and kidney function). However, animals of all the groups that experienced burns had a significantly lower body weight gain and mesenteric lymph nodes weight compared to healthy rats. Conclusions. So, the application of carbon dots mixed with hydrogel speeded up alkali-induced burn healing without negative impact on the organism.

Staged cluster transformers for intracranial aneurysms segmentation from structure fused 3D MRA

AbstractIntracranial aneurysms (IAs) manifest as atypical dilatation within the intracranial arterial structures, the rupture of which accounts for high mortality and morbidity rates. Current clinical protocols require radiologists to manually annotate IAs on Magnetic Resonance Angiography (MRA) images, which is inherently subjective and time‐consuming. Given these limitations, there is an urgent need to explore methods for automated and accurate segmentation of IAs from MRA images. In particular, recent years have witnessed the proliferation of sophisticated computational techniques, with deep learning algorithms—especially the 3D U‐Net and its derivatives—gaining prominence in segmentation works. Nevertheless, convolutional neural network (CNN)‐based models have an inherent limitation in capturing long‐range spatial dependencies, which inadvertently compromises the retention of global features critical for segmentation. In response to this challenge, we introduce an avant‐garde architectural design, dubbed staged cluster transformers (SCTR), which incorporates cluster mechanism into vision transformers to perform volumetric MRA image segmentation. In addition to the MRA clustering branch, the spatially aligned brain Magnetic Resonance Imaging (MRI) representation branch is also combined to extract the structural features and assist the network in learning richer contextual and boundary information for accurate voxel prediction. For validation, we utilized both a publicly available challenge dataset and an internal clinical dataset in this study. Our proposed model achieves dice similarity coefficients (DSC) of 0.5587 and 0.8110 on these two datasets, respectively, outperforming other state‐of‐the‐art approaches. The results suggest that SCTR is a promising method for automatic segmentation of IAs. Our code is available at https://github.com/guolilin/SCTR.

Personalizing the first dose of FSH for IVF/ICSI patients through machine learning: a non-inferiority study protocol for a multi-center randomized controlled trial

BackgroundAdequately selecting the initial follicle-stimulating hormone (FSH) dose during controlled ovarian stimulation (COS) is key for success in assisted reproduction. The objective of COS is to obtain an optimal number of oocytes to increase the chances of achieving a pregnancy, while avoiding complications for the patient. Current clinical protocols do achieve good results for the majority of patients, but further refinements in individualized FSH dosing may reduce the risk of poor ovarian response while also limiting the risk of ovarian hyperstimulation syndrome (OHSS) risk. Models to select the first FSH dose in COS have been presented in literature with promising results. However, most have only been developed and tested in normo-ovulatory women under the age of 40 years.MethodsThis is a randomized, controlled, multicenter, single blinded, clinical trial. This study will be performed in 236 first cycle in vitro fertilization (IVF) and/or ICSI (intracytoplasmic sperm injection) patients, randomized 1:1 in two arms. In the intervention arm, the dose of FSH will be assigned by a machine learning (ML) model called IDoser, while in the control arm, the dose will be determined by the clinician following standard practice. Stratified block randomization will be carried out depending on the patient being classified as expected low responder, high responder, or normo-responder. Patients will complete their participation in the trial once the first embryo transfer result is known. The primary outcome of the study is the number of metaphase II (MII) oocytes retrieved at ovarian pick up (OPU) and the hypothesis of non-inferiority of the intervention arm compared to the control. Secondary outcomes include the number of cycle cancelations (due to low response or no retrieval of mature oocytes), risk of ovarian hyperstimulation syndrome (OHSS), and clinical pregnancy and live birth rates per first transfer.DiscussionTo our knowledge, this is the first randomized trial to test clinical performance of an all-patient inclusive model to select the first dose of FSH for COS. Prospective trials for machine learning (ML) models in healthcare are scarce but necessary for clinical application.Trial registrationClinicalTrials.gov, NCT05948293. Registered on 14 July 2023.

EARLY DETECTION OF DEMENTIA AND MILD COGNITIVE IMPAIRMENT WITH BRAINCHECK

Abstract Dementia is projected to affect 14 million people in the United States and 152 million people globally in the coming decades. Early detection of dementia, which involves diagnosis of mild cognitive impairment (MCI), a possible prestage of dementia, is critical for intervention and care planning but remains a challenge with current clinical protocols. While brief screening tools are narrow in scope, comprehensive neuropsychological tests are time-consuming and require specialized training and expertise to conduct and interpret results. BrainCheck, a computerized cognitive assessment tool, provides an accessible and promising solution to address these current challenges. The aim of this study was to evaluate BrainCheck for its diagnostic accuracy and ability to distinguish the severity of cognitive impairment. A total of 99 participants clinically diagnosed with dementia (DEM; n=42), MCI (n=22), or normal cognition (NC; n=35) completed the BrainCheck battery. Statistical analyses compared participant performances on BrainCheck based on their diagnostic group. BrainCheck battery performance showed significant differences between the three groups, achieving 88% or higher sensitivity and specificity for separating DEM from NC, and 77% or higher sensitivity and specificity in separating the MCI group from the NC and DEM groups. Three-group classification found true positive rates of 80% or higher for the NC and dementia groups and true positive rates of 64% or higher for the MCI group. These results show that BrainCheck was able to distinguish between diagnoses of DEM, MCI, and NC, providing a potentially reliable tool for early detection of cognitive impairment.

Proton pencil beam scanning craniospinal irradiation (CSI) with a single posterior brain beam: Dosimetry and efficiency

This study explores the feasibility and potential dosimetric and time efficiency benefit of proton Pencil Beam Scanning (PBS) craniospinal irradiation with a single posterior-anterior (SPA) brain field. The SPA approach was compared to our current clinical protocol using Bilateral Posterior Oblique brain fields (BPO). Ten consecutive patients were simulated in the head-first supine position on a long BOS frame and scanned using 3 mm CT slice thickness. A customized thermoplastic mask immobilized the patient's head, neck, and shoulders. A vac-lock was used to secure the legs. PBS proton plans were robustly optimized with 3mm setup errors and 3.5% range uncertainties in the Eclipse V15.6 treatment planning system (n = 12 scenarios). In order to achieve a smooth gradient dose match at the junction area, at least 5 cm overlap region was maintained between the segments and 5 mm uncertainty along the cranial-cauda direction was applied to each segment independently as additional robust optimization scenarios. The brain doses were planned by SPA or BPO fields. All spine segments were planned with a single PA field. Dosimetric differences between the BPO and SPA approaches were compared, and the treatment efficiency was analyzed according to timestamps of beam delivery. Results: The maximum brain dose increases to 111.1 ± 2.1% for SPA vs. 109.0 ± 1.7% for BPO (p < 0.01). The dose homogeneity index (D5/D95) in brain CTV was comparable between techniques (1.037 ± 0.010 for SPA and 1.033 ± 0.008 for BPO). Lens received lower maximum doses by 2.88 ± 1.58 Gy (RBE) (left) and 2.23 ± 1.37 Gy (RBE) (right) in the SPA plans (p < 0.01). No significant cochlea dose change was observed. SPA reduced the treatment time by more than 4 minutes on average and ranged from 2 to 10 minutes, depending on the beam waiting and allocation time. SPA is dosimetrically comparable to BPO, with reduced lens doses at the cost of slightly higher dose inhomogeneity and hot spots. Implementation of SPA is feasible and can help to improve the treatment efficiency of PBS CSI treatment.

Repetitive transcranial magnetic stimulation (rTMS) triggers dose-dependent homeostatic rewiring in recurrent neuronal networks.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to induce neuronal plasticity in healthy individuals and patients. Designing effective and reproducible rTMS protocols poses a major challenge in the field as the underlying biomechanisms of long-term effects remain elusive. Current clinical protocol designs are often based on studies reporting rTMS-induced long-term potentiation or depression of synaptic transmission. Herein, we employed computational modeling to explore the effects of rTMS on long-term structural plasticity and changes in network connectivity. We simulated a recurrent neuronal network with homeostatic structural plasticity among excitatory neurons, and demonstrated that this mechanism was sensitive to specific parameters of the stimulation protocol (i.e., frequency, intensity, and duration of stimulation). Particularly, the feedback-inhibition initiated by network stimulation influenced the net stimulation outcome and hindered the rTMS-induced structural reorganization, highlighting the role of inhibitory networks. These findings suggest a novel mechanism for the lasting effects of rTMS, i.e., rTMS-induced homeostatic structural plasticity, and highlight the importance of network inhibition in careful protocol design, standardization, and optimization of stimulation.

Abstract 195: Changing Trends of Thrombolysis and Thrombectomy for Low Severity Stroke: National Inpatient Sample Analysis (2016‐2020)

Introduction Over the past decade, stroke management has significantly improved with the widespread use of intravenous thrombolysis (IVT) and the establishment of endovascular thrombectomy (EVT) as the standard of care for increasing patients. However, a dilemma arises in cases of low‐severity stroke (NIHSS ≤ 5), as the EVT clinical trials do not include patients with such low NIHSS. There is debate surrounding the topic of EVT and IVT for low‐severity stroke, and often practice does not reflect the patient populations included in the initial clinical trials. Some recent studies suggest a trend toward decreasing pre‐thrombectomy IVT. (1) This study aims to examine the evolving trends of intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), and their combination in low NIHSS acute ischemic stroke (AIS) management in the United States from 2016 to 2020. Methods We accessed the national inpatient sample database from 2016 through 2020. We included patients admitted with stroke and who had a recorded NIHSS ≤ 5. To determine if there were changes in the frequency of events over time, we compared the outcome measures utilizing logistic regression models with 2016 as the reference year. Results Compared to 2016 the rates of IVT have significantly decreased starting in 2018 through 2020. The rates of EVT have trended upward since 2016 and were significantly higher in the year 2020. The rates of thrombectomy plus thrombolysis have trended upward but have not significantly changed since 2016. These results can be visualized in the Figure below, * = p‐value &lt; 0.05. Conclusion Our findings highlight a significant shift in stroke treatment, with the growing use of EVT while simultaneously decreasing rates of IVT for low‐NIHSS strokes. Current clinical trials protocol are submitted to examine EVT's efficacy for low NIHSS stroke (2), but it's also crucial to understand what is driving this change in real‐world practice. This understanding will inform treatment decisions and ensure they align with evidence‐based standards, guaranteeing optimal, standardized patient care.

Magnetic separation and concentration of Aβ 1–42 molecules dispersed at the threshold concentration for Alzheimer’s disease diagnosis in clinically-relevant volumes of sample

BackgroundAlzheimer’s disease (AD) is the leading cause of dementia and loss of autonomy in the elderly, implying a progressive cognitive decline and limitation of social activities. The progressive aging of the population is expected to exacerbate this problem in the next decades. Therefore, there is an urgent need to develop quantitative diagnostic methodologies to assess the onset the disease and its progression especially in the initial phases.ResultsHere we describe a novel technology to extract one of the most important molecular biomarkers of AD (Aβ1−42) from a clinically-relevant volume − 100 µl – therein dispersed in a range of concentrations critical for AD early diagnosis. We demonstrate that it is possible to immunocapture Aβ1−42 on 20 nm wide magnetic nanoparticles functionalized with hyperbranced KVLFF aptamers. Then, it is possible to transport them through microfluidic environments to a detection system where virtually all (~ 90%) the Aβ1−42 molecules are concentrated in a dense plug of ca.50 nl. The technology is based on magnetic actuation by permanent magnets, specifically designed to generate high gradient magnetic fields. These fields, applied through submillimeter-wide channels, can concentrate, and confine magnetic nanoparticles (MNPs) into a droplet with an optimized shape that maximizes the probability of capturing highly diluted molecular biomarkers. These advancements are expected to provide efficient protocols for the concentration and manipulation of molecular biomarkers from clinical samples, enhancing the accuracy and the sensitivity of diagnostic technologies.ConclusionsThis easy to automate technology allows an efficient separation of AD molecular biomarkers from volumes of biological solutions complying with the current clinical protocols and, ultimately, leads to accurate measurements of biomarkers. The technology paves a new way for a quantitative AD diagnosis at the earliest stage and it is also adaptable for the biomarker analysis of other pathologies.

Image Segmentation for High-Density Surface Electromyography Mappings of Pelvic Floor Muscle Activity of Women with Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) can result in pelvic floor muscle (PFM) overactivity. Current clinical assessment protocols include basic electromyographic assessment of PFM activation; however, they do not provide a comprehensive assessment localized to each region of the PFM. We examined the ability of high-definition features from intravaginal high-density surface electromyography (HD-sEMG) to assess the severity of PFM overactivity in female IC/BPS patients. HD-sEMG was collected from fifteen female IC/BPS patients and fifteen urologically healthy female controls. The 2D mappings of root mean squared amplitude (RMS) at rest normalized by maximal voluntary contraction (resting RMS ratios) were segmented via k-means to identify areas of peak activity and surrounding activity. Female IC/BPS patients exhibited significantly greater resting RMS ratios for peak activity (p=0.0096), surrounding activity (p=0.0003), and average activity (p=0.0016) compared to healthy female controls. Furthermore, the area of peak activity was significantly larger for female IC/BPS patients than for healthy female controls (p=0.0063). Image segmentation of intravaginal HD-sEMG provides a more robust biomarker of PFM as compared to current methods.

Validation of the Ukrainian and Russian versions of the KPPS

Background. The purpose of the study is to validate the Ukrainian and Russian versions of the King’s Parkinson’s disease Pain Scale (KPPS). Materials and methods. The study was conducted at the Odesa Regional Clinical Hospital in 2018–2020. We examined 160 patients with Parkinson’s disease verified by the Parkinson’s UK Brain Bank criteria (main group) and 100 people of the same age without signs of extrapyramidal pathology (controls). All patients were examined in accordance with the requirements of current clinical protocols. Additionally, all study participants answered the questions of the KPPS provided in the Ukrainian or Russian version. Mann-Whitney method with Benjamini-Hochberg correction was used for multiple comparisons. Results. Pain of varying severity was detected in 121 of 160 (75.6 %) patients with PD. There were no cases of pain in the control group. The most common was nocturnal (52.5 %) and musculoskeletal pain, both isolated (23.1 %) and in various combinations (up to 65.6 %). Pain associated with motor fluctuations occurred in 27 (5.1 %) cases. Central chronic pain was detected in 22 (13.8 %) patients, visceral chronic pain — in 11 (6.9 %). Orofacial pain was noted in 19 (11.9%) cases. Pain associated with edema and signs of inflammation was found in 24 (15.0 %), radicular pain — in 17 (10.6%) people. Cronbach’s alpha for all domains of the scale was higher than 0.7. Pain severity by the visual analogue scale correlated with the KPSS score (r = 0.53). Conclusions. The study data indicated the acceptable validity of the Ukrainian and Russian versions of the KPSS. The questionnaire can be recommended for widespread use in assessing the phenotype of pain and its severity in patients with Parkinson’s disease.

Breast Sarcomas-How Different Are They from Breast Carcinomas? Clinical, Pathological, Imaging and Treatment Insights.

Breast sarcoma (BS) is a very rare and poorly studied condition. This has led to a lack of studies with a high level of evidence and to low efficacy of current clinical management protocols. Here we present our experience in treating this disease in the form of a retrospective case series study including discussion of clinical, imaging, and pathological features and treatment. We also compare the main clinical and biological features of six cases of BS (phyllodes tumors were excluded) with a cohort of 184 patients with unilateral breast carcinoma (BC) from a previous study performed at our institution. Patients with BS were diagnosed at a younger age, presented no evidence of lymph node invasion or distant metastases, had no multiple or bilateral lesions, and underwent a shorter length of hospital stay versus the breast carcinoma group. Where recommended, adjuvant chemotherapy consisted of an anthracycline-containing regimen, and adjuvant external radiotherapy was delivered in doses of 50 Gy. The comparison data obtained from our BS cases and the ones with BC revealed differences in diagnosis and treatment. A correct pathological diagnosis of breast sarcoma is essential for the right therapeutic approach. We still have more to learn about this entity, but our case series could add value to existing knowledge in a meta-analysis study.