Patient-specific Protocols Research Articles

Engineering and Technological Advancements in Repetitive Transcranial Magnetic Stimulation (rTMS): A Five-Year Review

In the past five years, repetitive transcranial magnetic stimulation (rTMS) has evolved significantly, driven by advancements in device design, treatment protocols, software integration, and brain-computer interfaces (BCIs). This review evaluates how these innovations enhance the safety, efficacy, and accessibility of rTMS while identifying key challenges such as protocol standardization and ethical considerations. A structured review of peer-reviewed studies from 2019 to 2024 focused on technological and clinical advancements in rTMS, including AI-driven personalized treatments, portable devices, and integrated BCIs. AI algorithms have optimized patient-specific protocols, while portable devices have expanded access. Enhanced coil designs and BCI integration offer more precise and adaptive neuromodulation. However, challenges remain in standardizing protocols, addressing device complexity, and ensuring equitable access. While recent innovations improve rTMS’s clinical utility, gaps in long-term efficacy and ethical concerns persist. Future research must prioritize standardization, accessibility, and robust ethical frameworks to ensure rTMS’s sustainable impact.

A machine learning approach to predict in vivo skin growth

Since their invention, tissue expanders, which are designed to trigger additional skin growth, have revolutionised many reconstructive surgeries. Currently, however, the sole quantitative method to assess skin growth requires skin excision. Thus, in the context of patient outcomes, a machine learning method which uses non-invasive measurements to predict in vivo skin growth and other skin properties, holds significant value. In this study, the finite element method was used to simulate a typical skin expansion protocol and to perform various simulated wave propagation experiments during the first few days of expansion on 1,000 individual virtual subjects. An artificial neural network trained on this dataset was shown to be capable of predicting the future skin growth at 7 days (avg. R2=0.9353\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2 = 0.9353$$\\end{document}) as well as the subject-specific shear modulus (R2=0.9801\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2 = 0.9801$$\\end{document}), growth rate (R2=0.8649\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2 = 0.8649$$\\end{document}), and natural pre-stretch (R2=0.9783\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2 = 0.9783$$\\end{document}) with a very high degree of accuracy. The method presented here has implications for the real-time prediction of patient-specific skin expansion outcomes and could facilitate the development of patient-specific protocols.

Protocol optimization for functional cardiac CT imaging using noise emulation in the raw data domain.

Four-dimensional (4D) wide coverage computed tomography (CT) is an effective imaging modality for measuring the mechanical function of the myocardium. However, repeated CT measurement across a number of heartbeats is still a concern. A projection-domain noise emulation method is presented to generate accurate low-dose (mA modulated) 4D cardiac CT scans from high-dose scans, enabling protocol optimization to deliver sufficient image quality for functional cardiac analysis while using a dose level that is as low as reasonably achievable (ALARA). Given a targeted low-dose mA modulation curve, the proposed noise emulation method injects both quantum and electronic noise of proper magnitude and correlation to the high-dose data in projection domain. A spatially varying (i.e., channel-dependent) detector gain term as well as its calibration method were proposed to further improve the noise emulation accuracy. To determine the ALARA dose threshold, a straightforward projection domain image quality (IQ) metric was proposed that is based on the number of projection rays that do not fall under the non-linear region of the detector response. Experiments were performed to validate the noise emulation method with both phantom and clinical data in terms of visual similarity, contrast-to-noise ratio (CNR), and noise-power spectrum (NPS). For both phantom and clinical data, the low-dose emulated images exhibited similar noise magnitude (CNR difference within 2%), artifacts, and texture to that of the real low-dose images. The proposed channel-dependent detector gain term resulted in additional increase in emulation accuracy. Using the proposed IQ metric, recommended kVp and mA settings were calculated for low dose 4D Cardiac CT acquisitions for patients of different sizes. A detailed method to estimate system-dependent parameters for a raw-data based low dose emulation framework was described. The method produced realistic noise levels, artifacts, and texture with phantom and clinical studies. The proposed low-dose emulation method can be used to prospectively select patient-specific minimal-dose protocols for functional cardiac CT.

Estimation of organ and effective doses of CBCT scans of radiotherapy using size-specific field of view (FOV): a Monte Carlo study.

The kV cone beam computed tomography (CBCT) is one of the most common imaging modalities used for image-guided radiation therapy (IGRT) procedures. Additional doses are delivered to patients, thus assessment and optimization of the imaging doses should be taken into consideration. This study aimed to investigate the influence of using fixed and patient-specific FOVs on the patient dose. Monte Carlo simulations were performed to simulate kV beams of the imaging system integrated into Truebeam linear accelerator using BEAMnrc code. Organ and size-specific effective doses resulting from chest and pelvis scanning protocols were estimated with DOSXYZnrc code using a phantom library developed by the National Cancer Institute (NCI) of the US. The library contains 193 (100 male and 93 female) mesh-type computational human adult phantoms, and it covers a large ratio of patient sizes with heights and weights ranging from 150 to 190cm and 40 to 125kg. The imaging doses were assessed using variable FOV of three sizes, small (S), medium (M), and large (L) for each scan region. The results show that the FOV and the patient size played a major role in the scan dose. The average percentage differences (PDs) for doses of organs that were fully inside the different FOVs were relatively low, all within 11% for both protocols. However, doses to organs that were scanned partially or near the FOVs were affected significantly. For the chest protocol, the inclusion of the thyroid in the scan field could give a dose of 1-7mGy/100mAs to the thyroid, compared to 0.4-1mGy/100mAs when it was excluded. Similarly, on average, testes doses could be 6mGy/100mAs for the male pelvis protocol compared to 3mGy/100mAs when it did not lie in the field irradiated. These dose differences resulted in an average increase of up to 27% in the size-specific effective dose of the protocols. Since changing the field size is possible for CBCT scans, the results suggest that patient-specific scanning protocols could be applied for each scan area in a manner similar to that used for CT scans. Adjustment of the FOV size should be subject to the clinical needs, and assist in improving the treatment accuracy. The patient's height and weight might be considered as the main factors upon which, the selection of the appropriate patient-specific protocol is based. This approach should optimize the imaging doses used for IGRT procedures by minimizing doses of a large ratio of patients.

Investigating nano-sized tumor-derived extracellular vesicles in enhancing anti-PD-1 immunotherapy.

Anti-PD1 immune checkpoint blockade (ICB) has shown promising results for treating several aggressive cancers, enhancing patient survival rates. The variability in clinical response to anti-PD1 ICB is thought to be driven by patient-specific biology and heterogeneity within the tumor microenvironment. Tumor-derived extracellular vesicles (TDEVs), nano-sized particles released from tumor cells, can modulate the tumor microenvironment, leading to immunosuppression and tumor progression. Hence, TDEVs may contribute to the variability in treatment response and play a crucial role in the failure of anti-PD1 immunotherapy. In this study, we develop a systems biology approach to interrogate the role of TDEVs on the response dynamics for anti-PD1 blockade. Our results suggest that the detection and profiling of TDEVs can help screen patients for anti-PD-1 immunotherapy. Moreover, the results in this study suggest that TDEVs and IL-12 can potentially be liquid biopsy biomarkers to profile patient response to anti-PD1 ICB and tailor patient-specific treatment protocols. Importantly, the methodology is generalizable to other types of cancer immunotherapies. Therefore, the collection of patient-specific liquid biopsy data, and the implementation of those data into the systems biology framework, may offer the opportunity to discover new biomarkers for patient drug screening and enable the continuous monitoring of patient response to treatment and adaptation of patient-specific immunotherapy treatment protocols to overcome therapeutic resistance.

Efficacy and safety of steroids for chronic subdural hematoma: A systematic review and meta-analysis

Background: Chronic subdural hematoma (CSDH) is a condition characterized by the accumulation of fluid, blood, and blood breakdown products between the brain’s arachnoid and dura mater coverings. While steroids have been explored as a potential treatment option, their efficacy and safety remain uncertain. This meta-analysis and systematic review aimed to assess the impact of steroids on CSDH management, including mortality, recurrence, complications, and functional outcomes. Methods: We conducted a comprehensive literature search in major electronic databases up to June 2023, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Cochrane Handbook for Systematic Reviews and Interventions. Inclusion criteria encompassed adult patients with CSDH, the use of steroids as monotherapy or adjuvant therapy, and clearly defined outcomes. Randomized controlled trials and cohort studies meeting these criteria were included in the study. Results: The initial search yielded 4315 articles, with 12 studies meeting the inclusion criteria. Our findings indicate a non-significant trend toward reduced mortality with steroids in combination with standard care (Odds ratios [OR] = 0.66, 95% confidence interval [CI] 0.20–2.18). However, substantial heterogeneity was observed (I2 = 70%). Sensitivity analysis, excluding influential studies, suggested a potential increased mortality risk associated with steroids (OR = 1.47, 95% CI 0.87–2.48). Steroids showed a possible benefit in reducing the recurrence of CSDH (OR = 0.58, 95% CI 0.20–1.67), but with significant heterogeneity (I2 = 89%). No clear advantage of steroids was observed in terms of functional outcomes at three months (modified Rankin scale scores). Furthermore, steroids were associated with a significantly higher incidence of adverse effects and complications (OR = 2.17, 95% CI 1.48–3.17). Conclusion: Steroids may have a potential role in reducing CSDH recurrence but do not appear to confer significant advantages in terms of mortality or functional outcomes. However, their use is associated with a higher risk of adverse effects and complications. Given the limitations of existing studies, further research is needed to refine the role of steroids in CSDH management, considering patient-specific factors and treatment protocols.

Benefits of Dual-Layer Spectral CT Imaging in Staging and Preoperative Evaluation of Pancreatic Ductal Adenocarcinoma.

Imaging of pancreatic malignancies is challenging but has a major impact on the patients therapeutic approach and outcome. In particular with pancreatic ductal adenocarcinoma (PDAC), usually a hypovascularized tumor, conventional CT imaging can be prone to errors in determining tumor extent and presence of metastatic disease. Dual-layer spectral detector CT (SDCT) is an emerging technique for acquiring spectral information without the need for prospective patient selection or specific protocols, with a detector capable of differentiating high- and low-energy photons to acquire full spectral images. In this review, we present the diagnostic benefits and capabilities of modern SDCT imaging with a focus on PDAC. We highlight the most useful virtual reconstructions in oncologic imaging and their benefits in staging and assessment of resectability in PDAC, including the assessment of tumor extent, vascular infiltration, and metastatic disease. We present imaging examples on a latest-generation SDCT scanner.

COAST Development Group's international consensus guidelines for the treatment of canine osteoarthritis.

This report describes consensus guidelines and recommendations for the treatment of canine osteoarthritis (OA) according to the "Canine OsteoArthritis Staging Tool excluding radiography" (COASTeR) stage of OA, by the COAST Development Group. The recommendations are based on evidence-based medicine and clinical experience and are proposed with international relevance in mind. The aim is to provide veterinarians with a practical reference to consolidated information and to support the development of patient-specific OA management protocols and informed treatment choices based on the stage of OA.

Widespread localized areas of annular patches, plaques, and erythema.

Without prompt diagnosis and treatment, patients with Lyme disease may develop life threatening multi-organ system complications. As such, we discuss the key diagnostic features of the condition along with patient-specific suggested treatment protocols. Additionally, Lyme disease is reportedly expanding to regions that were previously not impacted, key epidemiological features are outlined. We discuss a patient with severe Lyme disease who presented with widespread cutaneous involvement and atypical pathologic findings within an uncharacteristic geographic region. Erythematous, annular patches and plaques with dusky-to-clear centers were initially observed on the right thigh and later extended to the trunk and bilateral lower extremities. The diagnosis of Lyme disease was made clinically and confirmed with western blot testing that was positive for IgM antibodies. The patient additionally had a history of rheumatoid arthritis, for which he discontinued treatment prior to the current presentation with Lyme disease. During follow up visits, the patient noted lower extremity joint pain. Due to the overlapping clinical features of post-Lyme arthritis and rheumatoid arthritis, key differences are outlined to prevent misdiagnosis. Data revealing trends in the geographic distribution of the disease and possible need for increased surveillance and prevention strategies within previously unaffected areas are discussed.

Cumulative exposure and lifetime cancer risk from diagnostic radiation in patients undergoing orthognathic surgery: a cross-sectional analysis

Radiation doses in dentomaxillofacial imaging are typically very low. However, diagnostic and follow-up protocols in orthognathic surgery result in a patient-specific risk in effective dose. Estimating the cancer risks from these exposures remains abstract for many maxillofacial surgeons. In this study, 40 orthognathic patients were randomly sampled and their cumulative effective dose (ED) calculated. The lifetime attributable risk of cancer (LAR) was calculated based on the standard radiological protocol for orthognathic surgery follow-up using methods described in the BEIR VII report and RadRAT. The mean cumulative ED of the 40 sampled patients at the end of their 2-year follow-up period was 1.91 ± 0.58 mSv. The LAR at the end of follow-up was 17.65 (90% confidence interval 6.46–32.90) per 100,000 person-years for male orthognathic patients and 13.93 (90% confidence interval 6.27–25.24) per 100,000 person-years for female orthognathic patients. This represents 0.70% and 0.68%, respectively, of the baseline cancer risk for oral, thyroid, and brain cancer combined. Although theoretical, these results provide a framework for interpreting radiation doses and cancer risks in patients undergoing orthognathic surgery. Considering the increased radiation sensitivity in children and adolescents, indication-oriented and patient-specific imaging protocols should be advised.

Retrospective analysis of nurse-administered fall assessment scales in the Epilepsy Monitoring Unit

IntroductionInpatient falls within the Epilepsy Monitoring Unit (EMU) are a common, and potentially preventable adverse event contributing to morbidity for patients living with epilepsy. Accurate fall risk screening is important to identify and efficiently allocate proper safety measures to high-risk patients, especially in EMUs with limited resources. We sought to compare existing screening tools for the ability to predict falls in the EMU. MethodsThis is a retrospective, single-center, case-controlled, comparative analysis of 7 nurse-administered fall risk assessment tools (NAFRAT) of patients admitted to the Vanderbilt University Medical Center (VUMC) EMU. Analysis of categorical data was compared using chi-square analysis while quantitative distributions were compared using student’s t-test. ResultsA total of 56 patient records (28 falls and 28 controls) were included in the analysis. Epilepsy Monitoring Unit falls were most common within the first 3 days of admission (p = .0094). Pre-admission documentation of falls was a strong predictor of falls within the EMU (p < .0001). Epilepsy Monitoring Unit falls were associated with documented falls after EMU discharge (p = .011). The John Hopkins fall risk assessment tool (JHFRAT) accurately stratified fall risk in the fall group compared to the control (p = .008), however, none of the 7 NAFRATs demonstrated significant categorical differences among the epilepsy subgroups. There was a significant difference in the distribution of quantitative scores, higher in the fall group according to the Morse Fall Scale (MFS) (p = 0.012), JHFRAT (p = 0.003), Schmid Fall Risk Assessment Scale (p = 0.029) and Hester-Davis Scale (p = 0.049). The modified Conley (p = 0.03) and Morse scale (p = 0.025) demonstrated differences in the distribution of quantitative scores in the epilepsy subgroups. ConclusionThe findings of this study demonstrate variable accuracy of NAFRATs in assessing fall risk among patients admitted to the EMU, particularly among patients with epilepsy. The findings underscore the need for a validated, EMU-specific, fall assessment tool that accurately stratifies fall risk and inform efficient use of patient-specific fall prevention resources and protocols.

PO036 / #609 REFINEMENT OF GRANULARITY OF CORTICAL ATLAS TO MODEL EPILEPTIC INTERICTAL SPIKE PROPAGATION: E-POSTER VIEWING

In patients with drug-resistant partial epilepsy, intracerebral recordings with stereoelectroencephalography (SEEG) are performed in order to localize the activity arising from epileptogenic tissues and its propagation patterns. The clinical interpretation of SEEG signals is crucial to delimit surgery boundaries or to design patient-specific neuromodulation protocols. To assist these interpretations, physiologically relevant computational and anatomical models can be combined to reconstruct in silico intracerebral SEEG signals and to link the signal morphology with the geometry of underlying epileptic regions.

Personalizing repetitive transcranial magnetic stimulation for precision depression treatment based on functional brain network controllability and optimal control analysis

Brain neuromodulation effectively treats neurological diseases and psychiatric disorders such as Depression. However, due to patient heterogeneity, neuromodulation treatment outcomes are often highly variable, requiring patient-specific stimulation protocols throughout the recovery stages to optimize treatment outcomes. Therefore, it is critical to personalize neuromodulation protocol to optimize the patient-specific stimulation targets and parameters by accommodating inherent interpatient variability and intersession alteration during treatments. The study aims to develop a personalized repetitive transcranial magnetic stimulation (rTMS) protocol and evaluate its feasibility in optimizing the treatment efficiency using an existing dataset from an antidepressant experimental imaging study in depression. The personalization of the rTMS treatment protocol was achieved by personalizing both stimulation targets and parameters via a novel approach integrating the functional brain network controllability analysis and optimal control analysis. First, the functional brain network controllability analysis was performed to identify the optimal rTMS stimulation target from the effective connectivity network constructed from patient-specific resting-state functional magnetic resonance imaging data. The optimal control algorithm was then applied to optimize the rTMS stimulation parameters based on the optimized target. The performance of the proposed personalized rTMS technique was evaluated using datasets collected from a longitudinal antidepressant experimental imaging study in depression (n = 20). Simulation models demonstrated that the proposed personalized rTMS protocol outperformed the standard rTMS treatment by efficiently steering a depressive resting brain state to a healthy resting brain state, indicated by the significantly less control energy needed and higher model fitting accuracy achieved. The node with the maximum average controllability of each patient was designated as the optimal target region for the personalized rTMS protocol. Our results also demonstrated the theoretical feasibility of achieving comparable neuromodulation efficacy by stimulating a single node compared to stimulating multiple driver nodes. The findings support the feasibility of developing personalized neuromodulation protocols to more efficiently treat depression and other neurological diseases.

Young men are at higher risk of failure after ACL hamstring reconstructions: a retrospective multivariate analysis

BackgroundResults of ACL reconstruction are influenced by both patient and surgical variables. Until now a significant amount of studies have focused on the influence of surgical technique on primary outcome, often leaving patient variables untouched. This study investigates the combined influence of patient and surgical variables through multivariate analysis.MethodsSingle-center retrospective cohort study. All patients who underwent primary ACL hamstring reconstruction within a 5-year period were included. Patient characteristics (gender, age, height, weight, BMI at time of surgery) and surgical variables (surgical technique, concomitant knee injury, graft diameter, type of femoral and tibial fixation) were collected. Patients were asked about Tegner Activity Scale (TAS), complications and revision surgery. Multivariate logistic regression was used to study risk factors. First graft failure and potential risk factors (patient and surgical) were univariately assessed. Risk factors with a p-value ≤ 0.05 were included in the multivariate model.ResultsSix hundred forty-seven primary ACL hamstring reconstructions were included. There were 41 graft failures (failure rate 6.3%). Patient gender, age, height and preoperative TAS had a significant influence on the risk of failure in the univariate analysis. The multivariate analyses showed that age and sex remained significant independent risk factors. Patients with a failed ACL reconstruction were younger (24.3 vs 29.4 years, OR 0.937), with women at a lower risk for failure of their ACL reconstruction (90.2% males vs 9.8% females, female OR 0.123). ACL graft diameter and other surgical variables aren’t confounders for graft failure.ConclusionThis study shows that patient variables seem to have a larger influence on the failure rate of ACL hamstring reconstructive surgery than surgical variables. Identification of the right patient variables can help us make more informed decisions for our patients and create patient-specific treatment protocols. Young men’s higher risk of failure suggests that these patients may benefit from a different reconstruction technique, such as use of a patellar tendon or combined ligament augmentation.Level of evidenceRetrospective cohort III.

Transcranial magnetic stimulation for post-operative neurorehabilitation in neuro-oncology: a review of the literature and future directions.

Transcranial magnetic stimulation (TMS) is a neuromodulation technology capable of targeted stimulation and inhibition of cortical areas. Repetitive TMS (rTMS) has demonstrated efficacy in the treatment of several neuropsychiatric disorders, and novel uses of rTMS for neurorehabilitation in patients with acute and chronic neurologic deficits are being investigated. However, studies to date have primarily focused on neurorehabilitation in stroke patients, with little data supporting its use for neurorehabilitation in brain tumor patients. We performed a review of the current available literature regarding uses of rTMS for neurorehabilitation in post-operative neuro-oncologic patients. Data have demonstrated that rTMS is safe in the post-operative neuro-oncologic patient population, with minimal adverse effects and no documented seizures. The current evidence also demonstrates potential effectiveness in terms of neurorehabilitation of motor and language deficits. Although data are overall limited, both safety and effectiveness have been demonstrated for the use of rTMS for neurorehabilitation in the neuro-oncologic population. More randomized controlled trials and specific comparisons of contralateral versus ipsilateral rTMS protocols should be explored. Further work may also focus on individualized, patient-specific TMS treatment protocols for optimal functional recovery.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition.

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h–6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.

Physiological parameters related to oocyte nuclear differentiation for the improvement of IVM/IVF outcomes in women and cattle.

In vitro maturation (IVM) has been applied in numerous different contexts and strategies in humans and animals, but in both cases it represents a challenge still far from being overcome. Despite the large dataset produced over the last two decades on the mechanisms that govern antral follicular development and oocyte metabolism and differentiation, IVM outcomes are still unsatisfactory. This review specifically focuses on data concerning the potential consequences of using supraphysiological levels of FSH during IVM, as well as on the regulation of oocyte chromatin dynamics and its utility as a potential marker of oocyte developmental competence. Taken together, the data revisited herein indicate that a significant improvement in IVM efficacy may be provided by the integration of pre-OPU patient-specific protocols preparing the oocyte population for IVM and more physiological culture systems mimicking more precisely the follicular environment that would be experienced by the recovered oocytes until completion of metaphase II.

Forces Exerted in Craniofacial Distraction Osteogenesis.

The purpose of this study was to develop a methodology for quantifying linear forces of distraction osteogenesis, and thereafter apply this methodology to measure and compare distraction force magnitudes between cranial vault distraction osteogenesis (CVDO) and mandibular distraction osteogenesis (MDO). Patients undergoing CVDO or MDO as inpatients had distraction forces acquired with a digital torque-measuring screwdriver. Torque measurements were then converted into linear distraction force values, which were then compared across distraction types and protocols with appropriate statistics. CVDO was performed on 7 patients (41.2%), and MDO was performed on 10 patients (58.8%). Across the entire cohort, the average maximum force per activation was 27.0 N, and the average elastic force was 10.7 N. Maximum force (CVDO: 52.9 N versus MDO: 12.9 N; P < 0.001) and elastic force (CVDO: 22.0 N versus MDO: 4.5 N; P < 0.001) were significantly higher in patients undergoing CVDO than MDO. Multivariate regression demonstrated that maximum activation force was significantly associated with sequential days of distraction (B= + 1.1 N/day; P < 0.001), distraction rate (B= + 8.9 N/mm/day; P = 0.016), distractor hardware failure (B= + 10.3 N if failure; P = 0.004), and distraction type (B= + 41.4 N if CVDO; P < 0.001). Cranial vault distraction requires significantly more linear distraction force than mandibular distraction. Maximum forces increase with each day of distraction, as well as with increased distraction rates. Linear distraction force methodology from this study may provide the foundation for future development of optimized procedure-specific or patient-specific distraction protocols.

Minimal PK/PD model for simultaneous description of the maximal tolerated dose and metronomic treatment outcomes in mouse tumor models.

Metronomic chemotherapy (MC) is a promising approach where, in contrast to the conventional maximal tolerated dose (MTD) strategy, regular fractionated doses of the drug are used. This approach has proven its efficacy, although drug dosing and scheduling are often chosen empirically. Pharmacokinetic/pharmacodynamic (PK/PD) models provide a way to choose optimal protocols with computational methods. Existing models are usually too complicated and are valid for only a subset of drug schedules. To address this issue, we propose herein a simple model that can describe MC and MTD regimens simultaneously. The minimal model comprises tumor suppression due to antiangiogenic drug effect together with a cell-kill term, responsible for its cytotoxicity. The model was tested on data obtained on tumor-bearing mice treated with gemcitabine in ether MTD, MC, or combined (MTD + MC) regimens. We conducted a number of tests in which data were divided in various ways into training and validation sets. The model successfully described different trends in the MTD and MC regimens. With parameters obtained by fitting the model to MTD data, the simulations correctly predicted trends in both the MC and combined therapy groups. Our results demonstrate that the proposed model presents a minimal yet efficient tool for modeling outcomes in different treatment regimens in mice. We hope that this model has the potential for use in clinical practice in the development of patient-specific chemotherapy scheduling protocols based on observed treatment response.

Clinical and histopathological analysis of metastatic brain tumours: A single-centre experience

Objective: The aim of this study is to determine the demographic and clinical findings of cases which have been operated for a brain mass and have metastasis, to analyse the histopathological findings, to draw attention to the molecular tests that are effective in the treatment of the primary tumour, and to compare our results with the literature data.&#x0D; Material and Methods: One hundred seventy cases diagnosed with brain metastasis tumour between January 2012-2021 were analysed retrospectively. The clinical findings and demographic information of the cases were recorded from the hospital information system. The diagnoses of the patients diagnosed with metastasis, the analysis of the cases with or without a primary tumour at the time of diagnosis, and the immunohistochemical staining applied to detect the primary metastasis were recorded.&#x0D; Results: Sixty-seven of the cases were female, and one hundred three were male. The youngest case was 14, and the oldest case was 90 years old (Mean 55.6 ± 14). While the clinical findings in 35 of the cases were solely headache, 41 patients also had at least one of the symptoms such as dizziness, seizure, weakness, and ataxia in addition to headache. The primary was unknown at the time of diagnosis of brain metastasis in 63 of the cases. There was a single focus in 107 cases, and multiple metastasis focus in 63 patients. Among all cases, lung (84), breast (24) colorectal (15), kidney (9) metastases were the most common. Primary focus could not be detected in 2 of the cases (neuroendocrine carcinoma and adenocarcinoma) despite all imaging techniques as well as immunohistochemical findings.&#x0D; Conclusion: The possibility of metastasis is also present in cases with a single lesion and whose primary diagnosis is unknown, and histomorphological analysis become inevitable due to the increase in molecular examinations and the development of patient-specific treatment protocols. Besides, it should not be forgotten that the most common tumour-causing brain metastasis -whether or not the primary is known- is the lung. Kidney tumours may also present with metastasis without manifesting themselves.