The relationship between hematologic malignancies on male hypogonadism: a scoping review.

INTRODUCTION: The associated symptoms of hypogonadism have been reported in patients with various types of cancer. However, the prevalence and significance of hypogonadism among certain hematologic malignancies have not been completely summarized in recent literature. OBJECTIVE: In this review we aimed to examine the current literature on hypogonadism in patients with hematologic malignancies, with emphasis on leukemias, lymphomas, and multiple myeloma (MM). METHODS: This review included relevant studies published before July 2023 that were retrieved through a search of PubMed using the keywords "hematologic cancer," "hematologic malignancy," blood cancer," "leukemia," "lymphoma," "hypogonadism," "multiple myeloma," and "testosterone." RESULTS: The search yielded 214 studies, of which 21 met the inclusion criteria. Commonly reported findings were that patients who had received hematopoietic stem cell therapy for acute lymphoblastic leukemia and acute myelogenous leukemia as children had laboratory-confirmed hypogonadism as adults. However, the impact of these diseases on hypogonadal symptoms was variable in these studies.Studies reporting on lymphoma and hypogonadism had mixed results, with some studies finding that the degree of cytotoxic chemotherapy was associated with hypogonadism, while others showed no correlation. Regardless, multiple studies found that hypogonadism secondary to lymphoma treatment and symptoms of hypogonadism had no apparent association.The most comprehensive assessment of the frequency of hypogonadism in an MM cohort found that 74% of 561 MM patients were classified as hypogonadal compared to 33% of patients in a control population. Testosterone supplementation was found to lower interleukin-6 levels, which could potentially help manage some of the adverse effects of MM, including decreased bone mineral density. CONCLUSION: There is a relationship between hematologic malignancies and hypogonadism, which is likely multifactorial. In this review we established that the most plausible factors are related to the secondary effects of gonadotoxic treatments and/or systemic inflammatory responses to the diseases.

Depth-Dependent Strain Model (1D) for Anisotropic Fibrils in Articular Cartilage.

The mechanical response of articular cartilage (AC) under compression is anisotropic and depth-dependent. AC is osmotically active, and its intrinsic osmotic swelling pressure is balanced by its collagen fibril network. This mechanism requires the collagen fibers to be under a state of tensile pre-strain. A simple mathematical model is used to explain the depth-dependent strain calculations observed in articular cartilage under 1D axial compression (perpendicular to the articular surface). The collagen fibers are under pre-strain, influenced by proteoglycan concentration (fixed charged density, FCD) and collagen stiffness against swelling stress. The stiffness is introduced in our model as an anisotropic modulus that varies with fibril orientation through tissue depth. The collagen fibers are stiffer to stretching parallel to their length than perpendicular to it; when combined with depth-varying FCD, the model successfully predicts how tissue strains decrease with depth during compression. In summary, this model highlights that the mechanical properties of cartilage depend not only on proteoglycan concentration but also on the intrinsic properties of the pre-strained collagen network. These properties are essential for the proper functioning of articular cartilage.

Utilization of Re-VASC, the Novel Retroperitoneal Neovascularity Scoring System, for Characterization of T1a Small Renal Masses.

Purpose: Early characterization of small (T1a, <4 cm) renal masses is imperative for patient care and treatment planning. Renal biopsy is a sensitive and specific procedure that can accurately differentiate small renal masses as malignant or benign. However, it is an invasive procedure with a nonnegligible complication rate and is not performed routinely at most institutions. In this study, we sought to apply the Retroperitoneal Vascularity Assessment and Scoring in Carcinoma (Re-VASC) scoring system to T1a renal masses and analyzed whether it could differentiate these masses as benign or malignant. Methods: We obtained Institutional Review Board approval to retrospectively examine the records of all patients who presented to our single, urban academic referral center for surgical treatment of renal cell carcinoma (RCC). For the malignant group, patients with a diagnosis of T1a RCC from pathologic evaluation were included. Additionally, patients with a histopathological diagnosis of a T1a nonmalignant renal mass (fat poor-angiomyolipoma or oncocytoma) were included in our benign group. Results: This study includes 57 benign and 69 malignant T1a renal tumors. Average size for benign and malignant masses were 2.47 and 2.63, respectively (p = 0.267). Analysis demonstrated no significant difference between both groups in terms of sex, laterality, or size. The average Re-VASC score of benign and malignant masses was 0.175 and malignant masses was 0.784, respectively (p < 0.001). Additionally, the Re-VASC score was independently associated with malignancy with an odds ratio of 2.223 (p = 0.0109). Conclusion: The Re-VASC scoring system exhibits significantly greater values for malignant T1a renal masses when compared to benign masses. As a result, it shows promise as an adjunctive tool to renal biopsy for clinical decision-making. Further assessment of Re-VASC's true efficacy as a diagnostic marker will include prospective evaluation of a larger multicenter population.

Sperm DNA fragmentation testing in clinical management of reproductive medicine.

Background: Approximately 8%-12% of couples worldwide face infertility, with infertility of individuals assigned male at birth (AMAB) contributing to at least 50% of cases. Conventional semen analysis commonly used to detect sperm abnormalities is insufficient, as 30% of AMAB patients experiencing infertility show normal results in this test. From a genetic perspective, the assessment of sperm DNA fragmentation (SDF) is important as a parameter of sperm quality. Methods: In this narrative study, we review and discuss pathophysiological causes, DNA repair mechanisms, and management of high SDF. We then summarize literature exploring the association between SDF and reproductive outcomes. Main Findings: Recent systematic reviews and meta-analyses have revealed a significant association between high SDF in AMAB individuals and adverse reproductive outcomes including embryo development, natural conception, intrauterine insemination, and in vitro fertilization. However, the association with live birth rates and pregnancy rates following intracytoplasmic injection remains inconclusive. The disparities among quantitative assays, inconsistent reference range values, absent high-quality prospective clinical trials, and clinical heterogeneity in AMAB patients with elevated SDF represent the main limitations affecting SDF testing. Conclusion: The evaluation and management of SDF plays an important role in a subset of AMAB infertility, but widespread integration into clinical guidelines will require future high-quality clinical trials and assay standardization.

Artificial Intelligence for Improved Hepatosplenomegaly Diagnosis.

Hepatosplenomegaly is commonly diagnosed by radiologists based on single dimension measurements and heuristic cut-offs. Volumetric measurements may be more accurate for diagnosing organ enlargement. Artificial intelligence techniques may be able to automatically calculate liver and spleen volume and facilitate more accurate diagnosis. After IRB approval, 2 convolutional neural networks (CNN) were developed to automatically segment the liver and spleen on a training dataset comprised of 500 single-phase, contrast-enhanced CT abdomen and pelvis examinations. A separate dataset of ten thousand sequential examinations at a single institution was segmented with these CNNs. Performance was evaluated on a 1% subset and compared with manual segmentations using Sorensen-Dice coefficients and Pearson correlation coefficients. Radiologist reports were reviewed for diagnosis of hepatomegaly and splenomegaly and compared with calculated volumes. Abnormal enlargement was defined as greater than 2 standard deviations above the mean. Median Dice coefficients for liver and spleen segmentation were 0.988 and 0.981, respectively. Pearson correlation coefficients of CNN-derived estimates of organ volume against the gold-standard manual annotation were 0.999 for the liver and spleen (P < 0.001). Average liver volume was 1556.8 ± 498.7 cc and average spleen volume was 194.6 ± 123.0 cc. There were significant differences in average liver and spleen volumes between male and female patients. Thus, the volume thresholds for ground-truth determination of hepatomegaly and splenomegaly were determined separately for each sex. Radiologist classification of hepatomegaly was 65% sensitive, 91% specific, with a positive predictive value (PPV) of 23% and an negative predictive value (NPV) of 98%. Radiologist classification of splenomegaly was 68% sensitive, 97% specific, with a positive predictive value (PPV) of 50% and a negative predictive value (NPV) of 99%. Convolutional neural networks can accurately segment the liver and spleen and may be helpful to improve radiologist accuracy in the diagnosis of hepatomegaly and splenomegaly.

Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma.

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.

The Electric Field Induced by a Microcoil During Magnetic Stimulation.

OBJECTIVE: The purpose of this study is to calculate the electric field produced by an implanted microcoil during magnetic stimulation of the brain. METHODS: The electric field of a microcoil was calculated numerically. RESULTS: The maximum value of the induced electric field is approximately 0.000026 V/m for a 1 mA, 3 kHz current passed through the coil. CONCLUSION: This electric field value is too small to cause neural stimulation. SIGNIFICANCE: Previous studies reporting magnetic stimulation using a microcoil must have been exciting neurons by some other mechanism.

Revenue and Cost Analysis of a System Utilizing Natural Language Processing and a Nurse Coordinator for Radiology Follow-up Recommendations.

Radiology reports often contain recommendations for follow-up imaging, Provider adherence to these radiology recommendations can be incomplete, which may result in patient harm, lost revenue, or litigation. This study sought to perform a revenue assessment of a hybrid natural language processing (NLP) and human follow-up system. Reports generated from January 2020 to April 2021 that were indexed as overdue from follow-up recommendations by mPower Follow-Up Recommendation Algorithm (Nuance Communications Inc., Burlington, MA), were assessed for follow up and revenue. Follow-up exams completed because of the hybrid system were tabulated and given revenue amounts based on Medicare national reimbursement rates. These rates were then summated. A total of n =3011 patients were flagged via the mPower algorithm as having not received a timely follow-up indicated for procedure. Of these, n = 427 required the quality nurse to contact their healthcare provider to place orders. The follow-up imaging of these patients accounted for $62,937.66 of revenue. This revenue was calculated as higher than personnel cost (based on national average quality and safety nurse salary and time allotted on follow-ups). Our results indicate that a hybrid human-artificial intelligence follow-up system can be profitable, while potentially adding to patient safety. Our revenue figure likely significantly underestimates the true revenue obtained at our institution. This was due to the use of Medicare national reimbursement rates to calculate revenue, for the purposes of generalizability.

Biomagnetism: The First Sixty Years.

Biomagnetism is the measurement of the weak magnetic fields produced by nerves and muscle. The magnetic field of the heart-the magnetocardiogram (MCG)-is the largest biomagnetic signal generated by the body and was the first measured. Magnetic fields have been detected from isolated tissue, such as a peripheral nerve or cardiac muscle, and these studies have provided insights into the fundamental properties of biomagnetism. The magnetic field of the brain-the magnetoencephalogram (MEG)-has generated much interest and has potential clinical applications to epilepsy, migraine, and psychiatric disorders. The biomagnetic inverse problem, calculating the electrical sources inside the brain from magnetic field recordings made outside the head, is difficult, but several techniques have been introduced to solve it. Traditionally, biomagnetic fields are recorded using superconducting quantum interference device (SQUID) magnetometers, but recently, new sensors have been developed that allow magnetic measurements without the cryogenic technology required for SQUIDs.

Can MRI Be Used as a Sensor to Record Neural Activity?

Magnetic resonance provides exquisite anatomical images and functional MRI monitors physiological activity by recording blood oxygenation. This review attempts to answer the following question: Can MRI be used as a sensor to directly record neural behavior? It considers MRI sensing of electrical activity in the heart and in peripheral nerves before turning to the central topic: recording of brain activity. The primary hypothesis is that bioelectric current produced by a nerve or muscle creates a magnetic field that influences the magnetic resonance signal, although other mechanisms for detection are also considered. Recent studies have provided evidence that using MRI to sense neural activity is possible under ideal conditions. Whether it can be used routinely to provide functional information about brain processes in people remains an open question. The review concludes with a survey of artificial intelligence techniques that have been applied to functional MRI and may be appropriate for MRI sensing of neural activity.

Novel Retroperitoneal Neovascularity Scoring System in Renal Cell Carcinoma Tumor Staging.

Purpose: Renal cell carcinoma (RCC) is the most common type of kidney cancer worldwide. Although radiologists assess enhancement patterns of renal tumors to predict tumor pathology report, to our knowledge, no formal scoring system has been created and validated to assess the level of neovascularity in RCC, despite its critical role in cancer metastases. In this study, we characterized and analyzed the level of angiogenesis in tumor-burdened kidneys and their benign counterparts. We then created and validated a scoring scale for neovascularity that can help predict tumor staging for RCC. Methods: After Institutional Review Board approval, the charts of patients who had undergone operation for RCC between January 13, 2014 and February 4, 2020 were retrospectively reviewed for inclusion in this study. Inclusion criteria were a diagnosis of RCC, simple/radical nephrectomy, preoperative contrast-enhanced CT scans, and complete pathology reports. Neovascularity was scored on a scale of 0-4 where 0 = no neovascularity detected, 1 = a single vessel <3 mm wide, 2 = a single vessel ≥3 mm wide, 3 = multiple vessels <3 mm wide, and 4 = multiple vessels ≥3 mm wide. Results: A total of 227 patients were included in this study. Most of the tumor pathology reports were clear cell carcinoma, regardless of tumor staging. The average neovascularity score was 1.07 for pT1x tumors, 2.83 for pT2x tumors, and 3.04 for pT3x tumors. There was a significant difference in neovascularity score between pT1x and pT2x tumors (p = 0.0046), pT1x and pT3x tumors (p < 0.0001), and benign kidneys and kidneys with RCC (p < 0.0001). Conclusion: Our novel vascular scoring system for RCC demonstrates significant correlation with RCC pathological tumor staging. This scoring system may be utilized as part of a comprehensive radiological assessment of renal tumors, potentially improving tumor characterization and clinical decision making.

Association of Congenital and Acquired Cardiovascular Conditions With COVID-19 Severity Among Pediatric Patients in the US.

Importance: Identifying the associations between severe COVID-19 and individual cardiovascular conditions in pediatric patients may inform treatment. Objective: To assess the association between previous or preexisting cardiovascular conditions and severity of COVID-19 in pediatric patients. Design, Setting, and Participants: This retrospective cohort study used data from a large, multicenter, electronic health records database in the US. The cohort included patients aged 2 months to 17 years with a laboratory-confirmed diagnosis of COVID-19 or a diagnosis code indicating infection or exposure to SARS-CoV-2 at 85 health systems between March 1, 2020, and January 31, 2021. Exposures: Diagnoses for 26 cardiovascular conditions between January 1, 2015, and December 31, 2019 (before infection with SARS-CoV-2). Main Outcomes and Measures: The main outcome was severe COVID-19, defined as need for supplemental oxygen or in-hospital death. Mixed-effects, random intercept logistic regression modeling assessed the significance and magnitude of associations between 26 cardiovascular conditions and COVID-19 severity. Multiple comparison adjustment was performed using the Benjamini-Hochberg false discovery rate procedure. Results: The study comprised 171 416 pediatric patients; the median age was 8 years (IQR, 2-14 years), and 50.28% were male. Of these patients, 17 065 (9.96%) had severe COVID-19. The random intercept model showed that the following cardiovascular conditions were associated with severe COVID-19: cardiac arrest (odds ratio [OR], 9.92; 95% CI, 6.93-14.20), cardiogenic shock (OR, 3.07; 95% CI, 1.90-4.96), heart surgery (OR, 3.04; 95% CI, 2.26-4.08), cardiopulmonary disease (OR, 1.91; 95% CI, 1.56-2.34), heart failure (OR, 1.82; 95% CI, 1.46-2.26), hypotension (OR, 1.57; 95% CI, 1.38-1.79), nontraumatic cerebral hemorrhage (OR, 1.54; 95% CI, 1.24-1.91), pericarditis (OR, 1.50; 95% CI, 1.17-1.94), simple biventricular defects (OR, 1.45; 95% CI, 1.29-1.62), venous embolism and thrombosis (OR, 1.39; 95% CI, 1.11-1.73), other hypertensive disorders (OR, 1.34; 95% CI, 1.09-1.63), complex biventricular defects (OR, 1.33; 95% CI, 1.14-1.54), and essential primary hypertension (OR, 1.22; 95% CI, 1.08-1.38). Furthermore, 194 of 258 patients (75.19%) with a history of cardiac arrest were younger than 12 years. Conclusions and Relevance: The findings suggest that some previous or preexisting cardiovascular conditions are associated with increased severity of COVID-19 among pediatric patients in the US and that morbidity may be increased among individuals children younger than 12 years with previous cardiac arrest.

Bidomain modeling of electrical and mechanical properties of cardiac tissue.

Throughout the history of cardiac research, there has been a clear need to establish mathematical models to complement experimental studies. In an effort to create a more complete picture of cardiac phenomena, the bidomain model was established in the late 1970s to better understand pacing and defibrillation in the heart. This mathematical model has seen ongoing use in cardiac research, offering mechanistic insight that could not be obtained from experimental pursuits. Introduced from a historical perspective, the origins of the bidomain model are reviewed to provide a foundation for researchers new to the field and those conducting interdisciplinary research. The interplay of theory and experiment with the bidomain model is explored, and the contributions of this model to cardiac biophysics are critically evaluated. Also discussed is the mechanical bidomain model, which is employed to describe mechanotransduction. Current challenges and outstanding questions in the use of the bidomain model are addressed to give a forward-facing perspective of the model in future studies.

Mechanical bidomain model of cardiac muscle with unequal anisotropy ratios.

The properties of cardiac muscle are anisotropic, and the degree of anisotropy may be different in the intracellular and extracellular spaces. In the electrical bidomain model, such "unequal anisotropy ratios" of the conductivity lead to unanticipated behavior. In the mechanical bidomain model, unequal anisotropy ratios of the mechanical moduli might also result in unanticipated behavior. In this study, mathematical modeling based on the mechanical bidomain model is used to calculate the distribution of mechanotransduction in cardiac tissue when it is stretched. This analysis demonstrates that unexpected phenomena arise when the mechanical anisotropy ratios are unequal.

The mechanical bidomain model of cardiac muscle with curving fibers.

In the heart, cardiac muscle fibers curve creating zones of membrane forces resulting in regions of mechanotransduction. This study uses the finite difference method to solve the mechanical bidomain equations numerically for a complex fiber geometry. The magnitude of the active tension T is constant but its direction makes an angle with the x-axis that varies with position. Differences between the intracellular and extracellular displacements result from the bidomain behavior of the tissue that gives rise to forces on the integrin proteins in the membrane. The long-term goal is to use the mechanical bidomain model to suggest experiments and make predictions about growth and remodeling in the heart.

Modeling bipolar stimulation of cardiac tissue.

Unipolar stimulation of cardiac tissue is often used in the design of cardiac pacemakers because of the low current required to depolarize the surrounding tissue at rest. However, the advantages of unipolar over bipolar stimulation are not obvious at shorter coupling intervals when the tissue near the pacing electrode is relatively refractory. Therefore, this paper analyzes bipolar stimulation of cardiac tissue. The strength-interval relationship for bipolar stimulation is calculated using the bidomain model and a recently developed parsimonious ionic current model. The strength-interval curves obtained using different electrode separations and arrangements (electrodes placed parallel to the fibers versus perpendicular to the fibers) indicate that bipolar stimulation results in more complex activation patterns compared to unipolar stimulation. An unusually low threshold stimulus current is observed when the electrodes are close to each other (a separation of 1 mm) because of break excitation. Unlike for unipolar stimulation, anode make excitation is not present during bipolar stimulation, and an abrupt switch from anode break to cathode make excitation can cause dramatic changes in threshold with very small changes in the interval. These results could impact the design of implantable pacemakers and defibrillators.

Determining the light scattering and absorption parameters from forward-directed flux measurements in cardiac tissue.

We describe a method to accurately measure the light scattering model parameters from forward-directed flux (FDF) measurements carried out with a fiber-optic probe (optrode). Improved determination of light scattering parameters will, in turn, permit better modeling and interpretation of optical mapping in the heart using voltage-sensitive dyes. Using our optrode-based system, we carried out high spatial resolution measurements of FDF in intact and homogenized cardiac tissue, as well as in intralipid-based tissue phantoms. The samples were illuminated with a broad collimated beam at 660 and 532 nm. Measurements were performed with a plunge fiber-optic probe (NA=0.22) at a spatial resolution of up to 10 µm. In the vicinity of the illuminated surface, the FDF consistently manifested a fast decaying exponent with a space constant comparable with the decay rate of ballistic photons. Using a Monte Carlo model, we obtained a simple empirical formula linking the rate of the fast exponent to the scattering coefficient, the anisotropy parameter g, and the numerical aperture of the probe. The estimates of scattering coefficient based on this formula were validated in tissue phantoms. Potential applications of optical fiber-based FDF measurements for the evaluation of optical parameters in turbid media are discussed.