Comprehensive characterization of toxins during progression of inhalation anthrax in a non-human primate model.

Inhalation anthrax has three clinical stages: early-prodromal, intermediate-progressive, and late-fulminant. We report the comprehensive characterization of anthrax toxins, including total protective antigen (PA), total lethal factor (LF), total edema factor (EF), and their toxin complexes, lethal toxin and edema toxin in plasma, during the course of inhalation anthrax in 23 cynomolgus macaques. The toxin kinetics were predominantly triphasic with an early rise (phase-1), a plateau/decline (phase-2), and a final rapid rise (phase-3). Eleven animals had shorter survival times, mean±standard deviation of 58.7±7.6 hours (fast progression), 11 animals had longer survival times, 113±34.4 hours (slow progression), and one animal survived. Median (lower-upper quartile) LF levels at the end-of-phase-1 were significantly higher in animals with fast progression [138 (54.9-326) ng/mL], than in those with slow progression [23.8 (15.6-26.3) ng/mL] (p = 0.0002), and the survivor (11.1 ng/mL). The differences were also observed for other toxins and bacteremia. Animals with slow progression had an extended phase-2 plateau, with low variability of LF levels across all time points and animals. Characterization of phase-2 toxin levels defined upper thresholds; critical levels for exiting phase-2 and entering the critical phase-3, 342 ng/mL (PA), 35.8 ng/mL (LF), and 1.10 ng/mL (EF). The thresholds were exceeded earlier in animals with fast progression (38.5±7.4 hours) and later in animals with slow progression (78.7±15.2 hours). Once the threshold was passed, toxin levels rose rapidly in both groups to the terminal stage. The time from threshold to terminal was rapid and similar; 20.8±7.4 hours for fast and 19.9±7.5 hours for slow progression. The three toxemic phases were aligned with the three clinical stages of anthrax for fast and slow progression which showed that anthrax progression is toxin- rather than time-dependent. This first comprehensive evaluation of anthrax toxins provides new insights into disease progression.

Impact of radiomics on prostate cancer detection: a systematic review of clinical applications.

PURPOSE OF REVIEW: To systematically review the current literature to assess the role of radiomics in the detection and evaluation of prostate cancer (PCa). RECENT FINDINGS: Radiomics involves the high-throughput extraction of radiologic features from clinical imaging, using a panel of sophisticated data-characterization algorithms to make an objective and quantitative determination of diagnoses and clinical characteristics. Radiomics evaluation of existing clinical images would increase their clinical value in many cancer management pathways, including PCa. However, a consensus on the implementation of radiomics has not been established across different sites, delaying its implementation in clinical practice. There are many potential advantages to radiomics. The ability to extract features from existing clinical imaging is one such advantage. A second is the empiric nature of the analysis. The third lies in the application of new technologies, such as machine learning, to be able to evaluate large quantities of data to make clinical conclusions. In this systematic review, we identify publications regarding the role of radiomics in PCa detection and evaluation. Many of these studies noted that radiomics, when incorporated into predictive models, had an advantageous impact on detection of PCa, clinically significant PCa, and extracapsular extension. This may assist in individualized decision making not only for diagnosis of PCa, but also for surveillance and surgical planning. With additional validation in large sample sizes, and randomized, multicenter studies using a consensus driven methodology, radiomics has the potential to alter the landscape of PCa detection and management, necessitating further prospective randomized investigation. SUMMARY: Radiomics is a promising new field, allowing for high-throughput analysis of imaging features for PCa detection and evaluation. These features can be extracted from existing data; therefore, the potential for future study is immense.

Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice.

BACKGROUND: Kisspeptin is a neuropeptide that plays an integral role in the regulation of energy intake and reproduction by acting centrally on the hypothalamus-pituitary-gonadal axis. Our current study explores for the first time the effects of a pharmacological treatment of intraperitoneal kisspeptin-10 on murine feeding behavior, respirometry parameters, energy balance, and metabolic hormones. METHODS: Two groups (n = 16) of age- and sex-matched C57BL/6 wild-type adult mice were individually housed in metabolic cages and intraperitoneally injected with either kisspeptin-10 (2 nmol in 200 µl of saline) (10 µM) or vehicle before the beginning of a dark-phase cycle. Microstructure of feeding and drinking behavior, respirometry gases, respiratory quotient (RQ), total energy expenditure (TEE), metabolic hormones, oral glucose tolerance, and lipid profiles were measured. RESULTS: Intraperitoneal treatment with kisspeptin-10 caused a significant reduction in food intake, meal frequency, meal size, and eating rate. Kisspeptin-10 significantly decreased TEE during both the dark and light phase cycles, while also increasing the RQ during the dark-phase cycle. In addition, mice injected with kisspeptin-10 had significantly higher plasma levels of insulin (343.8 pg/ml vs. 106.4 pg/ml; p = 0.005), leptin (855.5 pg/ml vs. 173.1 pg/ml; p = 0.02), resistin (9411.1 pg/ml vs. 4116.5 pg/ml; p = 0.001), and HDL (147.6 mg/dl vs 97.1 mg/dl; p = 0.04). CONCLUSION: A pharmacological dose of kisspeptin-10 significantly altered metabolism by suppressing food intake, meal size, eating rate, and TEE while increasing the RQ. These changes were linked to increased levels of insulin, leptin, resistin, and HDL. The current results suggest that a peripheral kisspeptin treatment could alter metabolism and energy homeostasis by suppressing appetite, food intake, and fat accumulation.

Long-Term Intake of a High-Protein Diet Affects Body Phenotype, Metabolism, and Plasma Hormones in Mice.

Background: High-protein diets (HPDs) recently have been used to obtain body weight and fat mass loss and expand muscle mass. Several studies have documented that HPDs reduce appetite and food intake.Objective: Our goal was to determine the long-term effects of an HPD on body weight, energy intake and expenditure, and metabolic hormones.Methods: Male C57BL/6 mice (8 wk old) were fed either an HPD (60% of energy as protein) or a control diet (CD; 20% of energy as protein) for 12 wk. Body composition and food intakes were determined, and plasma hormone concentrations were measured in mice after being fed and after overnight feed deprivation at several time points.Results: HPD mice had significantly lower body weight (in means ± SEMs; 25.73 ± 1.49 compared with 32.5 ± 1.31 g; P = 0.003) and fat mass (9.55% ± 1.24% compared with 15.78% ± 2.07%; P = 0.05) during the first 6 wk compared with CD mice, and higher lean mass throughout the study starting at week 2 (85.45% ± 2.25% compared with 75.29% ± 1.90%; P = 0.0001). Energy intake, total energy expenditure, and respiratory quotient were significantly lower in HPD compared with CD mice as shown by cumulative energy intake and eating rate. Water vapor was significantly higher in HPD mice during both dark and light phases. In HPD mice, concentrations of leptin [feed-deprived: 41.31 ± 11.60 compared with 3041 ± 683 pg/mL (P = 0.0004); postprandial: 112.5 ± 102.0 compared with 8273 ± 1415 pg/mL (P < 0.0001)] and glucagon-like peptide 1 (GLP-1) [feed-deprived: 5.664 ± 1.44 compared with 21.31 ± 1.26 pg/mL (P = <0.0001); postprandial: 6.54 ± 2.13 compared with 50.62 ± 11.93 pg/mL (P = 0.0037)] were significantly lower, whereas postprandial glucagon concentrations were higher than in CD-fed mice.Conclusions: In male mice, the 12-wk HPD resulted in short-term body weight and fat mass loss, but throughout the study preserved body lean mass and significantly reduced energy intake and expenditure as well as leptin and GLP-1 concentrations while elevating postprandial glucagon concentrations. This study suggests that long-term use of HPDs may be an effective strategy to decrease energy intake and expenditure and to maintain body lean mass.

Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax.

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.

Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.

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.

Pathology and pathophysiology of inhalational anthrax in a guinea pig model.

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

Evaluation of intravenous anthrax immune globulin for treatment of inhalation anthrax.

Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. NCT00845650.).

The Surgical Management of Urolithiasis: A Review of the Literature.

The incidence of stone disease has increased significantly in the past 30 years, with a reported prevalence of 11% of the U.S. population in 2022, up from 9% in 2012 and 5.2% in 1994.1 While prevention is a vital aspect of management, many patients present with symptomatic urolithiasis requiring surgical management. Emerging advances in endoscopy and technology has led to a dynamic shift in the surgical management of stone disease. This paper will serve as a comprehensive review to inform urologic and non-urologic medical professionals alike, as well as the layperson, on the surgical treatment of nephrolithiasis, starting from the initial evaluation, laboratory and radiographic studies, and various surgical options. Additionally, the nuances of managing the pediatric and pregnant patient with nephrolithiasis will be explored. Using the most up-to-date urologic data, our aim is to provide a comprehensive resource for readers who interact with patients experiencing acute episodes of urolithiasis.

PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite, Satiety and Metabolism.

The overwhelming increase in the prevalence of obesity and related disorders in recent years is one of the greatest threats to the global healthcare system since it generates immense healthcare costs. As the prevalence of obesity approaches epidemic proportions, the importance of elucidating the mechanisms regulating appetite, satiety, body metabolism, energy balance and adiposity has garnered significant attention. Currently, gastrointestinal (GI) bariatric surgery remains the only approach capable of achieving successful weight loss. Appetite, satiety, feeding behavior, energy intake and expenditure are regulated by central and peripheral neurohormonal mechanisms that have not been fully elucidated yet. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Polypeptide (VIP) are members of a family of regulatory peptides that are widely distributed in parallel with their specific receptors, VPAC1R, VPAC2R and PAC1R, in the central nervous system (CNS) and in the periphery, such as in the gastrointestinal tract and its associated organs and immune cells. PACAP and VIP have been reported to play an important role in the regulation of body phenotype, metabolism and homeostatic functions. The purpose of this review is to present recent data on the effects of PACAP, VIP, VPAC1R, VPAC2R and PAC1R on the modulation of appetite, satiety, metabolism, calorie intake and fat accumulation, to evaluate their potential use as therapeutic targets for the treatment of obesity and metabolic syndrome.

Is Artificial Intelligence Replacing Our Radiology Stars? Not Yet!

Artificial intelligence (AI) is here to stay and will change health care as we know it. The availability of big data and the increasing numbers of AI algorithms approved by the US Food and Drug Administration together will help in improving the quality of care for patients and in overcoming human fatigue barriers. In oncology practice, patients and providers rely on the interpretation of radiologists when making clinical decisions; however, there is considerable variability among readers, and in particular for prostate imaging. AI represents an emerging solution to this problem, for which it can provide a much-needed form of standardization. The diagnostic performance of AI alone in comparison to a combination of an AI framework and radiologist assessment for evaluation of prostate imaging has yet to be explored. Here, we compare the performance of radiologists alone versus a combination of radiologists aided by a modern computer-aided diagnosis (CAD) AI system. We show that the radiologist-CAD combination demonstrates superior sensitivity and specificity in comparison to both radiologists alone and AI alone. Our findings demonstrate that a radiologist + AI combination could perform best for detection of prostate cancer lesions. A hybrid technology-human system could leverage the benefits of AI in improving radiologist performance while also reducing physician workload, minimizing burnout, and enhancing the quality of patient care. Patient summary: Our report demonstrates the potential of artificial intelligence (AI) for improving the interpretation of prostate scans. A combination of AI and evaluation by a radiologist has the best performance in determining the severity of prostate cancer. A hybrid system that uses both AI and radiologists could maximize the quality of care for patients while reducing physician workload and burnout.

Maximizing outcomes in penile prosthetic surgery: exploring strategies to prevent and manage infectious and non-infectious complications.

Inflatable Penile Prostheses (IPP) implantation is a surgical treatment for patients desiring definitive treatment for erectile dysfunction. While this procedure has proven to be effective, it also carries its own set of unique risks that need to be carefully considered. The article reviews the current understanding of complications associated with penile prosthetic surgery and provides strategies to mitigate these adverse events. This article covers various aspects of IPP implantation, including the risks of infection, bleeding, injury to nearby structures, glans ischemia, and device malfunction. It also discusses the importance of careful preoperative screening to identify risk factors and the implementation of infection reduction strategies such as antimicrobial prophylaxis, skin prep, and operative techniques. In addition, it emphasizes the need for postoperative vigilance and prompt management of any complications that may arise. Overall, the article provides a comprehensive overview of the risks and strategies for mitigating complications associated with IPP implantation. Our recommendations are given based on the current consensus in the field and highlight the importance of careful planning, attention to detail, and effective communication between healthcare providers and patients. Despite the potential risks, this review underscores the fact that complications following penile prosthesis implantation are relatively rare.

NHP BurkPx: A multiplex serodiagnostic bead assay to monitor Burkholderia pseudomallei exposures in non-human primates.

BACKGROUND: Melioidosis is a disease caused by the bacterium Burkholderia pseudomallei, infecting humans and non-human primates (NHP) through contaminated soil or water. World-wide there are an estimated 165,000 human melioidosis cases each year, but recordings of NHP cases are sporadic. Clinical detection of melioidosis in humans is primarily by culturing B. pseudomallei, and there are no standardized detection protocols for NHP. NHP are an important animal model for melioidosis research including clinical trials and development of biodefense countermeasures. METHODOLOGY/PRINCIPLE FINDINGS: We evaluated the diagnostic potential of the multiple antigen serological assay, BurkPx, in NHP using two sera sets: (i) 115 B. pseudomallei-challenged serum samples from 80 NHP collected each week post-exposure (n = 52) and at euthanasia (n = 47), and (ii) 126 B. pseudomallei-naïve/negative serum samples. We observed early IgM antibody responses to carbohydrate antigens followed by IgG antibody recognition to multiple B. pseudomallei protein antigens during the second week of infection. B. pseudomallei negative serum samples had low to intermediate antibody cross reactivity to the antigens in this assay. Infection time was predicted as the determining factor in the variation of antibody responses, with 77.67% of variation explained by the first component of the principal component analysis. A multiple antigen model generated a binary prediction metric ([Formula: see text]), which when applied to all data resulted in 100% specificity and 63.48% sensitivity. Removal of week 1 B. pseudomallei challenged serum samples increased the sensitivity of the model to 95%. CONCLUSION/SIGNIFICANCE: We employed a previously standardized assay for humans, the BurkPx assay, and assessed its diagnostic potential for detection of B. pseudomallei exposure in NHP. The assay is expected to be useful for surveillance in NHP colonies, in investigations of suspected accidental releases or exposures, and for identifying vaccine correlates of protection.

Raxibacumab for the treatment of inhalational anthrax.

BACKGROUND: Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin. METHODS: We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers. RESULTS: In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit. CONCLUSIONS: A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)

Hyperandrogenism and Hyperestrogenism Secondary to Mixed Germ-Cell Testicular Tumor.

Testicular cancer with androgen and estrogen secretion is classically associated with Leydig cell tumors. Rare case reports have described this finding in germ-cell tumors along with signs of androgen and estrogen excess including gynecomastia and infertility. We report the case of a 19-year-old male with a non-seminomatous testicular germ-cell tumor found to have hyperandrogenism, hyperestrogenism, and suppression of central sex hormones. Similar findings may be underreported in the literature, and males with suspected testicular malignancy should be appropriately screened for signs of androgen and/or estrogen excess so they can be offered appropriate monitoring and counseling.

Association of Suturing Technical Skill Assessment Scores Between Virtual Reality Simulation and Live Surgery.

Introduction: Robotic surgical performance, in particular suturing, has been linked to postoperative clinical outcomes. Before attempting live surgery, virtual reality (VR) simulators afford opportunities for training surgeons to learn fundamental technical skills. Herein, we evaluate the association of suturing technical skill assessments between VR simulation and live surgery, and functional clinical outcomes. Materials and Methods: Twenty surgeons completed a VR suturing exercise on the Mimic™ Flex VR simulator and the anterior vesicourethral anastomosis during robot-assisted radical prostatectomy (RARP). Three independent and blinded graders provided technical skill scores using a validated assessment tool. Correlations between VR and live scores were assessed by Spearman's correlation coefficients (ρ). In addition, 117 historic RARP cases from participating surgeons were extracted, and the association between VR technical skill scores and urinary continence recovery was assessed by a multilevel mixed-effects model. Results: A total of 20 (6 training and 14 expert) surgeons participated. Statistically significant correlations for scores provided between VR simulation and live surgery were found for overall and needle driving scores (ρ = 0.555, p = 0.011; ρ = 0.570, p = 0.009, respectively). A subanalysis performed on training surgeons found significant correlations for overall scores between VR simulation and live surgery (ρ = 0.828, p = 0.042). Expert cases with high VR needle driving scores had significantly greater continence recovery rates at 24 months after RARP (98.5% vs 84.9%, p = 0.028). Conclusions: Our study found significant correlations in technical scores between VR and live surgery, especially among training surgeons. In addition, we found that VR needle driving scores were associated with continence recovery after RARP. Our data support the association of skill assessments between VR simulation and live surgery and potential implications for clinical outcomes.

The VIP/VPAC1R Pathway Regulates Energy and Glucose Homeostasis by Modulating GLP-1, Glucagon, Leptin and PYY Levels in Mice.

Vasoactive Intestinal Peptide binds with high affinity to VPAC1R and VPAC2R, thus regulating key physiologic functions. Previously, we documented in VIP-/- mice a leaner body phenotype and altered metabolic hormones. Past reports described in VPAC2-/- mice impaired circadian rhythm, reduced food intake, and altered metabolism. To better define the effects of VPAC1R on body phenotype, energy/glucose homeostasis, and metabolism, we conducted a 12-week study in a VPAC1R null model. Our results reveal that VPAC1-/- mice experienced significant metabolic alterations during the dark cycle with greater numbers of feeding bouts (p = 0.009), lower Total Energy Expenditure (p = 0.025), VO2 (p = 0.029), and VCO2 (p = 0.016); as well as during the light cycle with lower Total Energy Expenditure (p = 0.04), VO2 (p = 0.044), and VCO2 (p = 0.029). Furthermore, VPAC1-/- mice had significantly higher levels of GLP-1 and PYY during fasting, and higher levels of GLP-1, glucagon leptin and PYY during postprandial conditions. In addition, VPAC1-/- mice had lower levels of glucose at 60' and 120', as assessed by insulin tolerance test. In conclusion, this study supports a key role for VPAC1R in the regulation of body glucose/energy homeostasis and metabolism.

Survival Analysis Using Surgeon Skill Metrics and Patient Factors to Predict Urinary Continence Recovery After Robot-assisted Radical Prostatectomy.

BACKGROUND: It has been shown that metrics recorded for instrument kinematics during robotic surgery can predict urinary continence outcomes. OBJECTIVE: To evaluate the contributions of patient and treatment factors, surgeon efficiency metrics, and surgeon technical skill scores, especially for vesicourethral anastomosis (VUA), to models predicting urinary continence recovery following robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: Automated performance metrics (APMs; instrument kinematics and system events) and patient data were collected for RARPs performed from July 2016 to December 2017. Robotic Anastomosis Competency Evaluation (RACE) scores during VUA were manually evaluated. Training datasets included: (1) patient factors; (2) summarized APMs (reported over RARP steps); (3) detailed APMs (reported over suturing phases of VUA); and (4) technical skills (RACE). Feature selection was used to compress the dimensionality of the inputs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The study outcome was urinary continence recovery, defined as use of 0 or 1 safety pads per day. Two predictive models (Cox proportional hazards [CoxPH] and deep learning survival analysis [DeepSurv]) were used. RESULTS AND LIMITATIONS: Of 115 patients undergoing RARP, 89 (77.4%) recovered their urinary continence and the median recovery time was 166 d (interquartile range [IQR] 82-337). VUAs were performed by 23 surgeons. The median RACE score was 28/30 (IQR 27-29). Among the individual datasets, technical skills (RACE) produced the best models (C index: CoxPH 0.695, DeepSurv: 0.708). Among summary APMs, posterior/anterior VUA yielded superior model performance over other RARP steps (C index 0.543-0.592). Among detailed APMs, metrics for needle driving yielded top-performing models (C index 0.614-0.655) over other suturing phases. DeepSurv models consistently outperformed CoxPH; both approaches performed best when provided with all the datasets. Limitations include feature selection, which may have excluded relevant information but prevented overfitting. CONCLUSIONS: Technical skills and "needle driving" APMs during VUA were most contributory. The best-performing model used synergistic data from all datasets. PATIENT SUMMARY: One of the steps in robot-assisted surgical removal of the prostate involves joining the bladder to the urethra. Detailed information on surgeon performance for this step improved the accuracy of predicting recovery of urinary continence among men undergoing this operation for prostate cancer.

Road to automating robotic suturing skills assessment: Battling mislabeling of the ground truth.

OBJECTIVE: To automate surgeon skills evaluation using robotic instrument kinematic data. Additionally, to implement an unsupervised mislabeling detection algorithm to identify potentially mislabeled samples that can be removed to improve model performance. METHODS: Video recordings and instrument kinematic data were derived from suturing exercises completed on the Mimic FlexVR robotic simulator. A structured human consensus-building process was developed to determine Robotic Anastomosis Competency Evaluation technical scores across 3 human graders. A 2-layer long short-term memory-based classification model used instrument kinematic data to automate suturing skills assessment. An unsupervised label analyzer (NoiseRank) was used to identify potential mislabeling of skills data. Performance of the long short-term memory model's technical skill score prediction was measured by best area under the curve over the training runs. NoiseRank outputted a ranked list of rated skills assessments based on likelihood of mislabeling. RESULTS: 22 surgeons performed 226 suturing attempts, which were broken down into 1,404 individual skill assessment points. Automation of needle entry angle, needle driving, and needle withdrawal technical skill scores performed better (area under the curve 0.698-0.705) than needle positioning (0.532) at baseline using all available data. Potential mislabels were subsequently identified by NoiseRank and removed, improving model performance across all domains (area under the curve 0.551-0.766). CONCLUSION: Using ground truth labels from human graders and robotic instrument kinematic data, machine learning models have automated assessment of detailed suturing technical skills with good performance. Further, an unsupervised mislabeling detection algorithm projected mislabeled data, allowing for their removal and subsequent improvement of model performance.