Vaginal Intraepithelial Neoplasia: Histopathological Upgrading of Lesions and Evidence of Occult Vaginal Cancer

Objective The aim of this study was to analyze women treated with excisional procedures for vaginal high-grade squamous intraepithelial lesions (HSILs). The histopathological upgrading of the lesions previously detected on vaginal biopsy and the presence of occult invasive vaginal cancer in the specimens excised were investigated, to identify a higher risk subset of women.Materials and Methods A retrospective analysis of the medical records of 86 women with a biopsy histopathologic diagnosis of vaginal HSIL (vaginal intraepithelial neoplasias [VaINs]: VaIN2 and VaIN3) and subsequent excisional therapy, consecutively referred to the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014, was performed.Results Of the 86 patients, 4 cases (4.6%) of occult vaginal cancer were detected, all of them in women previously diagnosed with VaIN3 on biopsy (4/39 cases, 10.3%). Women with diagnosis of VaIN2 on biopsy showed an upgrading of lesions, with diagnosis of VaIN3 on the final specimen in 5 (10.6%) of 47 cases, with no cases of VAIN2 upgraded to invasive cancer. In 33.3% of the women initially diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus-related disease, a final histopathological upgrading of lesions emerged. Furthermore, tobacco use was significantly related to the histopathological upgrading of lesions previously detected on vaginal biopsy.Conclusions Women diagnosed with VaIN3 should be treated with excisional procedures as first-line surgical approach, given the risk of occult invasive disease in 10% of the cases. Women diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus-related cervical diseases should always be carefully evaluated and possibly excised, given the higher risk of histopathological upgrading of lesions and thus the potential risk of occult vaginal cancer. Tobacco users should be considered as high-risk group

Scaling of oscillatory kinematics and Froude efficiency in baleen whales

High efficiency lunate-tail swimming with high-aspect-ratio lifting surfaces has evolved in many vertebrate lineages, from fish to cetaceans. Baleen whales (Mysticeti) are the largest swimming animals that exhibit this locomotor strategy, and present an ideal study system to examine how morphology and the kinematics of swimming scale to the largest body sizes. We used data from whale-borne inertial sensors coupled with morphometric measurements from aerial drones to calculate the hydrodynamic performance of oscillatory swimming in six baleen whale species ranging in body length from 5 to 25 m (fin whale, Balaenoptera physalus; Bryde\u27s whale, Balaenoptera edeni; sei whale, Balaenoptera borealis; Antarctic minke whale, Balaenoptera bonaerensis; humpback whale, Megaptera novaeangliae; and blue whale, Balaenoptera musculus). We found that mass-specific thrust increased with both swimming speed and body size. Froude efficiency, defined as the ratio of useful power output to the rate of energy input (Sloop, 1978), generally increased with swimming speed but decreased on average with increasing body size. This finding is contrary to previous results in smaller animals, where Froude efficiency increased with body size. Although our empirically parameterized estimates for swimming baleen whale drag were higher than those of a simple gliding model, oscillatory locomotion at this scale exhibits generally high Froude efficiency as in other adept swimmers. Our results quantify the fine-scale kinematics and estimate the hydrodynamics of routine and energetically expensive swimming modes at the largest scale

Energetic and physical limitations on the breaching performance of large whales

The considerable power needed for large whales to leap out of the water may represent the single most expensive burst maneuver found in nature. However, the mechanics and energetic costs associated with the breaching behaviors of large whales remain poorly understood. In this study we deployed whale-borne tags to measure the kinematics of breaching to test the hypothesis that these spectacular aerial displays are metabolically expensive. We found that breaching whales use variable underwater trajectories, and that high-emergence breaches are faster and require more energy than predatory lunges. The most expensive breaches approach the upper limits of vertebrate muscle performance, and the energetic cost of breaching is high enough that repeated breaching events may serve as honest signaling of body condition. Furthermore, the confluence of muscle contractile properties, hydrodynamics, and the high speeds required likely impose an upper limit to the body size and effectiveness of breaching whales

Scaling of swimming performance in baleen whales

The scale dependence of locomotor factors has long been studied in comparative biomechanics, but remains poorly understood for animals at the upper extremes of body size. Rorqual baleen whales include the largest animals, but we lack basic kinematic data about their movements and behavior below the ocean surface. Here, we combined morphometrics from aerial drone photogrammetry, whale-borne inertial sensing tag data and hydrodynamic modeling to study the locomotion of five rorqual species. We quantified changes in tail oscillatory frequency and cruising speed for individual whales spanning a threefold variation in body length, corresponding to an order of magnitude variation in estimated body mass. Our results showed that oscillatory frequency decreases with body length (proportional to length(-0.5)(3)) while cruising speed remains roughly invariant (proportional to length(0.08)) at 2 m s(-1). We compared these measured results for oscillatory frequency against simplified models of an oscillating cantilever beam (proportional to length(-1)) and an optimized oscillating Strouhal vortex generator (proportional to length(-1)). The difference between our length-scaling exponent and the simplified models suggests that animals are often swimming non-optimally in order to feed or perform other routine behaviors. Cruising speed aligned more closely with an estimate of the optimal speed required to minimize the energetic cost of swimming (proportional to length(-1)). Our results are among the first to elucidate the relationships between both oscillatory frequency and cruising speed and body size for free-swimming animals at the largest scale

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19

Background. This study’s primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods. This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray’s method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results. Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8–11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7–21.0) and 9.3 (95% CI, 7.9–11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018–3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions. In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections

Scaling of maneuvering performance in baleen whales: larger whales outperform expectations

Despite their enormous size, whales make their living as voracious predators. To catch their much smaller, more maneuverable prey, they have developed several unique locomotor strategies that require high energetic input, high mechanical power output and a surprising degree of agility. To better understand how body size affects maneuverability at the largest scale, we used bio-logging data, aerial photogrammetry and a high-throughput approach to quantify the maneuvering performance of seven species of free-swimming baleen whale. We found that as body size increases, absolute maneuvering performance decreases: larger whales use lower accelerations and perform slower pitch-changes, rolls and turns than smaller species. We also found that baleen whales exhibit positive allometry of maneuvering performance: relative to their body size, larger whales use higher accelerations, and perform faster pitch-changes, rolls and certain types of turns than smaller species. However, not all maneuvers were impacted by body size in the same way, and we found that larger whales behaviorally adjust for their decreased agility by using turns that they can perform more effectively. The positive allometry of maneuvering performance suggests that large whales have compensated for their increased body size by evolving more effective control surfaces and by preferentially selecting maneuvers that play to their strengths.We thank the crews of many research vessels including the R/V John Martin, R/V Fluke, ARSV Laurence M. Gould, R/V Sanna, M/V Antonie, M/V Northern Song, the Cascadia Research Collective and the Shallow Marine Surveys Group; in particular, we thank John Douglas, Andrew Bell, Shaun Tomlinson, Steve Cartwright, Tony D'Aoust, Dennis Rogers, Kelly Newton, Heather Riley, Gina Rousa and Mark Rousa. We also thank Brandon L. Southall, Alison K. Stimpert and Stacy L. DeRuiter for their role in collecting data as part of the SOCAL-BRS project. We thank Matt S. Savoca, Julian Dale and Danuta M. Wisniewska for assistance with data collection. Finally, we thank John H. Kennedy, Michael A. Thompson and the NSF Office of Polar Programs.Ye

Validation of a new HPLC-MS/MS method for quantification of 4,4'-DMAR in human and rat plasma: application to pharmacokinetic studies in rat

Introduction: 4,4′-DMAR is a para-methyl analog of the known psychostimulants 4-methylaminorex and aminorex. In light of the reports of deaths associated with its abuse, and the easy accessibility by Internet vendors, the European Council recently decided control measures across Member States. Here we describe a validated method for measuring plasmatic levels of 4,4′-DMAR, crucial either for preclinical studies and analysis in human blood. Methods: Chromatography was performed by gradient elution on a Kinetex C18 column; MS detection was achieved by ESI positive ionization in MRM mode. The HPLC-MS/MS methods was validated following EMA guidelines in both human and rat plasma. Pharmacokinetic studies were conducted in rats. Results: Calibration curve was linear in the range 2.5-1000 ng/mL (r2 always > 0.993). The method was accurate (bias always ≤ 11.5%) and reproducible (% CV always ≤ 13.1). The recovery was high (> 93%) with a negligible matrix effect. Analytes were stable under all tested conditions. After acute intravenous treatment of rats with 1 mg/kg, plasma levels declined rapidly (≥ 80% in 4 hours), followed by a slow elimination phase (t1/2 of 5.14 ± 0.65 h). Rapid absorption was found after intraperitoneal administration (tmax = 15 min) and a rapid decline thereafter; Cmax and AUC0-240min showed dose-proportionality over the dose range 1-10 mg/kg. Conclusions: This method provides an accurate, precise, and sensitive method for 4,4’-DMAR quantification in plasma and was successfully applied to investigate pharmacokinetic properties in rats. Moreover the method could be applied to quantify 4,4’-DMAR levels in human plasma

A validated, sensitive HPLC-MS/MS method for quantification of cis-para-methyl-4-methylaminorex (cis-4,4'-DMAR) in rat and human plasma: application to pharmacokinetic studies in rats

4,4\u2032-DMAR is an analogue of the known psychostimulants 4-methylaminorex and aminorex. In the light of reports of deaths associated with its abuse, and the easy access from Internet vendors, the EU Council recently decided on control measures across member states. Here we describe a validated method for measuring plasma levels of cis-4,4\u2032-DMAR, crucial for preclinical studies and analysis in human plasma. Chromatographic separation was done by gradient elution on a Kinetex C18 column with 0.1% formic acid in water and 0.1% formic acid in acetonitrile at 0.2mL/min. Detection was by positive electrospray ionization (ESI+) in multiple reaction monitoring mode monitoring the quantifier transitions m/z 191.4\u2192m/z 148.3 for cis-4,4'-DMAR and m/z 259.3\u2192m/z 194.2 for carbamazepine (internal standard). Protein precipitation with 1%of formic acid in acetonitrilewas used in cis-4,4'-DMAR extraction from plasma; recovery was high (>93%) with a negligible matrix effect. This method provides an accurate, precise, and sensitive method for cis-4,4\u2019-DMAR quantification in human and rat plasma, following European Medicine Agency guidelines for bioanalytical method validation. Pharmacokinetic studieswere conducted in rats. After an intravenous dose of 1mg/kg, plasma levels declined rapidly ( 6580% in 4 h), followed by a slow elimination phase (t1/2 of 5.14\ub1 0.65 h). Absorption was rapid after intraperitoneal injection (tmax = 15 min) with a rapid decline thereafter; Cmax and AUC0-240min showed doseproportionality over the dose range 1\u201310mg/kg. This method was successfully applied to investigate pharmacokinetic properties in rats and could be used to quantify cis-4,4\u2019-DMAR levels in human plasma

Characterization of 4,4\u2019-DMAR, a synthetic psychostimulant designer drug

Introduction: The new psychoactive drugs (NPS) are a wide series of new substances that have been designed to mimicking the psychotropic effect of traditional illicit drugs. The poor knowledge about these emerging NPS represents a serious problem for public health. In this study we evaluated the pharmacological profile, the brain penetration and the motivational propertiesof 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4\u2019-DMAR) a synthetic derivative of 4-methylaminorex and aminorex, both of which are stimulants and controlled under the 1971 United Nations Convention on Psychotropic Substances. Methods: Independent groups of na\uefve male Wistar rats were used in all experiments. The doses of 4,4\u2019-DMAR to be tested were selected on the basis of the primary observation Irwin test. Pharmacokinetics of 4,4\u2019-DMAR was evaluated by HPLC-MS/MS. Alterations in locomotor activity after 4,4\u2019-DMAR administration were measured in activity cages equipped with photobeams, while rewarding properties of the drug were assessed in an unbiased conditioned place preference (CPP) paradigm. Results: Pharmacokinetics studies found that the peak in plasma and brain is around 1 hr after the administration. The acute and chronic administration of 4,4\u2019-DMAR (3-10 mg/kg i.p.) produced a dose-dependent increase in locomotor activity with a sort of sensitization after 14 day treatment that is maintained also after a 48 hr wash-out. 4,4\u2019-DMAR 10 mg/kg i.p., but not 1 and 3 mg/kg, induces CPP that was similar to the one induced by cocaine (10 mg/kg i.p.). Conclusion: These data demonstrate that 4,4\u2019-DMAR is a potent psychostimulant drug eliciting positive motivational properties