Male genital lichen sclerosus associated with urological interventions and microincontinence: a case series of 21 patients.

BACKGROUND: Male genital lichen sclerosus (MGLSc) is an acquired, chronic, inflammatory cutaneous disease associated with significant morbidity and squamous cell carcinoma of the penis. Consideration of all of the evidence suggests that chronic exposure of susceptible epithelium to urinary occlusion by the foreskin is the most likely pathomechanism. MGLSc never occurs in men who were circumcised at birth, and has been associated with trauma, instrumentation and anatomical abnormalities, e.g. frank hypospadia that results in microincontinence. AIM: To describe 21 patients who developed MGLSc following urological diagnoses and procedures. METHODS: We conducted a retrospective review of patients with a diagnosis of MGLSc whose symptoms related to urological procedures who attended or saw one of the authors (CBB) privately during the period June-October 2018. RESULTS: In total, 21 patients (mean age 59 years) were identified. The referrals came from the local urology departments, primary care or extramural dermatology services. Most of the patients were uncircumcised men. All had developed symptoms and signs of MGLSc within 5 years following their urological procedure; on examination, 30% of the patients were found to have damp penile skin due to microincontinence. Of the 21 patients, 10 had undergone radical prostatectomy for prostate cancer, 4 had a diagnosis of Peyronie disease, 4 had undergone multiple cystoscopies and urethroscopies, 2 had undergone surgery on the bladder neck and 1 had undergone implantation of a penile prosthesis to treat erectile dysfunction. CONCLUSION: This case series further strengthens the urinary occlusion hypothesis for the causation of MGLSc. It is important to recognize that urological interventions can create incompetence of the naviculomeatal valve post voiding. In uncircumcised men, this creates a risk factor for MGLSc that was not previously present. Occlusion, the phenomenon of koebnerization and currently unelucidated epithelial susceptibility factors lead to inflammation, sclerosis and cancer. Patients and urologists should be aware of these possibilities and preventative measures instituted, e.g. adaptive voiding habits and barrier protection.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

New sonographic marker of borderline ovarian tumor: microcystic pattern of papillae and solid components.

OBJECTIVE: To describe and evaluate the utility of a new sonographic microcystic pattern, which is typical of borderline ovarian tumor (BOT) papillary projections, solid component(s) and/or septa, as a new ultrasound marker that is capable of distinguishing BOT from other adnexal masses, and to present/obtain histologic confirmation. METHODS: In this retrospective study, we identified women with a histologic diagnosis of BOT following surgical resection who had undergone preoperative transvaginal ultrasound (TVS) examination. All images were reviewed for presence or absence of thin-walled, fluid-filled cluster(s) of 1-3-mm cystic formations, associated with solid component(s), papillary projections and/or septa. From the same cases, histopathologic slides of each BOT were examined for presence of any of these microcystic features which had been identified on TVS. To confirm that the microcystic TVS pattern is unique to BOTs, we also selected randomly from our ultrasound and surgical database 20 cases of epithelial ovarian cancer and 20 cases of benign cystadenoma, for review by the same pathologists. To confirm the novelty of our findings, we searched PubMed for literature published in the English language between 2010 and 2018 to determine whether the association between microcystic tissue pattern and BOT has been described previously. RESULTS: Included in the final analysis were 62 patients (67 ovaries) with preoperative TVS and surgically confirmed BOT on pathologic examination. The mean patient age at surgery was 39.8 years. The mean BOT size at TVS was 60.7 mm. Of the 67 BOTs, 47 (70.1%) were serous, 15 (22.4%) were mucinous and five (7.5%) were seromucinous. We observed on TVS a microcystic pattern in the papillary projections, solid component(s) and/or septa in 60 (89.6%) of the 67 BOTs, including 46 (97.9%) of the 47 serous BOTs, 11 (73.3%) of the 15 mucinous BOTs and three (60.0%) of the five seromucinous BOTs. On microscopic evaluation, 60 (89.6%) of the 67 samples had characteristic 1-3-mm fluid-filled cysts similar to those seen on TVS. In seven cases there was a discrepancy between sonographic and histologic observation of a microcystic pattern. The 20 cystadenomas were mostly unilocular and/or multilocular and largely avascular. None of them or the 20 epithelial ovarian malignancies displayed microcystic characteristics, either on TVS or at histology. On review of 23 published articles in the English medical literature, containing 163 sonographic images of BOT, we found that, while all images contained it, there was no description of the microcystic tissue pattern. CONCLUSION: We report herein a novel sonographic marker of BOT, a 'microcystic pattern' of BOT papillary projections, solid component(s) and/or septa. This was seen in the majority of both serous and mucinous BOT cases. Importantly, based on comparison of sonographic images and histopathology of benign entities and malignancies, the microcystic appearance seems to be unique to BOTs. No similar description has been published previously. Utilization of this new marker should help to identify BOT correctly, discriminating it from ovarian cancer and benign ovarian pathology, and should ensure appropriate clinical and surgical management. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

The application of a haemorrhage assessment tool in evaluating control of bleeding in a pilot trauma haemorrhage trial.

OBJECTIVES: To determine whether it was feasible to use a haemorrhage assessment tool (HAT) within a trauma trial and whether the data obtained could differentiate patients who had achieved haemostasis. BACKGROUND: Major haemorrhage is one of the leading causes of death worldwide, affecting 40% of trauma patients. Clinical trials evaluating haemostatic interventions often use transfusion outcomes as a primary endpoint. Transfusion is highly dependent on local practice, limiting its reliability as a robust, transferable endpoint. METHODS: A five-point HAT questionnaire was applied to participants enrolled into the EFIT-1 trial. This RCT evaluated the feasibility of administering a 6 g fibrinogen concentrate to patients with severe trauma haemorrhage. RESULTS: Of participants, 98% completed a HAT; 75% participants had 'achieved haemostasis' at the time of tool completion, as determined by clinical acumen alone. HAT scores were able to differentiate which participants required transfusion after 3 h. Of participants, 56% were transfused red blood cells when they scored 0-2, compared to 17% with HAT scores between 3 and 5. CONCLUSION: This study has confirmed the feasibility of using a HAT during the emergency care of patients suffering trauma haemorrhage, and future studies should be conducted to determine its value as an endpoint in haemostasis studies.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

Perspectives on the underlying drivers of urgent and emergency care reconfiguration in Ireland.

BACKGROUND: There is an increasing tendency to reconfigure acute hospital care towards a more centralised and specialised model, particularly for complex care conditions. Although centralisation is presented as "evidence-based", the relevant studies are often challenged by groups which hold perspectives and values beyond those implicit in the literature. This study investigated stakeholder perspectives on the rationale for the reconfiguration of urgent and emergency care in Ireland. Specifically, it considered the hypothesis that individuals from different stakeholder groups would endorse different positions in relation to the motivation for, and goals of, reconfiguration. METHODS: Documentary analysis of policy documents was used to identify official justifications for change. Semi-structured interviews with 175 purposively sampled stakeholders explored their perspectives on the rationale for reconfiguration. RESULTS: While there was some within-group variation, internal and external stakeholders generally vocalised different lines of argument. Clinicians and management in the internal stakeholder group proposed arguments in favour of reconfiguration based on efficiency and safety claims. External stakeholders, including hospital campaigners and local political representatives expressed arguments that focused on access to care. A "voter" argument, focused on the role of local politicians in determining the outcome of reconfiguration planning, was mentioned by both internal and external stakeholders, often in a critical fashion. CONCLUSION: Our study adds to an emerging literature on the interaction between a technocratic approach to health system planning advocated by clinicians and health service managers, and the experiential "non-expert" claims of the public and patients.

The role of hydroxychloroquine in the treatment of lichen planopilaris: A retrospective case series and review.

A variety of systemic agents are used to treat lichen planopilaris (LPP) with a limited evidence base. The aim of our study was to retrospectively review the response rate to and tolerability of hydroxychloroquine in a cohort of patients with LPP in an effort to add to the evidence base for its use. Twenty-three patients with a clinical and histopathological diagnosis of LPP who had been treated with hydroxychloroquine for their disease in a single center were identified. A retrospective review of these patients' medical records was performed and physician rated response was documented. Complete response was observed in 61% of our patients, and a further 9% of patients demonstrated partial response. Thirteen percent of patients withdrew from treatment because of suspected adverse effects. Our sample size was small, and data was collected retrospectively. We found hydroxychloroquine to be a reasonable therapeutic choice in LPP.

Finite slice analysis (FINA)-A general reconstruction method for velocity mapped and time-sliced ion imaging.

Since the advent of ion imaging, one of the key issues in the field has been creating methods to reconstruct the initial 3D distribution of particles from its 2D projection. This has led to the development of a number of different numerical methods and fitting techniques to solve this fundamental issue in imaging. In recent years, slice-imaging methods have been developed that permit direct recording of the 3D distribution, i.e., a thin slice of the recoiling fragment distribution. However, in practice, most slice imaging experiments achieve a velocity slice width of around 10%-25% around the center of the distribution. This still carries significant out-of-plane elements that can blur the spectrum, lose fine resolution, and underestimate the contribution from slow recoiling products. To overcome these limitations, we developed a new numerical method to remove these out-of-plane elements from a sliced image. The finite sliced analysis method models the off-axis elements of the 3D particle distribution through the use of radial basis functions. Once applied, the method reconstructs the underlying central slice of the 3D particle distribution. The approach may be applied to arbitrarily sliced or unsliced data and has the further advantage that it neither requires nor enforces full cylindrical symmetry of the data. We demonstrate this reconstruction approach with a broad range of synthetic and experimental data that, at the same time, allows us to examine the impact of finite slicing on the recovered distributions in detail.

Finite slice analysis (FINA) of sliced and velocity mapped images on a Cartesian grid.

Although time-sliced imaging yields improved signal-to-noise and resolution compared with unsliced velocity mapped ion images, for finite slice widths as encountered in real experiments there is a loss of resolution and recovered intensities for the slow fragments. Recently, we reported a new approach that permits correction of these effects for an arbitrarily sliced distribution of a 3D charged particle cloud. This finite slice analysis (FinA) method utilizes basis functions that model the out-of-plane contribution of a given velocity component to the image for sequential subtraction in a spherical polar coordinate system. However, the original approach suffers from a slow processing time due to the weighting procedure needed to accurately model the out-of-plane projection of an anisotropic angular distribution. To overcome this issue we present a variant of the method in which the FinA approach is performed in a cylindrical coordinate system (Cartesian in the image plane) rather than a spherical polar coordinate system. Dubbed C-FinA, we show how this method is applied in much the same manner. We compare this variant to the polar FinA method and find that the processing time (of a 510 × 510 pixel image) in its most extreme case improves by a factor of 100. We also show that although the resulting velocity resolution is not quite as high as the polar version, this new approach shows superior resolution for fine structure in the differential cross sections. We demonstrate the method on a range of experimental and synthetic data at different effective slice widths.

Shiitake Flagellate Dermatitis: the First Case Reported in Ireland.

Shiitake (Lentinula edodes) is the second most commonly consumed mushroom worldwide. The first case of shiitake mushroom flagellate dermatitis was described in Japan in 1977 and it is now being reported in the western world. We describe the first reported case in Ireland.

A synthetic review of notoedres species mites and mange.

Notoedric mange, caused by obligately parasitic sarcoptiform Notoedres mites, is associated with potentially fatal dermatitis with secondary systemic disease in small mammals, felids and procyonids among others, as well as an occasional zoonosis. We describe clinical spectra in non-chiropteran hosts, review risk factors and summarize ecological and epidemiological studies. The genus is disproportionately represented on rodents. Disease in felids and procyonids ranges from very mild to death. Knowledge of the geographical distribution of the mites is highly inadequate, with focal hot spots known for Notoedres cati in domestic cats and bobcats. Predisposing genetic and immunological factors are not known, except that co-infection with other parasites and anticoagulant rodenticide toxicoses may contribute to severe disease. Treatment of individual animals is typically successful with macrocytic lactones such as selamectin, but herd or wildlife population treatment has not been undertaken. Transmission requires close contact and typically is within a host species. Notoedric mange can kill half all individuals in a population and regulate host population below non-diseased density for decades, consistent with frequency-dependent transmission or spillover from other hosts. Epidemics are increasingly identified in various hosts, suggesting global change in suitable environmental conditions or increased reporting bias.

Investment appraisal of automatic milking and conventional milking technologies in a pasture-based dairy system.

The successful integration of automatic milking (AM) systems and grazing has resulted in AM becoming a feasible alternative to conventional milking (CM) in pasture-based systems. The objective of this study was to identify the profitability of AM in a pasture-based system, relative to CM herringbone parlors with 2 different levels of automation, across 2 farm sizes, over a 10-yr period following initial investment. The scenarios which were evaluated were (1) a medium farm milking 70 cows twice daily, with 1 AM unit, a 12-unit CM medium-specification (MS) parlor and a 12-unit CM high-specification (HS) parlor, and (2) a large farm milking 140 cows twice daily with 2 AM units, a 20-unit CM MS parlor and a 20-unit CM HS parlor. A stochastic whole-farm budgetary simulation model combined capital investment costs and annual labor and maintenance costs for each investment scenario, with each scenario evaluated using multiple financial metrics, such as annual net profit, annual net cash flow, total discounted net profitability, total discounted net cash flow, and return on investment. The capital required for each investment was financed from borrowings at an interest rate of 5% and repaid over 10-yr, whereas milking equipment and building infrastructure were depreciated over 10 and 20 yr, respectively. A supporting labor audit (conducted on both AM and CM farms) showed a 36% reduction in labor demand associated with AM. However, despite this reduction in labor, MS CM technologies consistently achieved greater profitability, irrespective of farm size. The AM system achieved intermediate profitability at medium farm size; it was 0.5% less profitable than HS technology at the large farm size. The difference in profitability was greatest in the years after the initial investment. This study indicated that although milking with AM was less profitable than MS technologies, it was competitive when compared with a CM parlor of similar technology.

Preclinical cardiovascular safety assessment of pharmacology-toxicology relationship for a set of novel kinase inhibitors.

Cardiovascular toxicity is one of the more common causes of attrition in preclinical and clinical drug development. Preclinical cardiovascular safety assessment involves numerous in vitro and in vivo endpoints which are being continually reviewed and improved to lower the incidence of cardiovascular toxicity that manifests only after the initiation of clinical trials. An example of notable preclinical toxicity is necrosis in the papillary muscle of the left ventricle in dogs that is induced by exaggerated pharmacological effects of vasodilators or positive inotropic/vasodilating off-target drug effects. Two distinct, small-molecule inhibitors that target an intracellular kinase, Compound A and Compound B, were profiled in 2-week dose-range finding and 4-week toxicity studies. Serum cardiac troponin (cTnI) was evaluated after a single dose and after 2-week and 4-week repeat dose studies with each kinase inhibitor. Acute effects on hemodynamic (heart rate, blood pressures, left ventricular contractility) and electrocardiographic (QTcV, PR, QRS intervals) endpoints by each inhibitor were assessed in an anesthetized dog cardiovascular model. Cardiovascular degeneration/necrosis with and without fibrosis was observed in dogs and correlated to increases in serum cTnI in repeat-dose toxicity studies. At the same doses used in toxicologic assessments, both kinase inhibitors produced sustained increases in heart rate, left ventricular contractility, and cardiac output, and decreases in mean arterial pressure. Cardiac pathology findings associated with these 2 kinase inhibitors were accompanied not only by cardiac troponin elevations but also associated with hemodynamic changes, highlighting the importance of the link of the physiologic-toxicologic interplay in cardiovascular safety assessment.

Innovative approaches to cardiovascular safety pharmacology assessment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

Evaluation of the translation of multiple cardiovascular regulatory mechanisms in the anesthetized dog.

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of "non-QT" cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human.

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity.

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Conserving large populations of lions - the argument for fences has holes.

Packer et al. reported that fenced lion populations attain densities closer to carrying capacity than unfenced populations. However, fenced populations are often maintained above carrying capacity, and most are small. Many more lions are conserved per dollar invested in unfenced ecosystems, which avoid the ecological and economic costs of fencing.