Wiener filter reloaded: fast signal reconstruction without preconditioning

We present a high performance solution to the Wiener filtering problem via a formulation that is dual to the recently developed messenger technique. This new dual messenger algorithm, like its predecessor, efficiently calculates the Wiener filter solution of large and complex data sets without preconditioning and can account for inhomogeneous noise distributions and arbitrary mask geometries. We demonstrate the capabilities of this scheme in signal reconstruction by applying it on a simulated cosmic microwave background (CMB) temperature data set. The performance of this new method is compared to that of the standard messenger algorithm and the preconditioned conjugate gradient (PCG) approach, using a series of well-known convergence diagnostics and their processing times, for the particular problem under consideration. This variant of the messenger algorithm matches the performance of the PCG method in terms of the effectiveness of reconstruction of the input angular power spectrum and converges smoothly to the final solution. The dual messenger algorithm outperforms the standard messenger and PCG methods in terms of execution time, as it runs to completion around 2 and 3-4 times faster than the respective methods, for the specific problem considered.Comment: 13 pages, 10 figures. Accepted for publication in MNRAS main journa

Simulation-based inference of dynamical galaxy cluster masses with 3D convolutional neural networks

We present a simulation-based inference framework using a convolutional neural network to infer dynamical masses of galaxy clusters from their observed 3D projected phase-space distribution, which consists of the projected galaxy positions in the sky and their line-of-sight velocities. By formulating the mass estimation problem within this simulation-based inference framework, we are able to quantify the uncertainties on the inferred masses in a straightforward and robust way. We generate a realistic mock catalogue emulating the Sloan Digital Sky Survey (SDSS) Legacy spectroscopic observations (the main galaxy sample) for redshifts $z \lesssim 0.09$ and explicitly illustrate the challenges posed by interloper (non-member) galaxies for cluster mass estimation from actual observations. Our approach constitutes the first optimal machine learning-based exploitation of the information content of the full 3D projected phase-space distribution, including both the virialized and infall cluster regions, for the inference of dynamical cluster masses. We also present, for the first time, the application of a simulation-based inference machinery to obtain dynamical masses of around $800$ galaxy clusters found in the SDSS Legacy Survey, and show that the resulting mass estimates are consistent with mass measurements from the literature.Comment: 14 pages, 11 figures. Accepted for publication in MNRAS. Contains non-peer reviewed supplementary material on cluster mass function in appendi

AI-driven spatio-temporal engine for finding gravitationally lensed supernovae

We present a spatio-temporal AI framework that concurrently exploits both the spatial and time-variable features of gravitationally lensed supernovae in optical images to ultimately aid in the discovery of such exotic transients in wide-field surveys. Our spatio-temporal engine is designed using recurrent convolutional layers, while drawing from recent advances in variational inference to quantify approximate Bayesian uncertainties via a confidence score. Using simulated Young Supernova Experiment (YSE) images as a showcase, we find that the use of time-series images yields a substantial gain of nearly 20 per cent in classification accuracy over single-epoch observations, with a preliminary application to mock observations from the Legacy Survey of Space and Time (LSST) yielding around 99 per cent accuracy. Our innovative deep learning machinery adds an extra dimension in the search for gravitationally lensed supernovae from current and future astrophysical transient surveys.Comment: 6+8 pages, 10 figures, 2 tables. For submission to a peer-reviewed journal. Comments welcom

Development and assessment of ketoconazole intravaginal thermosetting hydrogel formulations

Imidazole compounds are commonly used as antifungal therapies and ketoconazole was the first broad spectrum orally active azole identified and registered. However, the risks of hepatotoxicity and drug interactions following systemic delivery and absorption of ketoconazole outweigh the therapeutic benefits and ketoconazole was therefore discontinued as first line systemic antifungal therapy in many countries. Although not yet banned in South Africa, the South African Medicine Formulary has ceased to recommend the use of ketoconazole for systemic treatment. Topical use of ketoconazole is, however, regarded as safe following extensive human use as low systemic absorption occurs following topical administration. Vulvo-vaginal candidiasis is a yeast infection that affects a large number of women, some of whom present with several infections annually. The topical treatment options for vulvo-vaginal candidiasis include the use of vaginal tablets, capsules, ovules and creams administered as a single dose or one to three times daily for three to fourteen days either alone or in combination with another dosage form depending on the regimen. Administration of the dose nightly is recommended for most vaginal creams and ovule formulation due to leakage and the uncomfortable feel of the dosage form if administered during the day. A thermosetting gel that remains in the vagina following administration and prolongs the release of ketoconazole from a once daily dose would be a useful addition to the arsenal for intra-vaginal antifungal therapy. Thermosetting gels would be more comfortable to administer as the gel would set in a form similar to naturally occurring mucous in the vagina and, if formulated with a low pH, irritation of the sensitive and fissured tissue would be minimised. A further benefit would be that once set the gel would loosely take on the anatomical shape of the vagina. A simple, precise, accurate, reproducible and sensitive stability-indicating reversed phase-high performance liquid chromatographic method using ultraviolet detection for the quantitation of ketoconazole was developed and validated. The method was specific and was applied to the determination of ketoconazole in commercial and experimental formulations in addition to samples from degradation studies and in vitro release testing. Product performance characteristics of commercial products were investigated with the goal to provide a strategy for the development of a novel intra vaginal gel in the shortest possible time. Characterisation of Xolegel®, Kez® shampoo and Ketazol® cream included an evaluation of pH, viscosity and assay, in addition to spectroscopic and thermal analysis, to identify ideal characteristics of topical products that could be used as targets during formulation development of the gel. An in vitro release method was developed and validated for precision and accuracy and the in vitro release profiles of commercial ketoconazole products were compared using analysis of variance, model dependent and independent approaches. Ketoconazole release data from test gel manufactured during formulation development were investigated to obtain information about the relationship between formulation content and drug release. Poloxamers marketed as Pluronic® and Lutrol® are synthetic non-ionic tri-block copolymers that consist of hydrophobic propylene oxide and hydrophilic polyethylene oxide blocks, which in solution interact to exhibit thermo-reversible behaviour. In situ forming hydrogels consisting of poloxamers, more specifically poloxamer 407, are activated following a temperature stimulus and undergo a sol to gel transition. This approach was used to produce a thermosetting vaginal gel that would exhibit a long residence time in the vagina with an associated enhancement of therapeutic efficacy. Ketoconazole- excipient compatibility was investigated during preformulation studies using spectroscopic and thermal analysis to enable the selection of excipients best suited for the production of a novel dosage form prior to formulation development activities. No obvious interactions between ketoconazole and excipient were observed and ketoconazole was found in an amorphous form when in combination with polysorbate 80 and poloxamers. A two-level factorial design was used to produce solvent systems with different amounts of polysorbate 80, citric acid and ethanol to identify a vehicle in which ketoconazole exhibited optimum solubility and at a pH that would be least irritating to the vaginal mucosa with a low content of excipients. The optimised vehicle consisted of 4% m/v citric acid, 1.5% v/v polysorbate 80 and 9.5% v/v ethanol made up to 50 g with citrate-phosphate buffer adjusted to pH 5.0, resulted in a vehicle of pH of 3.5 in which 71.41 mg of ketoconazole was dissolved per mL. A Central Composite Design was used to evaluate compositions for the modulation of viscosity of the thermosetting dosage form such that it was a liquid at 22 °C that rapidly formed a stiff gel when heated to 37 °C (intra-vaginal temperature) using different amounts of the poloxamer grades 407, 188 and 237. Thermosetting gels containing 2% m/v ketoconazole were manufactured using specifications generated using the Central Composite Design and the viscosity at 22 °C and 37 °C, solution to gel transition time, potency and ketoconazole release at 24, 48 and 72 hours investigated. Contour and three-dimensional response surface plots and mathematical relationships with target ranges set for responses were identified and with the aid of Central Composite Design the optimisation of a desirable thermosetting gel was achieved. The optimised composition included 16% m/v poloxamer 407, 10% m/v poloxamer 188 and 6% m/v poloxamer 237 in the gel that was used as the basis for further optimisation studies. The low ketoconazole release for ketoconazole observed indicated that the poloxamers had formed a gel matrix that sustained the release of ketoconazole and would therefore ensure that once daily administration of the gel was possible. The sol-gel transition test may be used as a simple and cheap alternative to viscosity testing for thermosetting formulations when expensive viscometers and rheometers are unavailable and was successfully used for this purpose.Ketoconazole is photolabile and is prone to degradation in aqueous solutions. The hydrophobic core of micelles formed in these dosage forms are believed to shield ketoconazole molecules and improve stability in aqueous solutions and acidic gels. The thermosetting gel optimised for poloxamer content was subjected to a further Central Composite Design in which sodium metabisulphite content and vehicle pH were investigated. The length of storage was used as a numeric variable and storage condition as a categoric variable at two levels to monitor the stability of the gels. The formulations were investigated at sample times of 0, 1, 2, 4 and 8 weeks at 5 °C, 25 °C and 40 °C. The use of a Central Composite Design facilitated an understanding of the interactions between input variables and their impact on the responses analysed including ketoconazole content, release at 24, 48 and 72 hours, gel pH and viscosity at 22 °C and 37 °C. Design of Experiments may be used as a rapid cost effective tool for an overall assessment of the stability of novel topical dosage forms. However, a more thorough assessment of stability may be required for product registration. Ketoconazole was found to be unstable in the acidic thermosetting gels despite the addition of antioxidant. The gels in liquid form at 5 °C and 25 °C have a low number of micelles for ketoconazole incorporation and therefore additional optimisation studies would be required to enhance the shelf-life of this product

Brain and lung metastasis of Bartholin’s gland adenoid cystic carcinoma: a case report

INTRODUCTION: Adenoid cystic carcinoma of Bartholin’s gland is a very rare disease. CASE PRESENTATION: A 48-year-old premenopausal woman of Caucasian origin was delivered adjuvant pelvic and inguinal radiotherapy after prior complete left Bartholin’s gland tumor excision and inguinal lymph node dissection for adenoid cystic carcinoma of Bartholin’s gland with one metastatic inguinal lymph node. Two years after primary treatment, she presented to the Emergency Room with acute headache, hypoacousia, decrease in visual acuity, and a decrease in right leg muscle strength. A cranial magnetic resonance imaging scan demonstrated three cystic brain lesions with associated perifocal edema. Chest and abdomen computed tomography scans and a magnetic resonance imaging scan of the pelvis did not find any metastatic or residual disease elsewhere. A physical examination found no local recurrence. Stereotactic brain biopsies with pathology examination revealed the presence of adenoid cystic carcinoma metastasis. She thus received 30Gy of brain radiotherapy but, three months later, the brain lesions did not decrease in size and left mid lobular lung lesions appeared on her chest computed tomography scan. A mid left lobe lung excision was undertaken followed by chemotherapy consisting of six cycles of cyclophosphamide, adriamycin and cisplatin. Five months after beginning chemotherapy, the brain disease progressed and our patient died. CONCLUSION: Our case report shows the difficulty in managing brain and lung metastasis of Bartholin’s gland adenoid cystic carcinoma as no consensus on the optimal treatment exists

Dynamical mass inference of galaxy clusters with neural flows

We present an algorithm for inferring the dynamical mass of galaxy clusters directly from their respective phase-space distributions, i.e. the observed line-of-sight velocities and projected distances of galaxies from the cluster centre. Our method employs normalizing flows, a deep neural network capable of learning arbitrary high-dimensional probability distributions, and inherently accounts, to an adequate extent, for the presence of interloper galaxies which are not bounded to a given cluster, the primary contaminant of dynamical mass measurements. We validate and showcase the performance of our neural flow approach to robustly infer the dynamical mass of clusters from a realistic mock cluster catalogue. A key aspect of our novel algorithm is that it yields the probability density function of the mass of a particular cluster, thereby providing a principled way of quantifying uncertainties, in contrast to conventional machine learning approaches. The neural network mass predictions, when applied to a contaminated catalogue with interlopers, have a mean overall logarithmic residual scatter of 0.028 dex, with a log-normal scatter of 0.126 dex, which goes down to 0.089 dex for clusters in the intermediate to high mass range. This is an improvement by nearly a factor of four relative to the classical cluster mass scaling relation with the velocity dispersion, and outperforms recently proposed machine learning approaches. We also apply our neural flow mass estimator to a compilation of galaxy observations of some well-studied clusters with robust dynamical mass estimates, further substantiating the efficacy of our algorithm.Comment: 14 pages, 9 figures, 1 table. Improved approach, saliency maps adde

Comparison of first versus second line sacrocolpopexies in terms of morbidity and mid-term efficacy

To compare pelvic organ prolapse (POP) recurrence and morbidity between first and second line sacrocolpopexies. We conducted a retrospective chart review of all laparoscopic or robotic sacrocolpopexies for POP-Q stage ≥ 2, with or without a history of previous prolapse repair, performed with a similar technique between January 2012 and June 2019 in 3 European Gynecologic Surgery Departments. Patients were separated into two groups: first line sacrocolpopexy (FLS) and second line sacrocolpopexy (SLS). Each patient from the SLS group was age-matched with a patient from the FLS group. The primary outcome measure was reoperation procedures for recurrent POP defined as a symptomatic POP-Q stage ≥ 2 POP in at least one vaginal compartment. Secondary outcomes included operative time, intraoperative organ trauma, intraoperative blood loss, postoperative POP recurrence (operated on or not), global reoperation and mesh-related complications. During this period, 332 patients were included. After age-matching, 170 patients were analyzed: 85 patients in the FLS and SLS groups, respectively. After a mean follow-up of 3 years, there was no statistically significant difference between the two groups in terms of recurrent POP (9.4% versus 10.6%, p = 0.7), recurrent POP reoperation (3.5% versus 5.9% p = 0.7), mesh-related reoperation (0% versus 2.4%, p = 0.5), global reoperation (3.5 versus 8.2%, p = 0.3), operative time (198 ± 67 min versus 193 ± 60 min, p = 0.5), intraoperative complications such as organ injury (4.7% versus 7.1%, p = 0.7) and blood loss > 500 mL (2.4% versus 0%, p = 0.5). Patients who underwent a first or a second line sacrocolpopexy seemed to have similar rates of prolapse recurrence and complications

In Vitro Release Testing (IVRT) of Topical Hydrocortisone Acetate Creams: a novel approach using positive and negative controls

The objective was to develop and validate an in vitro release testing (IVRT) method to assess the release of hydrocortisone acetate (HCA) from five topical formulations. A marketed generic cream containing 1% HCA was used as the reference product. Vertical diffusion cells (VDCs) were used to assess and compare the release rates of HCA from cream formulations containing 0.5%, 1%, and 1.5% HCA. The study describes a novel approach to test the discriminatory power by including both positive and negative controls to declare pharmaceutical equivalence or inequivalence. The validated method was found to be sensitive, linear, precise, reproducible, robust, and selective for the analysis of HCA from topical cream products. Equivalence or inequivalence was established based on SUPAC-SS acceptance criteria using a 90% CI with limits of 75–133.33%. The IVRT method was shown to have discriminatory ability to appropriately measure significant differences in drug release from various cream formulations. This approach also provides useful information for the future development of acceptable IVRT methods to assess topical dosage forms for local action containing different drugs

Metilación de sitios CpG del virus del papiloma humano tipo 16 en el sitio de unión 1 de E2 (E2BS1), E2BS2 y el sitio de unión de Sp1 en muestras de cáncer de cuello uterino, según lo determinado por análisis de fusión de alta resolución-PCR

High-risk (HR) human papillomavirus (HPV)-associated carcinogenesis is driven mainly by the overexpression of E7 and E6 oncoproteins following viral DNA integration and the concomitant loss of the E2 open reading frame (ORF). However, the integration of HR-HPV DNA is not systematically observed in cervical cancers. The E2 protein acts as a transcription factor that governs viral oncogene expression. The methylation of CpGs in the E2-binding sites (E2BSs) in the viral long control region abrogates E2 binding, thus impairing the E2-mediated regulation of E7/E6 transcription. Here, high-resolution melting (HRM)–PCR was developed to quantitatively analyze the methylation statuses of E2BS1, E2BS2, and the specificity protein 1 (Sp1)-binding site in 119 HPV16-positive cervical smears. This is a rapid assay that is suitable for the analysis of cervical samples. The proportion of cancer samples with methylated E2BS1, E2BS2, and Sp1-binding site CpGs was 47%, whereas the vast majority of samples diagnosed as being within normal limits, low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL) harbored unmethylated CpGs. Methylation levels varied widely, since some cancer samples harbored up to 60% of methylated HPV16 genomes. A pyrosequencing approach was used as a confirmation test and highlighted that quantitative measurement of methylation can be achieved by HRM-PCR. Its prognostic value deserves to be investigated alone or in association with other biomarkers. The reliability of this single-tube assay offers great opportunities for the investigation of HPV16 methylation in other HPV-related cancers, such as head and neck cancers, which are a major public health burden

Residual disease after re-excision lumpectomy for close margins

Introduction While a positive margin after an attempt at breast conservation therapy (BCT) is a reason for concern, there is more controversy regarding close margins. When re-excisions are performed, there is often no residual disease in the new specimen, calling into question the need for the procedure. We sought to examine the incidence of residual disease after re-excision for close margins and to identify predictive factors that may better select patients for re-excision. Methods Our IRB-approved prospective breast cancer database was queried for all breast cancer patients who underwent a re-excision lumpectomy for either close or positive margins after an attempt at BCT. Close margins are defined as ≤2 mm for invasive carcinoma and ≤3 mm for DCIS. Clinicopathologic features were correlated with the presence of residual disease in the re-excision specimen. Results Three hundred three patients (32%) underwent re-operation for either close (173) or positive (130) margins. Overall, 33% had residual disease identified, 42% of DCIS patients and 29% of patients with invasive disease, nearly identical to patients with positive margins. For patients with DCIS, only younger age was significantly related to residual disease. For patients with invasive cancer, only multifocality was significantly associated with residual disease (OR 3.64 [1.26–10.48]). However, patients without multifocality still had a substantial risk of residual disease. Discussion The presence of residual disease appears equal between re-excisions for close and positive margins. No subset of patients with either DCIS or invasive cancer could be identified with a substantially lower risk of residual disease. J. Surg. Oncol. 2009;99: 99–103. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61535/1/21215_ftp.pd