Searching for Heavy Dark Matter near the Planck Mass with XENON1T.

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10^{12} and 2×10^{17} GeV/c^{2}. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale.

First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment.

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03) ton yr exposure used for this search, the intrinsic ^{85}Kr and ^{222}Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3) events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10^{-47} cm^{2} for a WIMP mass of 28 GeV/c^{2} at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure.

CONGRESS REPORT OF THE 5TH NATIONAL CONGRESS OF THE BULGARIAN SOCIETY FOR DERMATOLOGIC SURGERY, SOFIA, 11TH MARCH 2023 WITH MAIN TOPICS: NITROSAMINES AS MOST POWERFUL TRIGGER FOR SKIN CANCER DEVELOPMENT AND PROGRESSION/PERSONALISED ONE STEP MELANOMA SURGERY AS POSSIBLE SKIN CANCER TREATMENT OPTION.

Deciphering the mutational pattern of skin tumours, remains a major challenge for clinicians and researchers. Over 80% of mutations in tumours are acquired, which in practice also means preventable. The surgical treatment of skin cancer and cancer in general is a worldwide, unsolved but at the same time not unsolvable problem. The problem concerning the dilemma of acquired mutations lies in the circumstance of their being allowed and subsequently treated. A more logical solution would be to eliminate the problem by making contact with mutagens in drugs public, clarifying it, studying it in detail and definitively stopping it. At present, there is an alarming and unexplained tendency worldwide : 1) Potential acquired mutations, caused in all probability by contact with known exogenous mutagens- the nitrosamines in most commonly prescribed drugs, are allowed to occur. 2) And subsequently, the diseases generated by them- treated (at a later stage) by multiple surgical interventions and unjustifiably expensive targeted therapy; 3) Mutagens - such as nitrosamines for example, to be in a permissive or possibly permissive availability regime. Moreover, this permissible availability turns out to be ubiquitous and affects the most common medicines worldwide: metformin, ranitidine, propranolol, rifampicin, irbesartan, olmesartan, valsartan, telmisartan, eprosartan, losartan, ACE inhibitors, thiazide diuretics, etc. In certain geographical regions, there is almost no patient taking this type of medication who has not had at least one tumour detected. These significant correlations (nitrosamines/cancer) are labeled by the regulatory institutions as possible, probable, or not currently relevant. But in spite of ˝this inconclusiveness˝, the drugs, containing nitrosamines, are withdrawn from the pharmaceutical market: quickly and quietly, despite the fact that ˝they did not pose a threat˝. The FDA was the only organization and the most important regulatory body worldwide, which lifted the veil from this ominous picture back in 2018: nitrosamines in blood medicines and cancer risk. Unfortunately, at the moment, the problems with this issue are proving to be more than the solutions, and at the same time it remains completely unclear who is to blame for this 'sporadic contamination': the packaging of the drug, the humidity in the rooms where the preparations are stored or the synthesis process itself - the explanations are divergent, the responsibility is blurred. This fuzzy liability does not affect the manufacturers and distributors of the preparations/nitrosamines themselves in the manner required by law for this (mis)act. The Bulgarian Society of Dermatological Surgery remains to be the only organization worldwide that for the 5th consecutive year continues to seek solutions to the above-mentioned problems by: 1) Officialising all cases of skin tumors (but not only) occurring after intake of nitrosamine-contaminated drugs, 2) also officialising a significant number of cases of patients with cutaneous melanomas treated by the one-stage surgical removal method within one surgical session (OSMS). The main priorities of the organization remain: 1) the complete elimination of nitrosamines from drugs worldwide, 2) the optimization of melanoma surgical treatment guidelines with the goal of treatment within 1 surgical session: for thin melanomas, dysplastic nevi and melanoma in situ, a surgical margin of safety of 1 cm in all directions and without detection and removal of the draining sentinel lymph node. Whereas for medium and thick melanomas, the focus should be directed to the following recommendation: 2 cm surgical margin of safety plus detection and removal of the draining lymph node within one surgical session. The indication for the surgical removal of these lesions should be made on the basis of radically different criteria from those used to date by the AJCC/EJC, namely: based on 1) clinical presentation/ clinical morphology, 2) dermatoscopic finding, and if there is a melanoma suspected lesion with possible tumour thickness greater than 1 mm , 3) ultrasonographic measurement for preoperative determination of tumor thickness should be additionally performed. The methodology is applicable in up to 80% of cases, excluding only some rare findings such as: amelanotic cutaneous melanomas, cutaneous melanomas with regression zones or those with localization in the neck and head. However, after careful individual assessment and a subsequent selected approach, even these exceptions could be included in the innovative algorithm for one step surgical removal of cutaneous melanomas. The resulting problems of not resolving these two dilemmas could lead to: 1) Generation of skin cancer (but not only), through the availability of nitrosamines in drugs. 2) Unnecessary and stressful /surgeries for the patients- 2 in number, which not infrequently lead to complication of their status (due to delay of histopathological analysis/ desire for second opinion/ delay regarding the timeframe for the second surgical intervention/ uncertainty regarding the resection lines within the first intervention/ failure to respect the recommended surgical security resection margins already within the first surgical session, etc.). 3) Huge additional costs to health care systems on the order of probably/roughly calculated about $50 billion per year. Resolution of these two dilemmas would likely result in a dramatic drop in cancer incidence worldwide and a significant improvement in the effectiveness/efficiency of surgical treatment for cutaneous melanoma.

MULTIFOCAL FIXED DRUG ERUPTION MIMICKING ACQUIRED DERMAL MELANOCYTOSIS.

Fixed drug eruptions (FDEs) are adverse drug reactions manifesting in the skin after exposure to a certain drug. The lesions can manifest as single or multiple eruptions followed by a post-inflammatory hyperpigmentation. The condition is very common among the young adult population and can be located on different parts of the body: the trunk, extremities, face, lips, etc. We report a case of a multifocal FDE following oral intake of Loratadine, Cetirizine dihydrochloride, Ibuprofen and/or Acetylsalicylic acid. Patch testing was recommended but later on declined by the patient. However, a small punch biopsy confirmed the diagnosis of multifocal fixed drug eruption. The lesions are often misdiagnosed or mistaken for other skin conditions. Differential diagnosis with an acquired dermal melanocytosis or other cutaneous eruptions could be done. Therefore, a brief review of the above-mentioned medications in the pathogenesis of the condition will be discussed.

SUBUNGUAL HEMATOMA OVERLAPPING WITH SUBUNGUAL LOCATED FOCAL MELANOCYTIC HYPERPLASIA: DERMATOSURGICAL APPROACH AS OPTIMAL TREATMENT CHOICE.

Subungual lesions present a serious challenge for clinicians. The following factors can cause certain problems in interpreting the data: 1) Changes in lesion morphology over time: It may indicate the presence of a malignant lesion (increased pigmentation over time and lack of distal growth) but may actually be a benign lesion (chronic persistent subungual hematoma). 2) Patient's medical history can be misleading or difficult to verify, especially in problematic patients, or those with mental health problems or communication disorders (e.g., Asperger's syndrome, autism, schizoid psychosis, etc.). 3) The morphology of the lesion itself can be difficult to determine in the presence of simultaneously overlapping lesions. These patient dilemmas primarily concern the differentiation between subungual hematomas from subungual melanomas. The clinicians's concerns are based on the potential for metastasis and the risk of significantly worse prognosis for patients affected by nail biopsy. We present a 19-year-old patient with a subungual pigmented lesion with a clinical/dermatoscopic suspicion for subungual melanoma. Primary complaints for about 3-4 months. Intensified pigmentation and increase in size within two months led to a partial surgical resection of the nail plate and nail bed, followed by adaptation of the wound edges with single interrupted sutures. The histopathological finding was indicative of a subungual hematoma located above a focal melanocytic hyperplasia of the nail bed, clear resection lines. After a literature review, we believe that this is the first case of a patient with simultaneously present subungual benign focal melanocytic hyperplasia overlapping with a chronic persistent subungual hematoma.

Search for New Physics in Electronic Recoil Data from XENONnT.

We report on a blinded analysis of low-energy electronic recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 ton liquid xenon target reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(ton×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 ton-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter.

Pragmatic diagnostic and therapeutic algorithms to optimize new potassium binder use in cardiorenal disease.

BACKGROUND: Pivotal randomized trials demonstrating efficacy, safety and good tolerance, of two new potassium binders (patiromer and sodium zirconium cyclosilicate) led to their recent approval. A major hurdle to the implementation of these potassium-binders is understanding how to integrate them safely and effectively into the long-term management of cardiovascular and kidney disease patients using renin angiotensin aldosterone system inhibitors (RAASi), the latter being prone to induce hyperkalaemia. METHODS: A multidisciplinary academic panel including nephrologists and cardiologists was convened to develop consensus therapeutic algorithm(s) aimed at optimizing the use of the two novel potassium binders (patiromer and sodium zirconium cyclosilicate) in stable adults who require treatment with RAASi and experience(d) hyperkalaemia in a non-emergent setting. RESULTS: Two dedicated pragmatic algorithms are proposed. The lowest intervention threshold (i.e. 5.1 mmol/L or greater) was the one used in the patiromer and sodium zirconium cyclosilicate) pivotal trials, both drugs being indicated to treat hyperkalaemia in a non -emergent setting. Acknowledging the heterogeneity across specialty guidelines in hyperkalaemia definition and thresholds to intervene when facing hyperkalaemia, we have been mindful to use soft language i.e. "it is to consider", not necessarily "to do". CONCLUSIONS: Providing the clinical community with pragmatic algorithms may help optimize the management of high-risk patients by avoiding the risks of both hyper and hypokalaemia and of suboptimal RAASi therapy.

Search for Coherent Elastic Scattering of Solar

We report on a search for nuclear recoil signals from solar ^{8}B neutrinos elastically scattering off xenon nuclei in XENON1T data, lowering the energy threshold from 2.6 to 1.6 keV. We develop a variety of novel techniques to limit the resulting increase in backgrounds near the threshold. No significant ^{8}B neutrinolike excess is found in an exposure of 0.6 t×y. For the first time, we use the nondetection of solar neutrinos to constrain the light yield from 1-2 keV nuclear recoils in liquid xenon, as well as nonstandard neutrino-quark interactions. Finally, we improve upon world-leading constraints on dark matter-nucleus interactions for dark matter masses between 3 and 11 GeV c^{-2} by as much as an order of magnitude.

Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis: development, characterization, biocompatibility, and anti-toxoplasma activity.

Ocular toxoplasmosis is the major cause of infectious posterior uveitis worldwide, inducing visual field defect and/or blindness. Despite the severity of this disease, an effective treatment is still lacking. In this study, spiramycin-loaded PLGA implants were developed aiming at the treatment of ocular toxoplasmosis. Implants were manufactured by a hot-molding technique, characterized by Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Differential Scanning Calorimetry, Scanning Electron Microscopy; evaluated in terms of ocular biocompatibility by immunofluorescence, flow cytometry, cell migration, Hen's egg test-chorioallantoic membrane (HET-CAM) irritation test; and investigated in terms of in vitro efficacy against Toxoplasma gondii . Characterization techniques indicated that spiramycin was dispersed into the polymeric chains and both substances preserved their physical structures in implants. The HET-CAM test indicated that implants did not induce hemorrhage or coagulation, being non-irritant to the CAM. ARPE-19 cells showed viability by MTT assay, and normality in cell cycle kinetics and morphology, without stimulating cell death by apoptosis. Finally, they were highly effective against intracellular parasites without inducing human retinal pigment epithelial cell death. In conclusion, spiramycin-loaded PLGA implants represent a promising therapeutic alternative for the local treatment of ocular toxoplasmosis.

Physicochemical, pharmacokinetic, and pharmacodynamic characterization of isradipine tablets for controlled release.

Isradipine is a dihydropyridine calcium channel blocker (CCB) commonly used as vasodilator with antihypertensive properties. A remote-controlled release formulation for isradipine would substantially improve the clinical outcomes of the patients requiring chronic long-term treatment. In this work, sustained release (SR) tablets of isradipine, composed of hydroxypropylmethyl cellulose (HPMC), have been produced by wet granulation and their in vitro and in vivo characterization was compared to a conventional tablet dosage form of immediate release (IR) as preliminary assessment. Tablets composed of 15.0% (wt/wt) HPMC exhibited a SR profile over a period of 24 hours. The release of isradipine followed a Fickian diffusion pattern obeying to the first order kinetics and the extent of absorption was even higher in comparison to the developed conventional tablets, which showed immediate drug release. In vivo studies were carried out in rabbits, showing that the extent of isradipine absorption from the developed tablets was higher in comparison to IR tablets due to the modified release profile obtained for the former (p < 0.05). Our results suggest that SR tablets of isradipine are an efficient solid dosage form to overcome the limitations encountered in conventional IR tablets.

Machine learning and glioma imaging biomarkers.

AIM: To review how machine learning (ML) is applied to imaging biomarkers in neuro-oncology, in particular for diagnosis, prognosis, and treatment response monitoring. MATERIALS AND METHODS: The PubMed and MEDLINE databases were searched for articles published before September 2018 using relevant search terms. The search strategy focused on articles applying ML to high-grade glioma biomarkers for treatment response monitoring, prognosis, and prediction. RESULTS: Magnetic resonance imaging (MRI) is typically used throughout the patient pathway because routine structural imaging provides detailed anatomical and pathological information and advanced techniques provide additional physiological detail. Using carefully chosen image features, ML is frequently used to allow accurate classification in a variety of scenarios. Rather than being chosen by human selection, ML also enables image features to be identified by an algorithm. Much research is applied to determining molecular profiles, histological tumour grade, and prognosis using MRI images acquired at the time that patients first present with a brain tumour. Differentiating a treatment response from a post-treatment-related effect using imaging is clinically important and also an area of active study (described here in one of two Special Issue publications dedicated to the application of ML in glioma imaging). CONCLUSION: Although pioneering, most of the evidence is of a low level, having been obtained retrospectively and in single centres. Studies applying ML to build neuro-oncology monitoring biomarker models have yet to show an overall advantage over those using traditional statistical methods. Development and validation of ML models applied to neuro-oncology require large, well-annotated datasets, and therefore multidisciplinary and multi-centre collaborations are necessary.

Antibacterial activity of chitosan/collagen membranes containing red propolis extract.

In this study we developed a mucoadhesive polymeric membrane wound dressing incorporating red propolis extract (HERP). Membranes were made using a casting method employing collagen, chitosan, polyethylene glycol (15, 20, and 30v%), and hydroethanolic extract of EtOH-H2O 70v% - 30v% (v/v) of HERP (0.5, 1.0, and 1.5%). Membranes were extensively characterized to assess the thickness, pH, morphology using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), mechanical properties, swelling, in vitro mucoadhesion, cytotoxicity, and minimum inhibitory concentration (MIC). Assessment of the thickness and mechanical properties of the membranes containing HERP revealed that the most significant thickness obtained was 40.7 µm; thermal analysis suggests suggesting the hydrogen bonds between hydroxyl groups of isoflavones and the free amine present in the region of chitosan. Cell viability decreased as the amount of HERP increased. Finally, the MICs were 7.8 and 1.9 µg.mL-1 for Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853, respectively. These results were suggesting that the 0.5 % HERP membrane has the potential for future studies for wound application.

First Results on the Scalar WIMP-Pion Coupling, Using the XENON1T Experiment.

We present first results on the scalar coupling of weakly interacting massive particles (WIMPs) to pions from 1 t yr of exposure with the XENON1T experiment. This interaction is generated when the WIMP couples to a virtual pion exchanged between the nucleons in a nucleus. In contrast to most nonrelativistic operators, these pion-exchange currents can be coherently enhanced by the total number of nucleons and therefore may dominate in scenarios where spin-independent WIMP-nucleon interactions are suppressed. Moreover, for natural values of the couplings, they dominate over the spin-dependent channel due to their coherence in the nucleus. Using the signal model of this new WIMP-pion channel, no significant excess is found, leading to an upper limit cross section of 6.4×10^{-46} cm^{2} (90% confidence level) at 30 GeV/c^{2} WIMP mass.

Constraining the Spin-Dependent WIMP-Nucleon Cross Sections with XENON1T.

We report the first experimental results on spin-dependent elastic weakly interacting massive particle (WIMP) nucleon scattering from the XENON1T dark matter search experiment. The analysis uses the full ton year exposure of XENON1T to constrain the spin-dependent proton-only and neutron-only cases. No significant signal excess is observed, and a profile likelihood ratio analysis is used to set exclusion limits on the WIMP-nucleon interactions. This includes the most stringent constraint to date on the WIMP-neutron cross section, with a minimum of 6.3×10^{-42} cm^{2} at 30 GeV/c^{2} and 90% confidence level. The results are compared with those from collider searches and used to exclude new parameter space in an isoscalar theory with an axial-vector mediator.

Light Dark Matter Search with Ionization Signals in XENON1T.

We report constraints on light dark matter (DM) models using ionization signals in the XENON1T experiment. We mitigate backgrounds with strong event selections, rather than requiring a scintillation signal, leaving an effective exposure of (22±3) tonne day. Above ∼0.4 keV_{ee}, we observe <1 event/(tonne day keV_{ee}), which is more than 1000 times lower than in similar searches with other detectors. Despite observing a higher rate at lower energies, no DM or CEvNS detection may be claimed because we cannot model all of our backgrounds. We thus exclude new regions in the parameter spaces for DM-nucleus scattering for DM masses m_{χ} within 3-6 GeV/c^{2}, DM-electron scattering for m_{χ}>30 MeV/c^{2}, and absorption of dark photons and axionlike particles for m_{χ} within 0.186-1 keV/c^{2}.

Search for Light Dark Matter Interactions Enhanced by the Migdal Effect or Bremsstrahlung in XENON1T.

Direct dark matter detection experiments based on a liquid xenon target are leading the search for dark matter particles with masses above ∼5 GeV/c^{2}, but have limited sensitivity to lighter masses because of the small momentum transfer in dark matter-nucleus elastic scattering. However, there is an irreducible contribution from inelastic processes accompanying the elastic scattering, which leads to the excitation and ionization of the recoiling atom (the Migdal effect) or the emission of a bremsstrahlung photon. In this Letter, we report on a probe of low-mass dark matter with masses down to about 85 MeV/c^{2} by looking for electronic recoils induced by the Migdal effect and bremsstrahlung using data from the XENON1T experiment. Besides the approach of detecting both scintillation and ionization signals, we exploit an approach that uses ionization signals only, which allows for a lower detection threshold. This analysis significantly enhances the sensitivity of XENON1T to light dark matter previously beyond its reach.

Dose to the interventional radiologist in CTF-guided procedures.

The aim of this work was to assess the occupational dose received by an interventional radiologist (IR) during computed tomography fluoroscopy (CTF)-guided procedures; to identify the most exposed areas of the body including the hands and fingers; to suggest recommendations for individual monitoring; and to improve radiation safety of the practice. A total of 53 CTF-guided procedures were studied. Twelve whole-body dosimeters were worn by the IR in each procedure for the assessment of the personal dose equivalent, Hp(10), on the chest, waist, and back, both over and under the lead apron, as well as the personal dose equivalent, Hp(0.07), on both arms, knees, and feet. Special gloves with casings to fit extremity dosimeters were prepared to assess Hp(0.07) to the fingers. The measured chest dose values were higher than those on the waist and back; the dominant hand or the left side was the most exposed. In general, the ring, middle, and index fingers of the dominant hand were the most exposed (maximum in the 36-39 mSv range), while wrist dose was negligible compared to finger doses. Based on the results obtained the following recommendations are suggested: protective devices (lead aprons, thyroid shield, and goggles) should be worn; Hp(10) should be assessed at the chest level both above and below the lead apron; finger doses can be measured on the basis of each middle finger; the arm closer to the beam should be monitored; and finally, a wrist dosimeter will not provide useful information.

Keratoacanthoma-like nodules as first manifestation of metastatic epithelioid trophoblastic tumor.

Cutaneous metastases are rarely the initial manifestation of a previously undiagnosed malignancy and keratoacanthoma-like lesions are a notoriously unusual presentation pattern of cutaneous dissemination of a primary tumor. Herein, we report a 40-year-old woman presenting to our dermatology department with multiple keratoacanthoma-like scalp nodules. Subsequent investigation determined it to be the first manifestation of a disseminated endometrial epithelioid trophoblastic tumor, eventually causing the patient's death. Epithelioid trophoblastic tumor, a rare form of gestational trophoblastic disease, is a recently described neoplasm whose cutaneous metastasis has not been previously reported in the literature.

Cross-Country Comparison of School Neighborhood Food Environments in Houston, Texas and Guadalajara, Mexico.

Studies in the U.S. and Mexico have observed the clustering of food resources around schools, which may promote the use of these resources. Our study characterized and compared school neighborhood food environments in Guadalajara, Jalisco, and Houston, Texas, and examined socioeconomic disparities in food resource availability across school neighborhoods. We used the Goods and Services Inventory to document the frequency and type of resources within each school neighborhood. School neighborhoods in Guadalajara had significantly more food resources than those in Houston. We found that convenience stores and table service restaurants were the most prevalent food resources in school neighborhoods in both cities. Guadalajara school neighborhoods had a higher prevalence of supermarkets and grocery stores than Houston. Low-income school neighborhoods in Guadalajara with poorly educated residents had significantly more food carts than high-income neighborhoods with more educated residents. In Houston, we found significantly more fast food restaurants and convenience stores in school neighborhoods with more educated residents than school neighborhoods with less educated residents. The influence of food resources within school neighborhoods on the dietary habits of schoolchildren should be further explored in both the U.S. and Mexico. The characterization of school neighborhood food environments can inform policymakers, city planners, and school officials who seek to implement policies to create healthier food environments.

Dark Matter Search Results from a One Ton-Year Exposure of XENON1T.

We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber with a fiducial mass of (1.30±0.01) ton, resulting in a 1.0 ton yr exposure. The energy region of interest, [1.4,10.6] keV_{ee} ([4.9,40.9] keV_{nr}), exhibits an ultralow electron recoil background rate of [82_{-3}^{+5}(syst)±3(stat)] events/(ton yr keV_{ee}). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6 GeV/c^{2}, with a minimum of 4.1×10^{-47} cm^{2} at 30 GeV/c^{2} and a 90% confidence level.