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We have investigated the pinning potential of high-quality single crystals of superconducting material CaKFe4As4 having high critical current density and very high upper critical field using both magnetization relaxation measurements and frequency-dependent AC susceptibility. Preliminary studies of the superconducting transition and of the isothermal magnetization loops confirmed the high quality of the samples, while temperature dependence of the AC susceptibility in high magnetic fields show absolutely no dependence on the cooling conditions, hence, no magnetic history. From magnetization relaxation measurements were extracted the values of the normalized pinning potential U*, which reveals a clear crossover between elastic creep and plastic creep. The extremely high values of U*, up to 1200 K around the temperature of 20 K lead to a nearly zero value of the probability of thermally-activated flux jumps at temperatures of interest for high-field applications. The values of the creep exponents in the two creep regimes resulted from the analysis of the magnetization relaxation data are in complete agreement with theoretical models. Pinning potentials were also estimated, near the critical temperature, from AC susceptibility measurements, their values being close to those resulted (at the same temperature and DC field) from the magnetization relaxation data. [ABSTRACT FROM AUTHOR]

Continuous rise in the number of COVID-19 cases, since it was first diagnosed in 2019, forced the entire medical fraternity to delay elective surgeries. The preoperative evaluation guidelines that were used in the pre-COVID-19 era underwent significant changes, adding modifications to meet the post-COVID patients' specific criteria and requirements. Currently, all patients before or at the time of hospital admission were tested using a nasopharyngeal swab, by RT-PCR for SARS-CoV-2. Apart from this, for a patient undergoing elective surgery in their post-COVID-19 period, it is mandatory to obtain a detailed history of COVID-19 dis-ease/SARS-CoV-2 infection, to identify residual symptoms or any organ dysfunction the infection might have caused. As well as the functional optimization of the patient to achieve the best clinical and biological status before the surgery. After all the systems have been thoroughly investigated, the risk-benefit ratio needs to be calculated, keeping in mind the cytokine storm and inflammatory responses encountered postoperatively. A mere negative RT-PCR test cannot be considered as the only decisive factor to operate, as the post-COVID-19 phase can influence postoperative outcome of the patient. Hence, the pre-operative evaluation protocols of post-COVID patients should be set and followed thoroughly, in order to avoid post-surgical complications. For better surgical and post-surgical management of post-COVID-19 patients, conducting clinical tests, assessing previously administered medications, evaluating the need for deep venous thrombosis prophylaxes, and identifying subclinical inflammatory state are the measures that should be taken. [ABSTRACT FROM AUTHOR]

This study aimed to validate the I-ADAPT scale to assess the individual adaptability to work within the Romanian population. Both a pilot study and a main study were conducted on a total sample of 966 Romanians. Following the application of standard scale validation procedures, the results of our study indicated that the I-ADAPT measure of work adaptability has good psychometric properties on the Romanian population. Our findings provide evidence that I-ADAPT continues to explain the unique variance in adaptability to work even if work patterns in the Covid-19 pandemic context moved more and more from a traditional to a virtual work environment. ROa I-ADAPT measure has excellent properties concerning convergent, discriminant, and criterion-related validity. One main finding was that the “Physical” dimension of adaptability to work had no empirical support in the Romanian population. Moreover, our results indicate that the “interpersonal adaptability” and the “cultural adaptability” dimensions cannot be empirically separated in the Romanian population. To our knowledge, this is the first validated instrument that can be used to assess the individual adaptability of Romanians in the context of work. Our study is relevant for decision-makers in Romania and such actors in other EU-member countries where Romanians represent the largest group of working-age EU citizens.

The purpose of this study was to analyze the influence of solar activity described by the sunspot number (SSN) on certain terrestrial variables that might impact the Southeastern European climate at different spatio-temporal scales (the North Atlantic Oscillation Index, NAOI, and the Greenland–Balkan Oscillation Index, GBOI—on a large scale; the Palmer Hydrological Drought Index, PHDI—on a regional scale; the Danube discharge at the Orsova (lower basin), Q, representative of the Southeastern European climate—on a local scale). The investigations were carried out for the 20th century using the annual and seasonal averages. To find the connections between terrestrial (atmospheric and hydrological) parameters and SSN, the wavelet coherence were used both globally and in the time–frequency domain. The analyses were carried out for the time series and considered simultaneously (in the same year or season), as well as with lags from 1 to 5 years between the analyzed variables. For the annual values, the type of correlation (linear/non-linear) was also tested using elements from information theory. The results clearly revealed non-linear links between the SSN and the terrestrial variables, even for the annual average values. By applying the wavelet transform to test the solar influence on the terrestrial variables, it was shown that the connections depend on both the terrestrial variable, as well as on the considered lags. Since, in the present study, they were analyzed using wavelet coherence, but only the cases in which the coherence was significant for almost the entire analyzed time interval (1901–2000) and the terrestrial variables were in phase or antiphase with the SSN were considered. Relatively few results had a high level of significance. The analysis of seasonal averages revealed significant information, in addition to the analysis of annual averages. Thus, for the climatic indices, the GBOI and NAOI, a significant coherence (>95%) with the solar activity, associated with the 22-year (Hale) solar cycle, was found for the autumn season for lag = 0 and 1 year. The Hale solar cycle, in the case of the PHDI, was present in the annual and summer season averages, more clearly at lag = 0. For the Danube discharge at Orsova, the most significant SSN signature (~95%) was observed at periods of 33 years (Brüuckner cycle) in the autumn season for lags from 0 to 3 years. An analysis of the redundancy–synergy index was also carried out on the combination of the terrestrial variables with the solar variable in order to find the best synergistic combination for estimating the Danube discharge in the lower basin. The results differed depending on the timescale and the solar activity. For the average annual values, the most significant synergistic index was obtained for the combination of the GBOI, PHDI, and SSN, considered 3 years before Q.

This paper presents the extent to which the combination of extra-atmospheric and hydroclimatic factors can be deciphered to record their contribution to the evolution and forecasting of the Danube discharge (Q) in the lower basin. A combination of methods such as wavelet filtering and deep learning (DL) constitutes the basic method for discriminating the external factors (solar activity through Wolf numbers) that significantly contribute to the evolution and prediction of the lower Danube discharge. An ensemble of some of the most important factors, namely, those representing the atmospheric components, i.e., the Greenland-Balkan Oscillation Index (GBOI) and the North Atlantic Oscillation Index (NAOI); the hydroclimatic indicator, the Palmer Hydrological Drought Index (PHDI); and the extra-atmospheric factor, constitutes the set of predictors by means of which the predictand, Q, in the summer season, is estimated. The external factor has to be discriminated in the Schwabe and Hale spectra to make its convolutional contribution to the Q estimation in the lower Danube basin. An interesting finding is that adding two solar predictors (associated with the Schwabe and Hale cycles) to the terrestrial ones give a better estimation of the Danube discharge in summer, compared to using only terrestrial predictors. Based on the Nash–Sutcliffe (NS) index, a measure of performance given by the extreme learning machine (ELM), it is shown that, in association with certain terrestrial predictors, the contribution of the Hale cycle is more significant than the contribution of the Schwabe cycle to the estimation of the Danube discharge in the lower basin.

The influence of solar/geomagnetic activity on climate variables still remains a fully unclarified problem, although many scientific efforts have been made to better understand it. In order to bring more information to this open problem, in the present study, we analyze the connection between solar/geomagnetic activity (predictors) and climate variables (predictands) by applying elements from information theory and wavelet transform analysis. The solar activity was highlighted by the Wolf number and geomagnetic activity was quantified by the aa index. For the climate variables, we considered seven Climate Indices (CIs) that influence atmospheric circulation on regional or global scales, such as the Greenland-Balkan Oscillation Index (GBOI), North Atlantic Oscillation Index (NAOI), Arctic Oscillation (AO), Atlantic Multidecadal Oscillation (AMO), Southern Oscillation Index (SOI), Bivariate ENSO Timeseries (BEST) and Trans-Niño Index (TNI). By using the difference between synergy and redundancy, a few cases were found where the two predictors can be considered together for CIs’ estimation. Coherence analysis through the wavelet transform for three variables, both through multiple and partial analysis, provides the time intervals and bands of periods, where the two considered predictors can be used together or separately. The results differ depending on the predictand, the season and the considered lags. Significant information is brought out by using the two predictors together, namely the summer season, for GBOI and NAOI, when the predictors were taken 2 years before, and the winter season, as AMO responds to the variations of both solar and geomagnetic activity after 4 years.

The purpose of this study was to obtain synergistic information and details in the time–frequency domain of the relationships between the Palmer drought indices in the upper and middle Danube River basin and the discharge (Q) in the lower basin. Four indices were considered: the Palmer drought severity index (PDSI), Palmer hydrological drought index (PHDI), weighted PDSI (WPLM) and Palmer Z-index (ZIND). These indices were quantified through the first principal component (PC1) analysis of empirical orthogonal function (EOF) decomposition, which was obtained from hydro-meteorological parameters at 15 stations located along the Danube River basin. The influences of these indices on the Danube discharge were tested, both simultaneously and with certain lags, via linear and nonlinear methods applying the elements of information theory. Linear connections were generally obtained for synchronous links in the same season, and nonlinear ones for the predictors considered with certain lags (in advance) compared to the discharge predictand. The redundancy–synergy index was also considered to eliminate redundant predictors. Few cases were obtained in which all four predictors could be considered together to establish a significant information base for the discharge evolution. In the fall season, nonstationarity was tested through wavelet analysis applied for the multivariate case, using partial wavelet coherence (pwc). The results differed, depending on the predictor kept in pwc, and on those excluded.

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare histomorphological variants of a disease spectrum. After ruling out other tumor entities by immunohistochemistry, PDS can be differentiated from AFX by infiltration into the subcutis, while AFX remains confined to the dermis. The therapeutic approach is more aggressive in PDS as it can potentially metastasize. We assessed the usefulness of preoperative sonography in differentiating between the two tumor entities by identifying a potential subcutaneous infiltration. In our patients (n = 13), preoperative sonography identified and differentiated AFX and PDS with 100% accuracy and even changed the initial histological suspicion of AFX to PDS in 3 cases (23%), which was confirmed after tumor resection. Preoperative sonography of these tumors could strengthen the clinical diagnosis, avoid a delay in therapy initiation and improve patient counseling. While for AFX, micrographic-controlled surgery suffices, for PDS, resection with 2 cm safety margins and lymph node sonography to rule out lymphonodal involvement is necessary. Hence, ultrasonography can improve clinical practice by providing helpful information for dermatosurgeons, which cannot be obtained during clinical examination., (© 2024 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Ultrasound and high-frequency ultrasound assessment of melanoma and non-melanoma skin cancer in the pre-therapeutical setting is becoming increasingly popular in the field of dermatosurgery and dermatooncology, as it can provide clinicians with relevant, "in vivo" parameters regarding tumor lateral and depth extension as well as potential locoregional spread, cancelling the need of more extensive imaging methods and avoiding a delay in diagnosis. Furthermore, preoperative sonography and color Doppler can aid in orienting the clinical diagnosis, being able in numerous situations to differentiate between benign and malignant lesions, which require a different therapeutic approach. This preoperative knowledge is of paramount importance for planning an individualized treatment regimen. Using sonography at the time of diagnosis, important surgical complications, such as neurovascular damage, can be avoided by performing a preoperative neurovascular mapping. Furthermore, sonography can help reduce the number of surgical steps by identifying the lesions' extent prior to surgery, but it can also spare unnecessary surgical interventions in cases of locally advanced lesions, which infiltrate the bone or already present with locoregional metastases, which usually require modern radiooncological therapies in accordance to European guidelines. With this review, we intend to summarize the current indications of sonography in the field of skin cancer surgery, which can help us improve the therapeutic attitude toward our patients and enhance patient counseling. In the era of modern systemic radiooncological therapies, sonography can help better select patients who qualify for surgical procedures or require systemic treatments due to tumoral extension.

Background and Objectives: The knowledge of depth infiltration in non-melanoma skin cancer (NMSC) using pre-operative ultrasound could enable clinicians to choose the most adequate therapeutic approach, avoiding unnecessary surgeries and expensive imaging methods, delaying diagnosis and treatment. Our single-center retrospective study determined the usefulness of high-frequency ultrasound (HFUS) for depth infiltration assessment in auricular and nasal NMSC and assessed the subsequent change in therapeutic approach., Patients and Methods: In 60 NMSC cases, we assessed the accuracy of HFUS in cartilaginous/bone infiltration detection as well as the correlation of sonographic and histological parameters., Results: In 16.6% of cases, a deep cartilaginous/bone involvement or locoregional disease was identified pre-operatively, resulting in a changed therapeutical scheme of radio-immunological treatment rather than surgery. In two cases, pre-operative HFUS identified local cartilage infiltration, reducing the number of surgical procedures. Forty-eight remaining lesions with no depth infiltration were excised; a correlation of > 99% between the histologic and sonographic tumor depth (p<0.001) was found., Conclusions: Pre-surgical HFUS influences the therapeutic management in NMSC by detecting subclinical involvement of deeper structures, avoiding more extensive diagnostics, reducing costs, and improving healthcare quality. High-frequency ultrasound should be implemented in dermatosurgery before tumor excision for optimized therapy and improved patient counseling., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

In this paper, we study the well-posedness properties of a stochastic rotating shallow water system. An inviscid version of this model has first been derived in Holm (Proc R Soc A 471:20140963, 2015) and the noise is chosen according to the Stochastic Advection by Lie Transport theory presented in Holm (Proc R Soc A 471:20140963, 2015). The system is perturbed by noise modulated by a function that is not Lipschitz in the norm where the well-posedness is sought. We show that the system admits a unique maximal solution which depends continuously on the initial condition. We also show that the interval of existence is strictly positive and the solution is global with positive probability., Competing Interests: Conflict of interestBoth authors declare no conflict of interest., (© The Author(s) 2023.)

Background and Objectives: This longitudinal study investigated the correlation between imaging findings and self-reported questionnaire outcomes in patients with tibiofibular diastasis, exploring the effects of surgical screw removal versus conservative treatment. This study was conducted at "Victor Babes" University of Medicine and Pharmacy in Timisoara between 2018 and 2023., Materials and Methods: The study involved 85 patients in the screw removal group and 44 in the conservative group, assessed at 2 and 6 months post-surgery, answering the SF-36, HADS, and WHOQOL questionnaires., Results: Significant differences were observed at 2 months post-surgery, with the screw removal group showing lower shear wave velocities in ankle dorsiflexion (8.9 ± 1.4) and anterior talofibular ligament (2.8 ± 0.9), indicating better mobility compared to the conservative group (ankle dorsiflexion: 10.1 ± 1.8, ATFL: 3.2 ± 1.1). Radiographically, lower tibiofibular overlap (8.1 ± 2.1) in the screw removal group suggested improved joint fixation quality. These physical improvements were mirrored in the quality-of-life assessments, where the screw removal group reported higher physical health scores on the SF-36 survey at 2 months, a trend that continued at 6 months. At 2 months, ankle dorsiflexion demonstrated a strong negative correlation with the SF-36 Physical score (r = -0.417) and WHOQOL Physical domain (r = -0.394), and a positive correlation with HADS Anxiety (r = 0.312). Similarly, ATFL and CFL velocities negatively correlated with the SF-36 Physical score (ATFL: r = -0.251; CFL: r = -0.237). Radiographic tibiofibular overlap and clear space positively correlated with WHOQOL Physical domain (TOL: r = 0.291; TCS: r = 0.276), with TCS also negatively correlating with HADS Anxiety (r = -0.228). At 6 months, these correlations persisted, with notable negative correlations between ultrasound ankle dorsiflexion and both SF-36 Physical score and WHOQOL Physical domain., Conclusions: These findings underscore the advantages of screw removal in enhancing physical recovery and reducing anxiety in the short term, while indicating similar long-term mental health outcomes between treatment approaches.

Background and Objectives: While numerous studies have been conducted on syndesmotic screw management following distal tibiofibular diastasis repair, a clear consensus remains unclear. This research aims to evaluate whether the postoperative removal of syndesmotic screws leads to improved patient outcomes, specifically in quality of life, mobility, and daily living activities, and whether it offers a cost-effective solution. Materials and Methods: Patients with a history of unimalleolar or bimalleolar ankle fractures, classified according to the Danis-Weber and Lauge-Hansen systems, were included. Comprehensive evaluations were made via standardized questionnaires like the SF-36 Health Survey, HADS, and WHOQOL-BREF, distributed approximately 2 months post surgery. A total of 93 patients underwent syndesmotic screw removal while 51 retained the screws (conservative approach). Results: Patients who underwent screw removal reported superior satisfaction in mobility, with a score of 7.8, compared to 6.7 in the conservative approach ( p = 0.018). Similarly, their ability to perform daily activities scored 8.1, higher than the 6.5 from the conservative cohort ( p < 0.001). Pain levels were also more favorable in the screw removal group, with a score of 5.3 against 6.8 in the conservative group ( p = 0.003). On the SF-36 physical domain, the screw removal group achieved a mean score of 55.9 versus 53.3 for the conservative group ( p = 0.027). Notably, the HADS anxiety subscale highlighted reduced anxiety levels in the screw removal cohort with a mean score of 5.8 against 7.3 in the conservative group ( p = 0.006). However, overall quality of life and recommendations to others showed no significant difference between the groups. Conclusions: Syndesmotic screw removal postoperatively leads to marked improvements in patients' mobility, daily activity abilities, and reduced postoperative pain and anxiety levels. However, overall quality of life was similar between the two approaches. The findings offer valuable insights for orthopedic decision making and patient-centered care concerning the management of syndesmotic screws after distal tibiofibular diastasis repair.

Background: Cellular senescence is the main cause of skin and organ aging and is associated with a wide range of aging-related diseases., Objectives: To understand which senolytics, senomorphics, and cell-based therapies have been developed to alleviate and even rejuvenate skin aging and reduce cellular senescence., Methods: Basic literature for the mode of action of senolytics and senomorphics and their clinical perspectives in daily routine are discussed., Results: Various causes lead to mitochondrial dysfunction and the activation of pro-aging signaling pathways, which eventually lead to cellular senescence with degradation of structural proteins of the dermal connective tissue and severe suppression of regenerative stem cell niches of the skin., Conclusions: Depletion of senescent cells suppress skin aging and enforce rejuvenation of skin and other organs and their function. The removal of senescent cells by cells of the native immune system is severely disturbed during aging. Selected senolytics and senomorphics are approved and are already on the market., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The preoperative assessment of infiltration depth in melanoma and non-melanoma skin cancer by means of high-frequency ultrasound (≥18 MhZ) is essential for optimizing the therapeutic approach in our patients. Often, histologically confirmed skin tumors are directly referred to surgical departments for resection, and sonography is increasingly helping us identify those subjects who are no longer candidates for extensive surgical interventions. In cases of deep tumor infiltration, with potential surgical failure e.g. impairment of the quality of life and significant esthetic and functional complications, preoperative sonography can guide the surgeon to withstand from an operation and decide instead in favor of less mutilating radiooncological or medical treatment options. Furthermore, in melanoma patients, the preoperative knowledge of the tumor depth is essential for the determination of the therapeutic approach, the correct safety margins and the need of a sentinelnode biopsy. We herein encourage the use of preoperative sonography in dermatologic surgery whenever possible as it represents an easy, painless, "in vivo" method, which provides clinicians with significant clinical information that can influence the therapy and improve patient compliance., (© 2023 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Rhinoplasty is considered a very challenging surgery since minimal changes of this central area of the face may significantly impact a person's appearance and self-awareness. This is even more challenging in thick-skinned patients because results are less predictable, and changes to the osseocartilaginous framework (OCF) may not be sufficiently visible due to the blanket effect of the thick skin. Furthermore, pre-existing skin conditions may exacerbate following surgery. Therefore, managing patients with extremely thick skin or patients who suffer from pre-existing dermatological conditions such as rosacea or acne requires a synergy of surgeons and dermatologists to achieve optimal results. In this article, we review the most significant pre- and post-surgical regimens that surgeons and dermatologists should apply in selected patients to achieve optimal results after rhinoplasty., (© 2022 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Parkinson's disease (PD) is one of the most common neurodegenerative illnesses, and is a major healthcare burden with prodigious consequences on life-quality, morbidity, and survival. Cardiovascular diseases are the leading cause of mortality worldwide and growing evidence frequently reports their co-existence with PD. Cardiac dysautonomia due to autonomic nervous system malfunction is the most prevalent type of cardiovascular manifestation in these patients, comprising orthostatic and postprandial hypotension, along with supine and postural hypertension. Moreover, many studies have endorsed the risk of patients with PD to develop ischemic heart disease, heart failure and even arrhythmias, but the underlying mechanisms are not entirely clear. As importantly, the medication used in treating PD, such as levodopa, dopamine agonists or anticholinergic agents, is also responsible for cardiovascular adverse reactions, but further studies are required to elucidate the underlying mechanisms. The purpose of this review was to provide a comprehensive overview of current available data regarding the overlapping cardiovascular disease in patients with PD., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Grosu et al.)

Extensive numerical evidence shows that the assimilation of observations has a stabilizing effect on unstable dynamics, in numerical weather prediction, and elsewhere. In this paper, we apply mathematically rigorous methods to show why this is so. Our stabilization results do not assume a full set of observations and we provide examples where it suffices to observe the model's unstable degrees of freedom.

We prove the existence of a unique global strong solution for a stochastic two-dimensional Euler vorticity equation for incompressible flows with noise of transport type. In particular, we show that the initial smoothness of the solution is preserved. The arguments are based on approximating the solution of the Euler equation with a family of viscous solutions which is proved to be relatively compact using a tightness criterion by Kurtz., (© The Author(s) 2022.)

There is still no general agreement about the most effective form of syndesmosis fixation with syndesmotic screws for patients affected by ankle fractures that are accompanied by syndesmotic injuries. In the same manner, no consensus has been reached yet on whether or not the tibiofibular syndesmotic screw is more beneficial if removed or not, as well as the exact timing of removal if this proves superiority. The purpose of this research was to verify whether or not removing syndesmotic screws reduces the risk of developing a diastasis and compare outcomes in patients whose syndesmotic screw was or was not removed at all. A retrospective observational study was carried out to cover a period of five years and a computed sample size of almost 300 cases. Patients were included in the current study if their history was positive for ankle fracture with distal tibiofibular diastasis repair with syndesmotic screws. Loss of reduction was more frequent after screw removal (8.5% vs. 2.1%), although the quality of reduction was generally excellent in both groups. The mean AOFAS score was significantly better in patients who had their tibiofibular screw removed (92.6 vs. 88.4), but the tibiofibular clear space and incisura fibularis depth widened more following the second intervention (3.8 mm vs. 3.6 mm, and, respectively, 4.3 vs. 4.1). Lastly, the same patients with tibiofibular screw removal had a significantly higher cost of total interventions and more days of medical leave (21 vs. 15 days on average). It seems that a strong conclusion in favor of removing or not removing syndesmotic screws after distal tibiofibular diastasis repair cannot be given. However, several radiographic findings lean toward the benefit of those patients whose tibiofibular screws were not removed, although mobility was notably better after the screw was removed. Furthermore, treatment expenses are greatly lowered if a subsequent operation for screw removal is avoided, as well as if individuals who have a single surgery take a shorter medical leave.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177 Lutetium (Lu)-high affinity (HA)-DOTATATE [ 177 Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [ 68 Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3-6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

Ultrasonography (US) is a modern, in vivo imaging method, which is increasingly being used in dermatology as a complementary tool to clinical examination and dermoscopy. At higher frequencies (15 MHz and above), US is an established method for assessing benign and malignant skin lesions, locoregional staging, monitoring the therapeutic efficacy in various inflammatory skin conditions, and patient follow-up. One field, which may increasingly benefit from performant imaging techniques such as US is dermatologic surgery. Preoperative imaging of cutaneous tumors, inflammatory skin conditions (hidradenitis suppurativa, abscesses, etc.), or nail pathology provide dermatologic surgeons with relevant information for an optimal surgical planning, identifying potential complex aspects which might require interdisciplinary approaches, herein sparing unnecessary surgical interventions and increasing patients' compliance. In this review, we discuss the increasing significance of US in the field of dermatologic surgery, as well as the spectrum of cutaneous pathology where sonography can aid in the preoperative setting to provide a more precise, individualized surgical planning for better counseling to our patients and improved surgical results., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Malnutrition predicts a worse outcome for critically ill patients. However, quick, easy-to-use nutritional risk assessment tools have not been adequately validated., Aims and Methods: The study aimed to evaluate the role of four biological nutritional risk assessment instruments (the Prognostic Nutritional Index-PNI, the Controlling Nutritional Status Score-CONUT, the Nutrition Risk in Critically Ill-NUTRIC, and the modified NUTRIC-mNUTRIC), along with CT-derived fat tissue and muscle mass measurements in predicting in-hospital mortality in a consecutive series of 90 patients hospitalized in the intensive care unit for COVID-19-associated ARDS., Results: In-hospital mortality was 46.7% ( n = 42/90). Non-survivors had a significantly higher nutritional risk, as expressed by all four scores. All scores were independent predictors of mortality on the multivariate regression models. PNI had the best discriminative capabilities for mortality, with an area under the curve (AUC) of 0.77 for a cut-off value of 28.05. All scores had an AUC above 0.72. The volume of fat tissue and muscle mass were not associated with increased mortality risk., Conclusions: PNI, CONUT, NUTRIC, and mNUTRIC are valuable nutritional risk assessment tools that can accurately predict mortality in critically ill patients with COVID-19-associated ARDS.

Lung cancers are broadly divided into two categories: non-small-cell lung carcinoma (NSCLC), which accounts for 80-85% of all cancer cases, and small-cell lung carcinoma (SCLC), which covers the remaining 10-15%. Recent advances in cancer biology and genomics research have allowed an in-depth characterization of lung cancers that have revealed new therapy targets ( EGFR , ALK , ROS , and KRAS mutations) and have the potential of revealing even more biomarkers for diagnostic, prognostic, and targeted therapies. A new source of biomarkers is represented by non-coding RNAs, especially microRNAs (miRNAs). MiRNAs are short non-coding RNA sequences that have essential regulatory roles in multiple cancers. Therefore, we aim to investigate the tumor microenvironment (TME) and miRNA tumor profile in a subset of 51 early-stage lung cancer samples (T1 and T2) to better understand early tumor and TME organization and molecular dysregulation. We analyzed the immunohistochemistry expression of CD4 and CD8 as markers of the main TME immune populations, E-cadherin to evaluate early-stage epithelial-to-mesenchymal transition (EMT), and p53, the main altered tumor suppressor gene in lung cancer. Starting from these 4 markers, we identified and validated 4 miRNAs that target TP53 and regulate EMT that can be further investigated as potential early-stage lung cancer biomarkers.

Cardiovascular assessment of oncological patients suggests that cancer can lead to subclinical damage of the heart. The aim of the present study was to analyze the value of baseline cardiovascular biomarkers in patients with newly diagnosed colon cancer prior to treatment. Additionally, another aim was to establish baseline cut-off alert values for this low-intensity neoplastic damage. A total of 51 patients with newly diagnosed colon cancer, without history of cardiac disease, were enrolled in a prospective, cross-sectional study. All patients underwent clinical, biochemical and basic echocardiographic evaluation before starting treatment. Patients were assessed for myocardial damage using high-sensitivity troponin T (hs-TnT), creatine kinase-MB (CK-MB) and N-terminal-pro B-type natriuretic peptide (NT-proBNP). A group of 28 healthy controls was included for comparison. Cardiac ultrasound revealed similar left ventricular (LV) ejection fraction but enlarged LV chambers compared with the control group (LV at end systole, 29.50 vs. 26.00 mm; LV at end diastole, 44.50 vs. 38.00 mm; P<0.001 in both cases). The levels of cardiovascular biomarkers of myocardial damage were higher in the patients than in the control group (CK-MB, 17.00 vs. 11.00 IU/l, P<0.001; hs-TnT, 8.20 vs. 3.00 ng/l, P<0.001; NT-proBNP, 155.40 vs. 48.50 pg/ml, P=0.001). In multivariate analysis, CK-MB and hs-TnT retained statistical significance (P=0.004 and P=0.045, respectively). Moreover, it was demonstrated that new cut-offs for hs-TnT (8.00 ng/l) and NT-proBNP (220.00 pg/ml) can identify cardiac damage in patients ≥65 years old. Thus, the present study confirmed the hypothesis that a basic cardiovascular assessment of treatment-naïve patients with colon cancer can identify important pre-treatment myocardial impact. Adapted cut-off values should be set for cardiovascular biomarkers in the cancer population, different from those currently accepted for acute coronary syndromes or heart failure., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Radulescu et al.)

Background and Aims: Fabry disease (FD) is a rare chronic genetic disorder that presents under a paucity of symptoms. Gastrointestinal (GI) involvement is a common event and can sometimes be debilitating, but relatively often it is overlooked. We aimed to provide a systematic review of main GI symptoms in FD patients and treatment possibilities., Methods: We completed a systematic review of literature, using the MeSH terms: "Fabry disease", "gastrointestinal", "gastrointestinal", "digestive", "manifestations", "symptoms", "clinical", "treatment", "therapy" and the supplementary concepts "enzyme replacement", "chaperone", "Migalastat", in different combinations, with defined inclusion and exclusion criteria., Results: From 221 initial studies identified, through our selection process we included a final date base of 51 articles on GI signs and symptoms and their treatment. The primary GI manifestations of the disease consist of abdominal pain, bowel movement disorders or nausea and vomiting. Less frequent manifestations such as diverticular bowel disease, gastroesophageal reflux or achalasia have also been described. Main treatment options in FD are represented by enzyme replacement therapy and chaperone treatment. Patients presenting with GI symptoms unfortunately do not always respond to enzyme replacement, necessitating symptomatic relief., Conclusion: Fabry disease is a rare disease that often involves the GI tract, affecting patients' quality of life and burdening the healthcare system. Physicians must be aware of the multitude of manifestations in this category of patients, to promptly recognize and treat them.

Background: Treatment of an open tibial shaft fracture (TSF) is complex, and many cases are associated with delayed bone union or malunion. Parathyroid hormone (PTH) plays a key role in bone metabolism. A peptide fragment of PTH (PTH1-34) has been shown to promote bone healing. The objective of this study was to evaluate the safety and efficacy of a novel PTH-based bone graft (KUR-113) in the treatment of subjects with an open TSF., Methods: The study was a randomized, controlled, open-label (dose-blinded), dose-finding study of 200 subjects who had an open TSF secondary to trauma. Subjects were randomized into 1 of 4 groups to receive the standard of care (SoC) alone (control) or the SoC plus a single application of 4 mL of KUR-113 containing TGplPTH1-34 in fibrin at a concentration of 0.133 mg/mL (KUR-113-low), 0.4 mg/mL (KUR-113-mid), or 1.0 mg/mL (KUR-113-high). KUR-113 was administered at the fracture site after internal fracture fixation and before wound closure. Subjects were followed for up to 12 months after treatment. The primary outcome measure was fracture healing at 6 months assessed by the study investigator using radiographic and clinical measures. The primary end point was the proportion of subjects with fracture healing at 6 months., Results: A total of 200 subjects were enrolled and randomized to 1 of the 4 treatments. The primary end point was met in the KUR-113-mid group, which showed a significantly higher prevalence of healing at 6 months than the control group (37 of 46; 80.4% versus 31 of 48; 64.6%). By 12 months, healing had occurred in the majority of subjects in all treatment groups, with the control group requiring more surgical interventions to achieve fracture healing. Adverse events occurred at similar frequencies between the KUR-113 groups and the SoC group. No ectopic bone formation or abnormal bone resorption at the fracture site was observed in any of the treatment groups., Conclusions: KUR-113 has the potential to be a good adjunctive therapy in the treatment of open TSFs., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G857)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Liver involvement in Coronavirus Disease 2019 (COVID-19) has been widely documented. However, data regarding liver-related prognosis are scarce and heterogeneous. The current study aims to evaluate the role of abnormal liver tests and incidental elevations of non-invasive fibrosis estimators on the prognosis of hospitalized COVID-19 patients. We conducted a retrospective cohort study to investigate the impact of elevated liver tests, non-invasive fibrosis estimators (the Fibrosis-4 (FIB-4), Forns, APRI scores, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio), and the presence of computed tomography (CT)-documented liver steatosis on mortality in patients with moderate and severe COVID-19, with no prior liver disease history. A total of 370 consecutive patients were included, of which 289 patients (72.9%) had abnormal liver biochemistry on admission. Non-survivors had significantly higher FIB-4, Forns, APRI scores, and a higher AST/ALT ratio. On multivariate analysis, severe FIB-4 (exceeding 3.25) and elevated AST were independently associated with mortality. Severe FIB-4 had an area under the receiver operating characteristic (AUROC) of 0.73 for predicting survival. The presence of steatosis was not associated with a worse outcome. Patients with abnormal liver biochemistry on arrival might be susceptible to a worse disease outcome. An FIB-4 score above the threshold of 3.25, suggestive of the presence of fibrosis, is associated with higher mortality in hospitalized COVID-19 patients.

Background and Aims: While immune checkpoint inhibitors therapy (ICI) is exceedingly effective, these drugs are associated with various immune-related adverse effects. As gastrointestinal, hepatic or pancreatic toxicity becomes more common, various reports of rare adverse effects have emerged, leading to a significant clinical and prognostic impact. We aimed to provide a systematic review of mainly case-reports on rare events, to help physicians to make an accurate and fast diagnosis., Methods: We performed a systematic review of the literature, using established MeSH terms: "immune checkpoint inhibitors", "gastrointestinal tract", "gastrointestinal diseases", "liver", "pancreas", "nivolumab", "ipilimumab", the subheadings "adverse effects", "toxicity" and the supplementary concepts "pembrolizumab", "tremelimumab", "atezolizumab", "avelumab", "durvalumab", with defined inclusion criteria., Results: From 419 manuscripts initially selected, 74 reports of rare adverse events were included in our review. Special cases of neutrophilic gastritis, hemorrhagic gastritis, or even perforations were described at upper digestive tract. Different types of colitis were found secondary to ICI such as pseudomembranous, granulomatous, collagenous and microscopic colitis or even inflammatory bowel disease. In terms of liver toxicity, we found rare reports of cholangitis, granulomatous hepatitis, lipodystrophy and hepatic sinusoidal obstruction syndrome. Pancreas toxicity was rarely reported as severe pancreatitis, exocrine failure and diabetes mellitus., Conclusion: Although a complete check-up of every organ at every routine visit may not be practical, focus on symptoms, targeted laboratory and imaging testing may reveal rare organ damage. Raising awareness of the uncommon toxicities related to the immunotherapy is essential, as some rare events can lead to fatal outcomes.

Surface-enhanced Raman scattering (SERS) is emerging as a novel strategy for biofluid analysis. In this review, we delineate four experimental SERS protocols that are frequently used for the profiling of biofluids: 1) liquid SERS for the detection of purine metabolites; 2) iodide-modified liquid SERS for the detection of proteins; 3) dried SERS for the detection of both purine metabolites and proteins; 4) resonant Raman for the detection of carotenoids. To explain the selectivity of each experimental SERS protocol, we introduce a heuristic model for the chemisorption of analytes mediated by adsorbed ions (adions) onto the SERS substrate. Next, we show that the promising results of SERS liquid biopsy stem from the fact that the concentration levels of purine metabolites, proteins and carotenoids are informative of the cellular turnover rate, inflammation, and oxidative stress, respectively. These processes are perturbed in virtually every disease, from cancer to autoimmune maladies. Finally, we review recent SERS liquid biopsy studies and discuss future steps that are required for translating SERS in the clinical setting., (Copyright © 2021 Elsevier B.V. All rights reserved.)