Background: Tumoral hypoxia is associated with aggressiveness in many cancers including breast cancer. However, measuring hypoxia is complicated. Carbonic anhydrase IX (CAIX) is a reliable endogenous marker of hypoxia under the control of the master regulator hypoxia-inducible factor-1α (HIF-1α). The expression of CAIX is associated with poor prognosis in many solid malignancies; however, its role in breast cancer remains controversial.Methods: The present study performed a meta-analysis to evaluate the correlation between CAIX expression and disease-free survival (DFS) and overall survival (OS) in breast cancer.Results: A total of 2,120 publications from EMBASE, PubMed, Cochrane, and Scopus were screened. Of these 2,120 publications, 272 full texts were reviewed, and 27 articles were included in the meta-analysis. High CAIX was significantly associated with poor DFS (HR = 1.70, 95% CI = 1.39–2.07, p < 0.00001) and OS (HR = 2.02, 95% CI 1.40–2.91, p = 0.0002) in patients with breast cancer. When stratified by subtype, the high CAIX group was clearly associated with shorter DFS (HR = 2.09, 95% CI =1.11–3.92, p = 0.02) and OS (HR = 2.50, 95% CI =1.53–4.07, p = 0.0002) in TNBC and shorter DFS in ER⁺ breast cancer (HR = 1.81 95% CI =1.38–2.36, p < 0.0001).Conclusion: High CAIX expression is a negative prognostic marker of breast cancer regardless of the subtypes.

Introduction: Variable D-dimer trends during hospitalization reportedly result in distinct in-hospital mortality. In this multinational case series from the first and second waves, we show the universality of such D-dimer trends.Methods: We reviewed 405 patients with COVID-19 during the first wave admitted to three institutions in the United States, Italy, and Colombia, and 111 patients admitted to the U.S. site during the second wave and 55 patients during the third wave. D-dimer was serially followed during hospitalization.Results: During the first wave, 66 (15%) patients had a persistently-low pattern, 33 (8%) had early-peaking, 70 (16%) had mid-peaking, 94 (22%) had fluctuating, 30 (7%) had late-peaking, and 112 (26%) had a persistently-high pattern. During the second and third waves, similar patterns were observed. D-dimer patterns were significantly different in terms of in-hospital mortality similarly in all waves. Patterns were then classified into low-risk patterns (persistently-low and early-peaking), where no deaths were observed in both waves, high-risk patterns (mid-peaking and fluctuating), and malignant patterns (late-peaking and persistently-high). Overall, D-dimer trends were associated with an increased risk for in-hospital mortality in the first wave (overall: HR: 1.73) and stayed the same during the second (HR: 1.67, p < 0.001) and the third (HR: 4.4, p = 0.001) waves.Conclusion: D-dimer behavior during COVID-19 hospitalization yielded universal categories with distinct mortality risks that persisted throughout all studied waves of infection. Monitoring D-dimer behavior may be useful in the management of these patients.

Background: Intervertebral disc (IVD) shows aging and degenerative changes earlier than any other body connective tissue. Its repair and regeneration provide a considerable challenge in regenerative medicine due to its high degree of infrastructure and mechanical complexity. Mesenchymal stem cells, due to their tissue resurfacing potential, represent many explanatory pathways to regenerate a tissue breakdown.Methods: This study was undertaken to evaluate the co-regulation of Sox9 and TGFβ1 in differentiating human umbilical cord mesenchymal stem cells (hUC-MSC) into chondrocytes. The combinatorial impact of Sox9 and TGFβ1 on hUC-MSCs was examined in vitro by gene expression and immunocytochemical staining. In in vivo, an animal model of IVD degeneration was established under a fluoroscopic guided system through needle puncture of the caudal disc. Normal and transfected MSCs were transplanted. Oxidative stress, pain, and inflammatory markers were evaluated by qPCR. Disc height index (DHI), water content, and gag content were analyzed. Histological examinations were performed to evaluate the degree of regeneration.Results: hUC-MSC transfected with Sox9+TGFβ1 showed a noticeable morphological appearance of a chondrocyte, and highly expressed chondrogenic markers (aggrecan, Sox9, TGFβ1, TGFβ2, and type II collagens) after transfection. Histological observation demonstrated that cartilage regeneration, extracellular matrix synthesis, and collagen remodeling were significant upon staining with H&E, Alcian blue, and Masson's trichrome stain on day 14. Additionally, oxidative stress, pain, and inflammatory markers were positively downregulated in the animals transplanted with Sox9 and TGFβ1 transfected MSCs.Conclusion: These findings indicate that the combinatorial effect of Sox9 and TGFβ1 substantially accelerates the chondrogenesis in hUC-MSCs. Cartilage regeneration and matrix synthesis were significantly enhanced. Therefore, a synergistic effect of Sox9 and TGFβ1 could be an immense therapeutic combination in the tissue engineering of cartilaginous joint bio-prostheses and a novel candidate for cartilage stabilization.

Background: This study aims to use fundus image material from a long-term retinopathy follow-up study to identify problems created by changing imaging modalities or imaging settings (e.g., image centering, resolution, viewing angle, illumination wavelength). Investigating the relationship of image conversion factor and imaging centering on retinal vessel geometric characteristics (RVGC), offers solutions for longitudinal retinal vessel analysis for data obtained in clinical routine.Methods: Retinal vessel geometric characteristics were analyzed in scanned fundus photographs with Singapore-I-Vessel-Assessment using a constant image conversion factor (ICF) and an individual ICF, applying them to macula centered (MC) and optic disk centered (ODC) images. The ICF is used to convert pixel measurements into μm for vessel diameter measurements and to establish the size of the measuring zone. Calculating a constant ICF, the width of all analyzed optic disks is included, and it is used for all images of a cohort. An individual ICF, in turn, uses the optic disk diameter of the eye analyzed. To investigate agreement, Bland-Altman mean difference was calculated between ODC images analyzed with individual and constant ICF and between MC and ODC images.Results: With constant ICF (n = 104 eyes of 52 patients) the mean central retinal equivalent was 160.9 ± 17.08 μm for arteries (CRAE) and 208.7 ± 14.7.4 μm for veins (CRVE). The individual ICFs resulted in a mean CRAE of 163.3 ± 15.6 μm and a mean CRVE of 219.0 ± 22.3 μm. On Bland–Altman analysis, the individual ICF RVGC are more positive, resulting in a positive mean difference for most investigated parameters. Arteriovenous ratio (p = 0.86), simple tortuosity (p = 0.08), and fractal dimension (p = 0.80) agreed well between MC and ODC images, while the vessel diameters were significantly smaller in MC images (p < 0.002).Conclusion: Scanned images can be analyzed using vessel assessment software. Investigations of individual ICF versus constant ICF point out the asset of utilizing an individual ICF. Image settings (ODC vs. MC) were shown to have good agreement.

Editorial on the Research TopicWomen in science—Regulatory science 2021 All publications in this Research Topic on Women in Regulatory Science have female first authors, and the diversity in scientific subjects and high quality of the publications truly underline that regulatory science is blessed with a high number of very specialized, extremely skillful and high performing women. The publications indeed demonstrate how women are moving science forward. Murphy et al. examine the contributions of patient participation in scientific advice procedures at the European Medicines Agency (EMA), describing methodology used to involve patients in scientific advice and presenting an analysis of feedback received from EMA procedure coordinators as well as patients who have participated. There is a significant added value from patient engagement in EMAs Scientific Advice procedures suggesting the need to further expand patient input to real-world evidence for the benefit of public health. Dekker et al. address new approaches in the use of remote monitoring technologies (RMT) in clinical registration trials by evaluating regulatory qualification opinions, qualification and scientific advices provided between 2013 and 2019 by the EMA Committee for Medicinal Products for Human Use (CHMP). The RMTs included accelerometers to measure activity and/or sleep, mobile applications and glucose monitoring devices, mostly proposed as secondary or exploratory endpoints. CHMP recommendations concerned relevance, validation, precision, compliance and actual use as well as privacy and data handling. RMTs in registration trials are still rare but use has increased over time. This insight may stimulate the use of novel RMTs in a regulatory context. Drug repurposing is the process of identifying a new use for an existing medicine in an indication outside the scope of the original approved indication. Asker-Hagelberg et al. address the issue of repurposing of authorized medicines taking the examples collected during the COVID-19 pandemic into consideration and stressing the need for initiatives. A European Union framework for repurposing of established medicines is described. The EU Pediatric Regulation was introduced in 2007 and is currently undergoing revision. A pediatric legislation has existed for even longer in the USA. Existing differences in the legislative framework may cause different pediatric requirements for similar indications granted for similar drugs across jurisdictions. In a cross-sectional study, Christiansen et al. study mandatory requirements for pediatric drug development in the EU and the US, comparing requirements for therapeutic indications granted at the time of initial approval for novel drugs approved in the two regions from 2010 to 2018. This is an important contribution to the evaluation of how aligned requirements for pediatric drug development are across the regions. Zhong et al. compared registration requirements to Proprietary Chinese medicine in Hong Kong and Canada based on publicly available information. Similarities and differences exist between the two regulatory systems in terms of quality, safety and efficacy requirements. Knowledge of the Proprietary Chinese Medicines product license application procedure and requirements in Hong Kong and Canada will enable an appropriate strategy for gaining product approval. Enticott et al. describe Australian experiences with a Learning Health System stressing the need for cross disciplinary work and data sharing. The study aimed to describe the process and present a perspective on a coproduced Learning Health System framework, with development led by publicly funded Academic Health Research Translation Centres with a mandate to integrate research into healthcare to deliver impact. This continuous learning approach aims to deliver evidence-based healthcare improvement. Diabetes Mellitus (DM) is one of the World Health Organization's priority diseases under research by the program of Innovative Medicines Initiative (IMI). Brito et al. reviewed the Impact of the IMI initiatives related to DM by analyzing publications from projects under the initiative. The IMI funded projects identified new biomarkers, medical and research tools, clinical trial designs, clinical endpoints and therapeutic targets, to name a few. Based on the scientific data produced, the authors provide a joint vision with strategies for integrating personalized medicine into healthcare practice. Janssens et al. studied patient preferences for Multiple Myeloma Treatments by qualitative interviews in 4 EU countries and thematic analysis. Results pointed at the need for Multiple Myeloma drug development, evaluation and individual treatment not only focusing on extending the life but also taking side effects into account as these significantly impact Multiple Myeloma patients' quality of life. Sessa et al. describe the role and limitations of the European Patients Academy on Therapeutic Innovation (EUPATI) in Switzerland (CH) in promoting patient involvement in medicines research and development. EUPATI CH initiated a multi-stakeholder survey involving patient representatives, academia, pharmaceutical industry, healthcare professionals, and government agencies. A need for collaboration amongst stakeholders as well as funding, knowledge and human resources was identified. Kearney et al. describe how various stakeholders can utilize regulatory affairs and clinical affairs to navigate the nuanced landscape behind the development and use of clinical diagnostic products. This work emphasizes the critical importance of utilizing regulatory affairs and clinical affairs as an integral part of product development to ensure sustained innovation. Monti et al. stress the need for academic follow-up studies postmarketing identifying barriers and possible solutions from experiences with breast cancer. The authors describe the regulatory hurdles of...

Based on our previously developed mono-color video-ophthalmoscope a multi-color video-ophthalmoscope was developed. Using narrow band transmission filters, this instrument allows to measure the pulsatile cardiac cycle induced blood volume changes in the human retina for any wavelength in the sensitivity range of the used CMOS-camera. In this key experiment, video sequences (8 s, 25 fps, 200 frames) of the optic nerve head (ONH) were acquire for seven wavelengths between 475 nm and 677 nm one after the other. After image registration of all frames of each video sequence (to compensate for eye movements) and trend correction (to compensate for slow intensity changes), the amplitude of the cardiac cycle induced light intensity changes (pulsatile absorption amplitude PAA) can be calculated for all seven wavelengths. The results confirmed that the spectral distribution of PAA (λ) follows the distribution of the light absorption of blood. The measured values correspond to the absorption of a thin blood layer of about 0.5 μm thickness.

Hansen’s disease (HD) is an infectious, treatable, and chronic disease. It is the main cause of infectious peripheral neuropathy. Due to the current limitations of laboratory tests for the diagnosis of HD, early identification of infected contacts is an important factor that would allow us to control the magnitude of this disease in terms of world public health. Thus, a cross-sectional study was conducted in the Brazilian southeast with the objective of evaluating humoral immunity and describing the accuracy of the immunoassay based on IgA, IgM, and IgG antibodies against surface protein Mce1A of Mycobacterium, the predictive potential of these molecules, the clinical significance of positivity, and the ability to segregate new HD cases (NC; n = 200), contacts (HHC; n = 105), and healthy endemic controls (HEC; n = 100) as compared to α-PGL-I serology. α-Mce1A levels for all tested antibodies were significantly higher in NC and HHC than in HEC (p < 0.0001). The performance of the assay using IgA and IgM antibodies was rated as highly accurate (AUC > 0.85) for screening HD patients. Among HD patients (NC), positivity was 77.5% for IgA α-Mce1A ELISA, 76.5% for IgM, and 61.5% for IgG, while α-PGL-I serology showed only 28.0% positivity. Multivariate PLS-DA showed two defined clusters for the HEC and NC groups [accuracy = 0.95 (SD = 0.008)] and the HEC and HHC groups [accuracy = 0.93 (SD = 0.011)]. IgA was the antibody most responsible for clustering HHC as compared to NC and HEC, evidencing its usefulness for host mucosal immunity and as an immunological marker in laboratory tests. IgM is the key antibody for the clustering of NC patients. Positive results with high antibody levels indicate priority for screening, new clinical and laboratory evaluations, and monitoring of contacts, mainly with antibody indexes ≥2.0. In light of recent developments, the incorporation of new diagnostic technologies permits to eliminate the main gaps in the laboratory diagnosis of HD, with the implementation of tools of greater sensitivity and accuracy while maintaining satisfactory specificity.

Background: Preeclampsia is a disease with far-reaching consequences that extend beyond the immediate postpartum period and have a significant impact later in life. Preeclampsia exerts an effect on most organ systems in the body. These sequelae are mediated in part by the incompletely elucidated pathophysiology of preeclampsia and the associated vascular changes.Content: Current research focuses on unraveling the pathophysiology of preeclampsia with the goal of implementing accurate screening and treatment modalities based on disease development and progression. Preeclampsia causes significant short- and long-term maternal morbidity and mortality, not only in the cardiovascular system but also in other organ systems throughout the body. This impact persists beyond pregnancy and the immediate postpartum period.Summary: The goal of this review is to discuss the current understanding of the pathophysiology of preeclampsia as it relates to the adverse health consequences in patients impacted by this disease, along with a brief discussion of ways to improve overall outcomes.

In recent years vitamin D has been in the spotlight of many researchers for its possible role in various disorders, including autoimmune and infectious diseases. Even if vitamin D deficiency remains a major public health problem, its symptomatic manifestations are less and less common in clinical practice, and pediatric age represents a “gray area” where vitamin D supplementation is often administered in the absence of an effective evaluation of its status. Moreover, a poor knowledge about different definitions of “deficiency,” “insufficiency,” and similar terms is spread among clinicians, while guidelines are not univocal, especially after the first year of life. The aim of this brief opinion paper is to sum up recent evidence about vitamin D status and its supplementation in pediatrics, in order to better clarify a common definition of its deficiency. The aim of this opinion article is to raise awareness on this topic among clinicians and encourage a discussion on the real need for routine 25-hydroxycholecalciferol serum evaluation and its supplementation. The role of vitamin D for calcium metabolism and, especially, for the treatment of rickets was first identified in 1922 by the American biochemist Elmer McCollum (1879–1967) (1). After his observations, thousands of papers have shed light on its important and multifaceted function for human health, not only regarding the musculoskeletal system (2, 3). At the same time, several investigators have observed that a surprising number of patients may present deficient levels of this micronutrient, regardless of their age and origin (4–6). Vitamin D deficiency remains a major public health problem, even after a century since its discovery (7). At least two under-rated factors might contribute to the persistence of this issue: the lack of a common definition of vitamin D deficiency and the existence of partially contrasting recommendations on vitamin D prophylaxis. The aim of this opinion article is to highlight recent evidence about vitamin D status and its supplementation in pediatrics, to better clarify a common definition of its deficiency. Our goal is to raise awareness among clinicians of this topic and encourage a discussion on the real need for routine 25-hydroxycholecalciferol serum evaluation and supplementation. Vitamin D plays an important role in bone growth and remodeling by osteoblasts and osteoclasts and is essential to maintain calcium, phosphate, and magnesium body homeostasis by regulating intestinal absorption, and renal absorption/excretion, alongside the parathyroid hormone (PTH). Plasma calcium and phosphate are mainly influenced by the active form of vitamin D (1α,25-dihydroxyvitamin D) and PTH, while a minor role is also attained by other humoral factors (8). Magnesium is influenced, though to a lesser degree, by the same factors that control calcium, and it indirectly influences calcium by altering PTH synthesis and secretion in response to hypocalcemia and by assisting in the activation of vitamin D (9). Indeed, magnesium functions as a cofactor in many kidneys and liver enzymatic reactions and it is required by all the enzymes that intervene in vitamin D metabolization (10). Consequently, a lack of magnesium may result in disruption to the calcium/phosphate homestays regulated by active vitamin D/PTH and may cause vitamin D–resistant hypocalcemia (9, 10). On the other hand, vitamin D deficiency or overload may result in hypermagnesemia (magnesium not utilized) or hypomagnesemia (excessive consumption of magnesium). In the early stages, vitamin D deficiency results in impaired calcium intestinal absorption and consequent low serum calcium levels (hypocalcemia). In turn, hypocalcemia stimulates PTH secretion which acts to normalize serum calcium by reducing renal calcium excretion, increasing renal phosphate excretion, and stimulating renal production of active vitamin D. High levels of PTH (hyperparathyroidism) also boost osteoclast activity which determines bone calcium release. The combination of low serum phosphate levels (hypophosphatasemia) and increased osteoclast activity results in bone demineralization (11). In children, severe vitamin D deficiency may cause rickets, a childhood metabolic bone disease caused by under-mineralization of the growing bone. Following the growth plate closure, in older children and adults, the term “osteomalacia” is used to describe the demineralization of bone at sites of bone remodeling (12). Vitamin D positive effects on the innate immune system are well known since the discovery of its historical beneficial effects on mycobacterium tuberculosis infection (13, 14). Vitamin D modulates monocytes, macrophages, dendritic cell responses, and the production of interleukins (15). Autoimmune diseases (ADs) are caused by an erroneous activation of the immune system, with subsequent destruction of tissues by autoreactive immune cells, which can react against self-antigens (16). Among the causes contributing to the development of ADs, an insufficient vitamin D serum concentration might play a significant role, as proven by epidemiologic findings of higher incidences of ADs among countries with lower sun exposures and high prevalence of vitamin D insufficiency (17, 18). Recent studies found the vitamin D’s involvement in the suppression of T lymphocyte proliferation and adaptive immune system, causing a shift from a Th1 to a Th2 phenotype and a subsequent alteration in the differentiation and maturation of T cells, inducing T regulatory cells function and immune self-tolerance (19, 20). Moreover, B lymphocytes have been found to express vitamin D receptors, which, when activated, can inhibit the differentiation into plasma cells and modulate immunoglobulin production (21). All these effects could explain the possible connection between variable vitamin D serum levels and the probability to develop an AD...

Purpose: To describe characteristics of eye-related emergency department (ED) visits and investigate differences in priorities assigned to patients by triage nurses and ophthalmologists.Methods: A prospective survey was conducted at the ED of Zhongshan Ophthalmic Center from January 1, 2021, to May 31, 2021. Clinical data from patients with acute ophthalmic conditions lasting less than 7 days were collected via a standard questionnaire and the urgency levels assigned by nurses and physicians were also recorded. Binary logistic regression was performed to identify characteristics associated with truly emergency conditions and up- or down-triage.Results: A total of 1907 patients were enrolled, with 582 (30.5%) classified as “non-emergency.” Red eye (69.7%), eye pain (53.0%), ocular trauma (44.1%), tearing (43.6%), and blurred vision (43.1%) were the most common complaints. Truly emergency tended to be male (OR 2.019, p < 0.001) and with unilateral eye involvement (OR 2.992, p < 0.001). Nurses prioritized conjunctival, scleral, closed ocular trauma and eyelid diseases over doctors while giving less priority to open ocular trauma, cornea, uveitis, and vitreoretinal diseases (p < 0.05). Overemphasis on mild blurred vision (OR 3.718, p = 0.001) and insufficient understanding of conjunctival diseases without red eye (OR 0.254, p = 0.001) were associated with conjunctival disease “up-triage.” Insufficient awareness of moderate and severe blurred vision was associated with “down-triage” for ocular trauma (OR 3.475, p = 0.001 and OR 2.422, p = 0.020, respectively).Conclusion: Ophthalmic EDs are typically flooded with patients suffering from acute ocular problems, with a considerable portion for non-emergency conditions. The identification of characteristics associated with truly emergency cases and nurses’ triage preferences is valuable in providing target guidance for future ED practice and facilitating the proper allocation of emergency resources.

Objective: The glycans on the mucosa of suckling mice are predominantly sialylated; upon weaning, fucosylated glycans preponderate. This manifestation of mutualism between fucotrophic bacteria and the mature host utilizes a sentinel receptor in the intestinal mucosa; this receptor was isolated to distinguish its structural and functional features.Design: Provisional identification of the sentinel gut receptor as fuc-TLR4 was through colonization of germ-free mutant mice. Conventional mice whose microbiota was depleted with a cocktail of antibiotics were used to further define the nature and functions of fuc-TLR4 sentinel, and to define the role of the fucotrophic microbiota in gut homeostasis and recovery from insult. The nature of the sentinel was confirmed in cultured human HEL cells.Results: Fuc-TLR4 activity is distinct from that of TLR4. Activated mucosal fuc-TLR4 induces a fuc-TLR4 dependent non-inflammatory (ERK and JNK dependent, NF-κB independent) signaling cascade, initiating induction of fucosyltransferase 2 (secretor) gene transcription. In vitro, either defucosylation or TLR4 knockdown abrogates FUT2 induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. In vivo, fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury in vivo.Conclusion: In mature mice, fucosyl-TLR4 mediated gut fucosylation creates a niche that supports the healthy fucose-dependent mutualism between the mammalian gut and its fucotrophic microbes. Such microbiota-induced Fuc-TLR4 signaling supports initial colonization of the secretor gut, recovery from dysbiosis, and restoration or preservation of intestinal homeostasis.

Background: Applying Extracorporeal membrane oxygenation (ECMO) to patients with acute fulminant myocarditis (AFM) reduces their mortality. The survival rate is 55.6-71.9% for adult AFM patients, which is lower than that for paediatric patients (63-81%). In our centre, the survival rate of ECMO for adult patients with AFM was 66.7% from January 2003 to 2012. In January 2013, the therapeutic regimen was optimised, and then the survival rate increased to 89.1% by January 2022. This article analyses the reasons for the improved survival rate following the optimisation of treatment protocols.Methods: The data for adult patients with AFM who underwent ECMO for a poor response conventional treatment from January 2003 to January 2022 were reviewed. According to different treatment regimens, the AFM patients were divided into an old and a new regimen group. Univariate and multivariate logistic regression analyses were performed on the data before and after ECMO.Results: Fifty-five patients were enrolled in the age (31.2 ± 11.3), including 24 males. Forty-nine patients were weaned successfully from ECMO [duration: (4.1 ± 1.8) d], all of whom were discharged from the hospital, with a survival rate of 89.1%. Compared with the old regimen group, the new regimen group had a shorter duration of shock to ECMO, a lower proportion of patients receiving extracorporeal cardiopulmonary resuscitation (ECPR), a lower Vasoactive Inotropic Score (VIS), and lower levels of lactic acid, and high-sensitivity troponin T before ECMO (p < 0.05). Compared with the old regimen group, after ECMO, the new regimen group had lower ECMO flow, lower proportion of left ventricular dilation and lower limb ischemia injury, the duration of ECMO was shorter, and significantly improved the survival rate, the difference was statistically significant (P < 0.05). The duration of shock to ECMO and VIS before ECMO were independent risk factors for the survival rate (p < 0.05).Conclusion: Early ECMO initiation in adult AFM patients with a poor response to conventional therapy and low-flow ECMO to meet metabolic needs can reduce serious complications affecting the prognosis, may be associated with better outcomes.

Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated with COVID-19 is a complex interaction between infection and autoimmunity and elevation of SAA is strongly correlated with severity of the inflammation. In this review we highlight the involvement of SAA in these different inflammatory conditions, consider its potential role and discuss whether it could be a potential target for treatment of the hyperinflammatory state of COVID-19 with many potential advantages and fewer adverse effects. Additional studies linking SAA to the pathophysiology of COVID-19 hyper-inflammation and autoimmunity are needed to establish the causal relationship and the therapeutic potential of inhibitors of SAA activity.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis as the most common clinical manifestation, and interstitial lung disease (RA-ILD) represents one of the most common and potentially severe extra-articular features. Our current understanding of the mechanisms and predictors of RA-ILD is limited despite the demonstration that an early identification of progressive fibrosing forms is crucial to provide timely treatment with antifibrotic therapies. While high resolution computed tomography is the gold standard technique for the diagnosis and follow-up of RA-ILD, it has been hypothesized that serum biomarkers (including novel and rare autoantibodies), new imaging techniques such as ultrasound of the lung, or the application of innovative radiologic algorithms may help towards predicting and detecting early forms of diseases. Further, while new treatments are becoming available for idiopathic and connective tissue disease-associated forms of lung fibrosis, the treatment of RA-ILD remains anecdotal and largely unexplored. We are convinced that a better understanding of the mechanisms connecting RA with ILD in a subgroup of patients as well as the creation of adequate diagnostic pathways will be mandatory steps for a more effective management of this clinically challenging entity.

Along with the pandemic COVID-19 spreads, new clinical challenges have emerged in the health care settings, among which there is a high risk of secondary invasive fungal infections with significant mortality. Here, we report a case of invasive fungal rhino orbital sinusitis due to the simultaneous co-infection by Rhizopus oryzae and Lomentospora prolificans, both identified by sequencing, in a 70-year-old Afghanistanian female with COVID-19. The patient was subjected to surgical debridement as well as taking liposomal amphotericin B, voriconazole, and on discharge, her condition was good. As far as we know, this is the first case of co-infection of COVID-19-associated mucormycosis (CAM) and Lomentospora prolificans infection. Multiple fungal co-infections in COVID-19 patients are reviewed.

Cataract is a leading cause of visual impairment in old age. Lens opacification is notoriously associated with several geriatric conditions, including frailty, fall risk, depression and cognitive impairment. The association is largely attributable to visual impairment, while other mechanisms, associated with extraocular comorbidity and lifestyle, might partly explain this correlation. Available literature suggests that cataract surgery may be effective in decreasing fall risk, improving depressive symptoms and limiting the risk of cognitive impairment and dementia incidence, although intervention studies on these outcomes are still limited. In this review we also emphasize the need to move from the concept of visual acuity to functional vision, especially in the context of the geriatric patient. Research is needed regarding the effect on the cited outcomes of different cataract treatment strategies, such as systematic bilateral versus monolateral surgery and use of different intraocular lenses.

Objective: This study was to explore the relationship between fibrinogen and advanced colorectal adenoma among inpatients.Methods: From April 2015 to June 2022, 3738 participants (566 case subjects and 3172 control subjects) who underwent colonoscopies enrolled, and smooth curve fitting and logistic regression models were applied to explore the association between fibrinogen and advanced colorectal adenoma. In addition, sensitivity and subgroup analyses were performed to assess the stability of the results.Results: Compared with lower fibrinogen quantile 1 (< 2.4 g/L), the adjusted OR values for fibrinogen and advanced colorectal adenoma in quantile 2 (2.4–2.75 g/L), quantile 3 (2.76–3.15 g/L), and quantile 4 (≥3.16 g/L) were 1.03 (95% confidence interval [CI]: 0.76–1.41), 1.37 (95% CI: 1.01–1.85), and 1.43 (95% CI: 1.06–1.94), respectively. A linear relationship between fibrinogen and advanced colorectal adenoma was observed. Sensitivity and subgroup analyses showed stable results.Conclusion: Complements the evidence that fibrinogen was positively associated with advanced adenomas, suggesting that fibrinogen may play a role in the adenoma-carcinoma sequence.

Progressive pulmonary fibrosis is generally diagnosed when interstitial lung disease progression occurs in the absence of any other cause, and a subset of patients with myositis and associated interstitial lung disease may develop progressive pulmonary fibrosis. Numerous autoantibodies (e.g., against tRNA-synthetase, MDA5, Ro52) increase the risk of this clinical feature in myositis and we speculate that serum biomarkers, sought using the most sensitive laboratory techniques available (i.e., immunoprecipitation) may predict pulmonary involvement and allow the early identification of progressive pulmonary fibrosis. We herein provide a narrative review of the literature and also present original data on pulmonary fibrosis in a cohort of patients with myositis and serum anti-Ro52 with interstitial lung disease. Our results fit into the previous evidence and support the association between anti-Ro52 and signs of pulmonary fibrosis in patients with inflammatory myositis. We believe that the combination of available and real-life data has significant clinical relevance as a paradigm of serum autoantibodies that prove useful in determining precision medicine in rare connective tissue diseases.

A Commentary onCommentary: Bullous pemphigoid associated with COVID-19 vaccines: An Italian multicenter study by Kasperkiewicz, M., and Tukaj, S. (2022). Front. Med. 9:1096867. doi: 10.3389/fmed.2022.1096867 We appreciate the insightful comments from Kasperkiewicz and Tukaj (1) regarding our study: “Bullous pemphigoid associated with COVID-19 vaccines: an Italian multicentre study”, recently published in Frontiers in Medicine (2). We fully agree with the authors about the need to reconsider the relationship between COVID-19 vaccination and bullous pemphigoid (BP) onset, especially in the light of a recent work of Birabaharan and coworkers (3). In fact, the authors found no difference in risk of BP onset among two large cohorts of COVID-19 vaccinated individuals and unvaccinated matched ones, suggesting that the previously observed associations may be a random coincidence. Likewise, a recent study showed that circulating anti-SARS-CoV-2 antibodies do not cross-react with autoimmune blistering diseases (AIBDs) autoantigens, challenging the causal relationship between COVID-19 vaccination and AIBD new-onset (4). However, we believe that other observations should be considered before drawing any conclusions. Recently, several autoimmune diseases have been reported to be a consequence of COVID-19 vaccination, such as immune thrombotic thrombocytopenia (ITT), autoimmune liver diseases, Guillain–Barré syndrome, IgA nephropathy, rheumatoid arthritis, and systemic lupus erythematosus (5). In particular, vaccine-induced ITT was probably caused by platelet factor 4 (PF4) antibody-mediated activation through IgG-FcγR interactions, in addition to complement activation (6, 7). Surprisingly, vaccination-induced PF4 antibodies do not cross-react with the SARS-CoV-2 spike protein, suggesting a mechanism other than molecular mimicry underlying this event (8). In this context, it should be acknowledged that, in addition to molecular mimicry, there may be other mechanisms that could trigger AIBD onset following COVID-19 vaccination such as: (i) polyclonal activation due to adjuvant reaction, (ii) “bystander activation” of self-reactive lymphocytes; (iii) somatic mutation of immunoglobulin variable genes, and (iv) epitope spreading (9, 10). After COVID-19 vaccination, acute increase of type I interferons (IFN) expression, oxidative stress and DNA damage could induce both innate and adaptive immune responses (11). On the other hand, although methylated mRNA in COVID-19 vaccines is not immunogenic, some reports suggested the involvement of the pattern-recognition receptors (TLRs) 4, 7/8 and STING (12–14), especially in genetically predisposed patients (15). A potent adjuvant activity is due to the lipid nanoparticles, carrier vehicles that protect mRNA from degradation and allow intracellular delivery and endosomal escape, that could trigger inflammatory responses. In a mouse model, massive neutrophil infiltration and production of various inflammatory cytokines/chemokines including, among others, interleukin (IL)-1β/IL-6 and macrophage inflammatory protein-α and -β have been demonstrated (16). Thus, the cytokine milieu following COVID-19 vaccination could provide a causative link to BP induction in at least some of the reported cases. Recently, Kasperkiewicz reported that in 932 post-SARS-CoV-2-vaccinal cases, only about 6% presented with new-onset AIBDs following COVID-19 vaccination, suggesting that this phenomenon is a very rare occurrence (17). Similar findings could be obtained considering that in 2021 only 30 Italian cases of new-onset AIBDs were reported (18). The only data on the Italian incidence of AIBDs was reported by Cozzani et al., on BP incidence in Liguria: ten BP cases per million per year were estimated (19), with a possible total incidence in Italy of 600 BP cases (10 x 60 millions of inhabitants) per year. Considering that most of the Italian population was vaccinated in 2021 and that BP is the most common AIBD, it could be estimated that < 5% of AIBD cases could occur following COVID-19 vaccination. As a result of this rare event, we think that the incidence rate estimation is not the ideal approach to assess the possible association between AIBD occurrence and COVID-19 vaccine. In fact, considering the data from Birabaharan et al., the rate of BP incidence per 100,000 person-years was 12 BP in the vaccinated cohort and 15 BP in the unvaccinated one, suggesting the risk of BP onset does not increase in vaccinated patients compared to non-vaccinated ones (3). The difference between 12 and 15 is not significant, but it should be noted that the data shown in Birabaharan et al. are compatible with a 57% excess in BP incidence due to vaccination (see the upper 95% confidence limit reported in the table 1 from Birabaharan et al.) (3). What would be expected in case of a causal association? Considering that 15 BP cases are not vaccination-dependent, if there was an actual causal relationship between BP onset and COVID-19 vaccination, we would expect a 6% increase of BP cases, corresponding to the frequency of this rare event. This would result in 15.9 cases per 100,000 person-years. Thus, to reach a statistically significant result (with α = 0.05 and β = 0.20), a sample size of over 2 billion individuals in each exposure group would be needed (20). In conclusion, the data from Birabaharan et al., that reported a not significant difference of BP onset between vaccinated and unvaccinated individuals, may suggest a random association with COVID-19 vaccination but cannot exclude that such association does exist. To date, the link between AIBD onset and COVID-19 vaccination is supported by many real-world clinical data. A recent review from Pira et al., reported 121 patients with new-onset AIBDs and 185 patients with relapse/worsening following SARS-CoV-2 vaccination (18). To...

Extensive diagnostic delays and deferred treatment impact the quality of life of patients suffering from an idiopathic inflammatory myopathy. In-depth subtyping of patients is a necessary effort to engage appropriate disease management and may require specialized and elaborate evaluation of the complex spectrum of clinical and pathological disease features. Blood samples are routinely taken for diagnostic purposes, with creatine kinase measurement and autoantibody typing representing standard diagnostic tools in the clinical setting. However, for many patients the diagnostic odyssey includes the invasive and time-consuming procedure of taking a muscle biopsy. It is proposed that further implementation of blood-based disease biomarkers represents a convenient alternative approach with the potential to reduce the need for diagnostic muscle biopsies substantially. Quantification of judicious combinations of circulating cytokines could be added to the diagnostic flowchart, and growth differentiation factor 15 and C-X-C motif chemokine ligand 10 come forward as particularly good candidates. These biomarkers can offer complementary information for diagnosis indicative of disease severity, therapeutic response and prognosis.

COVID-19 exhibits diverse and systemic clinical symptoms, much like systemic autoimmune diseases, and there are notable similarities in the immune responses seen in both conditions. There are rare reports of ulcerative colitis and autoimmune hepatitis triggered by COVID-19 infection. Reported herein is a case of a previously healthy patient who was diagnosed with chronic colitis resembling ulcerative colitis, autoimmune pancreatitis, and suspected immune-mediated hepatitis (AIH-like hepatitis) 2 months after a COVID-19 infection. A 33-year-old COVID-19-vaccinated male, presented with abdominal pain, nausea, and vomiting for 2 days. He also had bloody diarrhea that persisted for 2 months after recovering from a COVID-19 infection. A diagnosis of acute pancreatitis was confirmed by markedly elevated serum amylase and lipase and a CT scan of the abdomen. Colonoscopy and histopathology findings also confirmed a diagnosis of chronic colitis resembling ulcerative colitis (Mayo Endoscopy Subscore 3). Marked improvement in bloody diarrhea was observed within 72 h of treatment with IV prednisolone. MRI of the abdomen performed due to an unresolved clinical picture of pancreatitis revealed a bulky pancreas showing delayed diffuse homogenous enhancement, findings possibly consistent with autoimmune pancreatitis. Investigation for elevated liver transaminases showed high titers of antinuclear antibodies and anti-smooth muscle (anti-actin) antibodies while viral hepatitis markers were negative. The patient had already been started on steroid therapy before the lab results were available, with rapid normalization of liver enzymes following treatment. A liver biopsy was not performed. The patient is currently on mesalazine 4 gr/day, and azathioprine 100 mg/day – oral steroids had been tapered and discontinued. Seven months after the initial diagnosis, the patient remains symptom-free. A high level of suspicion for autoimmune disorders is required when assessing patients with a history of COVID-19 infection, although diagnostic pathways remain the same, with generally good response and remission rates to conventional treatment.

Background: Despite reports on troublesome contents created and shared online by healthcare professionals, a systematic inquiry of this potential problem has been missing. Our objective was to characterize the content of healthcare-associated social media memes in terms of common themes and how patients were portrayed.Materials and methods: This study applied a mixed methods approach to characterize the contents of Instagram memes from popular medicine- or nursing-associated accounts in Norway. In total, 2,269 posts from 18 Instagram accounts were included and coded for thematic contents. In addition, we conducted a comprehensive thematic analysis of 30 selected posts directly related to patients.Results: A fifth of all posts (21%) were related to patients, including 139 posts (6%) related to vulnerable patients. Work was, however, the most common theme overall (59%). Nursing-associated accounts posted more patient-related contents than medicine-associated accounts (p < 0.01), but the difference may be partly explained by the former focusing on work life rather than student life. Patient-related posts often thematized (1) trust and breach of trust, (2) difficulties and discomfort at work, and (3) comical aspects of everyday life as a healthcare professional.Discussion: We found that a considerable number of Instagram posts from healthcare-associated accounts included patients and that these posts were diverse in terms of contents and offensiveness. Awareness that professional values also apply online is important for both healthcare students and healthcare providers. Social media memes can act as an educational resource to facilitate discussions about (e-)professionalism, the challenges and coping of everyday life, and ethical conflicts arising in healthcare settings.

Editorial on the Research TopicReviews in: Radiopharmaceuticals in nuclear medicine Medical application of radiopharmaceuticals began in the 1920s. The first diagnostic procedure utilizing a radiotracer was performed with ²¹⁴Bi, then known as radium C, to measure arm-to-arm blood transit time (1, 2). Applications are far more sophisticated now, with nuclear medicine currently using radiopharmaceuticals for both clinical care and research evaluations. For example, ¹⁸F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is commonly used to detect metabolically active cancer lesions; it is also being evaluated for ability to detect Human Immunodeficiency Virus (HIV) reservoirs (3). In addition to diagnostic uses, radiopharmaceuticals can be employed therapeutically or as theranostics, which combine diagnostic with therapeutic functions that share a specific target (4). This collection of reviews of radiopharmaceuticals in nuclear medicine (https://www.frontiersin.org/research-topics/38645/reviews-in-radiopharmaceuticals-in-nuclear-medicine) highlights ongoing innovation in the field. Two articles in the collection address PET imaging for lung cancer. Martucci et al. have performed a meta-analysis to quantitatively assess the impact of ¹⁸F-FDG PET/Computed tomography (CT) on small cell lung cancer (SCLC) staging. This builds on prior evidence, which relied primarily on ¹⁸F-FDG PET without concordant anatomical imaging. Based on 6 publications, the meta-analysis indicates that ¹⁸F-FDG PET/CT changes binary stage (limited vs. extensive disease) in approximately 15% of cases when compared to conventional staging. Since clinical management depends on the disease stage, incorporation of ¹⁸F-FDG PET/CT into SCLC staging has the potential to improve outcomes. Prospective studies will be helpful to validate this finding and to assess actual impact on outcomes such as morbidity and mortality. As the armamentarium of radiopharmaceuticals is continuously expanding, Zhu et al. provide a helpful review of PET tracers for lung cancer beyond ¹⁸F-FDG. These alternative radioligands target tumor markers and cellular function, including proliferation, amino acid metabolism and transport, tumor hypoxia, angiogenesis, tyrosine kinases and cancer-associated fibroblasts. Many of these tracers are still under evaluation. As the more promising candidates progress to clinical and human research applications, they present the opportunity to target specific features of lung cancer and personalize patient management. Furthermore, the rational approach to ligand discovery, based on understanding of lung cancer pathogenesis, can be applied to diverse other conditions. Identifying and understanding CNS disease via molecular imaging has long been a goal of the field. As exemplified by the pursuit of radiotracers for Alzheimer's Disease, for which targets include β-amyloid plaques, TAU tangles, and neurodegeneration (5), diverse targets must be explored based on the current understanding of disease features. Tong et al. offer an overview of Poly (ADP-ribose) polymerases (PARPs) as radioligand targets in central nervous system (CNS) diseases. Building on recent studies demonstrating PARP1 activation in neurodegenerative conditions and aging (6), the authors delve into how the PARP1 pathway might be targeted for diagnostic and therapeutic purposes. The development of PARP1 radiotracers, which are being evaluated in clinical trials for CNS conditions as well as malignancies, will hopefully lead to new insights in efforts to mitigate CNS disease. A major question will be how and if they contribute to improved outcomes. The last article in the collection focuses on radionuclide therapy for metastatic or otherwise inoperable paragangliomas and pheochromocytomas (Prado-Wohlwend et al.). Radionuclide therapy serves as an alternative to chemotherapy and other targeted medications currently under investigation. Using modeling, Prado-Wohlwend et al. found that ¹⁷⁷Lu-Lu-DOTA-TATE resulted in better progression free survival when compared to ¹³¹I-metaiodobenzylguanidine (MBG). Progression free survival with ¹⁷⁷Lu-Lu-DOTA-TATE improved with proportion of adrenal lesions and pheochromocytomas. Understanding the impact of different therapies on disease course, particularly when treatment options are limited, is critical and should be validated with prospective clinical studies. While these reviews demonstrate incredible progress in nuclear medicine over the past several decades, they also highlight the great potential for further advancement. Identification of novel disease-specific ligands will engender greater clinical relevance and support more personalized use of radiopharmaceuticals. Researchers should strive to optimize the impact on disease course by using these agents to elucidate pathogenesis and identify novel opportunities for intervention. The development of such probes must consider disease attributes, current treatment and management approaches, and target characteristics. For results stemming from use of diagnostic radioligands, potential ethical concerns about whether knowledge it provides regarding a condition is actionable must be considered when seeking full licensure of the agent. Ensuring that radioligands can access protected sites, particularly the CNS will also be necessary. In addition to optimizing the size and isoelectric point of a candidate, modifications can be made to use carriers or metabolic pathways that actively accumulate the ligand at the desired site. Another burgeoning arm of nuclear medicine is targeting of specific pathogens. For example, progress made in imaging tuberculosis and HIV must be continued (7–9). A particular challenge will be imaging of diffuse, low-concentration targets as is the case with certain infections....

Renal fibrosis is a hallmark of diabetic nephropathy (DN) and is characterized by an epithelial-to-mesenchymal transition (EMT) program and aberrant glycolysis. The underlying mechanisms of renal fibrosis are still poorly understood, and existing treatments are only marginally effective. Therefore, it is crucial to comprehend the pathophysiological mechanisms behind the development of renal fibrosis and to generate novel therapeutic approaches. Acrolein, an α-,β-unsaturated aldehyde, is endogenously produced during lipid peroxidation. Acrolein shows high reactivity with proteins to form acrolein-protein conjugates (Acr-PCs), resulting in alterations in protein function. In previous research, we found elevated levels of Acr-PCs along with kidney injuries in high-fat diet-streptozotocin (HFD-STZ)-induced DN mice. This study used a proteomic approach with an anti-Acr-PC antibody followed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis to identify several acrolein-modified protein targets. Among these protein targets, pyruvate kinase M2 (PKM2) was found to be modified by acrolein at Cys358, leading to the inactivation of PKM2 contributing to the pathogenesis of renal fibrosis through HIF1α accumulation, aberrant glycolysis, and upregulation of EMT in HFD-STZ-induced DN mice. Finally, PKM2 activity and renal fibrosis in DN mice can be reduced by acrolein scavengers such as hydralazine and carnosine. These results imply that acrolein-modified PKM2 contributes to renal fibrosis in the pathogenesis of DN.

This paper provides an overview of current linguistic and ontological challenges which have to be met in order to provide full support to the transformation of health ecosystems in order to meet precision medicine (5 PM) standards. It highlights both standardization and interoperability aspects regarding formal, controlled representations of clinical and research data, requirements for smart support to produce and encode content in a way that humans and machines can understand and process it. Starting from the current text-centered communication practices in healthcare and biomedical research, it addresses the state of the art in information extraction using natural language processing (NLP). An important aspect of the language-centered perspective of managing health data is the integration of heterogeneous data sources, employing different natural languages and different terminologies. This is where biomedical ontologies, in the sense of formal, interchangeable representations of types of domain entities come into play. The paper discusses the state of the art of biomedical ontologies, addresses their importance for standardization and interoperability and sheds light to current misconceptions and shortcomings. Finally, the paper points out next steps and possible synergies of both the field of NLP and the area of Applied Ontology and Semantic Web to foster data interoperability for 5 PM.

Primary cardiac tumors are extremely uncommon and primary cardiac lymphoma (PCL) is an even rarer subset. A definite diagnosis can be delayed, which increases the likelihood of a poor prognosis. We report a case involving a 64-year-old male who presented with dyspnea, palpitation, and third-degree atrioventricular block (AVB) secondary to primary cardiac B-cell lymphoma that was diagnosed via endomyocardial biopsy (EMB) and multimodality imaging. Chemotherapy was initiated using rituximab, cyclophosphamide, vindesine, and prednisone (R-COP) followed by implantation of an artificial capsule pacemaker. Third-degree AVB vanished, and the subsequent cycle of treatment was adjusted as R-CDOP (rituximab, cyclophosphamide, doxorubicin liposome, vindesine, and prednisone), with aspirin and rosavastatin to prevent ischemic events. So far, the patient had a good clinical course and normal electrocardiogram. This case underscores the importance of EMB in the diagnosis of heart neoplasms. It is worth noting that anthracycline is not contraindicated in PCL.

Interleukin-1 (IL-1)-blocking therapies are effective in reducing disease severity and inflammation in Schnitzler syndrome. Here, we present a patient with Schnitzler syndrome treated successfully using canakinumab for over 10 years. Complete clinical response was associated with a decrease in dermal neutrophil number and expression of the pro-inflammatory cytokines IL-1β, IL-8, and IL-17 as assessed by immunohistochemical studies.

Background: Disseminated intravascular coagulation (DIC) can lead to multiple organ failure and death in patients with heatstroke. This study aimed to identify independent risk factors of DIC and construct a predictive model for clinical application.Methods: This retrospective study included 87 patients with heatstroke who were treated in the intensive care unit of our hospital from May 2012 to October 2022. Patients were divided into those with DIC (n = 23) or without DIC (n = 64). Clinical and hematological factors associated with DIC were identified using a random forest model, least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE). Overlapping factors were used to develop a nomogram model, which was diagnostically validated. Survival at 30 days after admission was compared between patients with or without DIC using Kaplan-Meier analysis.Results: Random forest, LASSO, and SVM-RFE identified a low maximum amplitude, decreased albumin level, high creatinine level, increased total bilirubin, and aspartate transaminase (AST) level as risk factors for DIC. Principal component analysis confirmed that these independent variables differentiated between patients who experienced DIC or not, so they were used to construct a nomogram. The nomogram showed good predictive power, with an area under the receiver operating characteristic curve of 0.976 (95% CI 0.948–1.000) and 0.971 (95% CI, 0.914–0.989) in the internal validation. Decision curve analysis indicated clinical utility for the nomogram. DIC was associated with significantly lower 30 days survival for heatstroke patients.Conclusion: A nomogram incorporating coagulation-related risk factors can predict DIC in patients with heatstroke and may be useful in clinical decision-making.

Aim: To analyze the clinical profile of patients with acute hypertriglyceridemic pancreatitis (HTGP) and explore risk factors for recurrence.Methods: A retrospective observational study was conducted in patients who experienced an attack of HTGP for the first time. Patients were followed until the recurrence of acute pancreatitis (AP) or 1 year. The detailed clinical profile was compared between patients with or without recurrence. Multivariate logistic regression analysis was conducted to explore independent risk factors for recurrence.Results: A total of 108 HTGP patients were included in this study with 73.1% being male, and the median age being 37 (interquartile range, IQR, 30.3–44.8) years. Recurrence occurred in 70 patients (64.8%). Compared with the nonrecurrent group, serum triglyceride (TG) levels before discharge [4.1 (2.8,6.3) mmol/L vs. 2.9 (2.2,4.2) mmol/L; p = 0.002], at 1 month [3.7 (2.3,9.7) mmol/L vs. 2.0 (1.4,2.7) mmol/L; p = 0.001], at 6 months [6.1 (3.1,13.1) mmol/L vs. 2.5 (1.1,3.5) mmol/L; p = 0.003] and 12 months [9.6 (3.5,20.0) mmol/L vs. 2.7 (1.6,5.5) mmol/L; p = 0.001] after discharge were higher in the recurrent group. Poor control of TG levels (TG > 3.1 mmol/l) at the 1-month follow-up after discharge and a high Charlson’s Comorbidity Index score (≥ 2 points) increased the risk of recurrence of HTGP.Conclusion: High TG levels during follow-up and Charlson’s Comorbidity Index score were independently associated with recurrence in patients with HTGP.

Introduction: Well-trained colposcopists are in huge shortage worldwide, especially in low-resource areas. Here, we aimed to evaluate the Colposcopic Artificial Intelligence Auxiliary Diagnostic System (CAIADS) to detect abnormalities based on digital colposcopy images, especially focusing on its role in assisting junior colposcopist to correctly identify the lesion areas where biopsy should be performed.Materials and methods: This is a hospital-based retrospective study, which recruited the women who visited colposcopy clinics between September 2021 to January 2022. A total of 366 of 1,146 women with complete medical information recorded by a senior colposcopist and valid histology results were included. Anonymized colposcopy images were reviewed by CAIADS and a junior colposcopist separately, and the junior colposcopist reviewed the colposcopy images with CAIADS results (named CAIADS-Junior). The diagnostic accuracy and biopsy efficiency of CAIADS and CAIADS-Junior were assessed in detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+), CIN3+, and cancer in comparison with the senior and junior colposcipists. The factors influencing the accuracy of CAIADS were explored.Results: For CIN2 + and CIN3 + detection, CAIADS showed a sensitivity at ~80%, which was not significantly lower than the sensitivity achieved by the senior colposcopist (for CIN2 +: 80.6 vs. 91.3%, p = 0.061 and for CIN3 +: 80.0 vs. 90.0%, p = 0.189). The sensitivity of the junior colposcopist was increased significantly with the assistance of CAIADS (for CIN2 +: 95.1 vs. 79.6%, p = 0.002 and for CIN3 +: 97.1 vs. 85.7%, p = 0.039) and was comparable to those of the senior colposcopists (for CIN2 +: 95.1 vs. 91.3%, p = 0.388 and for CIN3 +: 97.1 vs. 90.0%, p = 0.125). In detecting cervical cancer, CAIADS achieved the highest sensitivity at 100%. For all endpoints, CAIADS showed the highest specificity (55–64%) and positive predictive values compared to both senior and junior colposcopists. When CIN grades became higher, the average biopsy numbers decreased for the subspecialists and CAIADS required a minimum number of biopsies to detect per case (2.2–2.6 cut-points). Meanwhile, the biopsy sensitivity of the junior colposcopist was the lowest, but the CAIADS-assisted junior colposcopist achieved a higher biopsy sensitivity.Conclusion: Colposcopic Artificial Intelligence Auxiliary Diagnostic System could assist junior colposcopists to improve diagnostic accuracy and biopsy efficiency, which might be a promising solution to improve the quality of cervical cancer screening in low-resource settings.

Aim: To explore obstetric nurses and midwifery professionals’ experiences with the Perinatal Bereavement Care Training Programme (PBCTP) after implementation.Design: A qualitative descriptive design was used.Method: This qualitative study was conducted at a tertiary level maternity hospital in China. The PBCTP was implemented at Women’s Hospital School of Medicine, Zhejiang University from March to May 2022. A total of 127 nurses and 44 midwives were invited to participate in the training. Obstetric nurses and midwives studied a 5-module training programme comprised of eight online theoretical courses and submitted a reflective journal after each session. Semi-structured interviews were conducted with 12 obstetric nurses and four midwives from May to July 2022 as a post-intervention evaluation. Thematic analysis was used in data analysis.Findings: A total of 16 participants in this study ranged in age from 23 to 40 years [mean age (SD), 30 (4) years]. Six main themes within participants’ experiences of PBCTP intervention were identified: participants’ aims of undertaking the training; personal growth and practice changes after training; the most valuable training content; suggestions for training improvement; directions for practice improvement; influencing factors of practice optimization.Conclusion: Nursing and midwifery professionals described the PBCTP as satisfying their learning and skills enhancement needs and supporting positive changes in their care providing for bereaved families. The optimized training programme should be widely applied in the future. More efforts from the hospitals, managers, obstetric nurses, and midwives are needed to jointly contribute to forming a uniform care pathway and promoting a supportive perinatal bereavement care practice.

Background: In the clinical context, the assessment of pain in patients with inadequate communication skills is standardly performed externally by trained medical staff. Automated pain recognition (APR) could make a significant contribution here. Hereby, pain responses are captured using mainly video cams and biosignal sensors. Primary, the automated monitoring of pain during the onset of analgesic sedation has the highest relevance in intensive care medicine. In this context, facial electromyography (EMG) represents an alternative to recording facial expressions via video in terms of data security. In the present study, specific physiological signals were analyzed to determine, whether a distinction can be made between pre-and post-analgesic administration in a postoperative setting. Explicitly, the significance of the facial EMG regarding the operationalization of the effect of analgesia was tested.Methods: N = 38 patients scheduled for surgical intervention where prospectively recruited. After the procedure the patients were transferred to intermediate care. Biosignals were recorded and all doses of analgesic sedations were carefully documented until they were transferred back to the general ward.Results: Almost every biosignal feature is able to distinguish significantly between ‘before’ and ‘after’ pain medication. We found the highest effect sizes (r = 0.56) for the facial EMG.Conclusion: The results of the present study, findings from research based on the BioVid and X-ITE pain datasets, staff and patient acceptance indicate that it would now be appropriate to develop an APR prototype.

An Erratum onDigital pathology – Rising to the challenge by Dawson, H. (2022). Front. Med. 9:888896. doi: 10.3389/fmed.2022.888896 An omission to the funding section of the original article was made in error. The following sentence has been added: “Open access funding was provided by the University of Bern.” The original article has been updated. Keywords: digital pathology, scanner acquisition, validation, image analysis, artificial intelligence Citation: Frontiers Production Office (2023) Erratum: Digital pathology – Rising to the challenge. Front. Med. 10:1180693. doi: 10.3389/fmed.2023.1180693 Received: 06 March 2023; Accepted: 06 March 2023; Published: 15 March 2023. Approved by: Copyright © 2023 Frontiers Production Office. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Frontiers Production Office, [email protected]

Paraneoplastic pemphigus (PNP) is a rare life-threatening disease which always associated with an underlying neoplasm. Tumor-related PNP most commonly precedes the detection of a hematological malignancy, with some cases seen during disease remission following cytotoxic drug therapy or radiotherapy. The lung is the most frequently-involved site in PNP, second only to the eyes, and involvement is seen in 59.2% to 92.8% of PNP cases. Bronchiolitis obliterans (BO) is the end stage of respiratory involvement and is regarded as life-threatening. The key point in treatment of PNP is to control the associated underlying hematologic neoplasia. High-dose systemic corticosteroids combined with other immunosuppressants are considered the first line of treatment. Other therapies that have shown beneficial effects include plasmapheresis, intravenous immunogloblin (IVIG), and more recently, daclizumab, alemtuzumab, and rituximab. There is no effective treatment for BO with PNP, and suppression of the cellular immune response may be necessary. Patients with PNP-BO associated with lymphoma mostly die within approximately 1 year. Herein, we reported a patient who diagnosed with PNP-BO concurrent with chronic lymphocytic leukemia. He was successful treated with ibrutinib and had achieved the longest survival which suggested that ibrutinib may be the best treatment choice for such patient.

Introduction: The practice of thoracic surgery for lung cancer is subject to authorization in France. We evaluated the performance of hospitals using 30-day post-operative mortality as a quality indicator, estimating its distribution within each region and measuring its variability between regions.Material and methods: All data for patients who underwent pulmonary resection for lung cancer in France (2013–2020) were collected from the national hospital administrative database. Thirty-day mortality was defined as any patient who died in hospital (including transferred patients) within the first 30 days after the operation and those who died later during the initial hospitalization. The Standardized Mortality ratio (SMR) was the smoothed, adjusted, hospital-specific mortality rate divided by the expected mortality. To describe the variation in hospital mortality between hospitals in each region, we used different commonly used indicators of variation such as coefficients of variation (CV), interquartile interval or range (IQR), extreme ratio, and systematic component of variance (SCV).Results: In 2013–2020, 87,232 patients underwent lung resection for cancer in France. The number of deaths was 2,537, a rate of 2.91%. The median SMR of 199 hospitals was 0.99 with an IQR of 0.86 to 1.18 and a CV of 0.25. Among the regions that had the most hospitals performing lung resections for cancer, the extreme ratio was >2, which means that the maximum value is twice as high as the minimum value. The SCV between hospitals was >10 for two of these regions, which is considered indicative of very high variation. For the other regions (with few hospitals performing lung resections for cancer), the variation between hospitals was lower. Globally, the variability between regions concerning the SMR was moderate, 6% of the variance was due to differences across regions. On the contrary, the hospital volume was significantly related to the SMR (p = 0.003) with a negative linear trend, whatever the region.Conclusion: This work shows significant differences in the practices of the various hospitals within regions. However, overall, the variability in the 30-day mortality rate between regions was moderate. Our findings raises questions regarding the regionalization of major surgical procedures in France.

Introduction: Optimal anticoagulation therapy is essential for the prevention of thrombotic and hemorrhagic complications in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated bivalirudin has the potential to surpass and replace heparin as the anticoagulant of choice.Methods: We conducted a systematic review comparing the outcomes of heparin-based versus bivalirudin-based anticoagulation in pediatric patients supported on ECMO to identify the preferred anticoagulant to minimize bleeding events, thrombotic complications, and associated mortality. We referenced the PubMed, Cochrane Library, and Embase databases. These databases were searched from inception through October 2022. Our initial search identified 422 studies. All records were screened by two independent reviewers using the Covidence software for adherence to our inclusion criteria, and seven retrospective cohort studies were identified as appropriate for inclusion.Results: In total, 196 pediatric patients were anticoagulated with heparin and 117 were anticoagulated with bivalirudin while on ECMO. Across the included studies, it was found that for patients treated with bivalirudin, trends were noted toward lower rates of bleeding, transfusion requirements, and thrombosis with no difference in mortality. Overall costs associated with bivalirudin therapy were lower. Time to therapeutic anticoagulation varied between studies though institutions had different anticoagulation targets.Conclusion: Bivalirudin may be a safe, cost-effective alternative to heparin in achieving anticoagulation in pediatric ECMO patients. Prospective multicenter studies and randomized control trials with standard anticoagulation targets are needed to accurately compare outcomes associated with heparin versus bivalirudin in pediatric ECMO patients.

The lymphatic vasculature maintains tissue homeostasis via fluid drainage in the form of lymph and immune surveillance due to migration of leukocytes through the lymphatics to the draining lymph nodes. Lymphatic endothelial cells (LECs) form the lymphatic vessels and lymph node sinuses and are key players in shaping immune responses and tolerance. In the healthy lung, the vast majority of lymphatic vessels are found along the bronchovascular structures, in the interlobular septa, and in the subpleural space. Previous studies in both mice and humans have shown that the lymphatics are necessary for lung function from the neonatal period through adulthood. Furthermore, changes in the lymphatic vasculature are observed in nearly all respiratory diseases in which they have been analyzed. Recent work has pointed to a causative role for lymphatic dysfunction in the initiation and progression of lung disease, indicating that these vessels may be active players in pathologic processes in the lung. However, the mechanisms by which defects in lung lymphatic function are pathogenic are understudied, leaving many unanswered questions. A more comprehensive understanding of the mechanistic role of morphological, functional, and molecular changes in the lung lymphatic endothelium in respiratory diseases is a promising area of research that is likely to lead to novel therapeutic targets. In this review, we will discuss our current knowledge of the structure and function of the lung lymphatics and the role of these vessels in lung homeostasis and respiratory disease.

We present two cases of transmission of a pancreatic adenocarcinoma from a single donor to two kidney transplant recipients. Autopsy of the donor revealed a pancreatic adenocarcinoma that had already spread locally to the regional lymph nodes and had not been detected at the time of organ procurement. Both recipients were carefully monitored, as neither consented to graft nephrectomy. In one patient, the tumor was discovered on surveillance biopsy of the graft approximately 14 months after transplantation, and in the second patient, ultrasound-guided aspiration needle biopsy of a growing formation in the lower pole of the graft revealed poorly differentiated metastatic adenocarcinoma. Both patients were successfully treated with graft nephrectomy and complete discontinuation of immunosuppression. None of the follow-up imaging showed persistent or recurrent malignancy, and both patients were candidates for re-transplantation. These exceptional cases of donor-derived pancreatic adenocarcinoma suggest that removal of the donor organ and restoration of immunity may lead to complete recovery.

Background: Osteoarthritis (OA) is a chronic disease that is a major cause of pain and functional disability. Warm needle acupuncture (WA) therapy has been widely used to treat OA. This overview summarizes the evidence from systematic reviews (SRs) and assesses the methodological quality of previous SRs that evaluated the use of WA therapy for OA.Methods: We searched electronic databases to identify SRs that evaluated the efficacy of WA therapy for OA. Two reviewers independently extracted data and assessed the methodological quality of the reviews according to the A Measurement Tool to Assess Systematic Reviews (AMSTAR 2) tool. The reporting quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 (PRISMA 2020) guidelines. The quality of evidence was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.Results: Fifteen SRs were included in this study. WA therapy was more effective than control conditions for the treatment of OA. The results of the AMSTAR 2 tool showed that the methodological quality of all included studies was critically low. The items with the lowest scores were item 2 (reporting the protocol), item 7 (listing excluded studies and justifying the exclusions), and item 16 (including conflicts of interest). Regarding the PRISMA guidelines, 2 SRs exhibited greater than 85% compliance. The overall quality of evidence in the included SRs ranged from “very low” to “moderate.”Conclusion: This overview shows that WA therapy was more effective than the control treatment for OA. However, the methodological quality of the reviews was low, indicating the need for improvements in the collection of evidence. Future studies are needed to collect high-quality evidence regarding the use of WA for OA.Systematic review registration: https://www.researchregistry.com/, Research Registry (reviewregistry1317).

Pemphigus is a rare group of autoimmune mucocutaneous blistering conditions for which the mainstay of treatment is immunosuppression. This is usually achieved with high dose corticosteroids as well as steroid sparing agents. Rituximab is now recommended as a first line treatment for moderate to severe pemphigus vulgaris, the commonest form of pemphigus, alongside corticosteroids. During the early stages of the COVID-19 pandemic the use of rituximab was reduced in our department due to its long term irreversible B-cell suppression. During the COVID-19 pandemic careful pharmacological selection was undertaken for our pemphigus patients to balance the risks of immunosuppression. To demonstrate this, we report three pemphigus patients who required treatment for COVID-19 and assessment throughout the pandemic. To date there has been limited published data regarding the clinical outcomes of pemphigus patients who have developed COVID-19 infections following rituximab infusions, especially in those patients who have received COVID-19 vaccinations. Following careful personalized consideration, all three pemphigus patients presented received rituximab infusions since the start of the COVID-19 pandemic. These patients had also received COVID-19 vaccinations prior to becoming infected with COVID-19. Each patient had a mild COVID-19 infection after receiving rituximab. We advocate for all pemphigus patients to have a full course of COVID-19 vaccinations. Antibody response to COVID-19 vaccinations should ideally be confirmed by measuring pemphigus patient’s SARS-CoV-2 antibodies prior to receiving rituximab.

Ferroptosis is a type of regulated cell death caused by iron overload and lipid peroxidation, and its core is an imbalance of redox reactions. Recent studies showed that ferroptosis played a dual role in liver diseases, that was, as a therapeutic target and a pathogenic factor. Therefore, herein, we summarized the role of ferroptosis in liver diseases, reviewed the part of available targets, such as drugs, small molecules, and nanomaterials, that acted on ferroptosis in liver diseases, and discussed the current challenges and prospects.

Background: Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome occurs in pregnant and postpartum individuals. We observed serum syndecan-1 (SDC-1) levels, which is a component of the glycocalyx, in a patient with HELLP syndrome from admission to the postpartum period and examined their association as reflecting the pathophysiology related to endothelial injury.Case presentation: A 31-year-old primiparous female patient without a previous medical history at a gestational age of 37 weeks and 6 days was transferred to our hospital the morning after a visit to a previous hospital with headache and nausea. Elevated transaminase, platelet count, and proteinuria were noted. Head magnetic resonance imaging revealed a caudate nucleus hemorrhage and posterior reversible encephalopathy syndrome. After she delivered her newborn through an emergency cesarean section, she was admitted to the intensive care unit. On day 4 post-delivery, the patient’s D-dimer concentration was elevated, and contrast-enhanced computed tomography was performed. The results indicated pulmonary embolism, and heparin administration was initiated. The serum SDC-1 level was highest on day 1 post-delivery and quickly decreased subsequently; however, it remained elevated during the postpartum period. Her condition gradually improved, and she was extubated on day 6 and discharged from the ICU on day 7 post-delivery.Conclusion: We measured SDC-1 concentration in a patient with HELLP syndrome and found that the clinical course correlated with SDC-1 levels, indicating that SDC-1 is elevated immediately before and after pregnancy termination in patients with HELLP syndrome. Therefore, SDC-1 fluctuations, combined with the elevation of the D-dimer level, may be a potential marker for the early detection of HELLP syndrome and estimation of the syndrome’s severity in the future.

Introduction: The SARS-CoV-2 outbreak has threatened the human population globally as the numbers of reinfection cases even after large-scale vaccination. Trials have been carried out to find drugs effective in fighting the disease, as COVID-19 is being considered a treatable disease only after we have antivirals. A clinical candidate originally developed for HIV treatment, AZVUDINE (FNC), is a promising drug in the treatment of COVID-19.Methods: To predict the clinical outcome of COVID-19, we examined the course of viral load, every 48 h, by RT-PCR, and disease severity using an antiviral drug, FNC, with 281 participants. A randomized clinical trial was performed to evaluate the efficacy of FNC added to standard treatment, compared with placebo group added to standard treatment, for patients with mild COVID-19. RT-qPCR and ddPCR were applied to estimate the viral load in samples from patients. Also, the clinical improvement was evaluated as well as the liver and kidney function.Results and discussion: Notably, the FNC treatment in the mild COVID-19 patients may shorten the time of the nucleic acid negative conversion (NANC) versus placebo group. In addition, the FNC was effective in reducing the viral load of these participants. The present clinical trial results showed that the FNC accelerate the elimination of the virus in and could reduce treatment time of mild patients and save a lot of medical resources, making it a strong candidate for the outpatient and home treatment of COVID-19.Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT05033145, identifier NCT05033145.

Background: Prostaglandin analogs have been found to have more versatile uses: treatment of open-angle glaucoma, high intraocular pressure, vitiligo, and other treatments. And prostaglandin analogs have been found to have an important role in the hair growth cycle. However, prostaglandin analogs have not been sufficiently studied for hair (including hair, eyelashes, and eyebrows) regeneration. In this study, a systematic review and meta-analysis of topical prostaglandin analogs on hair loss was performed.Objective: The purpose of this meta-analysis is to determine the efficacy and safety of topical prostaglandin analogs for treating hair loss.Methods: We searched PubMed, Embase, and Cochrane Library databases comprehensively. Data were pooled using Review Manager 5.4.1, and subgroup analyses were performed if necessary.Results: There were six randomized controlled trials included in this meta-analysis. All studies compared prostaglandin analogs with placebo, and one trial consisted of two sets of data. The results showed that prostaglandin analogs could significantly improve the hair length and density (p &lt; 0.001). As far as adverse events are concerned, there was no significant difference between the experimental group and the control group.Conclusion: In patients with hair loss, the topical prostaglandin analogs have better therapeutic efficacy and safety than placebo. However, the best dose and frequency of experimental treatment require further studies.

Background: Elderly people are known to be vulnerable to virus infection. However, this has not been appropriately tested in in vitro studies due to a lack of appropriate virus infection models. In this report, we investigated the impact of age on respiratory syncytial virus (RSV) in pseudostratified air-liquid-interface (ALI) culture bronchial epithelium, which more closely mimic human airway epithelium morphologically and physiologically, than submerged cancer cell line cultures.Methods: RSV A2 was inoculated apically to the bronchial epithelium obtained from 8 donors with different ages (28–72 years old), and time-profiles of viral load and inflammatory cytokines were analyzed.Results: RSV A2 replicated well in ALI-culture bronchial epithelium. The viral peak day and peak viral load were similar between donors at ≤60 years old (n = 4) and > 65 years old (n = 4; elderly group), but virus clearance was impaired in the elderly group. Furthermore, area under the curve (AUC) analysis, calculated from viral load peak to the end of sample collection (from Day 3 to 10 post inoculation), revealed statistically higher live viral load (PFU assay) and viral genome copies (PCR assay) in the elderly group, and a positive correlation between viral load and age was observed. In addition, the AUCs of RANTES, LDH, and dsDNA (cell damage marker) were statistically higher in the elderly group, and the elderly group showed a trend of higher AUC of CXCL8, CXCL10 and mucin production. The gene expression of p21^CDKN1A (cellular senescence marker) at baseline was also higher in the elderly group, and there was a good positive correlation between basal p21 expression and viral load or RANTES (AUC).Conclusion: Age was found to be a key factor affecting viral kinetics and biomarkers post virus infection in an ALI-culture model. Currently, novel or innovative in vitro cell models are introduced for virus research, but when virus studies are conducted, similarly to working with other clinical samples, the age balance is important to obtain more accurate results.

Editorial on the Research TopicNuclear medicine in rheumatological diseases' therapy and diagnosis Rheumatological diseases are common conditions in the general population and their diagnosis in clinical practice is challenging due to their unspecific clinical presentation. Nuclear medicine has a great potential for the management of the rheumatological diseases providing a tool for diagnosis, assessment of prognosis, and treatment efficacy. Furthermore, radiopharmaceuticals may be used as therapeutic options in patients with rheumatological diseases. The application of nuclear medicine techniques in the diagnosis and management of rheumatological diseases relies on the detection of in vivo functional abnormalities at an early stage of the diseases, earlier compared to the structural changes detected by conventional imaging (1–7). This Research Topic comprises 11 articles (four reviews, six original articles, and one study protocol) that highlight the role of nuclear medicine techniques in the management of rheumatological diseases. The mini-review of Wenger and Schirmer provides an overview on the current use of nuclear medicine imaging modalities in the diagnosis of rheumatological diseases. In particular the authors described that, at present, [¹⁸F]FDG PET/CT is the hybrid imaging method most often used in rheumatology, in particular for diagnosis of large vessel vasculitis. Despite the current limited value of bone scintigraphy as diagnostic procedure in rheumatological diseases, this nuclear medicine technique has a role before and after radiosynovectomy. In the review of Nassarmadji et al. the evidence on the role of [¹⁸F]FDG PET/CT for diagnosis, treatment monitoring and follow-up in large vessel vasculitis was summarized. [¹⁸F]FDG PET/CT is currently not recommended for diagnosis of chronic inflammatory rheumatism including rheumatoid arthritis, spondyloarthritis, and polymyalgia rheumatica. However, this imaging tool seems promising in chronic inflammatory rheumatism as described in the mini-review of De Ponfilly-Sotier et al. as it may provide an overview of systemic involvement occurring in this setting. Lastly, the review of van der Geest et al. illustrates novel PET radiopharmaceuticals that may be useful for diagnosis and treatment monitoring of polymyalgia rheumatica and large vessel vasculitis. Four original articles included in this Research Topic are focused on polymyalgia rheumatica. French researchers evaluated periarticular [¹⁸F]FDG uptake scores using PET/CT images to identify polymyalgia rheumatica within a group of patients with rheumatic diseases. The presence of at least three sites with significant uptake identified polymyalgia rheumatica with a sensitivity of 86% and a specificity of 85.5%, suggesting that [¹⁸F]FDG PET/CT has good performance to identify polymyalgia rheumatica within a population presenting rheumatic diseases (Amat et al.). A research article from the same group demonstrated that machine learning algorithm is useful for diagnosis of polymyalgia rheumatica using [¹⁸F]FDG PET/CT in a group of patients with inflammatory rheumatisms providing accurate sensitivity and specificity (Flaus et al.). In a large Belgian retrospective study, researchers scored [¹⁸F]FDG uptake through visual analysis of PET images taking into account 12 articular regions (scores 0–2 for each articular region). A total skeletal score was calculated by summing the individual scores. These PET scores showed high diagnostic accuracy for the diagnosis of polymyalgia rheumatica (Moreel et al.). An Italian retrospective study demonstrated that [¹⁸F]FDG PET/CT performed in patients with polymyalgia rheumatica and persistent increase of acute phase reactants was able to detect persistence of active polymyalgia rheumatica, occult large vessel vasculitis, or other inflammatory diseases (Colaci et al.). In a retrospective study from China, researchers explored the value of [¹⁸F]FDG PET/CT for assessing disease activity and for predicting the prognosis of the Adult-onset Still's disease. The authors reported that increased radiopharmaceutical uptake was observed in bone marrow, lymph nodes, and spleen of patients with Adult-onset Still's disease. Taking into account the correlation among PET findings and laboratory inflammatory markers, the authors suggested to use [¹⁸F]FDG PET/CT for evaluating disease activity and for predicting clinical prognosis of Adult-onset Still's disease (Li et al.). In another retrospective study, Swiss researchers investigated the emerging role of quantification of ^99mTc-labeled diphosphonates uptake by using SPECT/CT in fibrous dysplasia bone lesions; furthermore, the authors correlated SPECT/CT findings with markers of disease activity. They found that bone turnover markers were correlated with diphosphonate uptake on bone scan, suggesting that bone scan, and in particular quantification using SPECT/CT, could be useful to assess the disease burden and to guide treatment and follow-up in patients with fibrous dysplasia (Jreige et al.). Lastly, this Research Topic also includes a study protocol on a new nuclear medicine imaging method for detecting cartilage disorders. ^99mTc-NTP 15-5 is a new radiopharmaceutical that can be used to target proteoglycans, which are a component of the cartilaginous extracellular matrix. Therefore, imaging of proteoglycans could be used for diagnosis, treatment monitoring and follow-up of cartilage disorders. French researchers published a study protocol to assess ^99mTc-NTP 15-5 uptake in healthy joints (Thivat et al.). Findings provided by the articles published in this Research Topic illustrate the current role and future perspectives of nuclear medicine in rheumatological disorders. Currently, among the different nuclear...

Background: Tuberculosis (TB) is a threat to public health that mostly affects people in developing countries. TB presenting as a soft tissue mass is rare and is usually seen in patients with muscular tuberculosis (MT).Case presentation: In this study, we present the clinical, radiographic, and pathological features of two cases and retrospective evaluations of an additional 28 patients who were diagnosed with MT. More patients were men (60.9%) than women (39.1%), with a male-to-female ratio of 1.6:1. The average age among male and female patients was 38.9 and 30.1 years, respectively. MT usually presents with painful or painless muscular nodules on the lower limbs. Imaging findings, including ultrasound, CT, and MRI, can be used to identify lesions and sites for biopsy. The most typical histopathological feature of MT is granulomatous inflammation with caseous necrosis and epithelioid granulomata. Acid-fast bacilli stain and polymerase chain reaction (PCR) assays are helpful in identifying tubercle bacillus.Conclusion: We describe two MT cases with lower-extremity muscular masses as the initial presentation. The results suggest that muscle biopsy and pathological analysis remain necessary for diagnosis. Most of the patients could be cured with standard antituberculosis therapy.

Hypothyroidism is a prevalent endocrine illness with a variety of clinical symptoms, but among which elevated serum creatinine is uncommon. Hypothyroidism is also common in acquired immunodeficiency syndrome (AIDS) patients, especially those receiving highly active antiretroviral treatment (HAART). Here we present a case of a young AIDS patient with hypothyroidism, increased serum creatinine, and obesity. Despite the lack of a kidney biopsy, following levothyroxine (LT4) therapy, his serum creatinine recovered to normal levels, and weight loss, edema, weakness, rough skin and other clinical symptoms obtained notable improvement. This highlights the need of clinicians paying attention to whether thyroid function is aberrant in human immunodeficiency virus (HIV) patients with increased creatinine, edema and significant weight gain since prompt thyroid hormone therapy can restore the alterations in renal function and avoid invasive renal biopsy.

Background: Patients admitted to hospital with sepsis are at persistent risk of poor outcome after discharge. Many tools are available to risk-stratify sepsis patients for in-hospital mortality. This study aimed to identify the best risk-stratification tool to prognosticate outcome 180 days after admission via the emergency department (ED) with suspected sepsis.Methods: A retrospective observational cohort study was performed of adult ED patients who were admitted after receiving intravenous antibiotics for the treatment of a suspected sepsis, between 1^st March and 31^st August 2019. The Risk-stratification of ED suspected Sepsis (REDS) score, SOFA score, Red-flag sepsis criteria met, NICE high-risk criteria met, the NEWS2 score and the SIRS criteria, were calculated for each patient. Death and survival at 180 days were noted. Patients were stratified in to high and low-risk groups as per accepted criteria for each risk-stratification tool. Kaplan–Meier curves were plotted for each tool and the log-rank test performed. The tools were compared using Cox-proportional hazard regression (CPHR). The tools were studied further in those without the following specified co-morbidities: Dementia, malignancy, Rockwood Frailty score of 6 or more, long-term oxygen therapy and previous do-not-resuscitate orders.Results: Of the 1,057 patients studied 146 (13.8%) died at hospital discharge and 284 were known to have died within 180 days. Overall survival proportion was 74.4% at 180 days and 8.6% of the population was censored before 180 days. Only the REDS and SOFA scores identified less than 50% of the population as high-risk. All tools except the SIRS criteria, prognosticated for outcome at 180 days; Log-rank tests between high and low-risk groups were: REDS score p < 0.0001, SOFA score p < 0.0001, Red-flag criteria p = 0.001, NICE high-risk criteria p = 0.0001, NEWS2 score p = 0.003 and SIRS criteria p = 0.98. On CPHR, the REDS [Hazard ratio (HR) 2.54 (1.92–3.35)] and SOFA [HR 1.58 (1.24–2.03)] scores out-performed the other risk-stratification tools. In patients without the specified co-morbidities, only the REDS score and the SOFA score risk-stratified for outcome at 180 days.Conclusion: In this study, all the risk-stratification tools studied were found to prognosticate for outcome at 180 days, except the SIRS criteria. The REDS and SOFA scores outperformed the other tools.

Purpose: To investigate changes in retinal circulation and the choroid in patients with acute myeloid leukemia (AML) in the acute and remission stages, to analyze the correlation between retinal circulation and laboratory parameters, and to assess risk factors associated with leukemic retinopathy.Methods: Forty-eight patients (93 eyes) with AML were enrolled and divided into two groups according to fundus examination findings: the retinopathy and no retinopathy groups. Patients underwent eye measurements before treatment and after remission. Macular vessel density (VD), perfusion density (PD), foveal avascular zone (FAZ), and choroidal thickness (ChT) were measured using optical coherence tomography angiography. Patients with healthy eyes were recruited as control participants.Results: Patients with leukemic retinopathy had higher measurements of white blood cells (WBCs), circulating blasts, fibrin degradation products, and cross-linked fibrin degradation products (D-dimer) and a lower hemoglobin (HB) count (p < 0.05). In the acute phase of the disease, the VD and PD were lower and the ChT was thicker in patients with AML than in controls (p < 0.05), irrespective of the presence of leukemic retinopathy; however, the patients were partially recovered in the remission stage. The VD was lower in patients with higher WBC (r = −0.217, p = 0.036), D-dimer (r = −0.279, p = 0.001), fasting blood glucose (FBG) (r = −0.298, p = 0.004) and triglyceride (r = −0.336, p = 0.001) levels. The FAZ area was negatively correlated with HB (r = −0.258, p = 0.012).Conclusion: Patients with AML appear to have subclinical retinal perfusion loss and choroidal thickening in the acute phase of the disease, but this is reversible. Injury to bone marrow function may cause a decrease in retinal perfusion. Leukemic retinopathy is associated with abnormal hematologic parameters and coagulopathy.