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Trija Vaidya,1 Véronique Thomas-Ollivier,2 François Hug,2,3 Alain Bernady,4 Camille Le Blanc,5 Claire de Bisschop,1 Arnaud Chambellan2,6 1Laboratory MOVE (EA6314), Université de Poitiers, Faculty of Sport Sciences, Poitiers, France; 2Faculty of Sport Sciences, Movement–Interactions–Performance, MIP, EA 4334, Université de Nantes, Nantes F-4000, France; 3Institut Universitaire de France (IUF), Paris, France; 4Toki-Eder Centre Médical Cardio-Respiratoire, Cambo-Les-Bains, France; 5Physical Medicine and Rehabilitation Department, University Hospital of Nantes, Nantes, France; 6L’institut du Thorax, Laboratory MIP, UNIV Nantes, University Hospital of Nantes, Nantes, FranceCorrespondence: Arnaud ChambellanExplorations fonctionnelles, l’institut du thorax, CHU de Nantes, Bd Jacques Monod, Nantes Cedex 1 44093, FranceTel +33 240 165 511Fax +33 240 165 391Email arnaud.chambellan@chu-nantes.frIntroduction: The recently developed daily and clinical visit PROactive physical activity in COPD (PPAC) instruments are hybrid tools to objectively quantify the level of physical activity and the difficulties experienced in everyday life. Our aim was to translate these instruments for the French-speaking chronic obstructive pulmonary disease (COPD) community worldwide and evaluate the influence of weather and pollution on difficulty score.Methods: The translation procedure was conducted following the guidelines for cross-cultural adaptation process. The translated clinical visit (C-PPAC) was tested among COPD patients in France. A retest was conducted after an interval of at least 2 weeks. The C-PPAC difficulty score was then tested to see how sensitive it was to the influence of weather and outdoor pollution.Results: One hundred and seventeen COPD patients (age 65± 9 years; FEV1: 51± 20%) from 9 regions in France were included. The French version of C-PPAC was found comprehensible by the patients with an average score of 4.8/5 on a Likert-scale. It showed good internal consistency with Cronbach’s α> 0.90 and a good test retest reliability with an intraclass correlation coefficient of ≥ 0.80. The difficulty score was negatively correlated with duration of daylight (ρ=− 0.266; p< 0.01) and influenced by the intensity of rainfall (light vs. heavy rainfall: 68± 16 vs. 76± 14 respectively, p=0.045). The score was lower in patients receiving long term oxygen therapy (60± 15 vs. 71± 15, p< 0.01), but not correlated with the pollution indices.Conclusion: The French versions of the questionnaires of the PPAC instruments are accepted and comprehensible to COPD patients. The difficulty score of C-PPAC is sensitive to duration of daylight and rainfall. Such weather factors must be taken into consideration when evaluating the physical activity behavior using these tools in COPD.Keywords: COPD, physical activity, questionnaire, reliability

Trija Vaidya,1,2 Marc Beaumont,3,4 Claire de Bisschop,1 Lucie Bazerque,5 Camille Le Blanc,6 Anne Vincent,7 Hakima Ouksel,8 Arnaud Chambellan2,9 1Laboratory MOVE (EA6314), Faculty of Sport Sciences, University of Poitiers, Poitiers, France; 2Laboratory “Movement, Interactions, Performance” (EA4334), Faculty of Sport Sciences, University of Nantes, Nantes, France; 3Pulmonary Rehabilitation unit, Morlaix Hospital Centre, Morlaix, France; 4EA3878 (G.E.T.B.O), CHU Brest, Brest, France; 5Institute of Physical Education and Sports Sciences (IFEPSA), Université Catholique de l’Ouest (UCO), Angers, France; 6Physical Medicine and Rehabilitation Department, University Hospital of Nantes, Nantes, France; 7Respiratory Rehabilitation Service, la Tourmaline, UGECAM, Nantes, France; 8Dept of Pulmonary Medicine, Angers University Hospital, Angers, France; 9l’institut du Thorax, University Hospital of Nantes, Nantes, France Background: Measurement of quadriceps muscular force is recommended in individuals with COPD, notably during a pulmonary rehabilitation program (PRP). However, the tools used to measure quadriceps maximal voluntary contraction (QMVC) and the clinical relevance of the results, as well as their interpretation for a given patient, remain a matter of debate. The objective of this study was to estimate the minimally important difference (MID) of QMVC using a fixed dynamometer in individuals with COPD undergoing a PRP. Methods: Individuals with COPD undergoing a PRP were included in this study. QMVC was measured using a dynamometer (MicroFET2) fixed on a rigid support according to a standardized methodology. Exercise capacity was measured by 6-minute walk distance (6MWD) and evaluation of quality of life with St George’s respiratory questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS) total scores. All measures were obtained at baseline and the end of the PRP. The MID was calculated using distribution-based methods. Results: A total of 157 individuals with COPD (age 62.9±9.0 years, forced expiratory volume in 1 second 47.3%±18.6% predicted) were included in this study. At the end of the PRP, the patients had improved their quadriceps force significantly by 8.9±15.6 Nm (P

Trija Vaidya,1,2 Claire de Bisschop,2 Marc Beaumont,3,4 Hakima Ouksel,5 Véronique Jean,6 François Dessables,7 Arnaud Chambellan,1,8 On behalf of IRSR RéhaEffort cohort group 1Explorations Fonctionnelles Respiratoires, l’institut du thorax, CHU de Nantes, 2Université de Poitiers, Laboratoire MOVE EA 6314, F-86000 Poitiers, 3Pulmonary Rehabilitation Unit, Morlaix Hospital Centre, 4European University of Occidental Brittany, EA3878, Brest, 5Service de Pneumologie, CHU d’Angers, Angers, 6Service de Réhabilitation Respiratoire, Soins de Suite et Rééducation, CHU de Nantes, 7Service de Réhabilitation Respiratoire, la Tourmaline, UGECAM, 8Université de Nantes, Laboratory EA 4334 “Mouvement, Interactions, Performance,” Nantes, France Background: The 1-minute sit-to-stand (STS) test could be valuable to assess the level of exercise tolerance in chronic obstructive pulmonary disease (COPD). There is a need to provide the minimal important difference (MID) of this test in pulmonary rehabilitation (PR).Methods: COPD patients undergoing the 1-minute STS test before PR were included. The test was performed at baseline and the end of PR, as well as the 6-minute walk test, and the quadriceps maximum voluntary contraction (QMVC). Home and community-based programs were conducted as recommended. Responsiveness to PR was determined by the difference in the 1-minute STS test between baseline and the end of PR. The MID was evaluated using distribution and anchor-based methods.Results: Forty-eight COPD patients were included. At baseline, the significant predictors of the number of 1-minute STS repetitions were the 6-minute walk distance (6MWD) (r=0.574; P

Yesenia L Franco,* Tanaya R Vaidya,* Sihem Ait-Oudhia Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA *These authors contributed equally to this work Abstract: Breast cancer (BC) is a highly prevalent disease, accounting for the second highest number of cancer-related mortalities worldwide. The anthracycline doxorubicin (DOX), isolated from Streptomyces peucetius var. caesius, is a potent chemotherapeutic drug that is successfully used to treat various forms of liquid and solid tumors and is currently approved to treat BC. DOX exerts its effects by intercalation into DNA and inhibition of topoisomerases I and II, causing damage to DNA and the formation of reactive oxygen species (ROS), resulting in the activation of caspases, which ultimately leads to apoptosis. Unfortunately, DOX also can cause cardiotoxicity, with patients only allowed a cumulative lifetime dose of 550 mg/m2. Efforts to decrease cardiotoxicity and to increase the blood circulation time of DOX led to the US Food and Drug Administration (FDA) approval of a PEGylated liposomal formulation (L-DOX), Doxil® (known internationally as Caelyx®). Both exhibit better cardiovascular safety profiles; however, they are not currently FDA approved for the treatment of metastatic BC. Here, we provide detailed insights into the mechanism of action of L-DOX and its most common side effects and highlight results of its use in clinical trials for the treatment of BC as single agent and in combination with other commonly used chemotherapeutics. Keywords: doxil, caelyx, breast cancer, anti-tumor activity, cardiotoxicity

Abstract Background Leishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania. Yet, how META1 contributes to virulence remains unclear. We sought insights into the possible functions of META1 by studying its evolutionary origins. Results Using multiple criteria including sequence similarity, nucleotide composition, phylogenetic analysis and selection pressure on gene sequence, we present evidence that META1 originated in trypanosomatids as a result of a lateral gene transfer of a bacterial heat-inducible protein, HslJ. Furthermore, within the Leishmania genome, META1 sequence is under negative selection pressure against change/substitution. Using homology modeling of Leishmania META1 based on solved NMR structure of HslJ, we show that META1 and HslJ share a similar structural fold. The best hit for other proteins with similar fold is MxiM, a protein involved in the type III secretion system in Shigella. The striking structural similarity shared by META1, HslJ and MxiM suggests a possibility of shared functions. Upon structural superposition with MxiM, we have observed a putative hydrophobic cavity in META1. Mutagenesis of select hydrophobic residues in this cavity affects the secretion of the secreted acid phosphatase (SAP), indicating META1's involvement in secretory processes in Leishmania. Conclusions Overall, this work uses an evolutionary biology approach, 3D-modeling and site-directed mutagenesis to arrive at new insights into functions of Leishmania META1.

Abstract Background Simple ligation of the vas with suture material and excision of a small vas segment is believed to be the most common vasectomy occlusion technique performed in low-resource settings. Ligation and excision (LE) is associated with a risk of occlusion and contraceptive failure which can be reduced by performing fascial interposition (FI) along with LE. Combining FI with intra luminal thermal cautery could be even more effective. The objective of this study was to determine the surgical vasectomy techniques currently used in five Asian countries and to evaluate the facilitating and limiting factors to introduction and assessment of FI and thermal cautery in these countries. Methods Between December 2003 and February 2004, 3 to 6 major vasectomy centers from Cambodia, Thailand, India, Nepal, and Bangladesh were visited and interviews with 5 to 11 key informants in each country were conducted. Vasectomy techniques performed in each center were observed. Vasectomy techniques using hand-held, battery-driven cautery devices and FI were demonstrated and performed under supervision by local providers. Information about interest and open-mindedness regarding the use of thermal cautery and/or FI was gathered. Results The use of vasectomy was marginal in Thailand and Cambodia. In India, Nepal, and Bangladesh, vasectomy was supported by national reproductive health programs. Most vasectomies were performed using the No-Scalpel Vasectomy (NSV) technique and simple LE. The addition of FI to LE, although largely known, was seldom performed. The main reasons reported were: 1) insufficient surgical skills, 2) time needed to perform the technique, and 3) technique not being mandatory according to country standards. Thermal cautery devices for vasectomy were not available in any selected countries. Pilot hands-on assessment showed that the technique could be safely and effectively performed by Asian providers. However, in addition to provision of supplies, introducing cautery with FI could be associated with the same barriers encountered when introducing FI in combination with LE. Conclusion Further studies assessing the effectiveness, safety, and feasibility of implementation are needed before thermal cautery combined with FI is introduced in Asia on a large scale. Until thermal cautery is introduced in a country, vasectomy providers should practice LE with FI to maximize effectiveness of vasectomy procedure.

Objective: Sporadic optic chiasmatic-hypothalamic gliomas (OCHGs), though histologically low-grade tumors, manifest as aggressive neoplasms radiologically, leading to difficulty in diagnosis. Molecular alterations of the BRAF gene are detectable in a majority of sporadic OCHGs. The purpose of our study was to elucidate the characteristic imaging features of sporadic OCHGs and to investigate whether imaging phenotypes could potentially correlate with specific BRAF gene alterations associated with these tumors., Methods: We retrospectively reviewed baseline magnetic resonance (MR) images and medical records of 26 patients with histopathologically proven sporadic OCHGs. MR imaging (MRI) features were systematically evaluated. Statistical analysis was performed to determine whether there was a significant association between imaging findings and BRAF molecular alterations., Results: Twenty-two cases (84.6%) presented with solid-cystic masses, while four (15.4%) presented with purely solid lesions. In all 26 cases, the solid component revealed central necrosis; there was minimal necrosis in 11 cases (42.3%), moderate in 8 (30.7%), and marked in 7 (26.9%). The presence of multiple cysts (>4) and minimal necrosis showed a significant association with BRAFV600E mutation (P < 0.005). Marked necrosis in the solid component significantly correlated with BRAF wild genotype (P < 0.001). The presence of a single peripheral cyst significantly correlated with BRAF fusion (P = 0.04)., Conclusion: Sporadic OCHGs have a distinctive appearance on imaging. The solid-cystic composition coupled with varying degrees of central necrosis are clues to the radiological diagnosis of this entity and can facilitate early recognition in clinical practice. Imaging could potentially serve as a non-invasive predictor of the BRAF alteration status, thereby serving as a prognostic marker and guiding personalized management., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Objective: Acne vulgaris is a common skin condition treated with various medications targeting different aspects of its pathogenesis. Though increasing in popularity, the United States Food and Drug Administration (FDA) does not evaluate the safety or efficacy of dietary supplements marketed for the treatment of acne, calling into question the veracity of their labels. This review aimed to assess the safety and effectiveness of ingredients in popular acne supplements., Methods: A comprehensive review was conducted on 13 popular supplements marketed for acne, found through a Google search. Their ingredients, prices, ratings, and existing literature on efficacy and safety were analyzed. A literature review was performed regarding the most common ingredients contained in these supplements., Results: The most common ingredients in acne supplements were probiotics, diindolylmethane (DIM), vitamin A, vitamin B complex, and zinc. Despite the increasing popularity of dietary supplements, including those for skin health and acne, the absence of FDA regulation and evidence-based data raises concerns about their safety and efficacy. The safety of acne supplement ingredients raises significant worries, with reported cases of thrombotic events and adverse effects, even during pregnancy. The lack of standardized labeling and clear dosing information further complicates the understanding and potential risks of these supplements. Additionally, there is a potential for interactions with other medications, yet this information is often not provided on the product labels., Limitations: A Google search was used to identify popular acne supplements. Search engine algorithms determine the ranking and presentation of results based on various factors, such as popularity, keywords, as well as user preferences and location, thus posing a potential sampling bias., Conclusion: It is crucial to exercise caution and prioritize evidence-based information when counseling patients regarding the use of acne supplements., Competing Interests: DISCLOSURES: The authors have no conflicts of interest relevant to the contents of this article., (Copyright © 2024. Matrix Medical Communications. All rights reserved.)

Introduction: Thyroglossal duct cyst (TGDC) is the most frequently encountered developmental anomaly in thyroid genesis with a reported incidence of 7% in the adult population. The cyst is known to develop anywhere along the pathway of thyroid descent but is more frequently seen in the infrahyoid neck in the midline. The incidence of malignancy in a TGDC is approximately 1%; a majority of these are papillary carcinomas. This study was conducted at a single tertiary care centre which spanned over a decade which adds practice changing evidence-based knowledge to existing literature on this rare entity. A comprehensive study which conclusively establishes the imaging features predictive of malignancy in TGDC carcinomas (TGDCa), the protocol for optimal management, clinical outcome and long-term survival of these patients is not available. Although TGDC carcinoma is thought to have an excellent prognosis, there is not enough data available on the long-term survival of these patients. The aim of this study was to identify whether neck ultrasound (US) can serve as an accurate imaging tool for the preoperative diagnosis of TGDC carcinomas., Methods: We accessed the electronic medical records of 86 patients with TGDC between January 2005 to December 2021. Of these, 22 patients were detected with TGDC papillary carcinoma on histopathologic examination. Relevant imaging, treatment and follow up information for all cases of TGDC carcinoma were retrospectively reviewed. We compared US characteristics predictive of malignancy across outcomes groups; malignant vs benign using the Chi-square test. Based on the results, a TGC-TIRADS classification was proposed with calculation of the percentage likelihood of malignancy for each category., Results: Compared to benign TGDCs, malignant TGDCs were more likely to present with following US characteristics: irregular or lobulated margins (90.40 vs. 38.10%), solid-cystic composition (61.90 vs. 17.07%), internal vascularity (47.62 vs. 4.88 %), internal calcification (76.19 vs. 7.32 %) (each p value < 0.005). Calcifications and internal vascularity were the most specific while irregular/lobulated margins were the most sensitive feature for malignancy. AUC under the ROC curve was 0.88. Allpatients were operated and were disease free at the end of 5 years or till the recent follow up., Discussion: US is the imaging modality of choice for pre-operative diagnosis of TGDC carcinoma. Thepre-operative diagnosis and risk stratification of thyroglossal lesions will be aided by the application of the proposed TGC-TIRADS classification, for which the percentage likelihood of malignancy correlated well with the results in our study. Sistrunk procedure is adequate for isolated TGDC carcinoma; suspicious neck nodes on imaging also necessitates selective nodal dissection. Papillary carcinomas have an excellent prognosis with low incidence of disease recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mahajan, Deokar, Suryavanshi, Agarwal, Vaish, Shukla, Vaidya, Smriti, Tuljapurkar, Rastogi, Shaikh, Chaturvedi, Dcruz, Patil, Bal, Rane, Mittal, Noronha, Prabhash, Patil and Pai.)

Purpose: To measure the levels of inflammatory factors in tear fluid of pre-term infants with and without retinopathy of prematurity (ROP)., Methods: The cross-sectional pilot study included 29 pre-term infants undergoing routine ROP screening. Pre-term infants were grouped as those without ROP (no ROP; n = 14) and with ROP (ROP; n = 15). Sterile Schirmer's strips were used to collect the tear fluid from pre-term infants. Inflammatory factors such as interleukin (IL)-6, IL-8, MCP1 (Monocyte Chemoattractant Protein 1; CCL2), RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and soluble L-selectin (sL-selectin) were measured by cytometric bead array using a flow cytometer., Results: Birth weight (BW) and gestation age (GA) were significantly (P < 0.05) lower in pre-term infants with ROP compared with those without ROP. Higher levels of RANTES (P < 0.05) and IL-8 (P = 0.09) were observed in the tear fluid of pre-term infants with ROP compared with those without ROP. Lower levels of tear fluid IL-6 (P = 0.14) and sL-selectin (P = 0.18) were measured in pre-term infants with ROP compared with those without ROP. IL-8 and RANTES were significantly (P < 0.05) higher in the tear fluid of pre-term infants with stage 3 ROP compared with those without ROP. Tear fluid RANTES level was observed to be inversely associated with GA and BW of pre-term infants with ROP and not in those without ROP. Furthermore, the area under the curve and odds ratio analysis demonstrated the relevance of RANTES/BW (AUC = 0.798; OR-7.2) and RANTES/MCP1 (AUC = 0.824; OR-6.8) ratios in ROP., Conclusions: Distinct changes were observed in the levels of tear inflammatory factors in ROP infants. The status of RANTES in ROP suggests its possible role in pathobiology and warrants further mechanistic studies to harness it in ROP screening and management., Competing Interests: None

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

Competing Interests: Conflicts of interest None disclosed.

Prolonged daily face mask wearing over several months might affect health of the ocular surface and is reported to be associated with complaints of discomfort and dry-eye-like symptoms. We studied the ocular surface clinical parameters, tear soluble factors and immune cell proportions in ophthalmologists practicing within similar environmental conditions ( n = 17) at two time points: pre-face-mask period (Pre-FM; end of 2019) and post-face-mask-wearing period (Post-FM; during 2020 COVID-19 pandemic), with continuous (~8 h/day) mask wear. A significant increase in ocular surface disease index (OSDI) scores without changes in tear breakup time (TBUT), Schirmer's test 1 (ST1) and objective scatter index (OSI) was observed Post-FM. Tear soluble factors (increased-IL-1β, IL-33, IFNβ, NGF, BDNF, LIF and TSLP; decreased-IL-12, IL-13, HGF and VEGF-A) and mucins (MUC5AC) were significantly altered Post-FM. Ex vivo, human donor and corneoscleral explant cultures under elevated CO 2 stress revealed that the molecular profile, particularly mucin expression, was similar to the Post-FM tear molecular profile, suggesting hypercapnia is a potential contributor to ocular surface discomfort. Among the immune cell subsets determined from ocular surface wash samples, significantly higher proportions of leukocytes and natural killer T cells were observed in Post-FM compared to Pre-FM. Therefore, it is important to note that the clinical parameters, tear film quality, tear molecular factors and immune cells profile observed in prolonged mask-wear-associated ocular surface discomfort were distinct from dry eye disease or other common ocular surface conditions. These observations are important for differential diagnosis as well as selection of appropriate ocular surface treatment in such subjects.

Memory B cells and differentiated plasma cells combine to confer sustained humoral immunity. Nonetheless, we are yet to understand how B cells decide between these fates. Although pan-T cell help augments plasma cell differentiation, signaling via CD40 alone is considered to be inhibitory. Here, we examine the capacity of CD40 signaling to interfere with lipopolysaccharide-induced differentiation. Whereas lipopolysaccharide stimulation yielded only short-lived plasmablasts, co-stimulation of CD40 enhanced activation, proliferation, survival, and isotype-switching, leading to alternate fate choices such as germinal center and memory B cells during early divisions. Contrary to the notion that CD40 signaling simply arrests differentiation, the survivors, at later time points, developed into long-lived mature plasma cells, after progressively losing their ability to get restimulated. Counterintuitively, as constitutive lipopolysaccharide stimulation itself hampered differentiation, we identified that the proliferation potential of cells acted alongside CD40 signaling. Accordingly, we propose a bi-layered regulation of differentiation - CD40 signaling and proliferation potential of cells independently inhibit the commitment to and maturation of differentiation, respectively. Elucidating such cell fate decision mechanisms will aid in better vaccine design and disease management., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls ( p = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia.

Inflammatory factors have been considered to contribute to keratoconus (KC) pathogenesis. This study aims to determine the immune cells subsets and soluble inflammatory factor profile on the ocular surface of KC patients. 32 KC subjects (51 eyes) across different grades of severity and 15 healthy controls (23 eyes) were included in the study. Keratometry and pachymetry measurements were recorded. Ocular surface immune cells (collected by ocular surface wash) immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer (NK) cells, pan-T cells, gamma delta T (γδT) cells and NKT cells. Tear fluid collected using Schirmer's strip was used to measure 50 soluble factors by multiplex ELISA. Proportions of activated neutrophils, NK cells and γδT cells were significantly increased in KC patients. Significantly higher levels of tear fluid IL-1β, IL-6, LIF, IL-17A, TNFα, IFNα/β/γ, EPO, TGFβ1, PDGF-BB, sVCAM, sL-selectin, granzyme-B, perforin, MMP2, sFasL and IgE, along with significantly lower levels of IL-1α and IL-9 were observed in KC patients. Alterations observed in few of the immuno-inflammatory parameters correlated with grades of disease, allergy, eye rubbing and keratometry or pachymetry measurements. The observation implies a distinct immuno-inflammatory component in KC pathogenesis and its potential as an additional therapeutic target in KC management., (© 2021. The Author(s).)

Monocultures of several cell types result in the formation of robust clusters called homotypic aggregates (HAs). How this physical aggregation affects cell fates in immune cell cultures, is poorly understood. We studied anti-CD40-stimulated primary B cell cultures, where cells assembled into large three-dimensional LFA1-driven HAs by 72 h. The dense packing in these aggregates restricts the infiltration of stimulants, such as antibodies, to cells inside the clusters. This creates a concentration gradient of stimulant availability across the cross-section of HAs. We describe a method to retain this positional information even after the disruption of HAs, for analysis by flow cytometry. Comparison of stage-specific cell-surface markers showed that the extent of stimulant-binding affected multiple fates non-uniformly. While germinal center and lineage markers were moderately upregulated, immunoglobulins and markers associated with memory were more than doubled in the peripheral cells binding more anti-CD40. These cells also experienced a strong repression of the plasma cell regulator Prdm1 and an upregulation of the oncogene Myc. Thus, cells at different locations in HAs are subjected to unequal doses of stimulants, leading to a hitherto unreported source of heterogeneity in cell fates. These findings can be extrapolated to understand the dose-dependent effects of stimulants in other three-dimensional cell clusters., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) has posed a serious threat to global public health with its rapid spread, high fatality, and severe burden on health care providers all over the world. Although COVID-19 has been established as a respiratory tract infection, it can manifest with gastrointestinal symptoms as a consequence of direct infection by the virus or due to inflammation-mediated cytotoxicity. It has been observed that COVID-19 patients presenting with gastrointestinal symptoms tend to progress to a severe form of disease with increased morbidity and mortality, thus indicating the need for timely management. COVID-19 manifests with a wide spectrum of radiologic findings on gastrointestinal tract imaging, encompassing bowel abnormalities, hepato-biliary and pancreatic involvement, vascular occlusion, and solid organ infarction. Early recognition of these imaging features can facilitate timely treatment of COVID-19 associated gastrointestinal tract complications and may prompt the diagnosis of COVID-19 in patients with atypical disease manifestations. The aim of this article is to provide an overview of the various gastrointestinal imaging manifestations that can be encountered in patients with COVID-19, with an emphasis on early diagnosis of the disease as well as treatment related complications., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interests for this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: To determine the status of proangiogenic factors in the tear fluid of preterm infants with and without retinopathy of prematurity (ROP)., Methods: Preterm infants (n = 36) undergoing routine ROP screening included in the prospective study were categorized as No-ROP (n = 13, no ROP at any visits), ROP (if ROP was present at first visit; n = 18), or No-ROP to ROP (no disease at first visit, but developed ROP subsequently; n = 5). Infants with ROP were also grouped as progressing (n = 7) and regressing (n = 16) based on ROP evolution between the first and subsequent visits. Schirmer's strips were used to collect tear fluid and proangiogenic factors (VEGF, angiogenin, soluble vascular cell adhesion molecule, and fractalkine) levels (in picograms per milliliter) in tear fluid were measured by multiplex ELISA., Results: Lower levels of VEGF (135 ± 69; mean ± standard deviation) and higher levels of angiogenin (6568 ± 4975) were observed in infants with ROP compared with infants without ROP (172.5 ± 54.0; 4139 ± 3909) at the first visit. Significantly lower levels of VEGF were observed in the No-ROP to ROP group compared with the No-ROP and ROP groups. The VEGF and angiogenin levels at the first visit were significantly lower in infants with ROP with progressing disease. Angiogenin levels negatively correlated with birth weight and gestational age in ROP. The area under the curve (AUC) and odds ratio (OR) analysis demonstrated that angiogenin/birth weight (AUC = 0.776; OR, 8.6); angiogenin/gestational age (AUC = 0.706; OR, 7.3) and Angiogenin/VEGF (AUC = 0.806; OR, 14.3) ratios were able to differentiated preterm infants with and without ROP., Conclusions: The association between angiogenin and ROP suggests its possible role in ROP. The ratio of angiogenin level with birth weight, gestational age, and/or VEGF could serve as a potential noninvasive screening biomarker for ROP.

βA3/A1-crystallin, a lens protein that is also expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome high-throughput array, we found that βA3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of βA3/A1-crystallin in metabolism of retinal astrocytes. We found that βA1-crystallin acts as an uncompetitive inhibitor of PTP1B, but βA3-crystallin does not. Loss of βA1-crystallin in astrocytes triggers metabolic abnormalities and inflammation. In CRISPR/cas9 gene-edited βA1-knockdown (KD) mice, but not in βA3-knockout (KO) mice, the streptozotocin (STZ)-induced diabetic retinopathy (DR)-like phenotype is exacerbated. Here, we have identified βA1-crystallin as a regulator of PTP1B; loss of this regulation may be a new mechanism by which astrocytes contribute to DR. Interestingly, proliferative diabetic retinopathy (PDR) patients showed reduced βA1-crystallin and higher levels of PTP1B in the vitreous humor.

Black-Scholes (BS) is a remarkable quotation model for European option pricing in financial markets. Option prices are calculated using an analytical formula whose main inputs are strike (at which price to exercise) and volatility. The BS framework assumes that volatility remains constant across all strikes; however, in practice, it varies. How do traders come to learn these parameters? We introduce natural agent-based models, in which traders update their beliefs about the true implied volatility based on the opinions of other agents. We prove exponentially fast convergence of these opinion dynamics, using techniques from control theory and leader-follower models, thus providing a resolution between theory and market practices. We allow for two different models, one with feedback and one with an unknown leader., Competing Interests: We declare we have no competing interests., (© 2020 The Authors.)

Immunological memory is a critical characteristic of a successful long-term adaptive immune response. During the initial phases of antigen:B lymphocyte interactions, B cells participate in the germinal center reaction, in which T-B cell interactions take place. CD154 on T cells acts as a ligand that binds to the CD40 receptor on B cells and facilitates the differentiation of B cells to memory B cells. However, cell fate determinants controlled by CD40 signal for cellular differentiation are unclear. In this study, we explored miRNA and miRNA-targets as cell fate determinants in CD40 signaled B cells. We selected candidate miRNAs based on their involvement in the regulation of B cell development, activation, and differentiation. We found that CD40 signal reduced transcript levels of miR150-5p, 17-5p, 146a-5p, 26a-5p and increased levels of miR292a-5p. Gene set enrichment analyses of previously submitted microarray data revealed accordant changes in levels of gene targets of these miRNA. Gene ontology analysis of miRNA-targets showed enrichment of genes participating in pathways such as DNA damage response, RNA/protein metabolism, and cell cycle regulation. Subsequently, studies on candidate miRNA-targets showed a CD40 signal driven differential regulation of Ccnd2, Pten, Traf6, c-Myb, and Btla. Further, 'gain of function' studies using mimics of the downregulated miRNAs, confirmed a predicted reduction in miRNA responsive targets; such as reduction of Ccnd2 levels in mimic treated groups of miR146a-5p, 26a-5p, and 17-5p. In conclusion, our study reveals that CD40 signal modulates levels of selected miRNAs as well as their cognate targets, whose enriched participation in diverse processes may help delineate downstream cell fate decisions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Rosai-Dorfman disease (RDD) is a rare lympho-histiocytic disorder of indeterminate etiology usually presenting with lymph node involvement, and infrequently with extra-nodal manifestations. The diagnosis of this condition is challenging due to the wide spectrum of disease manifestations., Purpose: To elucidate the radiologic features of this disease using multimodality imaging in histopathologically proven cases and to identify characteristic features that would enable its differentiation from its mimics., Material and Methods: We retrospectively evaluated imaging studies of 19 patients with histopathologically confirmed RDD presenting to our institute between January 2004 and March 2016. Imaging modalities included magnetic resonance imaging (MRI), computed tomography, FDG-positron emission tomography (PET) CT, mammography, and ultrasonography., Results: Lymphadenopathy was the most common imaging feature in our study, seen in 11 (57.8%) cases followed by sino-nasal involvement in 7 (36.8%) cases and intracranial masses in 5 (26.3%) cases. Bilateral homogeneously enhancing cervical lymphadenopathy with avidity on FDG-PET scans was the predominant abnormality on imaging. Sino-nasal involvement manifested as homogeneously enhancing soft-tissue masses occupying the paranasal sinuses. Intracranial disease manifested as sellar/suprasellar masses, dural-based lesions along the cerebral hemispheres and choroid plexus enlargement. Unusual disease manifestations included spinal, osseous, and breast lesions., Conclusion: Due to the high likelihood of multifocal involvement, the recognition of RDD at one site necessitates screening of other sites for disease. Homogeneously enhancing, FDG-avid lymphadenopathy and sino-nasal masses in association with hypointense extra-nodal lesions on T2-weighted MRI are imaging features which could aid the diagnosis of RDD and facilitate its differentiation from pathologies that present in a similar manner., (© The Foundation Acta Radiologica 2020.)

To date, only twenty cases of cutaneous legionellosis have been reported. Cutaneous legionellosis has heterogeneous manifestations including abscesses, nodules, and cellulitis. The detection of most cutaneous Legionella species requires specific diagnostic cultures and assays. Herein, we report a case of cutaneous legionella in a hematopoietic cell transplantation recipient with culture-negative nodules unresponsive to empiric antibiotics. We also discuss the varied morphology of cutaneous legionellosis and important diagnostic considerations.

Purpose of Review: Graft-versus-host disease (GVHD) is an immune mediated disorder affecting 30 - 70% of patients after allogeneic hematopoietic stem cell transplantation (alloHSCT), and is a major cause of morbidity and non-relapse mortality (NRM) [1]. Dermatologists play a critical role in acute and chronic GVHD, as skin involvement is common and often the earliest involved site of disease [2]., Recent Findings: GVHD shares clinical and histopathological features with a variety of other skin diseases, requiring thorough consideration of differential diagnoses in hematopoietic stem cell transplantation (HSCT) recipients with lesions suggestive of cutaneous GVHD. Treatment considerations for GVHD are influenced by factors such as disease classification, overall grading, organ involvement, associated symptoms, and immunological anti-tumor effect. Several treatments are available and may be indicated as monotherapy or adjuvant therapy to allow faster withdrawal or tapering of immunosuppression. While corticosteroids are often first line therapy, oral ruxolitinib has been recently approved for treatment of steroid-refractory aGHVD, and oral ibrutinib has been approved for steroid-refractory cGHVD., Summary: This article provides current clinical, diagnostic, and therapeutic considerations relevant to the hospitalist for both acute and chronic mucocutaneous GVHD. Optimal inpatient management of these diseases requires an interdisciplinary team., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ- activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD., Competing Interests: Competing interestsA.J. and D.S. are inventors in a US patent filed by F. Hoffmann-La Roche, Ltd., Basel, Switzerland on an AKT2 inhibitor for treatment of dry AMD. The remianing authors declare no competing interests.

The current practice of oncology focuses not only on early diagnosis, staging, and treatment of cancer but also defies the concept of "One size fits all." This paradigm shift of the 8 th edition American Joint Committee on Cancer (AJCC) manual to a "personalized medicine" approach sets the stage for introducing Imaging TNM (iTNM). The iTNM would provide physicians with a clear assessment of the disease extent derived exclusively from a combination of anatomical and functional imaging modalities and simplify decision-making in practice. Introduction of iTNM will complement the existing cTNM and pTNM and help to guide a personalized approach to patient management., Competing Interests: None

Purpose: The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED)., Methods: A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tear-soluble factors levels including vitamin D., Results: Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1β, IL-17A, MMP9, MMP10, MMP9/TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms., Conclusions: Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.

Aims: S100A8 and S100A9 are myeloid-related damage-associated molecular patterns (DAMPs) primarily involved in the modulation of innate immune response to cellular injury. This study evaluated the correlation between circulating concentrations of S100A8 and S100A9 proteins with the severity of diabetic retinopathy (DR) in patients with type 2 diabetes (T2DM)., Methods: T2DM patients with HbA1c levels >7%, fasting blood glucose >126 mg/dl and history of diabetes were included in this study. DR severity was graded based on ETDRS and Gloucestershire classifications. Plasma samples were evaluated for S100A8 and S100A9 levels using ELISA., Results: In this comparative study, DR patients (n = 89) had increased plasma S100A8 and S100A9 proteins compared to age-matched T2DM controls (n = 28), which was directly related to the severity of DR. Female DR subjects had increased S100A8 expression compared to their male counterparts. Substantial retention of S100A8 and S100A9 production was seen in DR patients above 50 years of age. Duration of T2DM was not found to affect protein levels, however T2DM onset at >50 years old significantly increased S100A8 and S100A9 concentrations., Conclusions: Our findings suggest that systemic circulation levels of S100A8 and S100A9 are correlated with the progression of DR in T2DM patients, indicating their potential role in DR pathogenesis., (Copyright © 2019 Diabetes India. All rights reserved.)

An Online First version of this article was made available online at http://link.springer.com/journal/40291/onlineFirst/page/1 on 01 Nov 2018. An error was subsequently identified in the article, and the following correction should be noted.

The present era of precision medicine sees "cancer" as a consequence of molecular derangements occurring at the commencement of the disease process, with morphological changes happening much later in the process of tumourigenesis. Conventional imaging techniques, such as computed tomography (CT), ultrasound (US) and magnetic resonance imaging (MRI) play an integral role in the detection of disease at the macroscopic level. However, molecular functional imaging (MFI) techniques entail the visualisation and quantification of biochemical and physiological processes occurring during tumourigenesis. MFI has the potential to play a key role in heralding the transition from the concept of "one-size-fits-all" treatment to "precision medicine". Integration of MFI with other fields of tumour biology such as genomics has spawned a novel concept called "radiogenomics", which could serve as an indispensable tool in translational cancer research. With recent advances in medical image processing, such as texture analysis, deep learning and artificial intelligence, the future seems promising; however, their clinical utility remains unproven at present. Despite the emergence of novel imaging biomarkers, the majority of these require validation before clinical translation is possible. In this two part review, we discuss the systematic collaboration across structural, anatomical and molecular imaging techniques that constitute MFI. Part I reviews positron emission tomography, radiogenomics, AI, and optical imaging, while part II reviews MRI, CT and ultrasound, their current status, and recent advances in the field of precision oncology.

Metastases to the breast from extra-mammary malignancies are extremely uncommon. The discovery of a breast mass in a patient with a known primary tumor elsewhere poses a diagnostic challenge to the clinician. An awareness of the various malignancies that can metastasize to the breast and accurate diagnosis of the same is essential to avoid an unnecessary mastectomy and to guide further therapy. In this case series, we describe such clinical scenarios with an emphasis on the imaging features of metastases to the breast, which will enable radiologists to recognize this entity with greater ease., Competing Interests: There are no conflicts of interest.