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In this research, we conduct a computational investigation into the mixed convection flow of copper/water nanofluids (NFs) within a rectangular cavity, utilizing the Lattice Boltzmann Method (LBM). The cavity is uniquely configured with five high-temperature obstructions (HOBs), and we vary their dimensions and positions to evaluate Nusselt numbers (Nu) across a range of Richardson numbers (Ri). The three walls of the cavity, excluding the moveable top wall, are thermally insulated, while the latter is maintained at a lower temperature. A constant magnetic field (MCF) exerts influence within the cavity, with Ri spanning from 0.01 to 100, HOBs ranging from 0.1 to 0.5, and HOBs at the bottom wall spanning from 0.25 to 0.4. This numerical investigation is executed using a customized in-house code, focusing on examining heat transfer (HTR) dynamics within the cavity. Our findings reveal that augmenting the height of the HOBs and positioning them closer to the cold wall significantly enhances the average Nusselt number (Nuav). Conversely, an increase in Ri leads to a reduction in Nuav on the cold wall. Specifically, the most notable enhancement, with a 66.7 % increase in Nuav, occurs at Ri = 0.01 when HOBs are elevated from 0.1 to 0.5. On the other hand, an increment in Ri from 0.01 to 100 results in a 79.4 % reduction in Nuav. Furthermore, elevating the HOBs from 0.25 to 0.4 produces a substantial 44.3 % increase in Nuav.

Abstract Background: Post-transplant infections remain a leading cause of morbidity and mortality in solid organ transplant recipients (SOTRs) and local standardized antimicrobial treatment guidelines may contribute to improved clinical outcomes. Our study assessed the rate of therapeutic compliance with local standard guidelines in the treatment of common infections in SOTR, and their associated outcomes. Methods: Consecutive adult SOTRs admitted to the transplant floor from January–September 2020 and were treated for an infectious syndrome were followed until discharge or for 30 days following the date of diagnosis, whichever was shorter. Data was extracted from electronic medical records. Guideline compliance was characterized as either appropriate, effective but unnecessary, undertreatment, or inappropriate. Results: Nine hundred and thirty-six SOTR were admitted to the transplant ward, of which 328 patients (35%) received treatment for infectious syndromes. Guidelines were applicable to 252 patients, constituting 275 syndromes: 86 pneumonias; 82 urinary tract infections; 40 intra-abdominal infections; 38 bloodstream infections; and 29 C. difficile infections. 200/246 (81%) of infectious syndromes received appropriate or effective but unnecessary empiric treatment. In addition, appropriate tailoring of antimicrobials resulted in a significant difference in 30-day all-cause mortality (adjusted OR of 0.07, 95% CI 0.01–0.38; P = .002). Lastly, we found that guideline-compliant empiric therapy was found to prevent the development of multi-drug resistance in a time-dependent analysis (adjusted HR of 0.21, 95% CI 0.08–0.52; P = .001). Conclusion: Our data show that adherence to locally developed guidelines was associated with reduced mortality and resistant-organism development in our cohort of SOTR.

Solid organ transplant (SOT) recipients have a higher risk of developing invasive mould diseases (IMD). Isavuconazole is a novel broad-spectrum azole active against Aspergillus spp. and Mucor, well tolerated, with an excellent bioavailability and predictable pharmacokinetics, that penetrates in most tissues rapidly, and has few serious adverse effects, including hepatic toxicity. Contrary to other broad-spectrum azoles, such as voriconazole and posaconazole, isavuconazole appears to show significant smaller drug-drug interactions with anticalcineurin drugs. We have performed an extensive literature review of the experience with the use of isavuconazole in SOT, which included the SOTIS and the ISASOT studies, and published case reports. More than 140 SOT recipients treated with isavuconazole for IMD were included. Most patients were lung and kidney recipients treated for an Aspergillus infection. Isavuconazole was well tolerated (less than 10% of patients required treatment discontinuation). The clinical responses appeared comparable to that found in other high-risk patient populations. Drug-drug interactions with immunosuppressive agents were manageable after the reduction of tacrolimus and the adjustment of mTOR inhibitors at the beginning of treatment. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IMD in SOT. More clinical studies are warranted.

Abstract The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.

Abstract The heterogeneity of clinical responses to antifungals in aspergillosis is partially understood. We hypothesized that besides direct antifungal effects, these discrepancies may be related to different immunomodulatory profiles. Human THP-1 monocytes were coincubated in vitro with Aspergillus fumigatus and variable concentrations of voriconazole (0.5, 1 and 2 mg/l), caspofungin (1 and 2 mg/l), amphotericin B deoxycholate (0.25, 0.5 and 1 mg/l) and liposomal amphotericin B (1, 2 and 3 mg/l). After 6 h of coincubation, total cellular RNA was extracted, converted into cDNA, and transcription of 84 genes involved in antifungal immunity was measured through RT-qPCR. The presence of A. fumigatus was the main driver of the global immune-related transcriptomic response. After Aspergillus infection, thirty genes were upregulated, while 19 genes were downregulated. Discrepancies across antifungals were also evident; voriconazole-containing conditions showed similar reaction to natural infection, while the use of liposomal Amphotericin B significantly decreased the inflammatory response. Chemokines (notably CCL20 and CXCL2) and pro-inflammatory cytokines (IL1A, IL1B, IL23, G-CSF) exhibited the most pronounced differences across antifungals. Pattern recognition receptors and adaptor protein transcription were minimally affected. Protein–protein-interaction network analysis showed that IL23A played a dominant role in upregulated genes. Pathway enrichment analysis indicated that cytokine-cytokine receptor integration, TNF signaling pathways and Toll-like receptor pathways were highly involved. This exploratory study confirms the heterogeneous immunomodulatory role of antifungals. Overall, voriconazole appears to maintain an early pro-inflammatory response seen in natural infection. Assessment of immunomodulatory response with clinical response may provide a better rationale for differences observed across antifungals.

In the data-driven world, data is created in huge volume and then analyzed by several organizations to get benefit from them. Smart city is one of the examples to use big data to offer improved services for its resident and tourist. However, some countries face certain obstacles to analyze the big data integration for sustainability in smart city development. Therefore, the purpose of this research paper is to identify and analyze the significant barriers related to sustainable smart city development. To accomplish this objective, fourteen barriers of big data analytics are selected through the combined approach of literature review and expert input. After that, these barriers are evaluated using the best worst method for obtaining deeper insights. The result of this study reveals that the most significant barrier is ‘lack of technologies for BDA’, ‘lack of BDA framework’, ‘nature of big data’, and ‘low availability of analytics platforms for big data’. These barriers need to address on priority to develop a sustainable smart city. This study is helpful to the urban planner, government, and consultancy agencies to decide on the adoption of BDA for sustainable smart city development. Further, they can also optimize their resources in the best possible manner to achieve the sustainable development of the existing smart cities.

Summary: Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of target-organ damage.Thrombopoietin (THPO), a growth factor essential to megakariocyte proliferation, is known to prime platelet activation and leukocyte-platelet interaction. In addition, THPO concentrations increase in several critical diseases, such as acute cardiac ischemia and sepsis, thus representing a potential diagnostic and prognostic biomarker. Furthermore, several data suggest that interleukin (IL)-6 is one of the most important inflammatory mediators involved in these phenomena, which led to explore the potential therapeutic role of IL-6 inhibitors.In this prospective cohort study, we aimed to study THPO and IL-6 concentrations in COVID-19 patients at the time of first clinical evaluation in the Emergency Department (ED), and to investigate their potential use as diagnostic and prognostic biomarkers. In addition, we sought to explore the role of THPO contained in plasma samples obtained from COVID-19 patients in priming in vitro platelet activation and leukocyte-platelet interaction. Methods: We enrolled 66 patients presenting to the ED with symptoms suggestive of COVID-19, including 47 with confirmed COVID-19 and 19 in whom COVID-19 was excluded (Non-COVID-19 patients). As controls, we also recruited 18 healthy subjects.In vitro, we reproduced the effects of increased circulating THPO on platelet function by adding plasma from COVID-19 patients or controls to platelet-rich plasma or whole blood obtained by healthy donors, and we indirectly studied the effect of THPO on platelet activation by blocking its biological activity. Findings: THPO levels were higher in COVID-19 patients than in both Non-COVID-19 patients and healthy subjects. Studying THPO as diagnostic marker for the diagnosis of COVID-19 by receiver-operating-characteristic (ROC) statistics, we found an area under the curve (AUC) of 0.73, with an optimal cut-off value of 42.60 pg/mL. IL-6 was higher in COVID-19 patients than in healthy subjects, but did not differ between COVID-19 and Non-COVID-19 patients.THPO concentrations measured at the time of diagnosis in the ED were also higher in COVID-19 patients subsequently developing a severe disease than in those with mild disease. Evaluating THPO as biomarker for severe COVID-19 using ROC analysis, we found an AUC of 0.71, with an optimal cut-off value of 57.11 pg/mL.IL-6 was also higher in severe than in mild COVID-19 patients, with an AUC for severe COVID-19 of 0.83 and an optimal cut-off value of 23 pg/ml.THPO concentrations correlated with those of IL-6 (r=0.2963; p=0.043), and decreased 24 h after the administration of tocilizumab, an IL-6 receptor blocking antibody, showing that the increase of THPO levels depends on IL-6-stimulated hepatic synthesis.In vitro, plasma obtained from COVID-19 patients, but not from healthy subjects, primed platelet aggregation and leukocyte-platelet binding, and these effects were reduced by inhibiting THPO activity. Interpretation: Increased THPO may be proposed as an early biomarker for the diagnosis of COVID-19 and for the identification of patients at risk of developing critical illness. Elevated THPO may contribute to enhance platelet activation and leukocyte-platelet interaction in COVID-19 patients, thus potentially participating in immunothrombosis/thromboinflammation. Funding: This work was supported by Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST) ex 60% to GM and EL.

Background: Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. Objectives: We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. Design: An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. Setting: UK maternity units were randomised to either a strategy of rapid test or usual care. Participants: Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. Main outcome measures: Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. Results: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. Conclusions: The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. Future work: The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN74746075. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

We report the outcome of a 43 year old man who developed fatal ventriculoencephalitis due to cytomegalovirus (CMV) infection 7 months post allogeneic stem cell transplant. He failed multiple lines of treatment, including intravenous ganciclovir, foscarnet, and CMV-specific immunoglobulins, without improvement in CSF CMV copies. Novel intrathecal administration of CMV immunoglobulins was given but did not lead to clearance of CMV from CSF. No adverse effects related to intrathecal CMV immunoglobulins were observed. Notably, throughout this period, CMV in blood remained undetectable. This case highlights the difficulty in treating CMV encephalitis, and that novel therapeutic approaches are needed.

This paper presents the simulations of the cooling system of a battery pack (BTPC) consisting of lithium-ion (LIN) plate batteries. The BTPC includes six battery cells (BTCL) in two rows with three BTCLs, which are placed in a channel with one inlet and two outlets. The laminar and steady airflow flows in the channel. Phase-change material (PCM)-filled rectangular cubic enclosures enclose every BTCL. Transiently adjusting the cavity aspect ratio (AR) every 6000 s is how this investigation is conducted. For four values of AR, the values of the PCM volume percentage surrounding each BTCL in the BTPC, and the temperature of each BTCL are calculated. The simulations are performed using the FEM and COMSOL software. The results demonstrate that the maximum changes in temperature of the battery (TOB) pack by changing the AR occur when the TOB pack is reduced. The maximum temperature reduction at this time is 1.88 °C which occurs between AR2 and AR4 at 720 s. The maximum temperature corresponds to AR3 and AR4 and the minimum one is related to AR1 and AR2. From 1260 to 3500 s, the effect of AR on PCM volume fraction is maximal. The value of solid PCM for AR1 and AR2 is higher than that for AR3 and AR4 at different times. Additionally, an increment in the value of the AR enhances the amount of channel pressure drop by 14%.

In the present work, twelve machine learning (ML) models are developed for assessment of monthly average diffuse solar radiation (DSR) with solitary input forecaster as clearness index. Two categories of ML models were demarcated (i.e. diffusion coefficient and diffuse fraction) with six models for each group. The correctness of models was examined as a function of some frequently used statistical pointers. A comparision was also done between developed ML models and some well-recognised models available from previous works. The results show that ML models perform very well in comparision to models available in the literature. The top-performing models in category 1 are the k-nearest neighbours (KNN) model for both training and testing data. In category 2, for training data random forest (RF) model perform well while for testing data support vector regression (SVR) models perform well. The performance can be slightly improved by using two or more input parameters such as temperature difference, relative humidity and relative sunshine along with clearness index as input. Thus, ML models can be used to estimate DSR in the humid-subtropical climate of India.

Heat transfer enhancement caught the attention of researchers owing to the need for compact size heat exchangers. This is because of the development of micro-devices due to advancements in electronics. The heat transfer through natural convection in vertical annular geometry has many benefits and, if designed efficiently, will result in energy saving due to no/less moving parts. This paper reports the review of techniques used by researchers for heat transfer enhancement during natural convection flow in vertical annular geometry. Several techniques that have a significant impact on the design and performance are discussed here in detail viz. use of nanofluids, use of the magnetic field, use of cylinder wall rotation, use of discrete wall heating, use of porous material, use of boiling, use of rings, etc. The implementation of each technique along with its advantages and drawbacks are also discussed. The authors also suggested their recommendation of techniques to be used for heat transfer enhancement. The study highlights research gaps and weak points that have not received the researchers' attention so far. This article outlines areas that needed the most attention in the future.

For the various climatic zones of India, machine learning (ML) models are created in the current work to forecast monthly-average diffuse solar radiation (DSR). The long-term solar radiation data are taken from Indian Meteorological Department (IMD), Pune, provided for 21 cities that span all of India’s climatic zones. The diffusion coefficient and diffuse fraction are the two groups of ML models with dual input parameters (sunshine ratio and clearness index) that are built and compared (each category has seven models). To create ML models, two well-known ML techniques, random forest (RF) and k-nearest neighbours (KNN), are used. The proposed ML models are compared with well-known models that are found in the literature. The ML models are ranked according to their overall and within predictive power using the Global Performance Indicator (GPI). It is discovered that KNN models generally outperform RF models. The results reveal that in diffusion coefficient models perform well than diffuse fraction models. Moreover, functional form 2 is the best followed by form 6. The ML models created here can be effectively used to accurately forecast DSR in various climates.

The main challenge of the health risk assessment of the aerosol transport and deposition to the lower airways is the high computational cost. A standard large-scale airway model needs a week to a month of computational time in a high-performance computing system. Therefore, developing an innovative tool that accurately predicts transport behaviour and reduces computational time is essential. This study aims to develop a novel and innovative machine learning (ML) model to predict particle deposition to the lower airways. The first-ever study uses ML techniques to explore the pulmonary aerosol TD in a digital 17-generation airway model. The ML model uses the computational data for a 17-generation airway model and four standard ML regression models are used to save the computational cost. Random forest (RF), k-nearest neighbour (k-NN), multi-layer perceptron (MLP) and Gaussian process regression (GPR) techniques are used to develop the ML models. The MLP regression model displays more accurate estimates than other ML models. Finally, a prediction model is developed, and the results are significantly closer to the measured values. The prediction model predicts the deposition efficiency (DE) for different particle sizes and flow rates. A comprehensive lobe-specific DE is also predicted for various flow rates. This first-ever aerosol transport prediction model can accurately predict the DE in different regions of the airways in a couple of minutes. This innovative approach and accurate prediction will improve the literature and knowledge of the field.

Pneumocystis jirovecii is an important etiological agent of pneumonia that is underdiagnosed due to the inability to culture the organism. The 2019 PERCH study identified Pneumocystis as the top fungal cause of pneumonia in HIV-negative children using a PCR cutoff of 104 copies of Pneumocystis per mL of sample in nasopharyngeal/oropharyngeal (NP/OP) specimens. Given that Pneumocystis consists of an environmental ascus form and a trophic from (the latter is the form that attaches to the lung epithelium), it is possible that life-form-specific molecular assays may be useful for diagnosis. However, to accomplish this goal, these assays require genotypic information, as the current fungal genomic data are largely from the US and Europe. To genotype Pneumocystis across the globe, we developed an NGS-based genotyping assay focused on genes expressed in asci as well as trophs using PERCH throat swabs from Africa, Bangladesh, and Thailand, as well as North American samples. The NGS panel reliably detected 21 fungal targets in these samples and revealed unique genotypes in genes expressed in trophs, including Meu10, an ascospore assembly gene; two in mitochondrial gene ATP8, and the intergenic region between COX1 and ATP8. This assay can be used for enhanced Pneumocystis epidemiology to study outbreaks but also permits more accurate RT-CPR- or CRISPR-based assays to be performed to improve the non-bronchoscopic diagnosis of this under-reported fungal pathogen.

Background. We sought to determine whether invasive aspergillosis (IA) during the first year after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD). Methods. We retrospectively reviewed the records of 191 patients who underwent lung transplantation at our institution between January 2013 and December 2017. Screening for Aspergillus was with bronchial aspirates, bronchoalveolar lavage if indicated or during surveillance bronchoscopy, radiography, and computed tomography. We used Fine and Gray multivariable regression to identify potential risk factors for CLAD. Results. During the first posttransplant year, 72 patients had at least 1 deep-airway sample positive for Aspergillus; 63 were classified as having IA and were included in the study. Median number of endoscopies per patient during the first year was 9 (range, 1–44). Median time from transplantation to first Aspergillus-positive sample was 121 d. Bronchial aspirate samples and bronchoalveolar lavage fluid were positive in 71 and 44 patients, respectively. Aspergillus fumigatus (n = 36, 50%) predominated; bacterial samples were also positive in 22 (31%) patients. IA within 4 mo after transplantation was independently associated with CLAD development (subdistribution hazard ratio, 3.75; 95% confidence interval [CI], 1.61-8.73; P < 0.01) by regression analysis. Survival at 3 and 5 y conditional on 1-y CLAD-free survival was 37% (95% CI, 24%-58%), and 24% (95% CI, 11%-52%) in the IA

The main objective of this study was to determine the inhibition of pro-inflammatory cytokines and their associated signaling molecules by δ-opioid receptor activation by a selective ligand, SNC-121 in chronic rat glaucoma model. Intraocular pressure was raised in rat eyes by injecting 2 M hypertonic saline into the limbal veins. SNC-121 (1 mg/kg; i. p) or Stattic (5 mg/kg; i. p) was administered in Brown Norway rats daily for 7 days. The mRNA expression of IL-1β, TNF-α, Fas, IL-6, leukemia inhibitory factor, and IFN-γ was increased significantly in the retina of ocular hypertensive animals at day 7, post injury. Administration of SNC-121 (1 mg/kg; i. p. injection) for 7 days (once a day) completely inhibited the increase in the mRNA and protein expression of pro-inflammatory cytokines. Mechanistically, we provide data showing a significant increase in the phosphorylation of STAT3 at tyrosine 705 whereas a moderate but significant increase in the total STAT3 protein expression was also seen in the retina of ocular hypertensive animals. Data illustrated that SNC-121 administration completely abrogated ocular hypertension-induced increase in STAT3Y705 phosphorylation. Interestingly, acetylation of STAT3 at lysine 685 (AcK685) was reduced in ocular hypertensive animals and subsequently increased significantly by SNC-121 treatment. Stattic, a selective STAT3 inhibitor, administration resulted in a complete attenuation in the production of IL-1β and IL-6 in ocular hypertensive animals. In conclusion, δ-opioid receptor activation suppressed the phosphorylation of STAT3 at tyrosine 705 and increased acetylation at lysine 686 and these posttranslational modifications can regulate the production of some but not all pro-inflammatory cytokines in response to glaucomatous injury.

Candida spp. are common colonizers of the oral mucosa and respiratory tract in lung transplant recipients. Although thought to be non-pathogenic in most cases, donor derived infections related to Candida spp. have been described. Among the manifestations of invasive candidiasis, chronic meningitis is one of the rarest and one of the most challenging to diagnose, due to the indolence of the disease and the low yield of the CSF cultures. It is associated with severe morbidity and a high mortality. Fungal PCR and BD glucan assays can be assistance in its diagnosis, although these tests are not widely available. We report a case of a possible donor derived Candida dubliniensis infection in a lung transplant recipient, who initially presented with empyema that was treated successfully, but subsequently developed chronic meningitis. Diagnosis was delayed due to the low yield of CSF cultures, and was confirmed with fungal PCR and BD glucan assay. Keywords: Candida meningitis, Chronic meningitis, Candida dubliniensis, Lung transplant, Immunocompromised

Context: Carica papaya Linn. (Caricaceae) leaf (CPL) juice has long been traditionally used in ethnomedicine for dengue fever. Objective: The study examines the effects of standardized CPL aqueous extract (SCPLE) on platelet count, extramedullary haematopoiesis (EMH), and immunomodulation in cyclophosphamide (CP)-induced animal model of thrombocytopenia. Materials and methods: The extract was analyzed for myricetin, caffeic acid, trans-ferulic acid, and kaempferol using HPTLC for standardization followed by UPLC-qTOF/MS fingerprinting for metabolite signature. The effects of SCPLE (50 and 150 mg/kg p.o.) on proliferative response of platelet count and total leucocyte count (TLC) were observed up to 14 days in Wistar rat. However, delayed-type hypersensitivity (DTH), haemagglutination titre (HT), and in vivo carbon clearance were examined as immunomodulatory parameters in albino mice at 150 mg/kg p.o. against CP. Results: The quantitative HPTLC estimation of SCPLE showed the presence of myricetin, caffeic acid, trans-ferulic acid, and kaempferol up to 280.16 ± 5.99, 370.18 ± 6.27, 1110.86 ± 2.97, and 160.53 ± 2.48 (μg/g), respectively. Twenty-four metabolites were identified using UPLC-qTOF/MS. Oral administration of SCPLE (150 mg/kg) in thrombocytopenic rats exhibited significant (p

There are limited data on blastomycosis in solid organ transplant recipients with the subsequent development of the immune reconstitution inflammatory syndrome (IRIS). Herein we describe a case of pulmonary blastomycosis in a renal transplant recipient with the development of concomitant IRIS. Keywords: Transplantation, Immune Reconstitution Inflammatory Syndrome (IRIS), Blastomycosis

Summary: Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy. : Chakraborty et al. define the role for SphK1/S1P signaling via engaging lipid transcription factor PPARγ to attenuate lipolysis and spare respiratory capacity in T cells. Genetic ablation or pharmacological inhibition of SphK1 expression limits intrinsic S1P levels and improves T cell-mediated anti-tumor immunotherapeutic control. Keywords: T cell, Tcm, immunotherapy, melanoma, lipid signaling, SphK1, S1P, PPARγ, Foxo1

Invasive fungal infections are an increasingly important cause of human morbidity and mortality. We generated a next-generation sequencing (NGS)-based method designed to detect a wide range of fungi and applied it to analysis of the fungal microbiome (mycobiome) of the lung during fungal infection. Internal transcribed spacer 1 (ITS1) amplicon sequencing and a custom analysis pipeline detected 96% of species from three mock communities comprised of potential fungal lung pathogens with good recapitulation of the expected species distributions (Pearson correlation coefficients r = 0.63, p = 0.004; r = 0.71, p < 0.001; r = 0.62, p = 0.002). We used this pipeline to analyze mycobiomes of bronchoalveolar lavage (BAL) specimens classified as culture-negative (n = 50) or culture-positive (n = 39) for Blastomyces dermatitidis/gilchristii, the causative agent of North America blastomycosis. Detected in 91.4% of the culture-positive samples, Blastomyces dominated (>50% relative abundance) the mycobiome in 68.6% of these culture-positive samples but was absent in culture-negative samples. To overcome any bias in relative abundance due to between-sample variation in fungal biomass, an abundance-weighting calculation was used to normalize the data by accounting for sample-specific PCR cycle number and PCR product concentration data utilized during sample preparation. After normalization, there was a statistically significant greater overall abundance of ITS1 amplicon in the Blastomyces-culture-positive samples versus culture-negative samples. Moreover, the normalization revealed a greater biomass of yeast and environmental fungi in several Blastomyces-culture-positive samples than in the culture-negative samples. Successful detection of Coccidioides, Scedosporium, Phaeoacremonium, and Aspergillus in 6 additional culture-positive BALs by ITS1 amplicon sequencing demonstrates the ability of this method to detect a broad range of fungi from clinical specimens, suggesting that it may be a potentially useful adjunct to traditional fungal microbiological testing for the diagnosis of respiratory mycoses.

As the number of lung transplants performed worldwide each year continues to grow, the success of this procedure is threatened by the incidence of non-CMV infections such as invasive aspergillosis. Despite tremendous efforts and the availability of numerous diagnostic tests (especially in hematological malignancies) the diagnosis of invasive aspergillosis continues to be a challenge. Lung transplantation remains a unique clinical scenario, where additional host defenses are immunocompromized, making many of the available tests unsuitable. In this review we will navigate through the myriad of diagnostic tests currently available and how they apply to this unique patient population, as well as have a look into what the future holds.

The substantial disruption caused by the COVID-19 epidemic to the world's education system is only one of the many setbacks the world has recently experienced. The transition of the students from their offline learning mode to a fully digital approach was not easy from the beginning for them. The online teaching readiness heavily relied on their competencies and skills to adapt the pedagogy, training, technical skills, a proper mindset and new roles. This research endeavors to evaluate the readiness of the teachers belonging to higher education institutions (HEIs) to handle online education based on the online teaching readiness model. A systematic questionnaire with 30 statements was used by the researcher to collect and analyse data from 296 HEI lecturers in Saudi Arabia. Smart PLS3 was used to attain reliability, convergent, discriminate validity and model fitness. These programs will help equip the teachers with the necessary technical skills, pedagogy, competency and readiness to comprehend the requisite techniques of online teaching and the vital strategies for keeping their students engaged. Technical proficiency, pedagogy, competency and teaching readiness show a direct relationship with online education. On the other hand, attitude and training do not show any relationship with online education.

Unconventional myosins, linked to deafness, are also proposed to play a role in retinal cell physiology. However, their direct role in photoreceptor function remains unclear. We demonstrate that systemic loss of the unconventional myosin MYO1C in mice, specifically causes rhodopsin mislocalization, leading to impaired visual function. Electroretinogram analysis of Myo1c knockout (Myo1c-KO) mice showed a progressive loss of photoreceptor function. Immunohistochemistry and binding assays demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and identified a direct interaction of rhodopsin with MYO1C. In Myo1c-KO retinas, rhodopsin mislocalized to rod inner segments (IS) and cell bodies, while cone opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural examination of the phenotype of Myo1c-KO retinas showed progressively shorter photoreceptor OS. These results demonstrate that MYO1C is important for rhodopsin localization to the photoreceptor OS, and for normal visual function.

Long-term survival after lung transplantation is lower than that associated with other transplanted organs. Infectious complications, most importantly invasive fungal infections, have detrimental effects and are a major cause of morbidity and mortality in this population. Candida infections predominate in the early post-transplant period, whereas invasive mold infections, usually those related to Aspergillus, are most common later on. This review summarizes the epidemiology and risk factors for invasive fungal diseases in lung transplant recipients, as well as the current evidence on preventive measures. These measures include universal prophylaxis, targeted prophylaxis, and preemptive treatment. Although there is consensus that a preventive strategy should be implemented, current data show no superiority of one preventive measure over another. Data are also lacking regarding the optimal antifungal regimen and the duration of treatment. As all current recommendations are based on observational, single-center, single-arm studies, it is necessary that this longstanding debate is settled with a multicenter randomized controlled trial.

A 40-year-old male with a long-standing history of type 1 diabetes with end-stage renal failure underwent combined kidney-pancreas (KP) transplant from a standard criteria donor. Post-operative course was uncomplicated with good primary function of both transplant grafts. Induction was with thymoglobulin and maintenance immunosuppression was with tacrolimus, mycophenolate mofetil and prednisolone. Nine weeks post-transplant, the patient developed dysfunction of both grafts. Panel reactive antibody testing revealed that the patient had developed a de novo donor-specific antibody and considering an antibody-mediated rejection the patient was treated with intravenous pulse methyl prednisone 500 mg ×3 doses, IV immunoglobulin 2 mg/kg in two divided doses, and ATG 7 mg/kg (total dose of 700 mg). In addition, his baseline immunosuppression was increased. Cr decreased to baseline levels, and blood sugars were in the range of 7-8 mmol/L, serum amylase normalized to 63 U/L, and the patient was discharged home. Nine days post-discharge, the patient presented to the hospital with a five-day history of fever, pain, and swelling in the left knee along with subcutaneous, erythematous, tender, nodular lesions in both legs and both arms. Skin biopsy showed Ziehl-Neelsen stain positive rods and biopsy culture and blood culture grew Mycobacteria chelonae. Antimicrobials were switched to azithromycin 500 mg OD, moxifloxacin 400 mg OD, and linezolid 600 mg BID and baseline immunosuppression was reduced to tacrolimus trough target 8-10 ng/mL and MMF to 250 mg BID. The patient gradually improved and was discharged after 28 days in the hospital. Six weeks following the diagnosis of nontuberculous mycobacteria infection, the patient′s pancreas graft failed, presumably due to reduction in immuno-suppression and he is now back on insulin treatment. His renal graft continued to function well. Although rapidly growing mycobacterial infections are rare among transplant recipients, it should be suspected among those who have received augmented immunosuppression. Blood cultures and skin biopsy of the lesions are important to establish the diagnosis.

Background: Undergoing solid organ transplantation (SOT) exposes the recipient to various infectious risks, including possible transmission of pathogen by the transplanted organ, post-surgical infections, reactivation of latent pathogens, or novel infections. Recent advances: In the last few years, the emergence of Zika virus has raised concerns in the transplant community. Few cases have been described in SOT patients, and these were associated mainly with moderate disease and favorable outcome; the notable exception is a recent case of fatal meningo-encephalopathy in a heart transplant recipient. Because of the advances in treating hepatitis C, several teams recently started to use organs from hepatitis C-positive donors. The worldwide increasing incidence of multidrug-resistant pathogens, as well as the increasing incidence of Clostridioides difficile infection, is of particular concern in SOT patients. In the field of mycology, the main recent therapeutic advance is the availability of isavuconazole for the treatment of invasive aspergillosis and mucormycosis. This drug has the advantage of minimal interaction with calcineurin inhibitors. Regarding the viral reactivations occurring after transplant, cytomegalovirus (CMV) infection is still a significant issue in SOT patients. The management of resistant CMV remains particularly difficult. The approval of letermovir, albeit in bone marrow transplantation, and the therapeutic trial of maribavir bring a ray of hope. Another advancement in management of post-transplant infections is the development of in vitro tests evaluating pathogen-specific immune response, such as immunodiagnostics for CMV and, more recently, tests for monitoring immunity against BK virus. Conclusion: The increasing number of organ transplantations, the use of newer immunosuppressive drugs, and high-risk donors continue to define the landscape of transplant infectious diseases in the current era.

BACKGROUND: Invasive fungal infections are associated with morbidity and mortality in neutropenia secondary to hematological malignancies. Empirical antifungal agents are used to reduce their consequences. Caspofungin is the only echinocandin approved for this indication. Micafungin was compared with caspofungin for the treatment of patients with hematological malignancies and prolonged neutropenia.

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.

Invasive mold infections (IMI) are among the most devastating complications following chemotherapy and hematopoietic stem cell transplantation (HSCT), with high mortality rates. Yet, the molecular basis for human susceptibility to invasive aspergillosis (IA) and mucormycosis remain poorly understood. Herein, we aimed to characterize the immune profile of individuals with hematological malignancies (n = 18) who developed IMI during the course of chemotherapy or HSCT, and compared it to that of hematological patients who had no evidence of invasive fungal infection (n = 16). First, we measured the expression of the pattern recognition receptors pentraxin 3, dectin-1, and Toll-like receptors (TLR) 2 and 4 in peripheral blood of chemotherapy and HSCT recipients with IMI. Compared to hematological controls, individuals with IA and mucormycosis had defective expression of dectin-1; in addition, patients with mucormycosis had decreased TLR2 and increased TLR4 expression. Since fungal recognition via dectin-1 favors T helper 17 responses and the latter are highly dependent on activation of the signal transducer and activator of transcription (STAT) 3, we next used phospho-flow cytometry to measure the phosphorylation of the transcription factors STAT1 and STAT3 in response to interferon-gamma (IFN-γ) and interleukin (IL)-6, respectively. While IFN-γ/STAT1 signaling was similar between groups, naïve T cells from patients with IA, but not those with mucormycosis, exhibited reduced responsiveness to IL-6 as measured by STAT3 phosphorylation. Furthermore, IL-6 increased Aspergillus-induced IL-17 production in culture supernatants from healthy and hematological controls but not in patients with IA. Altogether, these observations suggest an important role for dectin-1 and the IL-6/STAT3 pathway in protective immunity against Aspergillus.

We have recently demonstrated the characterization of human tyrosinase TCR bearing h3T-A2 transgenic mouse model, which exhibits spontaneous autoimmune vitiligo and retinal dysfunction. The purpose of current study was to determine the role of T cells and IFN-γ in retina dysfunction and retinal ganglion cell (RGC) death using this model. RGC function was measured by pattern electroretinograms (ERGs) in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde-labeling. Expression of CD3, IFN-γ, GFAP, and caspases was measured by immunohistochemistry and Western blotting. All functional and structural changes were measured in 12-month-old h3T-A2 mice and compared with age-matched HLA-A2 wild-type mice. Both pattern-ERGs (42%, p = 0.03) and RGC numbers (37%, p = 0.0001) were reduced in h3T-A2 mice when compared with wild-type mice. The level of CD3 expression was increased in h3T-A2 mice (h3T-A2: 174 ± 27% vs. HLA-A2: 100%; p = 0.04). The levels of effector cytokine IFN-γ were also increased significantly in h3T-A2 mice (h3T-A2: 189 ± 11% vs. HLA-A2: 100%; p = 0.023). Both CD3 and IFN-γ immunostaining were increased in nerve fiber (NF) and RGC layers of h3T-A2 mice. In addition, we have seen a robust increase in GFAP staining in h3T-A2 mice (mainly localized to NF layer), which was substantially reduced in IFN-γ ((-/-)) knockout h3T-A2 mice. We also have seen an up-regulation of caspase-3 and -9 in h3T-A2 mice. Based on our data we conclude that h3T-A2 transgenic mice exhibit visual defects that are mostly associated with the inner retinal layers and RGC function. This novel h3T-A2 transgenic mouse model provides opportunity to understand RGC pathology and test neuroprotective strategies to rescue RGCs.

To determine the roles of nitric oxide in glaucomatous injury and its regulation by δ-opioid-receptor activation, animals were treated with: 1) a selective inducible nitric oxide synthase (iNOS) inhibitor (aminoguanidine; AG; 25 mg/kg, i.p.); 2) δ-opioid-receptor agonist (SNC-121; 1 mg/kg, i.p.); or 3) with both drugs simultaneously for 7 days, once daily. The loss in retinal ganglion cell (RGC) numbers and their function in glaucomatous eyes were significantly improved in the presence of AG or SNC-121; however, we did not see any significant additive or synergistic effects when animals were treated with both drugs simultaneously. The levels of nitrate-nitrite were significantly increased in the glaucomatous retina when compared with normal retina (normal retina 86±9 vs. glaucomatous retina 174±10 mM/mg protein), which was reduced significantly when animals were treated either with SNC-121 (121±7 mM/mg protein; P

Unique clinical characteristics and other variables influencing the outcome of Cryptococcus neoformans infection in organ transplant recipients have not been well defined. From a review of published reports, we found that C. neoformans infection was documented in 2.8% of organ transplant recipients (overall death rate 42%). The type of primary immunosuppressive agent used in transplantation influenced the predominant clinical manifestation of cryptococcosis. Patients receiving tacrolimus were significantly less likely to have central nervous system involvement (78% versus 11%, p =0.001) and more likely to have skin, soft-tissue, and osteoarticular involvement (66% versus 21%, p = 0.006) than patients receiving nontacrolimus-based immunosuppression. Renal failure at admission was the only independently significant predictor of death in these patients (odds ratio 16.4, 95% CI 1.9 - 143, p = 0.004). Hypotheses based on these data may elucidate the pathogenesis and may ultimately guide the management of C. neoformans infection in organ transplant recipients.

BACKGROUND: Immunocompromised individuals are more susceptible to complications produced by influenza infection. As a result, solid-organ transplant (SOT) recipients were targeted as a priority group to receive AS03-adjuvanted H1N1 influenza vaccine during 2009.