Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Efficacy of an oral lipid nanocrystal formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an orally administered lipid nanocrystal formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to Rhizopus arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. In R. arrhizus var. delemar-infected mice, 15 mg/kg of MAT2203 qd was as effective as 10 mg/kg of LAMB in prolonging median survival time vs placebo (13.5 and 16.5 days for MAT2203 and LAMB, respectively, vs 9 days for placebo) and enhancing overall survival vs placebo-treated mice (40% and 45% for MAT2203 and LAMB, respectively, vs 0% for placebo). A higher dose of 45 mg/kg of MAT2203 was not well tolerated by mice and showed no benefit over placebo. Similar results were obtained with mice infected with M. circinelloides. Furthermore, while both MAT2203 and LAMB treatment resulted in a significant reduction of ~1.0-2.0log and ~2.0-2.5log in Rhizopus delemar or M. circinelloides lung and brain burden vs placebo mice, respectively, LAMB significantly reduced tissue fungal burden in mice infected with R. delemar vs tissues of mice treated with MAT2203. These results support continued investigation and development of MAT2203 as a novel and oral formulation of amphotericin for the treatment of mucormycosis.

Spectrum of Nondiabetic Kidney Diseases in Patients with Type 2 Diabetes Mellitus Who Underwent Kidney Biopsy in Egypt.

INTRODUCTION: Diabetic kidney disease (DKD) affects 30-40% of patients with diabetes. The prevalence of nondiabetic kidney disease (NDKD) in patients with type 2 diabetes mellitus (T2D) in Egypt is unknown. This study aimed to assess the prevalence of NDKD in patients with T2D in Egypt. METHODS: In this cross-sectional study, we searched the data of patients with T2D who underwent a native kidney biopsy between January 2010 and December 2020 in a kidney pathology laboratory in Egypt. RESULTS: Of 12,006 patients who underwent kidney biopsy, 677 patients had T2D. NDKD was found in 285 patients (42.7%), DKD in 220 patients (33%), and mixed DKD and NDKD in 162 patients (24.3%). The total prevalence of NDKD was 67% in patients with T2D in our study group. Membranous nephropathy was the most common histopathological disease in patients with NDKD (20.6%) followed by acute tubular injury (ATI) (19.2%) and focal segmental glomerulosclerosis (15.2%). The presence of ATI in a kidney biopsy was associated with a significantly higher mean serum creatine level (p < 0.001). Minimal change disease was associated with a significantly higher proteinuria level (p < 0.001). In binary logistic regression analysis, combining NDKD and mixed groups, the duration of diabetes was a negative predictor of NDKD, with a longer duration decreasing the likelihood of NDKD. CONCLUSION: NDKD is prevalent among patients with T2D who underwent a kidney biopsy. Kidney biopsy remains the gold standard for diagnosing NDKD in patients with T2D.

The Combination Treatment of Fosmanogepix and Liposomal Amphotericin B Is Superior to Monotherapy in Treating Experimental Invasive Mold Infections.

Invasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in clinical development with demonstrated broad-spectrum activity in animal models of infections. We sought to evaluate the benefit of combination therapy of FMGX plus liposomal amphotericin B (L-AMB) in severe delayed-treatment models of murine IPA, IM, and IF. While FMGX was equally as effective as L-AMB in prolonging the survival of mice infected with IPA, IM, or IF, combination therapy was superior to monotherapy in all three models. These findings were validated by greater reductions in the tissue fungal burdens (determined by quantitative PCR) of target organs in all three models versus the burdens in infected vehicle-treated (placebo) or monotherapy-treated mice. In general, histopathological examination of target organs corroborated the findings for fungal tissue burdens among all treatment arms. Our results show that treatment with the combination of FMGX plus L-AMB demonstrated high survival rates and fungal burden reductions in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These encouraging results warrant further investigation of the FMGX-plus-L-AMB combination treatment for severely ill patients with IPA, IM, and IF.

Expression of microRNA-223 and microRNA-146b in serum and liver tissue of mice infected with Schistosoma mansoni.

MicroRNAs (miRNAs) play regulatory roles in several diseases. In schistosomiasis, the main pathological changes are caused by the granulomatous reaction induced by egg deposition. We aimed to study the changes in host miRNA-223 and miRNA-146b expression in relation to egg deposition and development of hepatic pathology in murine schistosomiasis mansoni. Blood and liver tissue samples were collected from non-infected mice (group I), S. mansoni-infected mice at the 4th, 8th, and 12th weeks post-infection (p.i.) (groups II-IV), and 4 weeks after praziquantel treatment (group V). The collected samples were processed for RNA extraction, reverse transcription, and real-time PCR analysis of miRNA-223 and miRNA-146b. miRNAs' relative expression was estimated by the ΔΔCt method. Liver tissue samples were examined for egg count estimation and histopathological evaluation. Results revealed that miRNA-223 was significantly downregulated in liver tissues 8 and 12 weeks p.i., whereas miRNA-146b expression increased gradually with the progression of infection with a significantly higher level at week 12 p.i. compared to week 4 p.i. Serum expression levels nearly followed the same pattern as the tissue levels. The dysregulated expression of miRNAs correlated with liver egg counts and was more obvious with the demonstration of chronic granulomas, fibrous transformation, and distorted hepatic architecture 12 weeks p.i. Restoration of normal expression levels was observed 4 weeks after treatment. Collectively, these findings provide new insights for in-depth understanding of host-parasite interaction in schistosomiasis and pave a new way for monitoring the progress of hepatic pathology before and after treatment.

Detection of soluble urokinase type plasminogen activator receptors in children with gingivitis and normal subjects.

BACKGROUND: Gingivitis is a reversible condition; however, if left untreated, it progresses to periodontitis, which a serious infection that leads to bone destruction. Soluble urokinase-type plasminogen activator receptor (suPAR) measurement may be of value in the early assessment of gingivitis in children, thereby minimizing risk of tooth loss. OBJECTIVES: In this observational study, we assessed salivary and serum concentrations of suPAR for the diagnosis of gingivitis and correlation of salivary suPAR with the periodontal clinical parameters. METHODS: Ninety children participated in the study, with 20 healthy subjects as controls and 70 patients with gingivitis. The gingivitis group was divided into mild, moderate, and severe cases. According to the gingival index (GI), salivary and serum samples were analyzed for the suPAR and C-reactive protein levels using an enzyme-linked immunosorbent assay. RESULTS: The salivary suPAR was significantly higher in patients with gingivitis (10.8 ± 2.9 ng/mL) than in the control group (7.0 ± 1.1 ng/mL) as P < 0.001. SuPAR was correlated with gingivitis severity. It was 7.7 ± 1.5 1 ng/mL in mild cases, 10.9 ± 1.2 ng/mL in moderate cases, and 14.4 ± 0.9 ng/mL in severe cases. The difference was significantly high (P < 0.001) between the groups; however, the difference between the mild cases and the control was nonsignificant as P < 0.066. The salivary suPAR was correlated with periodontal clinical parameters, which included GI and simple oral hygiene index (SOHI). Conversely the serum suPAR was not correlated with the salivary suPAR or the periodontal clinical parameters. CONCLUSION: The results of the present study demonstrated that the salivary suPAR is increased in proportionate with the degree of severity of gingivitis in children. Moreover, salivary suPAR was correlated with the periodontal clinical parameters.

Preserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial Infection.

The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization's and National Institutes of Health's high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host's vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, and CPKP. We show that the pharmacological inhibition of ARF6-GTP phenocopies endothelium-specific Arf6 disruption in enhancing the survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small-molecule inhibitors acts by the restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of the TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host's vasculature with small-molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and reemerging pathogens.

The Hyr1 protein from the fungus Candida albicans is a cross kingdom immunotherapeutic target for Acinetobacter bacterial infection.

Different pathogens share similar medical settings and rely on similar virulence strategies to cause infections. We have previously applied 3-D computational modeling and bioinformatics to discover novel antigens that target more than one human pathogen. Active and passive immunization with the recombinant N-terminus of Candida albicans Hyr1 (rHyr1p-N) protect mice against lethal candidemia. Here we determine that Hyr1p shares homology with cell surface proteins of the multidrug resistant Gram negative bacterium, Acinetobacter baumannii including hemagglutinin (FhaB) and outer membrane protein A (OmpA). The A. baumannii OmpA binds to C. albicans Hyr1p, leading to a mixed species biofilm. Deletion of HYR1, or blocking of Hyr1p using polyclonal antibodies, significantly reduce A. baumannii binding to C. albicans hyphae. Furthermore, active vaccination with rHyr1p-N or passive immunization with polyclonal antibodies raised against specific peptide motifs of rHyr1p-N markedly improve survival of diabetic or neutropenic mice infected with A. baumannii bacteremia or pneumonia. Antibody raised against one particular peptide of the rHyr1p-N sequence (peptide 5) confers majority of the protection through blocking A. baumannii invasion of host cells and inducing death of the bacterium by a putative iron starvation mechanism. Anti-Hyr1 peptide 5 antibodies also mitigate A. baumannii /C. albicans mixed biofilm formation in vitro. Consistent with our bioinformatic analysis and structural modeling of Hyr1p, anti-Hyr1p peptide 5 antibodies bound to A. baumannii FhaB, OmpA, and an outer membrane siderophore binding protein. Our studies highlight the concept of cross-kingdom vaccine protection against high priority human pathogens such as A. baumannii and C. albicans that share similar ecological niches in immunocompromised patients.

Herpes zoster might be an indicator for latent COVID 19 infection.

Various cutaneous manifestations have been observed in patients with COVID-19 infection. Herpes zoster is a viral skin disease caused by varicella zoster that remains dormant in the dorsal root ganglia of cutaneous nerves following a primary chicken pox infection. In this report, we describe two cases COVID infection who first presented with herpes zoster. We are here by suggesting that the clinical presentation of HZ at the time of the current pandemic even in patients giving mild or no suggestive history of upper respiratory symptoms should be considered as an alarming sign for a recent subclinical SARS CoV2 infection.

Levonorgestrel vs combined oral contraceptive pills in treatment of female acne and hirsutism.

Combined oral contraception was used in many studies for treatment of acne and hirsutism. However, levonorgestrel (LNG) alone has not been evaluated before. Our objective is to evaluate the efficacy of oral contraceptive (OC) pills containing LNG and ethinyl estradiol (EE) compared with LNG only for the treatment of acne and hirsutism in a randomized, controlled prospective clinical trial. Eighty females (20 with acne, 20 with hirsutism, and 40 healthy females) received LNG + EE or LNG only for 6 months. Assessment of acne by global acne grading system (GAGS) and hirsutism by modified Ferriman-Gallwey scale (MFGS) grading system and serum free testosterone was measured before and 6 months after treatment. Serum free testosterone was significantly higher before treatment in acne and hirsutism patients compared to control group (P < .000). In acne patients, after 6 months of treatment with LNG/EE, serum free testosterone, and (GAGS), were significantly decreased compared to LNG only (P < .000). In hirsutism group, after 6 months of treatment with LNG/EE, serum free testosterone and (MFGS), were nonsignificantly decreased compared to LNG only. OCs containing either LNG/EE or LNG seem to be effective and safe treatment for acne and hirsutism.

Reliability, Validity, and Sensitivity to Change Overtime of the Modified Melasma Area and Severity Index Score.

BACKGROUND: The new modified Melasma Area and Severity Index (mMASI) score, the recently used outcome measure for melasma, has not been tested to determine its sensitivity to change in melasma. OBJECTIVE: To determine the reliability, validity, and sensitivity to change overtime of the mMASI score in assessment of the severity of melasma. METHODS: Pearson correlation, Cronbach alpha, and intraclass correlation coefficient were calculated to assess the reliability of the mMASI score. Validity of the mMASI scale was carried out using Spearman correlation between mMASI total score (before and after treatment), clinical data, and patient's responses. RESULTS: The mMASI score showed excellent reliability and good validity for assessment of the severity of melasma. The authors also determined that the mMASI score demonstrated sensitivity to change over time. CONCLUSION: An excellent degree of agreement between the mMSAI and MASI scores was revealed. The mMASI score is reliable, valid, and responsive to change in the assessment of severity of melasma. Moreover, the mMASI score was found to be easier to learn and perform and simpler in calculation compared with the MASI score. Overall, the mMASI score can effectively replace the MASI score.

Calli Essential Oils Synergize with Lawsone against Multidrug Resistant Pathogens.

The fast development of multi-drug resistant (MDR) organisms increasingly threatens global health and well-being. Plant natural products have been known for centuries as alternative medicines that can possess pharmacological characteristics, including antimicrobial activities. The antimicrobial activities of essential oil (Calli oil) extracted from the Calligonum comosum plant by hydro-steam distillation was tested either alone or when combined with lawsone, a henna plant naphthoquinone, against MDR microbes. Lawsone showed significant antimicrobial activities against MDR pathogens in the range of 200-300 µg/mL. Furthermore, Calli oil showed significant antimicrobial activities against MDR bacteria in the range of 180-200 µg/mL, Candida at 220-240 µg/mL and spore-forming Rhizopus fungus at 250 µg/mL. Calli oil's inhibition effect on Rhizopus, the major cause of the lethal infection mucormycosis, stands for 72 h, followed by an extended irreversible white sporulation effect. The combination of Calli oil with lawsone enhanced the antimicrobial activities of each individual alone by at least three-fold, while incorporation of both natural products in a liposome reduced their toxicity by four- to eight-fold, while maintaining the augmented efficacy of the combination treatment. We map the antimicrobial activity of Calli oil to its major component, a benzaldehyde derivative. The findings from this study demonstrate that formulations containing essential oils have the potential in the future to overcome antimicrobial resistance.

Q-switched Nd: YAG laser versus trichloroacetic acid peeling in the treatment of melasma among Egyptian patients.

BACKGROUND: Melasma is a common disorder of facial hyperpigmentation that is often resistant to treatment. OBJECTIVE: To evaluate the efficacy of trichloroacetic acid (TCA) peeling in comparison with double frequency Q-switched neodymium-doped:yttrium aluminum garnet (QS-Nd:YAG) laser in the treatment of melasma. PATIENTS AND METHODS: Sixty-five adult Egyptian female patients with melasma were enrolled in this study. Wood light was used for determination of the histological type of melasma. The patients were divided into 4 groups according to treatment modalities: peeling with different concentrations of TCA and double frequency QS-Nd:YAG laser. Trichloroacetic acid peeling was performed every 2 weeks up to 8 sessions, whereas laser treatment was performed every month up to 6 sessions. Melasma area and severity index (MASI) score was used before and after treatment for evaluation. RESULTS: Improvement percentage of MASI score was significantly higher among patients treated with TCA 25% (p < .001). Epidermal type of melasma was significantly improved compared with the dermal type (p = .0029). Q-switched neodymium-doped:yttrium aluminum garnet laser showed the highest incidence of postinflammatory hyperpigmentation (53.3%). CONCLUSION: Trichloroacetic acid peeling is effective in the treatment of melasma, TCA 25% was the most effective concentration. Q-switched neodymium-doped:yttrium aluminum garnet laser is not recommended in the treatment of melasma because it was associated with the highest incidence of complications.

Intralesional Candida albicans antigen versus intralesional zinc sulfate in treatment of cutaneous warts.

Immunotherapy represents a promising therapeutic option for treatment of warts. Different concentrations of Candida antigen (1/100 and 1/1000) and zinc sulfate 2% were not previously compared regarding their efficacy in treatment of cutaneous warts. The present study compared the safety and efficacy of intralesional candida antigen versus intralesional 2% zinc sulfate for treatment of cutaneous warts. This prospective controlled clinical trial included one hundred and five patients presented with common, plantar, and plane warts. Patients were divided randomly into three groups, each group included 35 patients. Group 1 were treated with intralesional candida antigen (Ag) 1/100, Group 2 were treated with intralesional candida Ag 1/1000, and Group 3 were treated with intralesional zinc sulfate 2%. This study found that target warts of group 1 displayed higher rate of complete clearance compared to group 2 and group 3 (94.3%, 77.1, 74.2%), respectively. The present study concluded that intralesional immunotherapy with Candida antigen was more effective than Intralesional 2% zinc sulfate in treatment of cutaneous warts and less painful. Clinical trial registration number is (Clinical Trials.gov Identifier: NCT03158168).

Protective Efficacy of Anti-Hyr1p Monoclonal Antibody against Systemic Candidiasis Due to Multi-Drug-Resistant Candida auris.

Candida auris is a multi-drug-resistant fungal pathogen that can survive outside the host and can easily spread and colonize the healthcare environment, medical devices, and human skin. C. auris causes serious life-threatening infections (up to 60% mortality) in immunosuppressed patients staying in such contaminated healthcare facilities. Some isolates of C. auris are resistant to virtually all clinically available antifungal drugs. Therefore, alternative therapeutic approaches are urgently needed. Using in silico protein modeling and analysis, we identified a highly immunogenic and surface-exposed epitope that is conserved between C. albicans hyphal-regulated protein (Cal-Hyr1p) and Hyr1p/Iff-like proteins in C. auris (Cau-HILp). We generated monoclonal antibodies (MAb) against this Cal-Hyr1p epitope, which recognized several clinical isolates of C. auris representing all four clades. An anti-Hyr1p MAb prevented biofilm formation and enhanced opsonophagocytic killing of C. auris by macrophages. When tested for in vivo efficacy, anti-Hyr1p MAb protected 55% of mice against lethal systemic C. auris infection and showed significantly less fungal burden. Our study is highly clinically relevant and provides an effective alternative therapeutic option to treat infections due to MDR C. auris.

Pigment epithelium-derived factor (PEDF) represses the glucose transporter 1 (GLUT1) mRNA expression and may be a potential therapeutic agent in psoriasis: a case-control and experimental study.

We investigated the whole blood GLUT1 mRNA expression and serum pigment epithelium-derived factor (PEDF), interleukin-6 (IL-6), fetuin-A, and pentraxin-3 (PTX3) levels in psoriatic patients and tested their correlations with the severity of psoriasis using the psoriasis area and severity index (PASI) score. Also, we tested the GLUT1 mRNA expression after an in vitro treatment of human skin fibroblast (HSF) cell lines with PEDF. The case-control part of the study recruited 74 participants (44 psoriatic patients and 30 healthy volunteers). Whole blood GLUT1 mRNA fold changes were estimated by RT-PCR, and serum PEDF, IL-6, fetuin-A, and PTX3 levels were measured by ELISA kits. In the experimental part, the HSF cell lines were treated with different concentrations of PEDF for different times to test its effect on the GLUT1 mRNA expression. The whole blood GLUT 1 expression significantly increased in psoriatic patients and correlated positively with serum IL-6, fetuin-A, PTX3 levels and with the severity of psoriasis while negatively with serum PEDF levels. The PEDF-treated HSF cell lines showed a time- and dose-dependent decline in the GLUT 1 mRNA expression. The whole blood GLUT 1 mRNA is a non-invasive biomarker that is associated with the severity of psoriasis. PEDF represses GLUT 1 expression and may be a potential therapeutic agent in psoriasis.Trial registration: ClinicalTrials.gov Identifier: NCT04242082.

Comparison of T Lymphocyte Subsets and Natural Killer Lymphocytes in Moderate Versus Severe COVID-19 Patients.

Severe respiratory involvement that follows a process of immune dysregulation and intense cytokine production remains to be the most dreaded complication of Coronavirus Disease-2019 (COVID-19) infection. The aim of this study was to analyze T lymphocyte subsets and natural killer (NK) lymphocytes in moderate and severe cases of COVID-19 infection and assess their significance in disease severity and prognosis. Twenty moderate cases and 20 severe cases of COVID-19 were studied and compared regarding blood picture, biochemical markers, T lymphocyte population subsets, and NK lymphocytes, which were determined by flow cytometric analysis. On analyzing the flow cytometric data of T lymphocyte cells and their subsets and NK cells in two groups of COVID-19 infection (one group moderate and the other severe cases), some immature NK lymphocyte relative and absolute counts were higher in the severe patients with worse outcome and death, while some mature NK lymphocyte relative and absolute counts were depressed in both groups. Also, interleukin (IL)-6 was significantly higher in severe cases when compared to moderate cases, and there was a positive significant correlation between immature NK lymphocyte relative and absolute counts and IL-6. There was no statistically significant difference between T lymphocyte subsets (T helper and T cytotoxic) with disease severity or outcome. Some immature NK lymphocyte subsets contribute to the widespread inflammatory response that complicates severe cases of COVID-19; therapeutic approaches directed to enhancing NK maturation or drugs that block NK cell inhibitory receptors have a potential role in controlling COVID-19 induced cytokine storm.

Genetic Variations of ferroportin-1(FPN1-8CG), TMPRSS6 (rs855791) and Hemojuvelin (I222N and G320V) Among a Cohort of Egyptian ß-Thalassemia Major Patients.

Iron overload remains a major cause of morbidity and mortality among ß-thalassemia major (ß-TM) patients. Iron regulatory proteins and their genetic variants together with changes in hepcidin levels in thalassemic patients could affect the disease manifestations. This work aimed to study genetic variations of ferroportin-1 (FPN1-8CG), Transmembrane Serine Protease 6 (TMPRSS6 rs855791) and hemojuvelin (HJV I222N and G320V) genes within a cohort of 97 ß-TM Egyptian patients by Polymerase chain reaction Restriction Fragment Length Polymorphism (PCR-RFLP) in comparison to fifty normal control subjects. Among ß-TM patients; the CG variant of FPN1 was significantly higher, while the TT and TC variants of TMPRSS6 were significantly lower in comparison to controls. Liver Iron Concentration (LIC) was significantly higher among ß-TM patients harboring the FPN1 (GG) genotype and we found that FPN1gene mutation acts as independent predictor of MRI LIC (p = 0.011), Pulmonary artery pressure (PAP) was significantly higher in patients harboring the mutant FPN1 (GG and CG) genotypes (p value 0.04). ß-TM patients having the HJV I222N (AA) genotype were having significantly higher cardiac iron overload (p value = 0.026). The studied genetic variants of iron regulatory proteins could alter the manifestations of iron overload thus resulting in different clinical phenotypes of thalassemic patients, these findings need to be confirmed by larger cohorts of patients with longer follow-up periods. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01580-8.

Efficacy of an oral lipid nanocrystal (LNC) formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity and commonly afflicts patients with weakened immune systems. MAT2203 is an orally administered lipid nanocrystal (LNC) formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to R. arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. Treatment with placebo (diluent control), oral MAT2203 administered as BID and QD or intravenous LAMB for 4 days, began 16 h post infection and continued for 7 and 4 days, respectively. Survival through Day +21 and tissue fungal burden of lung or brain in animals euthanized on Day +4 served as a primary and secondary endpoint, respectively. In both infection types, MAT2203 was as effective as LAMB in prolonging median survival time (MST) and enhancing overall survival vs. placebo-treated mice ( P <0.05 by Log-Rank). Furthermore, both MAT2203 and LAMB treatment resulted in significant ∼1.0-1.5-log reduction and ∼2.0-2.2-log in R. delemar or M. circinelloides lung and brain burden, vs. placebo mice, respectively. These results support the potential efficacy of oral MAT2203 as an alternative to LAMB. Continued investigation and development of this novel oral formulation of the amphotericin B for the treatment of mucormycosis is warranted.

Relation between Soluble CD14 Levels, Inflammation, Subclinical Atherosclerosis and Mortality in Hemodialysis Patients.

BACKGROUND AND AIM: Chronic kidney disease (CKD) is characterized by persistent lowgrade inflammation. Soluble CD14 (sCD14) is involved in many pathological conditions, including inflammation and atherosclerosis. The present study aimed to assess the relationship between sCD14 levels, subclinical atherosclerosis (SCA), inflammation and mortality in Egyptian hemodialysis (HD) patients. PATIENTS AND METHODS: The present longitudinal study included 62 HD patients. All patients were submitted to careful history taking, thorough clinical examination and laboratory assessment for high-sensitivity C-reactive protein (hsCRP) and sCD14. Carotid intima-media thickness (CIMT) was also assessed. Patients were followed for a maximum of 18 months. The primary outcome is patients' mortality. Data were statistically analyzed using standard descriptive, comparative, correlative and regression methods. RESULTS: The present study was conducted on 62 HD patients. They comprised 34 males and 28 females with an age of 54.6 ± 9.0 years. At the end of follow-up, 12 patients (19.4 %) died. It was shown that survivors had significantly lower hsCRP levels (104.2 ± 38.2 versus 134.1 ± 15.3 mg/dL, p < 0.001), lower sCD14 levels (32.7 ± 10.3 versus 47.4 ± 18.4 µg/mL, p = 0.02) and lower CIMT (1.32 ± 0.5 versus 1.5 ± 0.2 mm, p = 0.049). sCD14 levels were significantly correlated with hsCRP (r = 0.4, p = 0.001) and CIMT (r = 0.31, p = 0.013). Multivariate analysis identified HD duration [HR (95% CI): 1.02 (1.0-1.04), p = 0.021] and sCD14 levels [HR (95% CI): 1.06 (1.0-1.12), p = 0.026] as significant predictors of patients' survival. CONCLUSIONS: sCD14 levels in this cohort of HD patients are well-correlated with hsCRP levels and CIMT. In addition, they are significant predictors of patients' mortality.