J Clin Transl Endocrinol. 2021 Dec 5;27:100289. doi: 10.1016/j.jcte.2021.100289. eCollection 2022 Mar.

ABSTRACT

As cystic fibrosis transmembrane regulator (CFTR) modulator therapies offer greater longevity and improved health quality, women living with cystic fibrosis (CF) are increasingly pursuing pregnancy. Maternal risks for pregnant women with CF largely depend on a woman's baseline pulmonary and pancreatic function, and the majority of CF pregnancies will successfully end in live births. Diabetes, either gestational or pre-existing cystic fibrosis-related diabetes (CFRD), is highly prevalent in women with CF, affecting 18 to 62% of pregnancies in recent CF center reports. In addition to the rising incidence of CFRD with age, gestational diabetes is also more common in women with CF due to lower insulin secretion, higher insulin resistance, and increased hepatic glucose production as compared to pregnant women without CF. Diabetes occurring during pregnancy has important implications for maternal and fetal health. It is well established in women without CF that glycemic control is directly associated with risks of fetal malformation, neonatal-perinatal mortality, cesarean delivery and need for neonatal intensive care. Small studies in women with CF suggest that pregnancies affected by diabetes have an increased risk of preterm delivery, lower gestational age, and lower fetal birth weight compared to those without diabetes. Women with CF preparing for pregnancy should be counseled on the risks of diabetes and should undergo routine screening for CFRD with oral glucose tolerance testing (OGTT) if not already completed in the past six months. Glycemic control in those with pre-gestational CFRD should be optimized prior to conception. Insulin is preferred for the management of diabetes in pregnant women with CF via multiple daily injections or insulin pump therapy, and continuous glucose monitors (CGM) can be useful in mitigating hypoglycemia risks. Women with CF face many unique challenges impacting diabetes care during pregnancy and would benefit from support by a multidisciplinary care team, including nutrition and endocrinology, to ensure healthy pregnancies.

PMID:34984172 | PMC:PMC8693285 | DOI:10.1016/j.jcte.2021.100289

J Clin Transl Endocrinol. 2021 Dec 6;27:100281. doi: 10.1016/j.jcte.2021.100281. eCollection 2022 Mar.

ABSTRACT

With increasing life expectancy in people with Cystic fibrosis (CF), the focus of clinical care has shifted to management and prevention of non-pulmonary comorbidities. CF related bone disease, defined by low bone mineral density (BMD), is prevalent across all age groups and acknowledges the increased fractures rates that negatively impact lung function and quality of life. Dual energy X-ray absorptiometry (DXA) measurement of bone mineral content (BMC) and "areal" BMD (aBMD) is recommended for identifying and monitoring bone health in children and adults due to its low cost, low radiation exposure, and widespread availability. Recent studies in children and adolescents with chronic illness focus on adjustment of BMC and aBMD measurements for height due to the effects of short stature and delayed maturation on bone size. Expanded reference databases for alternate imaging sites such as the ultradistal radius and hip present opportunities for research and long-term monitoring. As the two-dimensional nature of DXA imposes limitations, we highlight other imaging modalities including peripheral quantitative computed tomography QCT (pQCT), magnetic resonance imaging, and quantitative ultrasound (QUS). These tools, while primarily used in a research setting, can impart information on true volumetric bone density and bone microarchitecture as well as contribute to fracture assessment and prediction. Due to the high morbidity and mortality associated with vertebral and hip fracture, we will present on vertebral fracture assessment (VFA) in both children and adults as well as applied analyses including hip structural analysis (HSA), trabecular bone score (TBS), and fracture risk assessment (FRAX) for high risk groups. Questions remain on the future clinical applicability and accessibility of these assessment and prediction tools, longitudinal monitoring through adolescence and adulthood, and how outcome measures may guide bone modifying therapies.

PMID:34984171 | PMC:PMC8693345 | DOI:10.1016/j.jcte.2021.100281

Crit Care Med. 2022 Jan 5. doi: 10.1097/CCM.0000000000005427. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock.

DESIGN: Multicenter, double-blinded, randomized controlled trial.

SETTING: One academic medical ICU and four community ICUs.

PATIENTS: Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis.

INTERVENTIONS: IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline.

MEASUREMENTS AND MAIN RESULTS: Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569.

CONCLUSIONS: Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.

PMID:34982738 | DOI:10.1097/CCM.0000000000005427

Am J Respir Crit Care Med. 2022 Jan 4. doi: 10.1164/rccm.202109-2064TR. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) manifests with a variety of clinical presentations, reflecting its complex pathology. Currently, care focuses on symptom amelioration and prevention of complications, thus is generally tailored to disease severity rather than targeting specific pathophysiologic mechanisms. Chronic inflammation and mucus hypersecretion are key features of COPD. Epithelial ion channel dysfunction may be important as it results in airway dehydration and defective host defense, contributing to chronic airway inflammation. Recent evidence suggests considerable similarities between COPD and cystic fibrosis (CF), a disease in which chloride ion channel dysfunction has been extensively studied (in particular, CF transmembrane conductance regulator [CFTR]). Understanding commonalities between CF and COPD, and the role of CFTR in CF, may help in designing strategies targeting ion channel dysfunction, and lead to new treatments with potential to alter the natural history of disease progression. Here, we review the roles of airway mucus and CFTR in normal lung function, the previously underestimated contribution of mucus stasis to the development of COPD, and the evidence for targeting CFTR to counteract mucus accumulation.

PMID:34982651 | DOI:10.1164/rccm.202109-2064TR

Prenat Diagn. 2022 Jan 4. doi: 10.1002/pd.6083. Online ahead of print.

ABSTRACT

OBJECTIVE: To conduct a review of the literature on foetal volvulus with emphasis on prenatal imaging, pregnancy characteristics and clinical outcomes.

METHODS: A review of all published cases of foetal volvulus diagnosed prenatally and indexed in Medline, EBSCOhost, CINAHL, SOCIndex and Healthy Policy Reference Centre. Studies without antenatal sonographic signs of foetal volvulus and without a postpartum surgical diagnosis were excluded. Data were analysed for frequencies and distributions and tested for statistical significance.

RESULTS: Eighty-eight cases of foetal volvulus were identified from 58 published case reports/series. The most common ultrasound findings were dilated bowel/stomach (77.3%), polyhydramnios (30.7%) and whirlpool/snail sign (28.4%). Median gestation at diagnosis was 31.9 weeks (IQR 27-34) and mean gestation at delivery was 34.5 weeks (SD 2.8). Underlying aetiology included intestinal malrotation (15.9%), cystic fibrosis (14.8% of all cases, 32.5% of tested cases) and abnormal mesenteric fixation (12.5%). Complications included intestinal atresia (36.4%) and foetal anaemia (9.1%). The overall perinatal mortality rate was 14.5%.

CONCLUSION: Foetal volvulus is a rare condition with high rates of preterm birth and perinatal mortality. Intestinal malrotation and cystic fibrosis are common predisposing causes, although the majority are idiopathic. Bowel and/or gastric dilatation is by far the most common sonographic finding.

PMID:34981841 | DOI:10.1002/pd.6083

Anal Chem. 2022 Jan 3. doi: 10.1021/acs.analchem.1c02501. Online ahead of print.

ABSTRACT

The current methods for diagnosis of acute and chronic infections are complex and skill-intensive. For complex clinical biofilm infections, it can take days from collecting and processing a patient's sample to achieving a result. These aspects place a significant burden on healthcare providers, delay treatment, and can lead to adverse patient outcomes. We report the development and application of a novel multi-excitation Raman spectroscopy-based methodology for the label-free and non-invasive detection of microbial pathogens that can be used with unprocessed clinical samples directly and provide rapid data to inform diagnosis by a medical professional. The method relies on the differential excitation of non-resonant and resonant molecular components in bacterial cells to enhance the molecular finger-printing capability to obtain strain-level distinction in bacterial species. Here, we use this strategy to detect and characterize the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus as typical infectious agents associated with cystic fibrosis. Planktonic specimens were analyzed both in isolation and in artificial sputum media. The resonance Raman components, excited at different wavelengths, were characterized as carotenoids and porphyrins. By combining the more informative multi-excitation Raman spectra with multivariate analysis (support vector machine) the accuracy was found to be 99.75% for both species (across all strains), including 100% accuracy for drug-sensitive and drug-resistant S. aureus. The results demonstrate that our methodology based on multi-excitation Raman spectroscopy can underpin the development of a powerful platform for the rapid and reagentless detection of clinical pathogens to support diagnosis by a medical expert, in this case relevant to cystic fibrosis. Such a platform could provide translatable diagnostic solutions in a variety of disease areas and also be utilized for the rapid detection of anti-microbial resistance.

PMID:34978813 | DOI:10.1021/acs.analchem.1c02501

J Bacteriol. 2022 Jan 3:JB0044421. doi: 10.1128/JB.00444-21. Online ahead of print.

ABSTRACT

The evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA, encoding a regulator of biofilm formation, or lasR, encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF. These findings demonstrate that nutrient conditions and biofilm selection are sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing. Importance Pseudomonas aeruginosa produces dangerous chronic infections that are known for their rapid diversification and recalcitrance to treatment. We performed evolution experiments to identify adaptations selected by two specific aspects of the CF respiratory environment: nutrient levels and surface attachment. Propagation of P. aeruginosa in nutrients present within the CF airway was sufficient to drive diversification into subpopulations with identical mutations in regulators of biofilm and quorum sensing to those arising during infection. Thus, the adaptation of opportunistic pathogens to nutrients found in the host may select mutants with phenotypes that complicate treatment and clearance of infection.

PMID:34978461 | DOI:10.1128/JB.00444-21

J Vis Exp. 2021 Dec 17;(178). doi: 10.3791/63064.

ABSTRACT

Individualized therapy for cystic fibrosis (CF) patients can be achieved with an in vitro disease model to understand baseline Cystic Fibrosis Transmembrane conductance Regulator (CFTR) activity and restoration from small molecule compounds. Our group recently focused on establishing a well-differentiated organoid model directly derived from primary human nasal epithelial cells (HNE). Histology of sectioned organoids, whole-mount immunofluorescent staining, and imaging (using confocal microscopy, immunofluorescent microscopy, and bright field) are essential to characterize organoids and confirm epithelial differentiation in preparation for functional assays. Furthermore, HNE organoids produce lumens of varying sizes that correlate with CFTR activity, distinguishing between CF and non-CF organoids. In this manuscript, the methodology for culturing HNE organoids are described in detail, focusing on the assessment of differentiation using the imaging modalities, including the measurement of baseline lumen area (a method of CFTR activity measurement in organoids that any laboratory with a microscope can employ) as well as the developed automated approach to a functional assay (which requires more specialized equipment).

PMID:34978285 | DOI:10.3791/63064

Allergy. 2022 Jan 2. doi: 10.1111/all.15203. Online ahead of print.

ABSTRACT

Allergic asthma (AA) is a common asthma phenotype and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens, and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (e.g. long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1≥70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this Position Paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.

PMID:34978085 | DOI:10.1111/all.15203

Mol Ther Methods Clin Dev. 2021 Nov 24;24:11-19. doi: 10.1016/j.omtm.2021.11.008. eCollection 2022 Mar 10.

ABSTRACT

Cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the present work, we derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying disease-causing CFTR mutations. We evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner. Using this assay, we examined the effects of the sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and sotagliflozin on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts. Unexpectedly, both drugs promoted dF/dF HLO swelling. These results reveal SGLTs, especially SGLT1, as potential therapeutic targets for treating CF lung diseases and demonstrate the use of PSC-derived HLOs as a preclinical tool in CF drug development.

PMID:34977268 | PMC:PMC8666609 | DOI:10.1016/j.omtm.2021.11.008

Transl Pediatr. 2021 Nov;10(11):3104-3109. doi: 10.21037/tp-21-274.

ABSTRACT

The prevalence of cystic fibrosis (CF) is considerably lower in Asian populations compared with that of Caucasians. Cases of CF are typically due to mutations in the CF transmembrane conductance regulator gene with autosomal recessive inheritance. Here, we report two cases of newly diagnosed CF in Korea-a 13-year-old boy and his 5-year-old brother. The older brother was admitted to our hospital for evaluation and treatment of recurrent abdominal pain, frequent diarrhea, and failure to thrive. Fecal calprotectin (FC) was elevated, and when combining this with his clinical presentation, inflammatory bowel disease (IBD) or eosinophilic gastroenteritis (EoGE) was the first impression of his disease. Several ulcerative lesions were observed on ileocolonoscopy. However, incidental findings of suspicious bronchiectatic lesions were observed on plain radiography, which were confirmed by chest computed tomography. Moreover, diffuse bowel wall thickening with pancreatic atrophy was also incidentally detected by computed tomography of the abdomen. Comprehensively, these findings were highly suggestive of CF. Therefore, diagnostic exome sequencing was conducted, which revealed compound heterozygous variants of c.263T>G (p.Leu88*) and c.2977G>T (p.Asp993Tyr) in the CF transmembrane conductance regulator gene. Although symptoms in the younger brother were not as prominent as the older brother, genetic test was also conducted, which revealed the same mutation. We report the identification of a novel variant, p.Asp993Tyr, in siblings with Korean heritage. Although CF is rare in Koreans, it should be included in the differential diagnosis of IBD.

PMID:34976777 | PMC:PMC8649608 | DOI:10.21037/tp-21-274

Transl Pediatr. 2021 Nov;10(11):2952-2959. doi: 10.21037/tp-21-68.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multi-organ genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein. CF-associated liver disease (CFLD) is a common complication; diagnosis is based on clinical, laboratory findings and abdominal imaging. However, non-invasive diagnostic approaches are needed to early detect CFLD, its progression and severity. Recent studies demonstrate a possible role of point shear wave elastography (p-SWE) with liver stiffness measurement (LSM) as a tool for CFLD diagnosis also in children. This non-invasive technique measures liver stiffness to assess liver fibrosis and is suggested to be less operator-dependent compared to ultrasonography. Aim of our prospective observational study is to investigate the role of p-SWE with LSM for CFLD diagnosis in children and adolescents with CF and to compare this finding with aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on four factors (FIB-4) and gamma-glutamyl-transpeptidase to platelet ratio (GPR) indices.

METHODS: Fifty-nine children with CF, who had routinely undergone abdominal imaging, were consecutively enrolled. Laboratory findings and clinical data were recorded, as abdominal ultrasound and shear wave elastography at baseline. The cases were divided into two groups based on collected data and classified as CFLD and CFnoLD (without liver disease) according to Debray criteria. APRI, FIB-4 and GPR fibrosis indices were also evaluated.

RESULTS: Twenty-four/59 (40.7%) were defined as CFLD. LSM test is superior to the APRI (P<0.001), the FIB-4 test (P=0.001) and the GPR test for early detection of liver fibrosis. LSM had an area under receiver operating characteristic (ROC) curve =0.818 (95% CI: 0.702-0.934) compared with APRI (0.571, 95% CI: 0.421-0.722), FIB-4 (0.656, 95% CI: 0.511-0.801) and GPR (0.632, 95% CI: 0.485-0.779). At a cut-off of ≥6.2 LSM show a sensitivity of 75.0% and a specificity of 88.6%.

CONCLUSIONS: LSM by transient p-SWE is a non-invasive, highly accessible, reliable, and reproducible test that can be used to assess early detection of liver fibrosis and its severity in children and adolescents with CF, limiting the use of liver biopsy. These preliminary observations point to the need of larger study population to confirm our data.

PMID:34976761 | PMC:PMC8649592 | DOI:10.21037/tp-21-68

J Clin Transl Endocrinol. 2021 Dec 11;27:100292. doi: 10.1016/j.jcte.2021.100292. eCollection 2022 Mar.

ABSTRACT

The association of estrogen supplementation use and quality of life in women with cystic fibrosis (CF) is not well characterized. In this cross-sectional study, women with CF completed quality of life questionnaires during a routine CF clinic visit. The use of estrogen supplementation was associated with higher quality of life scores in all domains of the CF questionnaire-revised (CFQ-R) and was significant in the role limitations and respiratory domains. Most participants who were not currently using estrogen supplementation had previously used estrogen supplementation. Most participants had used estrogen to regulate menses, prevent pregnancy and control symptoms around menses. Use of estrogen supplementation was not associated with differences in life-space mobility or screening for sexual dysfunction. This is the largest study to date investigating the association of estrogen supplementation and quality of life in women with CF. Prospective randomized studies are needed to clarify the association of estrogen supplementation and quality of life in women with CF.

PMID:34976742 | PMC:PMC8688700 | DOI:10.1016/j.jcte.2021.100292

J Clin Transl Endocrinol. 2021 Dec 10;27:100287. doi: 10.1016/j.jcte.2021.100287. eCollection 2022 Mar.

ABSTRACT

Cystic fibrosis related diabetes (CFRD) generally reflects insufficient and/or delayed production of insulin, developing slowly over years to decades. Multiple mechanisms have been implicated in the pathogenesis of CFRD. CFTR function itself is a strong determinant of CFRD risk. Variants in CFTR that result in residual CFTR function and exocrine pancreatic sufficiency reduce the risk of CFRD by ten to twenty fold. Two groups of hypotheses have been proposed for the mechanism of CFTR impairing insulin secretion in CFRD: (1) β-cell dysfunction results from β cell intrinsic CFTR-dependent mechanisms of insulin secretion. (2) β-cell dysfunction results from factors outside the β cell. Genome-wide association studies have identified multiple susceptibility genes for type 2 diabetes, including TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2, as containing genetic modifiers of CFRD. These findings support the presence of intrinsic β cell defects playing a role in CFRD pathogenesis. Oxidative stress and inflammation are β cell-extrinsic mechanisms involved with CFRD. CFTR mutations render β cells more susceptible to oxidative stress and also leads to defects in α-cell function, resulting in reduced suppression of glucagon secretion. Furthermore, CFRD is characterized by β cell loss secondary to intra-islet inflammation. Recent studies have demonstrated the presence of multiple inflammatory mediators within the human CF islet. This review presents a concise overview of the current understanding of genetic modifiers of CFRD, oxidative stress, islet inflammation, and the controversies about the role of CFTR in the islet.

PMID:34976741 | PMC:PMC8688704 | DOI:10.1016/j.jcte.2021.100287

Tanaffos. 2021 Feb;20(2):86-98.

ABSTRACT

BACKGROUND: In cystic fibrosis patients, the mucus is an excellent place for opportunistic bacteria and pathogens to cover. Chronic infections of upper and lower airways play a critical role in the mortality of cystic fibrosis. This study aimed to introduce the microbiota profiles in patients with cystic fibrosis.

MATERIALS AND METHODS: In this study, a comprehensive literature search was done for studies on upper and lower airway microbiota in cystic fibrosis patients. International and national databases were searched for the following MeSH words: microbiota, microbiome, upper airway, lower airway, cystic fibrosis, cystic fibrosis, upper airway microbiome, lower airway microbiome, microbiome pattern in cystic fibrosis, microbiome pattern in cystic fibrosis, upper airway microbiota, lower airway microbiota, and microbiota pattern.

RESULTS: Streptococcus spp. are in significantly higher relative abundance in infants and children with cystic fibrosis; however, Pseudomonas spp. are in higher relative abundance in adults with cystic fibrosis. Molecular diagnostic techniques can be remarkably accurate in detecting microbial strains.

CONCLUSION: For the detection and isolation of most bacterial species, independent-culture methods in addition to the standard culture method are recommended, and sampling should include both upper and lower airways.

PMID:34976079 | PMC:PMC8710221

Front Microbiol. 2021 Dec 15;12:789774. doi: 10.3389/fmicb.2021.789774. eCollection 2021.

ABSTRACT

The COVID-19 pandemic has highlighted genetic vaccination as a powerful and cost-effective tool to counteract infectious diseases. Invasive fungal infections (IFI) remain a major challenge among immune compromised patients, particularly those undergoing allogeneic hematopoietic bone marrow transplantation (HSCT) or solid organ transplant (SOT) both presenting high morbidity and mortality rates. Candidiasis and Aspergillosis are the major fungal infections among these patients and the failure of current antifungal therapies call for new therapeutic aids. Vaccination represents a valid alternative, and proof of concept of the efficacy of this approach has been provided at clinical level. This review will analyze current understanding of antifungal immunology, with a particular focus on genetic vaccination as a suitable strategy to counteract these diseases.

PMID:34975811 | PMC:PMC8715041 | DOI:10.3389/fmicb.2021.789774

Front Cell Neurosci. 2021 Dec 16;15:770472. doi: 10.3389/fncel.2021.770472. eCollection 2021.

ABSTRACT

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer's disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.

PMID:34975408 | PMC:PMC8716782 | DOI:10.3389/fncel.2021.770472

Gen Hosp Psychiatry. 2021 Dec 23:S0163-8343(21)00173-0. doi: 10.1016/j.genhosppsych.2021.12.010. Online ahead of print.

NO ABSTRACT

PMID:34974927 | DOI:10.1016/j.genhosppsych.2021.12.010

J Heart Lung Transplant. 2021 Dec 1:S1053-2498(21)02612-7. doi: 10.1016/j.healun.2021.11.015. Online ahead of print.

NO ABSTRACT

PMID:34973873 | DOI:10.1016/j.healun.2021.11.015

BMJ Case Rep. 2021 Dec 31;14(12):e245441. doi: 10.1136/bcr-2021-245441.

ABSTRACT

We present the first reported case of Candida parapsilosis pulmonary infection presenting as lung nodules. The patient is a 31-year-old man with cystic fibrosis (CF) colonised with multidrug-resistant Escherichia coli and increased frequency of pulmonary exacerbations in the preceding months. While on intravenous antibiotics for a pulmonary exacerbation, he developed bilateral pulmonary nodules. Bronchoalveolar lavage cultures grew C. parapsilosis He was initially treated with dual antifungal therapy, voriconazole and micafungin. Discontinuation of voriconazole due to transaminitis resulted in the development of new nodules, and isavuconazonium was added. Repeat imaging revealed no progression of disease. Micafungin was eventually discontinued. Monotherapy with isavuconazonium is planned for 1 year post lung transplant. In the CF population, C. parapsilosis may be an opportunistic pathogen. The case highlights that frequent CF exacerbations and antibiotic exposure increase the risk for opportunistic infections including Candida species and the implications for lung transplantation in this setting.

PMID:34972773 | DOI:10.1136/bcr-2021-245441