Recurrent Infections Research Articles

Molecular mechanism and application of emerging technologies in study of bacterial persisters.

Since the discovery of antibiotics, they have served as a potent weapon against bacterial infections; however, natural evolution has allowed bacteria to adapt and develop coping mechanisms, ultimately leading to the concerning escalation of multidrug resistance. Bacterial persisters are a subpopulation that can survive briefly under high concentrations of antibiotic treatment and resume growth after lethal stress. Importantly, bacterial persisters are thought to be a significant cause of ineffective antibiotic therapy and recurrent infections in clinical practice and are thought to contribute to the development of antibiotic resistance. Therefore, it is essential to elucidate the molecular mechanisms of persister formation and to develop precise medical strategies to combat persistent infections. However, there are many difficulties in studying persisters due to their small proportion in the microbiota and their non-heritable nature. In this review, we discuss the similarities and differences of antibiotic resistance, tolerance, persistence, and viable but non-culturable cells, summarize the molecular mechanisms that affect the formation of persisters, and outline the emerging technologies in the study of persisters.

Survival of a Patient Following Initial LVAD Implantation and Two Successive LVAD Exchanges: case report

Abstract Background Initially conceptualized as a bridge to heart transplantation, the Left Ventricular Assist Device (LVAD) has become an important option for improving survival in patients with severe heart failure and poor prognosis. Case summary We report the case of a patient suffering from severe chronic heart failure, complicated by ST-elevation myocardial infarction (STEMI) due to left main coronary artery (LMCA) stenosis (NYHA IV, INTERMACS profile 1). Despite support with veno-arterial extracorporeal membrane oxygenation (VA-ECMO), inotropes and catecholamine therapy, the patient´s cardiac function did not recover sufficiently. Consequently, the decision was made to proceed with LVAD implantation as destination therapy. The initial LVAD implantation was uneventful, and the patient received anticoagulant therapy according to standard operating procedure (SOP). However pump thrombosis occurred on the first postoperative day, necessitating an LVAD exchange. Following an extended stay in the cardiac surgery intensive care unit (ICU), the patient was eventually discharged. Approximately 15 months later, the patient developed a driveline infection, involving most of the intrapericardial components of the LVAD. A second LVAD exchange was required and the patient received a third LVAD. To mitigate the risk of recurrent infection, suppressive antibiotic therapy with ampicillin/sulbactam was initiated. Discussion This is the first reported case of a patient surviving three LVAD implantations and highlights an instance of off-label use of lifelong antibiotic therapy following a driveline infection.

A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.

Genetic variants in Folliculin interacting protein 1 (FNIP1) were recently discovered as monogenic causes for immunodeficiency and cardiomyopathy, with only a few patients diagnosed thus far. In this study, we describe a patient harboring a novel genetic variant in FNIP1 causing immunodeficiency with cardiac involvement. Clinical and immunological workups were performed. Genetic evaluation utilizing whole-exome sequencing (WES) and Sanger sequencing was conducted. The index patient (subject II-4) presented with hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes. Genetic evaluation identified a homozygous 13-bp duplication variant in FNIP1 (c.52_64dupGCGCCCGGCCGCG, p. Asp22GlyfsTer21) resulting in a frameshift in exon 1/18. She was treated with supplemental intravenous immunoglobulins (IVIg) with good control of sinopulmonary and gastrointestinal manifestations. Her sibling (subject II-1) had similar clinical features, along with dysmorphic facial features and hypotony, and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation. Diagnosis of novel immunodeficiencies promotes our understanding of the immune system, enabling genetic counseling as herein, and may assist in the development of novel medical therapies in the future. FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia).

True Median Cleft With Sinus Tract in the Nasal Septum: A Case Report.

A true median cleft is an extremely rare congenital anomaly characterized by a midline vertical cleft and various deformities, also known as Tessier number 0 cleft. Here we report a case of a 5-year-old Asian boy with true median cleft associated with sinus tracts in the nasal septum, a phenomenon not previously reported in the literature. The tracts were identified as the cause of recurrent infections around the oral vestibule and upper lip. The tracts were resected successfully, and postoperative progress has been satisfactory. We discuss the importance of preoperative image evaluations and the selection of a suitable surgical approach.

Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19

Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis.

BN SO54 - Complex Management of a Gastrocutaneous Fistula Following Pancreatic Necrosectomy: A Case Report

Abstract Background Gastrocutaneous fistulas are rare but serious complications that can arise following the surgical treatment of necrotizing pancreatitis. This post-operatory complication can be refractory to conservative management and may be further aggravated by severe skin injuries and malnutrition. This case report describes the comprehensive and multidisciplinary approach of a challenging case of gastrocutaneous fistula, ultimately requiring re-intervention. Method A 78-year-old female with a history of severe necrotizing pancreatitis underwent pancreatic necrosectomy by laparotomy. Postoperatively, she developed a gastric fistula, initially repaired with a double-layered suture. Recurrence led to a gastrocutaneous fistula with continuous gastric drainage and chemical burn of the surrounding skin. Initial conservative management included insertion of a nasogastric tube for gastric decompression, followed by placement of a PEG tube to redirect the drainage and prevent further skin damage and an esophagojejunal feeding tube to bypass the fistula and maintain nutrition. Nevertheless, the fistula persisted, resulting in significant skin erosion and deterioration of the patient’s condition. Results Given the failure of conservative measures and a concurrent diagnosis of a pancreatic fistula, a surgical approach was deemed necessary. The patient was transferred to a specialized hospital center, where she underwent fistulectomy with partial gastrectomy and wound closure. Negative pressure wound therapy (NPWT) was applied to the ulcerated skin to promote healing. This approach led to the successful closure of the gastrocutaneous fistula and healing of the skin wound. The patient showed marked clinical recovery, with no signs of infection or fistula recurrence and the nutritional status was successfully managed through enteral feeding leading to a notable functional recovery. Conclusion This case underlines the complexity of managing gastrocutaneous fistulas, demonstrating the efficacy of combining surgical and supportive therapies, serving as a reference for similar future cases and emphasizing the need for comprehensive management strategies for complex postoperative complications.

Antibiotic efficacy and resistance patterns of urinary tract infection-causing bacteria in dogs and resistome of multidrug-resistant Klebsiella pneumoniae via whole genome sequencing in South Korea

Bacterial urinary tract infections (UTIs) are prevalent in dogs and necessitate antibiotic intervention. However, the emergence of multidrug-resistant (MDR) bacteria poses significant challenges to antibiotic therapy. Although fosfomycin has been demonstrated to achieve and maintain high concentrations in urine, suggesting its potential for treating UTIs in dogs, its efficacy and the resistance profiles of urinary pathogens from canine UTIs remain elusive. Therefore, this study was conducted to investigate the antibiotic susceptibility of bacterial pathogens isolated from companion dogs with UTIs, with a particular focus on their susceptibility and resistance to fosfomycin. A total of 70 isolates from urine samples were analyzed, of which Escherichia coli (n = 18), Proteus mirabilis (n = 9), Klebsiella pneumoniae (n = 5), and Staphylococcus pseudintermedius (n = 5) were predominant. Resistance to erythromycin was most prevalent (94.59%), followed by clindamycin (91.89%) and ampicillin (78.37%), whereas the lowest resistance rate was observed for amikacin (5.40%). Resistance to fosfomycin was observed in 15 out of the 37 predominant isolates (40.54%), including all K. pneumoniae isolates (100%). All isolates, except 4 E. coli strains, were categorized as MDR (33 out of 37; 89.18%). The resistance rates for amoxicillin/clavulanic acid and trimethoprim-sulfamethoxazole, which are common first-line antibiotics for canine UTIs, were 48.64 and 56.75%, respectively. Whole-genome sequencing of K. pneumoniae isolates, which exhibited high resistance to fosfomycin, revealed multiple antibiotic resistance genes, with chromosomal fosA present in all isolates. Among the 27 dogs with recurrent infection included in this study, 2 were administered fosfomycin, resulting in clinical remission, as evidenced by negative urine culture tests. Overall, this study is the first to demonstrate the importance of assessing fosfomycin resistance profile for optimal treatment of canine UTIs, particularly in cases involving MDR strains.

Intracellular ATP concentration is a key regulator of bacterial cell fate.

ATP, most widely known as the primary energy source for numerous cellular processes, also exhibits the characteristics of a biological hydrotrope. The viable but nonculturable (VBNC) and persister states are two prevalent dormant phenotypes employed by bacteria to survive challenging environments, both of which are associated with low metabolic activity. Here, we investigate the intracellular ATP concentration of individual VBNC and persister cells using a sensitive ATP biosensor QUEEN-7μ and reveal that both types of cells possess a lower intracellular ATP concentration than culturable and sensitive cells, although there is a certain overlap in the intracellular ATP concentrations between antibiotic-sensitive cells and persisters. Moreover, we successfully separated VBNC cells from culturable cells using fluorescence-activated cell sorting based on the intracellular ATP concentration threshold of 12.5 µM. Using an enriched VBNC cell population, we confirm that the precipitation of proteins involved in key biological processes promotes VBNC cell formation. Notably, using green light-illuminated proteorhodopsin (PR), we demonstrate that VBNC cells can be effectively resuscitated by elevating their intracellular ATP concentration. These findings highlight the crucial role of intracellular ATP concentration in the regulation of bacterial cell fate and provide new insights into the formation of VBNC and persister cells.IMPORTANCEThe viable but nonculturable (VBNC) and persister states are two dormant phenotypes employed by bacteria to counter stressful conditions and play a crucial role in chronic and recurrent bacterial infections. However, the lack of precise detection methods poses significant threats to public health. Our study reveals lower intracellular ATP concentrations in these states and establishes an ATP threshold for distinguishing VBNC from culturable cells. Remarkably, we revive VBNC cells by elevating their intracellular ATP levels. This echoes recent eukaryotic studies where modulating metabolism impacts outcomes like osteoarthritis treatment and lifespan extension in Caenorhabditis elegans. Our findings underscore the crucial role of intracellular ATP levels in governing bacterial fate, emphasizing ATP manipulation as a potential strategy to steer bacterial behavior.

Inflammatory Bowel Disease in Activated PI3Kδ Syndrome: An Uncommon Complication of a Rare Condition

Background/Objectives: Monogenic primary immunodeficiencies represent a group of disorders with varying levels of severity, many of which remain poorly understood. Activated phosphoinositide-3 kinase delta syndrome (APDS) is a rare genetic condition resulting from dominant point mutations in the phosphoinositide-3 kinase delta (PI3Kδ) gene, which leads to hyperactivation of the PI3Kδ enzyme, primarily expressed in T and B lymphocytes. Children with this mutation often have recurrent sinopulmonary infections and immunodeficiency. Additional complications may include increased susceptibility to herpes virus infections, lymphoid hyperplasia, and autoimmune conditions. In this case, report, we describe the clinical course of a young boy diagnosed with APDS who developed unclassified inflammatory bowel disease (U-IBD) and explore a personalized treatment approach. Methods: We detail the clinical course of a 12-year-old boy with APDS who presented with fever, diarrhea, anemia, and significant weight loss. Diagnostic evaluations, including endoscopy and histological analysis, led to a diagnosis of U-IBD. Genetic testing confirmed a heterozygous PIK3CD mutation (c.G3061A, p.E1021K). Results: Although APDS is characterized by a broad spectrum of immune dysregulation, the occurrence of IBD in this context is rare. We managed the patient’s IBD with exclusively enteral nutrition to induce remission, followed by a maintenance regimen combining the Crohn’s Disease Exclusion Diet (CDED) and mesalamine, achieving sustained long-term clinical remission. Conclusions: This case underscores the importance of personalized treatment approaches in managing the complex manifestations of APDS.

Transfibular Total Ankle Arthroplasty: Clinical, Functional, and Radiographic Outcomes and Complications at a Minimum of 5-Year Follow-up.

The Trabecular Metal Total Ankle Implant differs from other newer-generation implants in the transfibular approach, multiplanar external frame for alignment, tantalum trabecular metal interfaces, curved geometry, and shallow resection depths. The primary aim of this study was to report midterm clinical and radiographic results, as well as survivorship and adverse events at a minimum of 5-year follow-up. A total of 83 ankles (81 patients, average age 60.6 years old, 50.6% females) with average 6.3 years' (range, 5.0-10.1) follow-up were included. Postoperative patient-reported outcome measures (PROMs) included SF-12 physical (PCS) and mental component summary (MCS) scores, Ankle Osteoarthritis Scale (AOS), pain visual analog scale (VAS). Radiographic outcomes included postoperative range of motion (ROM) and coronal/sagittal alignment. Adverse events were reported using the Canadian Orthopaedic Foot and Ankle Society Reoperation Coding System (CROCS). Preoperative tibiotalar coronal deformity included 27 valgus (10 degrees, range 2-20 degrees) and 25 varus ankles (-9 degrees, range -2 to -25 degrees), corrected to neutral postoperatively. Postoperative tibiopedal ROM was 17.8 degrees dorsiflexion and 21.8 degrees plantarflexion. Adverse events occurred at average 28.7 months, most commonly gutter debridement (n = 17, 16.7%) and subsequent operative treatment unrelated to metal components (n = 10, 12.0%). There were 2 cases (2.4%) of acute deep infection treated with irrigation and debridement, polyethylene exchange, and retention of metal components without recurrence of infection. There were no cases of fibular nonunion, septic or aseptic loosening, or implant subsidence. Postoperative PROMS included SF-12 PCS: 40.4; SF-12 MCS: 56.0; VAS: 2.3; AOS Pain: 17.0; and AOS Disability: 24.9. Overall implant survival, defined by retention of the metal components, was 100% at final follow-up. At a minimum of 5 years, patients who underwent TM TAA reported minimal ankle pain and regained neutral ankle alignment and mobility, without septic or aseptic implant loosening. Although having certain limitations, this study suggests that TM TAA is a viable option for the treatment of end-stage ankle arthritis.

CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome

BackgroundWHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood.MethodsIn the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies.ResultsCxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation.ConclusionsOur study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

Implementing a Digital Platform for Recurrent Urinary Tract Infections.

A patient-centered care model is needed for recurrent urinary tract infection (UTI) management. The aim of this study was to develop a conceptual model for a digital platform to implement evidence-based guidelines for recurrent UTI management. This was a qualitative, 3-stage mixed methods study that included (1) developing an evidence-based prototype texting platform; (2) qualitative feedback from recurrent UTI patients using the platform; and (3) quantitative data on acceptability (proportion of patients engaging with the platform), accuracy (proportion of patient messages interpreted accurately by the platform), and usability (score 0-100). Thirty-one women with recurrent UTI (median age, 71 years; range, 60-74 years) participated in testing over 4 months. The prototype platform was modified through iterative rounds of qualitative and quantitative analysis until engagement ≥85%, accuracy ≥90%, and usability score of ≥80 were achieved in 10 patients. Qualitative feedback indicated that patients valued rapid access to treatment through fewest possible health encounters during an acute episode, evidence-based education about prevention, and ability to participate in self-management with support from health care providers. Based on this feedback, a conceptual model consisting of 3 main components was developed: (1) an algorithm to triage acute symptoms, (2) educational videos emphasizing prevention strategies, and (3) supportive messages. Patient feedback identified 4 key implementation outcomes-usability, acceptability (engagement), fidelity (accuracy), and cost-and 3 clinical outcomes-self-efficacy, health care utilization, and rate of unnecessary antibiotics for testing the model. The proposed model can be used to implement and test a patient-centered evidence-based digital platform for the management of recurrent UTI.

Dent’s disease: case series from a single center

Background. Dent’s disease (DD) is a rare X-linked recessive tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis and chronic kidney disease. With this manuscript, we reported three patients diagnosed as DD in our department in the last 10 years and thereby described the genetics, pathophysiology, clinical presentation, course and management of the disease. Cases. The first case was a male newborn who was consulted to our department after medullary nephrocalcinosis was detected. The second case was a 4-year-old boy who was treated with a diagnosis of urinary tract infection but was found to have proteinuria. Our last case was an 11-month-old male infant who was being followed up for recurrent urinary tract infection and who had millimetric crystalloids in the renal collecting system. Proteinuria and hypercalciuria were present in all cases. Variants were observed in the CLCN5 gene for the first two cases (c.1852G>A and c.1557+1G>T, respectively) and OCRL gene (c.952C>T) for the last case. All patients were recommended oral hydration and a low-salt diet, and hydrochlorothiazide and enalapril were started. No deterioration in kidney function was observed in any patient. Conclusion. DD is a disease that shows different phenotypes even among individuals with mutations in the same gene. Therefore, it should be considered in all patients with hypercalciuria, proteinuria, nephrolithiasis or nephrocalcinosis with/without proximal tubular dysfunction especially in the early childhood period. Classical treatments for hypercalciuria should be utilized, and a patient-based treatment plan should be drawn especially for proteinuria.

Microbial profile of diabetic foot osteomyelitis from the northwest of England

BackgroundOsteomyelitis of the diabetic foot is a common and challenging complication affecting patients with diabetic foot ulcers and infections. The complexity of these infections lies in their polymicrobial nature, high rates of persistence and recurrence. This study examined the microbiological profile of diabetic foot osteomyelitis from a teaching hospital in Northwest England and their resistance patterns to understand its impact on infection persistence and to direct effective treatment.MethodsA retrospective review of 105 patients who underwent surgical management for diabetic foot osteomyelitis between 2019 and 2024. We analysed three consecutive culture samples for each patient to assess for the microbiological profile and resistance patterns of these infections and to monitor infection recurrence and persistence rates.ResultsA total of 105 patients were identified. Infection eradication was noted in 42% of the cohort, infection persistence in 18%, and late infection recurrence in 40%. Polymicrobial growth was evident in 72% of our study sample. Gram-positive bacteria made up the majority of the bacterial isolates in all 3 culture samples, 74.81% in sample 1, 69.31% in sample 2, and 55.1% in sample 3. Staphylococcus aureus was the most prevalent gram-positive bacteria, at 52.38% in sample 1, 36.19% in sample 2, and 18.09% in sample 3, followed by Haemolytic Streptococcus, Enterococcus and Corynebacterium. The frequently identified gram-negative bacteria were Pseudomonas in sample 1 (7.61%), E. coli and Proteus in sample 2 (5,71%), Pseudomonas and Proteus in sample 3 (2.85%). Gram-positive bacteria were resistant to penicillin and macrolides with resistance of staphylococcus aureus to clarithromycin identified among all 3 culture samples. Gram-negative bacteria were most resistant to amoxicillin. Staphylococcus aureus was responsible for infection persistence in most of our cohort (12/19) 63.15%. Among those patients, Staphylococcus was resistant to clarithromycin in 6 of the cases. The 5-year mortality rate for our study sample was 32.38%.ConclusionThis study highlights the prevalence of polymicrobial growth and multi-drug resistant pathogens in the scope of diabetic foot osteomyelitis. It highlights the predominance of Staphylococcus aureus and its resistant strains among patients affected by diabetic foot osteomyelitis in Greater Manchester.

Altered genomic methylation promotes Staphylococcus aureus persistence in hospital environment

Staphylococcus aureus can cause outbreaks and becomes multi-drug resistant through gene mutations and acquiring resistance genes. However, why S. aureus easily adapts to hospital environments, promoting resistance and recurrent infections, remains unknown. Here we show that a specific S. aureus lineage evolved from a clone that expresses the accessory gene regulator (Agr) system to subclones that reversibly suppressed Agr and caused an outbreak in the hospital setting. S. aureus with flexible Agr regulation shows increased ability to acquire antibiotic-resistant plasmids, escape host immunity, and colonize mice. Bacteria with flexible Agr regulation shows altered cytosine genomic methylation, including the decreased 5mC methylation in transcriptional regulator genes (pcrA and rpsD), compared to strains with normal Agr expression patterns. In this work, we discover how altered genomic methylation promotes flexible Agr regulation which is associated with persistent pathogen colonization in the hospital environment.

Analysis of clinical characteristics and risk factors for recurrence of combined EB virus infection in patients with inflammatory bowel disease treated with biological agents

To investigate the degrees of EB virus reactivation in patients with inflammatory bowel disease (IBD) treated with different biologics and the levels of important cytokines associated with relapse under the influence of this virus, and to assess its diagnostic efficacy as a risk factor for identifying disease relapse. A case-control retrospective study based on patients' hospitalization history data was conducted to select a total of 105 patients who were hospitalized in the Department of Gastroenterology, Huashan Hospital, Fudan University, with a confirmed diagnosis of IBD from 2021 to 2023. Based on the quantitative copy level of whole blood EBV DNA to determine the status of EB virus infection in patients, integrated cytokine 8 (IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17, TNF-α, IFN-γ), C-reactive protein, and fecal calreticulin, to find the risk variable associated with treatment relapse. Logistic regression was used to analyze the relative risk between this variable and treatment relapse, and ROC curves were used to predict the diagnostic efficacy of cytokine multifactorial thresholds for treatment relapse. Results showed that the median age of the study was 37(26, 54)years, with a minimum of 18 years and a maximum of 70 years, with a median age of 34(24, 51) years for Crohn's Disease (CD) patients and 46(35, 60) years for Ulcerative colitis (UC) patients, with a statistically difference between the ages of the two groups (t=2.675, P=0.009). The median age at 50 years of patients treated with Vedolizumab (VDZ) in the UC group was higher than in the treatment groups other than VDZ. The highest rate of EB virusreactivation was found in the group treated with immunosuppressants Azathioprine (AZA) combined with anti-tumor necrosis factor-α (anti-TNF-α) and VDZ (62.5% in both groups), and the lowest in the group treated with Ustekinumab (UST) (0%). IL-2 levels were elevated in the AZA+anti-TNF-α and anti-TNF-α groups after EB virus entryreactivation. Three treatment groups, AZA+anti-TNF-α, anti-TNF-α, and VDZ, had elevated levels of IL-6 expression after EB virus entry reactivation.In the anti-TNF-α treatment-related group IL-2was associated with treatment relapse in IBD (OR=1.127, 95%CI: 1.044-1.256, P=0.007). ROC analysis showed that the AUC for IL-2 combined with EB virus in a replicative state was 0.8282 (P=0.006), with a negative predictive value and a positive value of 90% and 75%, respectively. As well as IL-6 was associated with treatment relapse of IBD in the anti-TNF-αtreatment-related group as well as in the VDZ-treated group (OR=1.049, 95%CI: 1.017-1.095, P=0.008). ROC analysis showed that the diagnostic sensitivity and specificity for post-treatment relapse at a critical value of 6.10 pg/ml for IL-6 was 83.33% and 82.93%, respectively. The AUC for IL-6 combined with EB virus in a replicative state was 0.900 (P<0.000 1), with negative and positive predictive value of 84.09% and 73.33%, respectively. In summary, the imbalance of proinflammatory and anti-inflammatory cytokines varies between drugs, with EBV in a replication-activated state, combined with elevated levels of IL-2 as well as IL-6 expression being a risk factor for relapse in patients treated with anti-TNF-α-related drugs and VDZ.

Natural Antimicrobial Monoterpenes as Potential Therapeutic Agents in Vaginal Infections: A Review

The recurrence and relapse of vaginal infections in women is a major issue and a challenging pathway to identify and develop new approaches to treatment. In the case of antibiotic therapy, contraceptives, and dietary changes, the recurrence of vaginitis is more common these days. Anaerobic bacteria, Candida spp., and trichomonas in the vaginal microflora cause both symptomatic and asymptomatic vaginitis, which includes vaginal inflammation. It changes the vaginal microbiota and decreases Lactobacilli spp. growth, which is maintaining the vaginal pH (3.5-4.5) through lactic acid production, antimicrobial peptides, bacteriocin, and bacteriocin-like inhibitory substances. The remarkable antimicrobial activity of plant’s producing metabolites like alkaloids, tannins, phenolic compounds, flavonoids and terpenoids for several vaginal infections have been reported in previous studies. Presented review focuses on the pivotal role of monoterpenes, providing a detailed description of thymol, geraniol, limonene, eugenol, eucalyptol, and α-terpineol as antimicrobial molecules in the treatment of vaginal infections. These monoterpenes are very good at killing E. coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus niger, Trichomonas vaginalis and Candida albicans which are the main microbes that cause vaginitis. Future research could explore the latent combinations of such monoterpenes as synergistic antimicrobial agents to treat bacterial and fungal vaginal infections, trichomoniasis, among other conditions.

Highly Effective Modulator Therapy: Implications for the Microbial Landscape in Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive multisystem disorder caused by mutations in the cystic fibrosis conductance regulator (CFTR) anion channel. In the lungs specifically, CFTR mutations lead to changes in mucus viscosity and defective mucociliary clearance. Moreover, people with CF (pwCF) mount an insufficient immune response to invading pathogens, which predisposes individuals to chronic airway disease associated with chronic inflammation, colonization, and recurrent infections by mainly opportunistic pathogens. These chronic infections in the CF lung are typically polymicrobial and frequently harbour multidrug-resistant pathogens, making both treatment and eradication very challenging. During the last decade, the development of highly effective CFTR modulator therapy (HEMT) has led to a breakthrough in treatment options for pwCF. While the majority of pwCF now live longer and have fewer CF exacerbations, colonisation with common respiratory pathogens persists, thereby contributing to chronic inflammation and infection. Interestingly, there are limited reports examining the lung microbiome in the post-modulator era. Since ETI treatment is still quite novel and has only been used for about five years by now, this review will be one of the first discussing the current literature on the effect of ETI on CF pathogens. In addition, we will identify unanswered questions that remain from the effect of HEMT on the CF microbiome.

The effectiveness of a synthetic analogue purine nucleoside bases in the treatment of acute respiratory viral infections

Introduction. The aggravation of the comorbid background of patients with ARVI is the main reason for the addition of secondary pathogenic and conditionally pathogenic bacterial flora and, as a result, the development of local and general complications.Аim. To conduct a clinical assessment of the efficacy and safety of the drug Triazavirin based on riamilovir in the treatment of acute respiratory viral infections.Materials and methods. The study conducted on the basis of the medical center of the Federal State Budgetary Educational Institution of the Russian Ministry of Health involved 56 patients with acute recurrent viral infection. Regarding the prescribed therapy, the patients were divided into 2 groups: group 1 (n = 27) from day 2, triazavirin was taken as an antiviral drug (riamilo- vir) 250 mg (1 capsule) 3 times a day for 5 days; group 2 (n = 29) – as an antiviral drug, Kagocel took 2 tablets 3 times a day for 2 days, then 1 tablet 3 times a day for 5 days. The effect of the therapy was assessed by the severity of intoxication syndrome, rhinorrhea, difficulty in nasal breathing, decreased olfactory function, pain syndrome localized in the nasopharynx and throat, cough severity and laboratory results.Results. In patients with 7 days of therapy, the indicator of psychological health increased by 34.7 points in the first group, by 28.8 points in the second group. Vital activity increased by 33.7 points in patients of group 1 and by 23.8 points in the second group. Physical activity tended to increase by 19.5 points and 6.0 points in the first and second groups, respectively.Conclusions. The analysis of changes in the severity of clinical symptoms affecting the quality of life of patients confirmed the effectiveness and safety of the drug Triazavirin.

The long lost denture: a rare case of an acquired, non-malignant tracheo-oesophageal fistula

BackgroundIngested dental prosthesis are susceptible to impaction in the gastrointestinal tract due to their sharp edges, size and contour. Delays in presentation arise from the lack of clear history of ingestion and misdiagnosis occurs due to the radiolucency of denture material on plain radiography. An acquired, non-malignant tracheo-oesophageal fistula (TOF) may develop from a chronically impacted denture. Surgical management of a TOF secondary to denture is a challenging clinical problem that is rarely reported in the literature and no previous case reports have described the two-staged reconstruction approach that we present here.Case presentationWe report a case of a male in his early 60s who presented to an acute general hospital with symptoms ongoing for over one year of dysphagia, recurrent chest infections and weight loss. Barium swallow and computed tomography identified an ingested dental prosthesis (denture) that had caused a TOF. He was transferred to our specialist thoracic surgery unit where an attempt to remove the foreign body endoscopically was abandoned due to firm impaction and risk of further injury. The subsequent multi-disciplinary management of this complex case required a two-staged reconstruction approach. The first procedure involved extracting the foreign body, repairing the underlying defects with tracheal resection and anastomosis, and creating an oesophageal diversion with cervical oesophagostomy. The second procedure achieved continuity of the gastrointestinal tract with gastric pull-up and pharyngo-gastric anastomosis. Following rehabilitation, the patient was discharged on oral intake alongside percutaneous jejunostomy feeding.ConclusionsEarly recognition and removal of impacted dental prosthesis is essential to prevent morbidity and mortality. Delayed diagnosis can lead to acquired TOF with associated consequences such as recurrent pulmonary infection, mediastinitis and nutritional deficit. Challenges we encountered, such as failed attempts at endoscopic retrieval and the difficult dissection of fibrotic tissue, were directly due to the delayed identification of the denture. We highlight the importance of holding a high index of clinical suspicion of foreign body ingestion in dental prosthesis wearers who present with recurrent chest infections and ongoing dysphagia. We also promote the need for a collaborative multi-disciplinary approach in the surgical management of complex cases.