Refractory Infection Research Articles

The journey towards safely restarting faecal microbiota transplantation services in the UK during the COVID-19 era

Faecal microbiota transplantation (FMT) is a potentially life-saving treatment for patients with refractory and recurrent Clostridioides difficile infection with cure rates of 90%.1 Substantial implications with regard to the safe provision of FMT were made evident with emerging reports of detectable SARS-CoV-2 virus in stool even before the declaration of the COVID-19 pandemic.2 Furthermore, data suggesting prolonged and potentially infectious faecal virus shedding in stool samples in asymptomatic carriers who tested negative on nasopharyngeal swabs meant FMT donor screening protocols could no longer rely on symptoms and a nasopharyngeal swab alone.

Molecular Epidemiology of Cytomegalovirus UL97 and UL54 variants in Taiwan.

The antiviral resistance of cytomegalovirus (CMV) infections is associated with mutations in the CMV UL54 and UL97 gene regions and is a serious problem in immunocompromised patients. However, the molecular epidemiology of UL54 and UL97 in Taiwan is unclear. We conducted a retrospective study of patients with CMV infections between January and December 2016 in two tertiary hospitals, one regional hospital in Taiwan. CMV DNAemia was confirmed by elevated CMV DNA titers. Then the regions of the UL54 and UL97 mutations were amplified by PCR and sequenced. Of 729 patients with CMV syndrome, 112 CMV DNAemia patients were enrolled. Twelve novel variants in UL54 (P342S, S384F, K434R, S673F, T754M, R778H, C814S, M827I, G878E, S880L, E888K, and S976N) and one novel variant in UL97 (M615T) were discovered. UL97 antiviral resistance mutations (L595S, M460I, and M460V) were found in four patients (3.6%). In the drug resistance strains, the mutation events occurred after 83-150 days of therapy, and drug resistance was also observed in these patients. The following high frequency variants were observed: D605E in UL97 and A885T, N898D, V355A, N685S, and A688V in UL54. The results demonstrate that the positive rate of CMV DNAemia was 15.3% (112/729) among the patients with clinical CMV infection symptoms. The proportion of antiviral resistance CMV strains within CMV DNAemia patients was 3.6%. With the information of polymorphism incidence in the UL54 and UL97 patients from our study, determination of the genetic profile of UL54 and UL97 among immunocompromised populations with refractory CMV infection is recommended.

409 - Safety and Efficacy of GMP Clinical Grade Manufacturing of Virus Specific Cytotoxic T Lymphocytes (vCTLS) Against Cytomegalovirus (CMV), Epstein Barr Virus ( EBV), Adenovirus (ADV) and BKV to Treat Medically Refractory Viral Infections Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in Children, Adolescents and Young Adults (CAYA) (IND# 17449)

409 - Safety and Efficacy of GMP Clinical Grade Manufacturing of Virus Specific Cytotoxic T Lymphocytes (vCTLS) Against Cytomegalovirus (CMV), Epstein Barr Virus ( EBV), Adenovirus (ADV) and BKV to Treat Medically Refractory Viral Infections Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in Children, Adolescents and Young Adults (CAYA) (IND# 17449)

Minimally invasive debridement and drainage using intraoperative CT-Guide in multilevel spondylodiscitis: a long\u2010term follow\u2010up study

BackgroundSpondylodiscitis is an unusual infectious disease, which usually originates as a pathogenic infection of intervertebral discs and then spreads to neighboring vertebral bodies. The objective of this study is to evaluate percutaneous debridement and drainage using intraoperative CT-Guide in multilevel spondylodiscitis.MethodsFrom January 2002 to May 2017, 23 patients with multilevel spondylodiscitis were treated with minimally invasive debridement and drainage procedures in our department. The clinical manifestations, evolution, and minimally invasive debridement and drainage treatment of this refractory vertebral infection were investigated.ResultsOf the enrolled patients, the operation time ranged from 30 minutes to 124 minutes every level with an average of 48 minutes. Intraoperative hemorrhage was minimal. The postoperative follow-up period ranged from 12 months to 6.5 years with an average of 3.7 years. There was no reactivation of infection in the treated vertebral segment during follow-up, but two patients with fungal spinal infection continued to progress by affecting adjacent segments prior to final resolution. According to the classification system of Macnab, one patient had a good outcome at the final follow-up, and the rest were excellent.ConclusionsMinimally invasive percutaneous debridement and irrigation using intraoperative CT-Guide is an effective minimally invasive method for the treatment of multilevel spondylodiscitis.

A novel treatment strategy using continuous local antibiotic perfusion: A case series study of a refractory infection caused by hypervirulent Klebsiella pneumoniae

BackgroundConventional topical antimicrobial therapy cannot maintain a constant local concentration, resulting in uncontrolled infection and complications. We propose continuous local antibiotic perfusion (CLAP), which can maintain a constant appropriate local antibiotic concentration for a long time with less invasiveness and complications. CLAP is clearly different from traditional treatment because it uses negative pressure to direct the continuously infused antibiotic solution to the center of infection and excrete it outside the body. This study aimed to demonstrate the effectiveness of CLAP by presenting cases in which even refractory bone and soft-tissue infections caused by the hypervirulent Klebsiella pneumoniae (hvKp) could be cured without significant tissue loss and dysfunction. MethodsThis study is a case series in which four patients with limb infection due to hvKp were treated by CLAP. hvKp was defined by a positive string test. The therapy included intra-soft-tissue antibiotic perfusion and intramedullary antibiotic perfusion. Gentamicin (60 mg/50 cc) was infused continuously through dual-lumen tubes and bone marrow needles at low-flow rates (2 mL/h). Negative pressure was used to collect the antimicrobial solution and eliminate the dead space. ResultsThe infection was controlled in all four patients after a mean period of 44.3 days. The mean maximum blood concentration of gentamicin was 1.6 μg/dL, and no cases of renal dysfunction or ototoxicity occurred. After CLAP, wound closure was required in two patients and iliac bone grafting was required in one patient. As sequelae, there were one case of osteoarthritis and one case of higher brain dysfunction due to hypoxia. ConclusionsOur results suggest that intractable hvKp infections can be controlled by CLAP. CLAP may give us the option to directly control local infections with less systemic complications. Therefore, it is considered a valuable treatment for further basic and clinical research, and this research report may be a first step.

Complex HeartWare left ventricular assist device infection treated with pump exchange: clinical alert for the driveline location.

Infection is a major complication in patients with a left ventricular assist device (LVAD). Once a driveline exit-site infection (DLI) reaches the LVAD component, LVAD exchange may become necessary for radical treatment, although clinical results are not satisfactory. In this report, we describe two cases of LVAD infection successfully treated with pump exchange. During LVAD support, the DLI extended into the pump pocket and the outflow graft despite aggressive surgical debridement and negative pressure wound therapy. These two patients required LVAD exchange for radical treatment, because the estimated waiting period for heart transplantation was at least more than 1year. The LVAD exchange was performed through median re-sternotomy, and the infected HeartWare ventricular assist device (HVAD) was completely removed under cardiopulmonary bypass. Then, a new LVAD covered with the omentum flap was implanted. These two patients were successfully bridged to heart transplantation after 10months and 2years of support without recurrence of infection. These two cases may suggest that the driveline of the HVAD needs to be kept away from the outflow graft to prevent refractory outflow graft infection.

Decreased Biofilm Formation Ability of a Multidrug-Resistant Pseudomonas aeruginosa Strain After Exposure to a Simulated Microgravity Environment

Background: The refractory infection induced by multidrug-resistant (MDR) Pseudomonas aeruginosa has become one of the most urgent problems in hospitals. The biofilms formed by P. aeruginosa increase its resistance to antibiotics. A simulated microgravity (SMG) environment provides a platform to understand the factors affecting biofilm formation in bacteria. Objectives: This study aimed to investigate the SMG effects on MDR P. aeruginosa biofilm formation and explore the relevant mechanisms. Methods: In this study, a clinostat was used to simulate a microgravity (MG) environment. The motility and biofilm formation ability of MDR P. aeruginosa were observed using the swimming test and the crystal violet staining method, respectively. The underlying mechanism of phenotypic changes was further investigated by comparative transcriptomic analysis. Results: Multidrug-resistant P. aeruginosa grown under the SMG condition exhibited decreased swimming motility and biofilm formation ability compared to those under the normal gravity (NG) condition. Further analysis revealed that the decreased swimming motility and biofilm formation ability could be attributed to the downregulated expression of genes responsible for flagellar synthesis (flhB, fliQ, and fliR) and type IV pili biogenesis (pilDEXY1Y2VW). Conclusions: This is the first study to perform experiments on MDR P. aeruginosa under the SMG condition. It will be beneficial to understand the mechanism of MDR P. aeruginosa biofilm formation and develop new treatment strategies for infectious diseases induced by MDR P. aeruginosa in the future.

Novel therapies for treatment of resistant and refractory nontuberculous mycobacterial infections in patients with cystic fibrosis.

Respiratory infections caused by non-tuberculous mycobacteria (NTM) are a major cause of morbidity for patients living with cystic fibrosis (CF), as NTM pulmonary disease (NTM-PD) is challenging to both diagnose and eradicate. Despite the lengthy courses of the established regimens recommended by the Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) consensus guidelines, only about 50% to 60% of patients achieve culture conversion, and treatment regimens are often complicated by antibiotic resistance and toxicities. Since publication of the CFF/ECFS guidelines, several new or alternative antibiotic regimens have been described for patients with CF who have NTM-PD. These regimens offer new options for patients who do not clear NTM with standard therapies or cannot utilize the usual regimens due to toxicities or drug-drug interactions.

Lateral retroperitoneal approach for surgical treatment of lumbar diskitis/osteomyelitis with post-infectious spinal deformity

Lumbar diskitis/osteomyelitis (LDO) can cause destruction of the anterior and middle spinal column leading to loss of structural integrity further compounded by iatrogenic violation of the posterior tension band during initial decompressive surgeries. Progressive deformity and/or medically refractory infection may necessitate aggressive debridement and reconstructive arthrodesis. Anterior debridement and reconstruction with posterior stabilization is an effective treatment option; however, existing open surgical techniques have limited efficacy for correction of the focal deformity, which can expose the patient to long term sagittal imbalance, pain, and disability. The aim of this chapter is to briefly review the epidemiology, pathophysiology, clinical presentation, and the role of medical versus surgical management in LDO. The role of the lateral retroperitoneal approach to the lumbar spine is then discussed and illustrated with two clinical cases.

Ca-Si mesoporous nanoparticles with the optimal Ag-Zn ratio inhibit the Enterococcus faecalis infection of teeth through dentinal tubule infiltration: an in vitro and in vivo study.

Enterococcus faecalis is the main cause of refractory root canal infections in human teeth. The control of root canal infection is one of the conditions necessary for the successful treatment of refractory root canal infections. In the present study, nano-scale silver-zinc-calcium-silica particles loaded with different ratios of silver-zinc were successfully prepared (Ag0.5Zn3-MCSNs and Ag0.5Zn10-MCSNs). The release profiles, antibacterial activity against E. faecalis, infiltration depth into dentinal tubules, biocompatibility and effects on dentin microhardness in vitro were investigated. In addition, the antimicrobial effects of the particles against Enterococcus faecalis reinfection were evaluated in vivo in the teeth of beagle dogs. Ag, Zn, Ca and Si were released from Ag-Zn-MCSNs, and the atomic ratio of silver and zinc released can reach the optimal value of 1 : 12 (Ag0.5Zn10-MCSNs). The particles also showed good biocompatibility and antibacterial activity against Enterococcus faecalis and did not reduce the hardness of dentin. The nanoparticles could be driven into the dentinal tubules of dentin slices by ultrasonic activation. In the root canals of beagle dogs, both Ag0.5Zn3-MCSNs and Ag0.5Zn10-MCSNs demonstrated strong preventive effects against E. faecalis infection. The Ag-Zn-Ca-Si mesoporous nanoparticles may develop into a new effective root canal disinfectant or root canal sealer.

Fecal Microbiota Transplantation is Safe and Effective for C. Difficile Infection

According to this study: In standard clinical practice, fecal microbiota transplantation has a high success rate in patients with refractory Clostridioides difficile infection. In most cases, cure can be achieved with only one treatment.

Generalized Shwartzman Reaction as an Experimental Endotoxin Shock Model: Role of Intermediate T Cell Receptor-Expressing Innate T Lymphocytes in its Pathogenesis

Endotoxin and its induced exaggerative responses of proinflammatory cytokines such as Tumor Necrosis Factor (TNF) cause human septic shock. The generalized Shwartzman reaction is considered as an experimental endotoxin shock model and its representative features are high lethality and hypersensitive inflammatory response to endotoxin, in particular excessive TNF production. The generalized Shwartzman reaction can be induced by Interleukin (IL)-12 priming and subsequent endotoxin challenge. IL-12 primes the intermediate T cell receptor (TCR)-expressing innate T lymphocytes (natural killer T cells and CD8+CD122+ T cells in mice, CD56+ T cells and CD57+ T cells in human) to produce IFN-γ, which in turn preconditions macrophages to produce a large amount of TNF in response to endotoxin. These intermediate TCR innate T lymphocytes play a pivotal role for the occurrence of this generalized Shwartzman reaction. Some of the intermediate TCR-expressing innate T lymphocytes (CD8+CD122+ T cells in mice and CD57+ T cells in human), which are considered as extrathymically developed T lymphocytes, are increased with age and closely involved in age-dependent augmentation of murine generalized Shwartzman reaction and human Shwartzman-like reaction, which may reflect an exacerbation of septic shock in elderly. However, these intermediate TCR innate T lymphocytes normally augment host immunity against malignant tumors and refractory bacterial infections, which are critical threats in aged hosts. Thus, intermediate TCR-expressing innate T lymphocytes may be a double-edged sword on the host defense, especially elderly hosts.

Comparison of Transplant Donor- and Third-Party Donor-Derived CMV-Specific T Cells for CMV Infection After Allogenic Stem Cell Transplantation

Background: Adoptive transfer of cytomegalovirus (CMV)-specific T cells (CTLs) from original transplant donors or third-party donors was effective for CMV infection after allogenic stem cell transplantation (allo-SCT), but the safety and antiviral activity of CTL types have not been compared. Additionally, mechanisms driving sustained antiviral immunity induced by these CTLs need to be established and compared. Methods: i) We compared antiviral abilities of transplant donor and third-party CTLs for CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity and analyzed underlying mechanisms driving sustained antiviral immunity induced by these CTLs therapies. ii) We collected data from 31 patients receiving third-party CTLs and selected matched pairs of 62 individuals who received donor CTLs for refractory CMV infection after allo-SCT, compared the safety and efficacy of the CTLs types for CMV infection, and evaluated the recovery of virus-specific immunity in patients. Findings: i) In mouse models, we observed that both donor and third-party CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days post-infusion. The in vivo recovery of CMV-specific immunity after CTLs infusion was comparable in both groups. A detailed analysis of the source of recovered CTLs showed the proliferation and expansion of graft-derived endogenous CTLs in both groups. ii) In patients, adoptive therapy with donor or third-party CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8 + tetramer + T cells and the proliferation of recipient’s endogenous CTLs after CTLs infusion, which were associated with a reduced or cleared of viral load. Interpretation: Adoptive therapy with transplant donor or third-party CTLs triggered comparable antiviral responses to CMV infection by helping to restore CMV-specific immunity. Funding: National Key Research and Development Program of China, National Natural Science Foundation of China. Declaration of Interest: The authors have no competing financial interests to declare. Ethical Approval: This study was approved by the ethics committee of Peking University People's Hospital

Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an Australian experience - effective, safe, yet room for improvement.

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real-world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti-nuclear antibody-positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune-mediated conditions, is required.

Viral infections after hematopoietic cell transplantation and treatment with virus-specific T-cell therapies

Viral infections are one of the leading causes of death in hematopoietic cell transplantation (HCT) and are a problem that should be resolved. For post-HCT viral infections, reduction of antiviral treatment or immunosuppressive drug dose is generally performed; however, the effect of antiviral drug is sometimes limited, and reduction of immunosuppressive treatment might worsen the graft-versus-host disease. Therefore, appropriate infection preventive measures and early diagnosis and therapeutic intervention for viral infections are important. In addition, virus-specific T-cell (VST) therapy is attracting attention as a new treatment method for intractable and refractory post-HCT viral infections. Various methods have been developed to establish VSTs, from a single- to multiple-virus targeting and from related- to third-party-derived donors. Its safety and efficacy have already been reported in clinical trials, and thereby, it is expected to be established as one of the important treatments for post-HCT viral infections.

580. Refractory and Resistant CMV Infections in Hematopoietic Cell Transplant Recipients in the Letermovir Primary Prophylaxis Era

BackgroundCMV reactivation is one of the most common infections after allogeneic hematopoietic cell transplantation (allo-HCT) and carries considerable morbidity and mortality. Primary prophylaxis with letermovir demonstrated in clinical trials reduction of the incidence of clinically significant CMV infection (CS-CMVi). This study aims at exploring the effect of letermovir primary prophylaxis on the occurrence of refractory or resistant CMV infections.MethodsThis is a single-center, retrospective cohort study of 537 consecutive allo-HCT CMV-seropositive recipients cared for between March 2016 and December 2018. Baseline demographics, transplant characteristics, CMV infections, treatment and mortality data were collected from the electronic medical record (Table 1). CMV outcomes were defined according to the standardized definitions for clinical trials. Data was analyzed on IBM® SPSS version 24 using a logistic regression model for multivariate analysis.ResultsOut of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days post-HCT and 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with a reduction in CS-CMVi (OR 0.11, 95% CI 0.06–0.20), CMV disease (OR 0.20, 95% CI 0.08–0.46) and refractory or resistant CMV infection (OR 0.11, 95% CI 0.02–0.49) (Table 2). Notably, there was no resistant CMV and no CMV-related mortality in the letermovir group. There was a trend towards lower all-cause mortality at day 100 in the letermovir group (OR 0.48, 95% CI 0.18–1.2).Table 1 - Baseline Characteristics. Table 2 - Multivariate Analysis of Clinical Outcomes. ConclusionOur study showed a strong association between primary prophylaxis with letermovir and reduction in refractory or resistant CMV infections and CMV disease in allo-HCT recipients.Disclosures Ella Ariza Heredia, MD, Merck Sharp & Dohme (Grant/Research Support)Oxford Immunotec (Grant/Research Support) Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix (Consultant, Research Grant or Support)Clinigen (Consultant)Merck (Consultant, Research Grant or Support)Novartis (Research Grant or Support)Oxford Immunotec (Consultant, Research Grant or Support)Shire/Takeda (Research Grant or Support)Viracor (Research Grant or Support)

1104. Risk Factors and Outcomes of Refractory and/or Resistant Cytomegalovirus (CMV) Infection after Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundThe epidemiology of CMV end-organ disease (EOD) after Hematopoietic Cell Transplant (HCT) in the era of preemptive therapy (PET) is defined. In contrast, less data exists on refractory and/or resistant (R/R) CMV. We report on 1) the incidence; 2) risk factors and outcomes of R/R CMV by 1-year post HCT.MethodsRetrospective review of 167 CMV seropositive (R+) recipients of first marrow or peripheral blood HCT from 1/2014 - 12/2017 managed by PET. Refractory CMV was defined as failure to achieve >1 log10 decrease in CMV viral load (VL) and having VL >1,000 IU/mL after ≥14 day of PET. Resistant CMV required genotypic confirmation of resistance mutation(s) in UL54 and/or UL97 genes. End organ disease (EOD) was defined by standard criteria. Patients (pts) were followed through 1-year post HCT and were categorized in two mutually exclusive groups as R/R and no R/R. Demographics, clinical characteristics and outcomes were extracted from medical records and hospital databases. Univariable and multivariable logistic models were used to identify risk factors for R/R CMV.ResultsOf 167 PET recipients, 91 (54.5%) received ex vivo T cell depleted (TCD) HCT; 40 (24.0%) had mismatched donor; and 26 (15.6%) had multiple myeloma. 66/167 (39.5%) pts developed refractory CMV (6 pts also had resistant CMV). Time from HCT to CMV viremia was shorter in R/R group: median (IQR) 21.5 (17.2-27.8) days compared to no R/R group: 26 (19-32) days (p=0.031). Maximum VL was higher for R/R compared to no R/R: median (IQR) 9,118 (2,849-18,456) and 868 (474-1,908), respectively (p< 0.001). In multivariable model, risk factors for R/R included TCD HCT (p< 0.0001) and higher VL at PET initiation (p=0.0002). In contrast, CMV seropositive donor (p=0.035) was protective (Figure 1). CMV EOD developed in 28.2% of R/R and 16.2% of no R/R groups (p=0.085) (Figure 2). Overall survival at 1 year was 59.1% for R/R compared to 83.1% for no R/R group (p=0.00027) (Figure 3).Figure 1. Adjusted odds ratio (OR) and 95% confidence interval (CI) from multivariable model evaluating risk factors of refractory/resistant (R/R) CMV. Figure 2. Cumulative incidence curves of CMV end-organ disease (EOD) at 1-year post HCT Figure 3. Kaplan-Meier survival curves of overall survival (OS) at 1-year post HCT Conclusion1) Refractory and/or resistant CMV occurred in 39,5% of PET recipients. 2) T-cell depletion and higher CMV VL at PET initiation were risk factors for R/R CMV in multivariable models. 3) R/R CMV was associated with more EOD and worse overall survival.Disclosures Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

Effective remission of an elderly patient with refractory atopic dermatitis and foot ulcers following infusion with human umbilical cord‑derived mesenchymal stem cells: A case report

Mesenchymal stem cells (MSCs) are excellent sources for use in the treatment of refractory and relapsing disorders mainly due to their hematopoietic‑supporting and immunoregulatory capacities. However, their safety and effectiveness for the treatment of refractory atopic dermatitis (AD) and multiple complications in elder patients are largely unknown. Therewith, the present study describes the case of a 65‑year‑old female patient with AD accompanied by foot ulcers and refractory urinary tract infection. Briefly, 5x10⁷ human umbilical cord‑derived MSCs (hUC‑MSCs) were intravenously infused into the body of the patient after obtaining the approval of the relevant ethics committee and the consent of the patient. The clinical and biochemical outcomes, including general symptoms, hemogram and blood constituents, medical images, together with tumour biomarkers, were observed and recorded. By conducting only one single intravenous infusion of hUC‑MSCs, the AD‑associated pathophysiological manifestations of the elderly patient, including an unbearable itch, diffuse erythema and eczema, and in particular, inflammatory foot ulcers and refractory urinary infection were completely attenuated. Simultaneously, the outcomes of the accompanied complications were effectively improved, whereas no recrudesce or adverse reactions were observed in the 14‑month follow‑up visit. The findings of the present study suggested that the administration of hUC‑MSCs was safe and effective for restricting the symptoms and of the patient preventing associated complications. Thus, the use of hUC‑MSCs may prove to be a promising treatment option for AD and foot ulcer management, even for elderly patients with multiple underlying conditions or complications.

Traditional Chinese medicine compound, Bu Sheng Hui Yang Fang, promotes the proliferation of lymphocytes in the immunosuppressed mice potentially by upregulating IL-4 signaling

The immune system plays a pivotal role in defending against infection and cancer immunosurveillance during the onset and procession of malignant disease. Cancer patients are frequently immunocompromised and subject to refractory infection and relapse of leukemia, due to the cytotoxic agents and immunosuppressive glucocorticoids in the chemotherapy regimens. Bu Shen Hui Yang Fang (BSHY), a traditional Chinese compound, was widely used in China to enhance the immune system of leukemia patients combined with chemotherapy and effectively lowered their risk of infection, with specific mechanism unknown yet. Thus, we investigated the effects of BSHY on the immune system using immunosuppressive mouse models. By analyzing the immune system of immunosuppressed BALB/C mice induced by hydrocortisone, we found an increase of CD4+ and CD8+ lymphocytes in the spleens of mice after BSHY treatment. Furthermore, we found the enhanced immune system in BSHY treated group was due to increased proliferation and decreased apoptosis of lymphocytes. Cytokine array analysis revealed that interleukin 4 (IL-4) was reduced in the plasma of immunosuppressed mice but returned to a normal level after BSHY treatment. Moreover, we found IL-4 was an adverse prognostic factor in acute myeloid leukemia patients and part of them could be elevated by BSHY. Mechanistically, we found BSHY enhances the proliferation of lymphocytes in a Stat6-dependent manner. In summary, our current study demonstrates that BSHY enhances the proliferation of lymphocytes in the immunosuppressed mice via upregulating IL-4 signaling.

Exogenous Nitric Oxide Improves Antibiotic Susceptibility in Resistant Bacteria.

Antibiotic resistance in bacteria is a major global threat and a leading cause for healthcare-related morbidity and mortality. Resistant biofilm infections are particularly difficult to treat owing to the protective biofilm matrix, which decreases both antibiotic efficacy and clearance by the host. Novel antimicrobial agents that are capable of eradicating resistant infections are greatly needed to combat the rise of antibiotic-resistant bacteria, particularly in patients with cystic fibrosis who are frequently colonized by multidrug-resistant species. Our research group has developed nitric oxide-releasing biopolymers as alternatives to conventional antibiotics. Here, we show that nitric oxide acts as a broad-spectrum antibacterial agent while also improving the efficacy of conventional antibiotics when delivered sequentially. Alone, nitric oxide kills a broad range of bacteria in planktonic and biofilm form without engendering resistance. In combination with conventional antibiotics, nitric oxide increases bacterial susceptibility to multiple classes of antibiotics and slows the development of antibiotic resistance. We anticipate that the use of nitric oxide in combination with antibiotics may improve the outcome of patients with refractory infections, particularly those that are multidrug-resistant.