Emergence and dissemination of three mild outbreaks of Neisseria gonorrhoeae with high-level resistance to azithromycin in Barcelona, 2016-18.

BACKGROUND: Neisseria gonorrhoeae (NG) isolates with high-level azithromycin resistance (HL-AziR) have emerged worldwide in recent decades, threatening the sustainability of current dual-antimicrobial therapy. OBJECTIVES: This study aimed to characterize the first 16 NG isolates with HL-AziR in Barcelona between 2016 and 2018. METHODS: WGS was used to identify the mechanisms of antimicrobial resistance, to establish the MLST ST, NG multiantigen sequence typing (NG-MAST) ST and NG sequence typing for antimicrobial resistance (NG-STAR) ST and to identify the clonal relatedness of the isolates with other closely related NG previously described in other countries based on a whole-genome SNP analysis approach. The sociodemographic characteristics of the patients included in the study were collected by comprehensive review of their medical records. RESULTS: Twelve out of 16 HL-AziR isolates belonged to the MLST ST7823/NG-MAST ST5309 genotype and 4 to MLST ST9363/NG-MAST ST3935. All presented the A2059G mutation in all four alleles of the 23S rRNA gene. MLST ST7823/NG-MAST ST5309 isolates were only identified in men who have sex with women and MLST ST9363/NG-MAST ST3935 were found in MSM. Phylogenomic analysis revealed the presence of three transmission clusters of three different NG strains independently associated with sexual behaviour. CONCLUSIONS: Our findings support the first appearance of three mild outbreaks of NG with HL-AziR in Spain. These results highlight the continuous capacity of NG to develop antimicrobial resistance and spread among sexual networks. The enhanced resolution of WGS provides valuable information for outbreak investigation, complementing the implementation of public health measures focused on the prevention and dissemination of MDR NG.

Experimental data on activity catalyst TiO2/Fe3O4 under natural solar radiation conditions.

In this document, the photocatalytic activity of TiO2/Fe3O4, prepared by the mixing of the pure oxides, was studied. The photocatalytic degradation of aqueous Methylene Blue (MB) solutions (10 and 30 ppm) was performed, the TiO2/Fe3O4 catalysts in 80/20, 50/50 and 20/80 mass ratios were used during the test, artificial sunlight and natural solar radiation were tested at laboratory and pilot plant scale respectively. Besides, the kinetic reactions were evaluated according to the Langmuir-Hinshelwood model, the apparent velocity constants (kapp) were obtained for the TiO2/Fe3O4 catalysts. In the laboratory test, the TiO2/Fe3O4 catalyst (80/20) had a performance for 93.04% of discoloration, kapp = 0.0238 min-1, while for TiO2/Fe3O4 (50/50, 20/80) had an 83.46%, 65.00% for discoloration of MB and the kapp values were 0.0154 min-1 and 0.0098 min-1, respectively. In the solar test at pilot scale, the percentages of discoloration of 24.32%, and 57.78%, with kapp values of 0.00037 min-1, 0.00121 min-1 respectively were obtained for TiO2/Fe3O4 (80/20), a MB solution of 30 ppm, a load of 0.1 g/L and 0.3 g/L of the catalyst respectively.

Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.

BACKGROUND: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). METHODS: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. RESULTS: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 µg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 µg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. CONCLUSIONS: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

A comparison of the National Center for Health Statistics and new World Health Organization growth references for school-age children and adolescents with the use of data from 11 low-income countries.

BACKGROUND: In 2007 new World Health Organization (WHO) growth references for children aged 5-19 y were introduced to replace the National Center for Health Statistics (NCHS) references. OBJECTIVE: This study aimed to compare the prevalence of stunting, wasting, and thinness estimated by the NCHS and WHO growth references. DESIGN: NCHS and WHO height-for-age z scores were calculated with the use of cross-sectional data from 20,605 schoolchildren aged 5-17 y in 11 low-income countries. The differences in the percentage of stunted children were estimated for each year of age and sex. The z scores of body mass index-for-age and weight-for-height were calculated with the use of the WHO and NCHS references, respectively, to compare differences in the prevalence of thinness and wasting. RESULTS: No systematic differences in mean z scores of height-for-age were observed between the WHO and NCHS growth references. However, z scores of height-for-age varied by sex and age, particularly during early adolescence. In children for whom weight-for-height could be calculated, the estimated prevalence of thinness (WHO reference) was consistently higher than the prevalence of wasting (NCHS reference) by as much as 9% in girls and 18% in boys. CONCLUSIONS: In undernourished populations, the application of the WHO (2007) references may result in differences in the prevalence of stunting for each sex compared with results shown when the NCHS references are used as well as a higher estimated prevalence of thinness than of wasting. An awareness of these differences is important for comparative studies or the evaluation of programs. For school-age children and adolescents across all ranges of anthropometric status, the same growth references should be applied when such studies are undertaken.

Correlation of volumetric mismatch and mismatch of Alberta Stroke Program Early CT Scores on CT perfusion maps.

INTRODUCTION: We aimed to determine if volumetric mismatch between tissue at risk and tissue destined to infarct on computed tomography perfusion (CTP) can be described by the mismatch of Alberta Stroke Program Early CT Score (ASPECTS). MATERIALS AND METHODS: Forty patients with nonlacunar middle cerebral artery infarct <6 h old who had CTP on admission were retrospectively reviewed. Two raters segmented the lesion volume on mean transit time (MTT) and cerebral blood volume (CBV) maps using thresholds of >6 s and <2.0 mL per 100 g, respectively. Two other raters assigned ASPECTS to the same MTT and CBV maps while blinded to the volumetric data. Volumetric mismatch was deemed present if >or=20%. ASPECTS mismatch (=CBV ASPECTS - MTT ASPECTS) was deemed present if >or=1. Correlation between the two types of mismatches was assessed by Spearman's coefficient (rho). ROC curve analyses were performed to determine the optimal ASPECTS mismatch cut point for volumetric mismatch >or=20%, >or=50%, >or=100%, and >or=150%. RESULTS: Median volumetric mismatch was 130% (range 10.9-2,031%) with 31 (77.5%) being >or=20%. Median ASPECTS mismatch was 2 (range 0-6) with 26 (65%) being >or=1. ASPECTS mismatch correlated strongly with volumetric mismatch with rho = 0.763 [95% CI 0.585-0.870], p < 0.0001. Sensitivity and specificity for volumetric mismatch >or=20% was 83.9% [95% CI 65.5-93.5] and 100% [95% CI 65.9-100], respectively, using ASPECTS mismatch >or=1. Volumetric mismatch >or=50%, >or=100%, and >or=150% were optimally identified using ASPECTS mismatch >or=1, >or=2, and >or=2, respectively. CONCLUSION: On CTP, ASPECTS mismatch showed strong correlation to volumetric mismatch. ASPECTS mismatch >or=1 was the optimal cut point for volumetric mismatch >or=20%.

An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy.

BACKGROUND: A phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer. PATIENTS AND METHODS: This open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumumab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated. RESULTS: One hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received >/=1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (CI): 8.0-13.4) weeks. Median overall survival time was 6.3 (95% CI: 5.1-6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample. CONCLUSIONS: These findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.

Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab.

In a randomised phase 3 trial, panitumumab significantly improved progression-free survival (PFS) in patients with refractory metastatic colorectal cancer (mCRC). This analysis characterises the association of PFS with CRC symptoms, health-related quality of life (HRQoL), and overall survival (OS). CRC symptoms (NCCN/FACT CRC symptom index, FCSI) and HRQoL (EQ-5D) were assessed for 207 panitumumab patients and 184 best supportive care (BSC) patients who had at least one post-baseline patient-reported outcome (PRO) assessment. Patients alive at week 8 were included in the PRO and OS analyses and categorised by their week 8 progression status as follows: no progressive disease (no PD; best response of at least stable disease) vs progressive disease (PD). Standard imputation methods were used to assign missing values. Significantly more patients were progression free at weeks 8-24 with panitumumab vs BSC. After excluding responders, a significant difference in PFS remained favouring panitumumab (HR=0.63, 95% CI=0.52-0.77; P<0.0001). At week 8, lack of disease progression was associated with significantly and clinically meaningful lower CRC symptomatology for both treatment groups and higher HRQoL for panitumumab patients only. Overall survival favoured no PD patients vs PD patients alive at week 8. Lack of disease progression was associated with better symptom control, HRQoL, and OS.

A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia.

BACKGROUND: This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia. PATIENTS AND METHODS: Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 mug/kg once weekly for 6 weeks (correction phase) followed by 4.5 mug/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase). RESULTS: During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6-1.5) g/dl in the i.v. group and 1.3 (0.9-1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1-1.9) g/dl and 1.6 (1.2-2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease < or =0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups. CONCLUSIONS: Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-naïve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.

Apendicitis complicada como enfermedad intercurrente en pacientes con cáncer gástrico avanzado / Complicated acute appendicitis as intercurrent disease in patient with advanced gastric cancer

Reportamos el caso de un paciente varón de 64 años atendido por abdomen agudo que es intervenido quirúrgicamente con el diagnóstico presuntivo de peritonitis por apendicitis complicada. El paciente estaba así mismo, cursando con deposiciones oscuras desde aproximadamente 2 semanas antes de su ingreso y melena franca los 3 días previos a su ingreso. Concomitantemente presentó dolor epigástrico severo, e intenso dolor en fosa iliaca derecha en las últimas horas. El hallazgo endoscópico determinó cáncer gástrico avanzado Borrmann II y el informe anatomopatológico respectivo, adenocarcinoma infiltrante tipo intestinal medianamente diferenciado. El informe operatorio fue peritonitis por apendicitis perforada en su base con coprolitos libres y carcinomatosis intra-abdominal, el informe anatomopatológico respectivo fue apéndice cecal con ulceración de mucosa, necrosis y perforación de pared muscular en su base; respecto a las muestras de epiplon y mesenterio tomadas en el intraoperatorio señala; tejido adiposo infiltrado por adenocarcinoma tubular medianamente diferenciado, compatible con cáncer gástrico primario.

[Complicated acute appendicitis as intercurrent disease in patient with advanced gastric cancer]. / Apendicitis complicada como enfermedad intercurrente en pacientes con cáncer gástrico avanzado.

We report a case of a male 64 years old with acute abdomen who was operated with the presumptive diagnosis of complicated acute appendicitis. However the patient had black stools for two months, associated with epigastric pain. Endoscopic diagnosis was: Advanced Gastric Cancer: Borrmann II. Histology was informed as: Infiltrating adenocarcinoma intestinal type middlingly differentiated. Surgery findings were: peritonitis with perforated appendicitis in its base: Free coprolites and carcinomatosis. Histology was reported as: ulcerated mucous in caecal appendix, necrosis and perforation of the muscular wall in the base. Mesentery samples were informed with fat tissue involvement by infiltration of tubular adenocarcinoma.middlingly differentiated, suitable with primary gastric cancer.

Nonmyeloablative approaches to the treatment of sickle hemoglobinopathies.

Significant advances in the field of sickle cell disease (SCD) in recent years have contributed to improving the life expectancy and symptoms of patients with this disease. These health care improvements include the implementation of infectious prophylaxis in children and the modulation of hemoglobin F production with chemotherapy. In spite of these advances, SCD continues to be associated with significant morbidity and mortality. Although standard allogeneic bone marrow transplantation can cure SCD and can halt the progression to end-organ damage, this treatment is associated with greater risk of toxicity and death in older patients and in those with evidence of severe end-organ damage. Nonmyeloablative conditioning regimens based on the use of purine analogs can induce sufficient immunosuppression to allow engraftment after allogeneic stem cell transplantation, resulting in less toxicity than standard conditioning regimens. We describe a clinical trial using a nonmyeloablative chemotherapy conditioning regimen followed by related allogeneic peripheral blood stem cell transplantation that represents a novel approach to the treatment of severe SCD in young adults. This study may afford chimeric engraftment resulting in the resolution or amelioration of disease-related symptoms and in the cessation of progression to organ failure.

Marking and gene expression by a lentivirus vector in transplanted human and nonhuman primate CD34(+) cells.

Recently, gene delivery vectors based on human immunodeficiency virus (HIV) have been developed as an alternative mode of gene delivery. These vectors have a number of advantages, particularly in regard to the ability to infect cells which are not actively dividing. However, the use of vectors based on human immunodeficiency virus raises a number of issues, not the least of which is safety; therefore, further characterization of marking and gene expression in different hematopoietic lineages in primate animal model systems is desirable. We use two animal model systems for gene therapy to test the efficiency of transduction and marking, as well as the safety of these vectors. The first utilizes the rhesus animal model for cytokine-mobilized autologous peripheral blood CD34(+) cell transplantation. The second uses the SCID-human (SCID-hu) thymus/liver chimeric graft animal model useful specifically for human T-lymphoid progenitor cell reconstitution. In the rhesus macaques, detectable levels of vector were observed in granulocytes, lymphocytes, monocytes, and, in one animal with the highest levels of marking, erythrocytes and platelets. In transplanted SCID-hu mice, we directly compared marking and gene expression of the lentivirus vector and a murine leukemia virus-derived vector in thymocytes. Marking was observed at comparable levels, but the lentivirus vector bearing an internal cytomegalovirus promoter expressed less efficiently than did the murine retroviral vector expressed from its own long terminal repeats. In assays for infectious HIV type 1 (HIV-1), no replication-competent HIV-1 was detected in either animal model system. Thus, these results indicate that while lentivirus vectors have no apparent deleterious effects and may have advantages over murine retroviral vectors, further study of the requirements for optimal use are warranted.

Reconstitution of human thymic implants is limited by human immunodeficiency virus breakthrough during antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4(+) cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Distinguishing between these processes is important for the development of therapeutic strategies aimed at reconstituting the CD4(+) T-cell compartment in HIV-1 infection. Using an HIV-1 strain engineered to express the murine HSA heat-stable antigen surface marker, we explored the relationship between HIV-1 expression and CD4(+) cell resurgence kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8 thymocytes, and the eventual secondary decline of DP thymocytes following therapy was associated with renewed viral expression in this cell subset. Thymocytes derived from exogenous T-cell progenitors induced to differentiate in HIV-1-depleted, drug-treated thymic implants also became infected. These results indicate that in this model, suppression of viral replication occurs transiently and that, in spite of drug therapy, virus resurgence contributes to the transient nature of the renewed thymic function.

Gene therapy for the treatment of AIDS: animal models and human clinical experience.

Although antiretroviral drug therapy has had a significant impact on the natural history of HIV infection, complete virus eradication still remains an unattainable goal. Drug-mediated virological control only occurs transiently, in part as a result of the development of drug resistance. Gene therapy for the treatment of AIDS is a promising area of research that has as its goal the replacement of the HIV-infected cellular pool with cells engineered to resist virus replication. A variety of anti-HIV genes have been designed and tested in laboratory systems, and available results from pilot clinical trials demonstrate the safety and feasibility of this approach. Obstacles to effective application of this technology include partial protection of HIV resistance genes, lack of effective vectoring systems, and unregulated gene expression. Herein, we review recent advances in transduction methods, data from in vivo preclinical studies in relevant animal models, and emerging results derived from pilot clinical gene therapy studies.

Effects of megakaryocyte growth and development factor on survival and retroviral transduction of T lymphoid progenitor cells.

Murine retroviral vectors have the potential to mediate stable gene transfer into hematopoietic progenitor cells. A known drawback to the use of these vectors is that transduction can only take place in cells actively progressing through the cell cycle. Thrombopoietin, the c-mpl ligand, is known to support division of hematopoietic precursors of primitive origin. Polyethylene glycol (PEG)-conjugated recombinant human megakaryocyte growth and development factor (MGDF) is a polypeptide related to thrombopoietin that stimulates megakaryocyte production. To investigate whether MGDF would also induce stem cell division and support retroviral transduction of CD34+ cells, we compared the effects of MGDF, stem cell factor (SCF), interleukin-3 (IL-3), and IL-6, alone or in combination, using amphotropic and vesicular stomatitis virus (VSV-G) pseudotyped murine retroviral vectors. Similar transduction efficiency was observed when CD34+ cells were transduced in the presence of SCF and MGDF as compared to SCF, IL-3, and IL-6. Using the SCID-hu mouse model of thymopoiesis, we investigated whether CD34+ cells transduced in the presence of these cytokines could reconstitute irradiated thymic implants, and whether vector sequences were present in mature thymocytes. At early timepoints, no significant differences were observed on engraftment of donor progenitors incubated with each cytokine combination. However, a significant difference in the percentage of donor derived CD4+/CD8+ immature thymocytes was observed 9 weeks after implantation of CD34+ cells exposed to the combination of SCF and MGDF as compared to SCF, IL-3, and IL-6 (p = 0.04), indicating that MGDF/SCF better supported the survival of thymocyte precursor cells. Approximately 4% of thymocytes in both cytokine groups harbored vector sequences. These studies provide evidence that MGDF and SCF in combination can mediate transduction of hematopoietic progenitors capable of contributing to long-term thymopoiesis. These results may have important applications for the implementation of gene therapy strategies in disorders affecting the T lymphoid system.

Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy.

Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.