Activity of imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae and imipenem-resistant Pseudomonas aeruginosa.

PURPOSE: Relebactam is a novel ß-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C ß-lactamases. To evaluate in vitro antimicrobial activity of imipenem/relebactam against a collection of recent clinical isolates of carbapenem-non-susceptible P. aeruginosa and K. pneumoniae ST258 and ST512 KPC producers belonging to different lineages from hospitals in Southern Spain. METHODS: Six hundred and seventy-eight isolates were tested: 265 K. pneumoniae (230 ST512/KPC-3 and 35 ST258/KPC-3) and 413 carbapenem-non-susceptible P. aeruginosa. Imipenem, piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, ceftolozane/tazobactam, meropenem, amikacin, ciprofloxacin, colistin, and ceftazidime/avibactam were used as comparators against P. aeruginosa. Against K. pneumoniae ceftazidime, cefepime, aztreonam, and ceftolozane/tazobactam were not tested, and tigecycline was studied instead. MICs were determined in duplicate by broth microdilution according to EUCAST guidelines. RESULTS: Imipenem/relebactam displayed potent in vitro activity against both sequence types of KPC-3-producing K. pneumoniae. MIC50 and MIC90 values were 0.25 mg/L and 1 mg/L, respectively, with percent of susceptible isolates >97%. Only three K. pneumoniae ST512/KPC-3 isolates and one ST258/KPC-3 were resistant to imipenem/relebactam. Relebactam sensitized 98.5% of K. pneumoniae isolates resistant to imipenem. The activity of imipenem/relebactam against P. aeruginosa was moderate (susceptibility rate: 62.7%). Analysis of the acquired and mutational resistome of isolates with high levels of resistance to imipenem/relebactam has not shown a clear association between them. CONCLUSION: Imipenem/relebactam showed excellent activity against K. pneumoniae KPC-3. The activity of imipenem/relebactam against imipenem-resistant P. aeruginosa was moderate.

An advanced biphasic porous and injectable scaffold displays a fine balance between mechanical strength and remodeling capabilities essential for cartilage regeneration.

An important challenge in tissue engineering is the regeneration of functional articular cartilage (AC). In the field, biomimetic hydrogels are being extensively studied as scaffolds that recapitulate microenvironmental features or as mechanical supports for transplanted cells. New advanced hydrogel formulations based on salmon methacrylate gelatin (sGelMA), a cold-adapted biomaterial, are presented in this work. The psychrophilic nature of this biomaterial provides rheological advantages allowing the fabrication of scaffolds with high concentrations of the biopolymer and high mechanical strength, suitable for formulating injectable hydrogels with high mechanical strength for cartilage regeneration. However, highly intricate cell-laden scaffolds derived from highly concentrated sGelMA solutions could be deleterious for cells and scaffold remodeling. On this account, the current study proposes the use of sGelMA supplemented with a mesophilic sacrificial porogenic component. The cytocompatibility of different sGelMA-based formulations is tested through the encapsulation of osteoarthritic chondrocytes (OACs) and stimulated to synthesize extracellular matrix (ECM) components in vitro and in vivo. The sGelMA-derived scaffolds reach high levels of stiffness, and the inclusion of porogens impacts positively the scaffold degradability and molecular diffusion, improved fitness of OACs, increased the expression of cartilage-related genes, increased glycosaminoglycan (GAG) synthesis, and improved remodeling toward cartilage-like tissues. Altogether, these data support the use of sGelMA solutions in combination with mammalian solid gelatin beads for highly injectable formulations for cartilage regeneration, strengthening the importance of the balance between mechanical properties and remodeling capabilities.

A novel porous hydrogel based on hybrid gelation for injectable and tough scaffold implantation and tissue engineering applications.

Although there have been many advances in injectable hydrogels as scaffolds for tissue engineering or as payload-containing vehicles, the lack of adequate microporosity for the desired cell behavior, tissue integration, and successful tissue generation remains an important drawback. Herein, we describe an effective porous injectable system that allowsin vivoformation of pores through conventional syringe injection at room temperature. This system is based on the differential melting profiles of photocrosslinkable salmon gelatin and physically crosslinked porogens of porcine gelatin (PG), in which PG porogens are solid beads, while salmon methacrylamide gelatin remains liquid during the injection procedure. After injection and photocrosslinking, the porogens were degraded in response to the physiological temperature, enabling the generation of a homogeneous porous structure within the hydrogel. The resultant porogen-containing formulations exhibited controlled gelation kinetics within a broad temperature window (18.5 ± 0.5-28.8 ± 0.8 °C), low viscosity (133 ± 1.4-188 ± 16 cP), low force requirements for injectability (17 ± 0.3-39 ± 1 N), robust mechanical properties after photo-crosslinking (100.9 ± 3.4-332 ± 13.2 kPa), and favorable cytocompatibility (>70% cell viability). Remarkably,in vivosubcutaneous injection demonstrated the suitability of the system with appropriate viscosity and swift crosslinking to generate porous hydrogels. The resulting injected porous constructs showed favorable biocompatibility and facilitated cell infiltration for desirable potential tissue remodeling. Finally, the porogen-containing formulations exhibited favorable handling, easy deposition, and good shape fidelity when used as bioinks in 3D bioprinting technology. This injectable porous system serves as a platform for various biomedical applications, thereby inspiring future advances in cell therapy and tissue engineering.

A Psychrophilic GelMA: Breaking Technical and Immunological Barriers for Multimaterial High-Resolution 3D Bioprinting.

The increasing demand for tissue replacement has encouraged scientists worldwide to focus on developing new biofabrication technologies. Multimaterials/cells printed with stringent resolutions are necessary to address the high complexity of tissues. Advanced inkjet 3D printing can use multimaterials and attain high resolution and complexity of printed structures. However, a decisive yet limiting aspect of translational 3D bioprinting is selecting the befitting material to be used as bioink; there is a complete lack of cytoactive bioinks with adequate rheological, mechanical, and reactive properties. This work strives to achieve the right balance between resolution and cell support through methacrylamide functionalization of a psychrophilic gelatin and new fluorosurfactants used to engineer a photo-cross-linkable and immunoevasive bioink. The syntonized parameters following optimal formulation conditions allow proficient printability in a PolyJet 3D printer comparable in resolution to a commercial synthetic ink (∼150 µm). The bioink formulation achieved the desired viability (∼80%) and proliferation of co-printed cells while demonstrating in vivo immune tolerance of printed structures. The practical usage of existing high-resolution 3D printing systems using a novel bioink is shown here, allowing 3D bioprinted structures with potentially unprecedented complexity.

Incidence and risk factors for incisional hernia after open abdominal aortic aneurysm repair.

INTRODUCTION: Incisional hernia (IH) is common after open abdominal aortic aneurysm (AAA) repair. Recent studies reported incidence rates higher than previously stated. The aim of this study was to quantify the IH incidence after open AAA surgery. The secondary outcome was to identify the risk factors associated with the development of an IH. METHODS: Retrospective observational study of all consecutive patients who underwent an open repair of AAA, from January 2010 to June 2018, at our institution. Patients were free of abdominal wall hernias at the moment of inclusion in the study. Data were extracted from electronic records: baseline characteristics, surgical factors, and postoperative events. Computed tomography (CT) scans performed during follow-up were analyzed. RESULTS: A total of 157 patients were analysed. The IH incidence after open repair of AAA was 46.5% (73 patients). The median time for IH development was 24.43 months (IQR: 10.40-45.27), while the median follow-up time was 37.20 months (IQR: 20.53-64.12). The risk factors linked to IH were: active (HR: 4.535; 95% CI: 1.369-15.022) or previous smoking habit (HR: 4.652; 95% CI: 1.430-15.131), chronic kidney disease (HR: 2.007; 95% CI: 1.162-3.467) and previous abdominal surgery (HR: 1.653; 95% CI: 1.014-2.695). CONCLUSION: The incisional hernia after open abdominal aortic aneurysm repair affected a high proportion of the intervened patients. Previous abdominal surgery, chronic kidney disease, and smoking habit were independent factors for the development of an incisional hernia.

Towards mesoporous silica as a pharmaceutical treatment for obesity - impact on lipid digestion and absorption.

Mesoporous silica particles (MSPs) are emerging as an interesting option to reduce calorific uptake as a treatment for obesity and other metabolic conditions. However, their further development under the pharmaceutical regulatory framework is hindered by poor understanding of the mechanisms by which they exert their effects. In the current study the interaction of MSPs with the lipid digestion process is investigated, specifically interactions with lipase enzymes and lipid digestion products as a key contributing factor to lipid absorption and calorific intake. The impact of exposing lipase to MSPs on the enzyme activity was assessed directly using the tributyrin digestion test. The extent of interaction of digestion products with MSPs was studied using selectively radiolabeled bile components and lipids, while the impact on in vivo absorption of lipids was studied by incorporation of radiolabelled lipid (triolein) into milk and administration with and without particles. The studies showed that particles that inhibited lipase activity also tended to interact more extensively with lipid digestion products. In vitro X-ray scattering studies revealed the interaction of some MSPs with lipid digestion products through changes in lipid self-assembly during digestion. The MSPs led to reduced lipid absorption in vivo compared to the control particles and MSP-free milk. While the specific properties of the MSPs that drive the differences between the behavior of MSPs during lipid digestion remain elusive, the studies highlight that interactions with the lipid digestion and absorption pathways are a likely mechanism for reducing calorific uptake.

Engineered mesoporous silica reduces long-term blood glucose, HbA1c, and improves metabolic parameters in prediabetics.

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15®, on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Lay abstract Prediabetes is a health condition in which blood sugar levels are higher than normal but below diabetes diagnosis level. Without intervention, prediabetic adults and children are most likely to progress to Type 2 diabetes. To try and prevent this progression, the authors of this article are proposing an innovative solution with an engineered material called SiPore15^®. SiPore15 is classified as a medical device, and is made up entirely of porous silica particles. It has been proven to be safe to take orally. The effects of SiPore15 were investigated in people with prediabetes and newly diagnosed Type 2 diabetes. SiPore15 was taken three times a day for 12 weeks. It significantly reduced long-term blood glucose levels and improved other factors related to the disease with minimal side effects. The results from this study show that SiPore15 has the potential to be used as a treatment for prediabetes. This may help to delay or prevent the onset of Type 2 diabetes. Clinical Trial Registration: NCT03823027 (ClinicalTrials.gov).

Incidence and risk factors for incisional hernia after open abdominal aortic aneurysm repair.

INTRODUCTION: Incisional hernia (IH) is common after open abdominal aortic aneurysm (AAA) repair. Recent studies reported incidence rates higher than previously stated. The aim of this study was to quantify the IH incidence after open AAA surgery. The secondary outcome was to identify the risk factors associated with the development of an IH. METHODS: Retrospective observational study of all consecutive patients who underwent an open repair of AAA, from January 2010 to June 2018, at our institution. Patients were free of abdominal wall hernias at the moment of inclusion in the study. Data were extracted from electronic records: baseline characteristics, surgical factors, and postoperative events. Computed tomography (CT) scans performed during follow-up were analyzed. RESULTS: A total of 157 patients were analysed. The IH incidence after open repair of AAA was 46.5% (73 patients). The median time for IH development was 24.43 months (IQR: 10.40-45.27), while the median follow-up time was 37.20 months (IQR: 20.53-64.12). The risk factors linked to IH were: active (HR: 4.535; 95% CI: 1.369-15.022) or previous smoking habit (HR: 4.652; 95% CI: 1.430-15.131), chronic kidney disease (HR: 2.007; 95% CI: 1.162-3.467) and previous abdominal surgery (HR: 1.653; 95% CI: 1.014-2.695). CONCLUSION: The incisional hernia after open abdominal aortic aneurysm repair affected a high proportion of the intervened patients. Previous abdominal surgery, chronic kidney disease, and smoking habit were independent factors for the development of an incisional hernia.

Perivascular Macrophages Regulate Blood Flow Following Tissue Damage.

[Figure: see text].

Comportamiento reproductivo, forrajeo y uso de hábitat de Coccyzus ferrugineus (Cuculiformes: Cuculidae) en la Isla del Coco, Costa Rica

Introducción: Coccyzus ferrugineus es el ave endémica menos estudiada de la Isla del Coco se desconocen muchos aspectos sobre su historia natural y comportamiento, siendo de las especies menos conocidas en Costa Rica. Objetivo: Describir el comportamiento reproductivo, de forrajeo, y el uso de hábitat de C. ferrugineus para generar información para la toma de decisiones de conservación de la especie. Métodos: Se hicieron observaciones directas de comportamiento (forrajeo, cortejo, vocalización, alimentación y cópula) durante dos periodos de observación (mañana y tarde), en parcelas entre los 0-400 m de altitud, clasificando el estrato de vegetación (bajo-medio-alto) para estudiar el uso de hábitat. Se presenta una descripción del comportamiento de forrajeo y del ciclo reproductivo. Resultados: Se demuestra que C. ferrugineus utiliza todo el gradiente altitudinal de la Isla del Coco, desde el nivel del mar hasta los 400 m de altitud en el bosque nuboso, para reproducirse y su época reproductiva está marcada por el inicio de la época seca. No se encontraron diferencias significativas entre las categorías de comportamiento establecidas y la hora del día (Fisher, P > 0.05). Sin embargo sí se mostró diferencias significativas para las categorías de comportamiento y el estrato vertical (Fisher, P < 0.05) demostrando que utiliza todo el estrato vertical de la estructura vegetal. Conclusiones: Este estudio representa la base para el conocimiento de la biología reproductiva e historia natural de C. ferrugineus, es urgente realizar más estudios sobre esta especie para poder protegerla y conservar el ecosistema terrestre de la Isla del Coco.

Introducción: Coccyzus ferrugineus is the least studied endemic bird of Isla del Coco, many aspects of its natural history and behavior remain unknown, being one the least known species in Costa Rica. Objective: To describe the reproductive behavior, foraging and habitat use of C. ferrugineus to generate information for making conservation decisions for the species. Methods: Direct behavioral observations (foraging, courtship, vocalization, feeding and intercourse) were made in plots between 0-400 m above sea level, during two observation periods (morning and afternoon). A description of the foraging behavior and the reproductive cycle is presented. Results: C. ferrugineus uses the entire altitudinal gradient of the island to reproduce, from sea level to 400 m altitude in the cloud forest. Its reproductive season is marked by the beginning of the dry season. No significant differences were found between the established behavior categories and the time of day (Fisher, P> 0.05). However, significant differences were shown for the behavioral categories and the vertical stratum (Fisher, P <0.05) demonstrating that it uses the entire vertical stratum of the vegetation structure. Conclusions: This study represents the basis for the knowledge of the reproductive biology and natural history of C. ferrugineus, it is urgent to carry out more studies on this species to be able to protect it and conserve the terrestrial ecosystem of Isla del Coco.

Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial : The CLAU Randomized Trial Long-Term Outcome.

INTRODUCTION: The Clinical and Endothelial Function Assessment after Endothelin Receptor Antagonist (CLAU) trial demonstrated the effect of bosentan on the endothelial function, inflammatory status and claudication distance in Hispanic patients with incipient peripheral arterial disease (PAD). Our aim was to assess the protective effect on cardiovascular events of bosentan versus conventional anti-atherosclerosis therapy. METHODS: CLAU included 56 patients with intermittent claudication, randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29), associating the best medical treatment. Log-rank and hazard ratio (HR) analyses were performed to estimate the relative efficacy of bosentan in preventing incidence of major adverse events (MAE) including target limb revascularization (TLR), amputation, myocardial infarction (MI), and all-cause death; major cardiovascular adverse events (MACE) including TLR, amputation, MI, stroke, and cardiovascular-cause death; and major adverse limb events (MALE), which combines TLR and amputation. RESULTS: During the follow-up period (34 ± 5 months), five MAE occurred in the control group only (17.2%), including two TLR, one amputation, one stroke, and an MI. The ratio of event-free survival for MAE to 3 years follow-up was higher in the group treated with bosentan (100% vs 66%, p = 0.01, HR = 76; 95% confidence interval 0.05-104,677, p = 0.24). A similar trend was observed in incidence of MACE (100% vs 66%, p = 0.01) and MALE (100% vs 80%, p = 0.15). CONCLUSION: Treatment with bosentan in the early low-to-mild stages of PAD may prevent cardiovascular events and the need for lower limb revascularization in the Hispanic population. Trial Registration ClinicalTrials.gov identifier NCT25102012.

Effect of monotherapy with darunavir/cobicistat on viral load and semen quality of HIV-1 patients.

Many patients previously using darunavir/ritonavir (DRV/r) (800/100mg) have switched to darunavir/cobicistat (DRV/C) (800/150 mg) either as part of triple therapy (ART) or as monotherapy with DRV (mDRV). The latter approach continues to be used in some countries for patients receiving long-term treatment. However, to date, the behaviour of DRV/C in the seminal compartment has not been analysed. This study explores how the combination behaves in monotherapy, with respect to the control of viral load and seminal quality. To this end, we studied 20 patients who were treated with mDRV/C after previous treatment with mDRV/r for at least 24 weeks. A viral load control in seminal plasma similar to that published in the literature was observed after 24 weeks of treatment with mDRV/C (viral load positivity in 20% of patients). Similarly, semen quality was confirmed (70% normozoospermic) in patients treated with this formulation, as has previously been reported for ART and mDRV/r. The DRV levels measured in seminal plasma were above EC50, regardless of whether the seminal viral load was positive or negative. We conclude that this mDRV/C co-formulation behaves like mDRV/r in seminal plasma in terms of viral load control and semen quality.

Differential mRNA expression of inflammasome genes NLRP1 and NLRP3 in abdominal aneurysmal and occlusive aortic disease.

NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD). We measure differential relative gene expression of NLRP1 and NLRP3 inflammasomes in aortic tissues from 30 patients undergoing AAA open repair compared to aortic biopsies from 30 patients undergoing surgery to treat AOD. Aortic wall samples from autopsy without aortic disease were used as controls. NLRP3 was overexpressed in patients with AAA and AOD (RQ 1.185 ± 0.15, and 1.098 ± 0.05, respectively) compared to donors (RQ 1.001 ± 0.08) (OR 2.8, 95% CI 1.2-4.3, p < 0.05 for AAA and OR 2.1, 95% CI 1.1-3.8, p < 0.05 for AOD). NLRP1 gene expression was significantly upregulated in patients with AOD (RQ 1.197 ± 0.09). Meanwhile, NLRP1 was normal expressed in AAA (RQ 1.003 ± 0.07) as well as in autopsy aortic specimens (RQ 1.005 ± 0.11). Enhanced NLRP1 expression in AOD was even significant when compared to AAA (OR 2.3, 95% CI 1.2-3.3, p < 0.05) or controls (OR 2.2, 95% CI 1.1-3.1, p < 0.05). According to our findings, NLRP3 could be involved in the common etiology of AAA and AOD, whereas NLRP1 appears to have a specific role in AOD development.

Differential mRNA expression of inflammasome genes NLRP1 and NLRP3 in abdominal aneurysmal and occlusive aortic disease.

NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD). We measure differential relative gene expression of NLRP1 and NLRP3 inflammasomes in aortic tissues from 30 patients undergoing AAA open repair compared to aortic biopsies from 30 patients undergoing surgery to treat AOD. Aortic wall samples from autopsy without aortic disease were used as controls. NLRP3 was overexpressed in patients with AAA and AOD (RQ 1.185 ± 0.15, and 1.098 ± 0.05, respectively) compared to donors (RQ 1.001 ± 0.08) (OR 2.8, 95% CI 1.2-4.3, p < 0.05 for AAA and OR 2.1, 95% CI 1.1-3.8, p < 0.05 for AOD). NLRP1 gene expression was significantly upregulated in patients with AOD (RQ 1.197 ± 0.09). Meanwhile, NLRP1 was normal expressed in AAA (RQ 1.003 ± 0.07) as well as in autopsy aortic specimens (RQ 1.005 ± 0.11). Enhanced NLRP1 expression in AOD was even significant when compared to AAA (OR 2.3, 95% CI 1.2-3.3, p < 0.05) or controls (OR 2.2, 95% CI 1.1-3.1, p < 0.05). According to our findings, NLRP3 could be involved in the common etiology of AAA and AOD, whereas NLRP1 appears to have a specific role in AOD development.

Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications.

The objective of this review is to outline existing artificial mitochondria transfer techniques and to describe the future steps necessary to develop new therapeutic applications in medicine. Inspired by the symbiotic origin of mitochondria and by the cell's capacity to transfer these organelles to damaged neighbors, many researchers have developed procedures to artificially transfer mitochondria from one cell to another. The techniques currently in use today range from simple coincubations of isolated mitochondria and recipient cells to the use of physical approaches to induce integration. These methods mimic natural mitochondria transfer. In order to use mitochondrial transfer in medicine, we must answer key questions about how to replicate aspects of natural transport processes to improve current artificial transfer methods. Another priority is to determine the optimum quantity and cell/tissue source of the mitochondria in order to induce cell reprogramming or tissue repair, in both in vitro and in vivo applications. Additionally, it is important that the field explores how artificial mitochondria transfer techniques can be used to treat different diseases and how to navigate the ethical issues in such procedures. Without a doubt, mitochondria are more than mere cell power plants, as we continue to discover their potential to be used in medicine.

[Suicide attempts and self inflicted harm: a one year follow up of risk behaviors among out of treatment cocaine users]. / Intentos de suicidio y heridas auto-inferidas: 12 meses de seguimiento de conductas de riesgo de consumidores de cocaína no consultantes de servicios de rehabilitación.

BACKGROUND: Cocaine users tend to have a higher frequency of risk behaviors. AIM: To compare risk behaviors of out -of -treatment Cocaine Base Paste (CBP) and Cocaine Hydrochloride (CH) users, by means of Privileged Access Interviewing in a one- year prospective study. MATERIAL AND METHODS: Twenty -eight interviewers were trained to recruit and administer a questionnaire on substance use patterns and related risk behaviors. Intentioned sampling was carried out in four municipalities of Santiago, Chile. Subjects who used CBP (group 1) or CH (group 2) at least once in the last month, with primary current use of CBP (group 1) or CH (group 2), and without treatment for substance abuse in the last six months were interviewed. Generalized Estimating Equations (GEE) were employed to compare risk behaviors during follow -up. RESULTS: Four hundred and two of 467 subjects (86.1%) were followed up for one year. CBP users (n = 204) reported greater frequency of self -inflicted injuries (Odds Ratio (OR): 1.97 [95% confidence intervals (CI): 1.07-3.66]) and suicide attempts (OR: 2.68 [95% CI: 1.19-6.01]) than CH users. CONCLUSIONS: CBP users had a greater frequency of self -inflicted injuries and suicide attempts, both life threatening risk behaviors, than CH users. This profile shows the high vulnerability of CBP users and should encourage further research and design of outreach interventions, particularly focused on this group.

Intentos de suicidio y heridas auto-inferidas: 12 meses de seguimiento de conductas de riesgo de consumidores de cocaína no consultantes de servicios de rehabilitación / Suicide attempts and self inflicted harm: a one year follow up of risk behaviors among out of treatment cocaine users

Background: Cocaine users tend to have a higher frequency of risk behaviors. Aim: To compare risk behaviors of out ­of ­treatment Cocaine Base Paste (CBP) and Cocaine Hydrochloride (CH) users, by means of Privileged Access Interviewing in a one­ year prospective study. Material and Methods: Twenty ­eight interviewers were trained to recruit and administer a questionnaire on substance use patterns and related risk behaviors. Intentioned sampling was carried out in four municipalities of Santiago, Chile. Subjects who used CBP (group 1) or CH (group 2) at least once in the last month, with primary current use of CBP (group 1) or CH (group 2), and without treatment for substance abuse in the last six months were interviewed. Generalized Estimating Equations (GEE) were employed to compare risk behaviors during follow ­up. Results: Four hundred and two of 467 subjects (86.1%) were followed up for one year. CBP users (n = 204) reported greater frequency of self ­inflicted injuries (Odds Ratio (OR): 1.97 [95% confidence intervals (CI): 1.07­3.66]) and suicide attempts (OR: 2.68 [95% CI: 1.19­6.01]) than CH users. Conclusions: CBP users had a greater frequency of self ­inflicted injuries and suicide attempts, both life threatening risk behaviors, than CH users. This profile shows the high vulnerability of CBP users and should encourage further research and design of outreach interventions, particularly focused on this group.

Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans.

Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

Factors associated with unreported tuberculosis cases in Spanish hospitals.

BACKGROUND: Under-reporting of tuberculosis (TB) cases complicates disease control, hinders contact tracing and alters the accuracy of epidemiological data, including disease burden. The objective of the present study is to evaluate the proportion of unreported TB cases in Spanish healthcare facilities and to identify the associated factors. METHODS: A multi-center retrospective study design was employed. The study included TB cases diagnosed in 16 facilities during 2011-2012. These cases were compared to those reported to the corresponding public health departments. Demographic, microbiological and clinical data were analyzed to determine the factors associated with unreported cases. Associated factors were analyzed on a bivariate level using the x(2) test and on a multivariate level using a logistic regression. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated. RESULTS: Of the 592 TB cases included in the study, 85 (14.4 %) were not reported. The percentage of unreported cases per healthcare center ranged from 0-45.2 %. The following variables were associated to under-reporting at a multivariate level: smear-negative TB (OR = 1.87; CI:1.07-3.28), extrapulmonary disease (OR = 2.07; CI:1.05-4.09) and retired patients (OR = 3.04; CI:1.29-7.18). A nurse case manager was present in all of the centers with 100 % reporting. The percentage of reported cases among the smear-positive cases was 9.4 % and 19.4 % (p = 0.001) among the rest of the study population. Smear-positive TB was no associated to under-reporting. CONCLUSIONS: It is important that TB Control Programs encourage thorough case reporting to improve disease control, contact tracing and accuracy of epidemiological data. The help from a TB nurse case manager could improve the rate of under-reporting.