Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise.

Major depressive disorder (MDD) has a high prevalence and is a major contributor to the global burden of disease. This psychiatric disorder results from a complex interaction between environmental and genetic factors. In recent years, the role of the gut microbiota in brain health has received particular attention, and compelling evidence has shown that patients suffering from depression have gut dysbiosis. Several studies have reported that gut dysbiosis-induced inflammation may cause and/or contribute to the development of depression through dysregulation of the gut-brain axis. Indeed, as a consequence of gut dysbiosis, neuroinflammatory alterations caused by microglial activation together with impairments in neuroplasticity may contribute to the development of depressive symptoms. The modulation of the gut microbiota has been recognized as a potential therapeutic strategy for the management of MMD. In this regard, physical exercise has been shown to positively change microbiota composition and diversity, and this can underlie, at least in part, its antidepressant effects. Given this, the present review will explore the relationship between physical exercise, gut microbiota and depression, with an emphasis on the potential of physical exercise as a non-invasive strategy for modulating the gut microbiota and, through this, regulating the gut-brain axis and alleviating MDD-related symptoms.

Caloric restriction improves inflammation in different tissues of the Wistar rats with obesity and 2K1C renovascular hypertension.

Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-ß1 (TGF-ß), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-ß in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. METHODS: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. RESULTS: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. CONCLUSIONS: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

BACKGROUND: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum ß-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. OBJECTIVES: To assess the pharmacodynamics of flomoxef and amikacin in combination. METHODS: The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. RESULTS: Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. CONCLUSIONS: We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

Prophylactic efficacy of ketamine, but not the low-trapping NMDA receptor antagonist AZD6765, against stress-induced maladaptive behavior and 4E-BP1-related synaptic protein synthesis impairment.

Ketamine enhances the resilience against stress-induced depressive-like behavior, but its prophylactic efficacy in anxiety-related behaviors remains to be elucidated. Moreover, there is a need for developing novel preventive strategies against depressive- and anxiety-like behavior. AZD6765, a low-trapping NMDA receptor antagonist, shares with ketamine common molecular targets and produces rapid-onset antidepressant effects, suggesting that it could be a prophylactic agent. Therefore, this study investigated the prophylactic effect of ketamine against the depressive- and anxiety-like behavior induced by chronic restraint stress (2 h/day, for 10 days) in mice. We also investigated if AZD6765 exerts a resilience-enhancing response against these maladaptive behaviors. The contribution of 4E-BP1-related synaptic proteins synthesis (PSD-95/GluA1) in the possible pro-resilience efficacy of ketamine and AZD6765 was investigated. A single administration of ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), given 1 week before the stress protocol, was effective in preventing stress-induced depressive-like behavior in the tail suspension test and splash test. Ketamine administered at 1 and 5 mg/kg (i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), prevented stress-induced anxiety-related self-grooming alterations. Stress-induced reduction on 4E-BP1 phosphorylation and PSD-95 and GluA1 immunocontent in the prefrontal cortex was prevented by ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.). The results indicate that ketamine, but not AZD6765, exerts a pro-resilience response against stress-induced maladaptive behavior, reinforcing that it could be a prophylactic agent to manage individuals at-risk to develop MDD and anxiety.

Relevance of TMPRSS2, CD163/CD206, and CD33 in clinical severity stratification of COVID-19.

Background: Approximately 13.8% and 6.1% of coronavirus disease 2019 (COVID-19) patients require hospitalization and sometimes intensive care unit (ICU) admission, respectively. There is no biomarker to predict which of these patients will develop an aggressive stage that we could improve their quality of life and healthcare management. Our main goal is to include new markers for the classification of COVID-19 patients. Methods: Two tubes of peripheral blood were collected from a total of 66 (n = 34 mild and n = 32 severe) samples (mean age 52 years). Cytometry analysis was performed using a 15-parameter panel included in the Maxpar® Human Monocyte/Macrophage Phenotyping Panel Kit. Cytometry by time-of-flight mass spectrometry (CyTOF) panel was performed in combination with genetic analysis using TaqMan® probes for ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants. GemStone™ and OMIQ software were used for cytometry analysis. Results: The frequency of CD163+/CD206- population of transitional monocytes (T-Mo) was decreased in the mild group compared to that of the severe one, while T-Mo CD163-/CD206- were increased in the mild group compared to that of the severe one. In addition, we also found differences in CD11b expression in CD14dim monocytes in the severe group, with decreased levels in the female group (p = 0.0412). When comparing mild and severe disease, we also found that CD45- [p = 0.014; odds ratio (OR) = 0.286, 95% CI 0.104-0.787] and CD14dim/CD33+ (p = 0.014; OR = 0.286, 95% CI 0.104-0.787) monocytes were the best options as biomarkers to discriminate between these patient groups. CD33 was also indicated as a good biomarker for patient stratification by the analysis of GemStone™ software. Among genetic markers, we found that G carriers of TMPRSS2 (rs2070788) have an increased risk (p = 0.02; OR = 3.37, 95% CI 1.18-9.60) of severe COVID-19 compared to those with A/A genotype. This strength is further increased when combined with CD45-, T-Mo CD163+/CD206-, and C14dim/CD33+. Conclusions: Here, we report the interesting role of TMPRSS2, CD45-, CD163/CD206, and CD33 in COVID-19 aggressiveness. This strength is reinforced for aggressiveness biomarkers when TMPRSS2 and CD45-, TMPRSS2 and CD163/CD206, and TMPRSS2 and CD14dim/CD33+ are combined.

Agmatine as a novel candidate for rapid-onset antidepressant response.

Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

Anti-inflammatory and antioxidant properties of Alternanthera brasiliana improve cutaneous wound healing in rats.

Alternanthera brasiliana (L.) Kuntze is recognized for its healing properties; however, its therapeutic effects remain unclear. Therefore, our study aimed to elucidate the wound healing activities of A. brasiliana using in vitro and in vivo assays. In vitro assays were used to evaluate the antibacterial, anti-inflammatory, and antioxidant effects of A. brasiliana extract. For the in vivo study, two dorsal excisions were established in Wistar rats using a punch (1.5 cm in diameter), which were topically treated daily with 2% carbopol gel (Ctrl group) or 20% hydroalcoholic plant extract with 2% carbopol gel (A. brasiliana-Ab group). After the 2nd, 7th, 14th, and 21st days, inflammation, oxidative damage, antioxidants, angiogenesis, tissue formation, and re-epithelialization were evaluated. In vitro, Ab reduced nitric oxide, anion superoxide, and pro-inflammatory cytokine production. In vivo, Ab presented lower levels of inflammatory infiltrate, although increased levels of IL-1ß and TGF-ß1 were observed. The plant extract controlled oxidative damage by antioxidants, which favored angiogenesis, collagenesis, and wound re-epithelialization. Thus, the topical application of the hydroalcoholic extract of 20% A. brasiliana was distinguished by its important anti-inflammatory and antioxidant activities both in vivo and in vitro. The plant extract also stimulated angiogenesis and tissue formation, accelerating total re-epithelization, which is promising for wound healing.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Uso de la sedación y anestesia en los pacientes pediátricos sometidos a radioterapia / Use of sedation and anesthesia in the pediatrics patients undergoing radiotherapy

Resumen Justificación: La radioterapia es esencial para el tratamiento del cáncer pediátrico. Al menos la mitad de los niños que requieren radioterapia van a necesitar sedación o anestesia. Es importante conocer las complicaciones potenciales asociadas con el uso repetitivo de medicamentos sedantes o anestésicos. El objetivo del estudio fue describir las características clínicas y epidemiológicas de los pacientes con diagnóstico de cáncer del Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera", de la Caja Costarricense de Seguro Social, que recibieron sedación o anestesia durante su tratamiento con radioterapia externa en el período de enero del 2016 a junio del 2019. Métodos: Es un estudio observacional, descriptivo y retrospectivo de una serie de casos. Se incluyeron pacientes pediátricos con diagnóstico de cáncer, sometidos a tratamiento con radioterapia y que requirieron sedación o anestesia durante esa intervención. Las técnicas estadísticas utilizadas para las variables cualitativas fueron tablas de frecuencias simples y de asociación o contingencia; las variables cuantitativas se describen mediante estadígrafos de tendencia central y posición, así como de variabilidad. Resultados: Un total de 61 pacientes con diagnóstico de cáncer y que recibieron radioterapia fueron estudiados. El 57,4% de los pacientes fueron hombres. El 75% de los pacientes tenía 4,0 años o menos. La localización anatómica más frecuente del tumor fue en sistema nervioso central. Una minoría (14,5%) recibió como tratamiento único la radioterapia. El 75% de los pacientes recibió 30 o menos sesiones de tratamiento bajo sedación o anestesia. El propofol se suministró al 100,0% de los pacientes en todas las sesiones de tratamiento. El tiempo promedio de sedación o anestesia fue de 67,9 ± 28,2 minutos. El 34,4% de los pacientes presentaron complicaciones respiratorias, cardiovasculares o ambas, en al menos una sesión de tratamiento. Conclusiones: En los pacientes pediátricos con cáncer quienes reciben tratamiento con radioterapia, fue requerido el uso de la sedación y anestesia principalmente en niños de corta edad; en general, las complicaciones de la radioterapia fueron transitorias y usualmente bien toleradas, sin presentar morbimortalidad. Como monoterapia, el Propofol no mostró complicaciones asociadas; sin embargo, al adicionar otros fármacos sí se observaron complicaciones respiratorias y predominó la desaturación transitoria de oxígeno.

Abstract Background: Radiation therapy is essential for the treatment of pediatric cancer. At least half of the children who require radiation therapy will need sedation or anesthesia. It is important to know the potential complications associated with repetitive use of sedative or anesthetic medications. The objective of the study was to describe the clinical and epidemiological characteristics of patients diagnosed with cancer at the National Children's Hospital "Dr. Carlos Sáenz Herrera" of the Costa Rican Social Security Fund, who received sedation or anesthesia during their treatment with external radiotherapy in the period from January 2016 to June 2019. Methods: It is an observational, descriptive and retrospective study of a series of cases. Pediatric patients diagnosed with cancer, who underwent radiotherapy treatment and who required sedation or anesthesia during that intervention were included. The statistical techniques used for the qualitative variables were simple frequency tables and association or contingency tables; quantitative variables are described using central tendency and position statistics, as well as variability. Results: A total of 61 patients diagnosed with cancer and receiving radiotherapy were studied. 57.4% of the patients were men. 75% of patients were 4.0 years or younger. The most frequent anatomic location of the tumor was in the central nervous system. A minority (14.5%) received radiotherapy as the only treatment. 75% of patients received 30 or fewer treatment sessions under sedation or anesthesia. Propofol was administered to 100.0% of patients in all treatment sessions. The average sedation or anesthesia time was 67.9 ± 28.2 minutes. 34.4% of the patients presented respiratory or cardiovascular complications, or both, in at least onetreatment session. Conclusions: In pediatric patients diagnosed with cancer, the use of sedation and anesthesia during radiotherapy treatment was required mainly in young children and in moderate frequency, the complications of the radiation therapy were temporary and usually well tolerated, without presenting morbidity and mortality. Propofol as monotherapy turned out to have no associated complications, however, when other drugs were added, adverse effects were observed in respiratory system, the most frequent being transient oxygen desaturation.

Pharmacodynamics of the Novel Metallo-ß-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

Enterobacteriaceae that produce metallo-ß-lactamases (MBLs) are an emerging threat to public health. The metallo-ß-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner ß-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

A Rare Presentation of Invasive Tuberculosis of the Central Nervous System in an Immunocompetent Patient in a Nonendemic Country.

We herein report a rare case of a 25-year-old immunocompetent male patient with disseminated tuberculosis of central nervous system (CNS), first presenting as multiple cerebral lesions with no meningeal involvement. Subsequent diagnostic workup disclosed extensive peritoneal involvement. A broad differential diagnosis was considered, including neoplastic and infectious diseases. The diagnosis was confirmed with positive PCR result for Mycobacterium tuberculosis in the biopsied mesenteric tissue. The patient was started on tuberculostatic regimen with favorable outcome. No acquired or hereditary immunodeficiency was documented. Disseminated tuberculosis in immunocompetent individuals is extremely rare. Genetic susceptibility factors have been reported in individuals with extensive forms of the disease and a high index of suspicion is required, as observed in our case.

Pulmonary arterial hypertension in Latin America: epidemiological data from local studies.

BACKGROUND: Pulmonary arterial hypertension is a rare, progressive disease with poor prognosis. However, there is limited information available on the characteristics of PAH patients outside of North America and Europe. This is particularly important as researchers have described that there are potential geographical and regional differences which are vital to consider in the design of clinical trials as well as PAH treatment. The aim of this study was to describe the epidemiology of PAH (PH group 1) in Latin America. METHODS: A search of electronic databases for studies published in English, Spanish or Portuguese was conducted specifying publication dates from the 1st of January 1987 until 10th October 2016. Two authors independently assessed papers for inclusion and extracted data. A narrative synthesis of the findings was conducted. RESULTS: The search revealed 22 conference abstracts and articles, and on application of the inclusion criteria, six conference abstracts and articles were included in the final review. Studies/registries were based in Argentina, Brazil and Chile. In contrast to the available literature from developed countries, in Latin America, most patients were diagnosed at younger age; nevertheless, the higher prevalence of idiopathic PAH (IPAH) and the advanced stage of the disease at diagnosis were comparable to the existing literature, as the long term survival, despite the lower availability of targeted therapies. CONCLUSION: This study highlights the regional characteristics in the epidemiology of group 1 PH. The recognition of these differences should be considered when developing clinical guidelines and extrapolating diagnostic and treatment algorithms. Equitable access to health care and therapies are also issues that need to be addressed in Latin America. Information coming from a large prospective registry representing the different populations in Latin America is of critical importance to increase disease awareness in the region and improve diagnosis and management.

DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.

DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow-channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS.

Screening for Pompe disease in a Portuguese high risk population.

Pompe disease is a rare metabolic disorder with available enzymatic replacement therapy. Contrasting with the classic infantile form, the others subtypes have a heterogeneous presentation that makes an early and accurate diagnosis difficult. We conducted a prospective, multicenter, observational study to identify undiagnosed patients. During a one-year period, patients followed in Portuguese neuromuscular outpatient clinics with proximal muscle weakness affecting upper and/or lower limbs, hyperCKemia in two or more determinations or hypotonia and hyperCKemia, were screened for acid α-glucosidase deficiency by dried blood spots. Lysosomal acid-alpha-1,4-glucosidase activity was determined by tandem mass spectrometry and positive results were confirmed by molecular study. From the 99 patients screened, Pompe disease was confirmed in 4, with age of onset ranging from 2.5 to 48 years, all with limb girdle muscle weakness, corresponding to a frequency of 4% in our cohort and 4.9% of limb girdle muscle weakness. Screening for Pompe disease in high risk populations, using dried blood spots, was already performed in some European populations. Apart from two negative Scandinavian studies, positive cases were confirmed in 2.8-7.9% of patients presenting with limb girdle muscle weakness and in 0-2.5% with isolated hyperCKemia.

A Case Report of Nonvasculitic Autoimmune Inflammatory Meningoencephalitis with Sensory Ganglionopathy: A Rare Presentation of Sjögren Syndrome.

A 68-year-old Caucasian female was admitted to the emergency department with a progressive history of behavioural symptoms and anxiety followed by visual and auditory hallucinations, forgetfulness, and impaired gait in the previous 3 months. On examination she was psychotic and had a postural and rest tremor of the upper limbs, cogwheel rigidity of the four limbs, retropulsion on standing position, and inability to walk. During the following 2 weeks she developed xerostomia and unilateral parotiditis that improved with steroids. A simultaneous improvement of the cognitive abilities allowed for the detection of sensory ataxia of the lower limbs. Sensory ganglionopathy was then detected with electrophysiological studies. A diagnosis of Sjögren syndrome was suspected and confirmed by salivary gland scintigraphy, Schirmer's test, and submaxillary gland biopsy. We report a case of Sjögren syndrome associated with central and peripheral nervous system involvement, without sicca symptoms preceding the neurological clinical picture. The coexistence of ganglionopathy and a favourable response to immunosuppression are key features that can lead to the correct diagnosis in cases with atypical CNS symptoms, mimicking a rapidly progressive dementia.