Rickettsia conorii survival in THP-1 macrophages involves host lipid droplet alterations and active rickettsial protein production.

Rickettsia conorii is a Gram-negative, cytosolic intracellular bacterium that has classically been investigated in terms of endothelial cell infection. However, R. conorii and other human pathogenic Rickettsia species have evolved mechanisms to grow in various cell types, including macrophages, during mammalian infection. During infection of these phagocytes, R. conorii shifts the host cell's overall metabolism towards an anti-inflammatory M2 response, metabolically defined by an increase in host lipid metabolism and oxidative phosphorylation. Lipid metabolism has more recently been identified as a key regulator of host homeostasis through modulation of immune signalling and metabolism. Intracellular pathogens have adapted mechanisms of hijacking host metabolic pathways including host lipid catabolic pathways for various functions required for growth and survival. In the present study, we hypothesised that alterations of host lipid droplets initiated by lipid catabolic pathways during R. conorii infection is important for bacterial survival in macrophages. Herein, we determined that host lipid droplet modulation is initiated early during R. conorii infection, and these alterations rely on active bacteria and lipid catabolic pathways. We also find that these lipid catabolic pathways are essential for efficient bacterial survival. Unlike the mechanisms used by other intracellular pathogens, the catabolism of lipid droplets induced by R. conorii infection is independent of upstream host peroxisome proliferator-activated receptor-alpha (PPARα) signalling. Inhibition of PPARÉ£ signalling and lipid droplet accumulation in host cells cause a significant decrease in R. conorii survival suggesting a negative correlation with lipid droplet production and R. conorii survival. Together, these results strongly suggest that the modulation of lipid droplets in macrophage cells infected by R. conorii is an important and underappreciated aspect of the infection process. TAKE AWAYS: Host lipid droplets are differentially altered in early and replicative stages of THP-1 macrophage infection with R. conorii. Lipid droplet alterations are initiated in a bacterial-dependent manner and do not require host peroxisome proliferator-activated receptors α or É£ activation. Pharmacological inhibition of host lipid catabolic processes during R. conorii infection indicates a requirement of lipid catabolism for bacterial survival and initiation of lipid droplet modulation. A significant increase in host lipid droplets during infection has a negative impact on R. conorii survival in THP-1 macrophages.

Factors associated with weight loss in people with overweight or obesity living with type 2 diabetes mellitus: Insights from the global DISCOVER study.

AIMS: To estimate real-world change in weight over 3 years and the factors influencing it in participants who are overweight and live with type 2 diabetes. MATERIALS AND METHODS: DISCOVER is a multinational prospective observational study that enrolled participants with type 2 diabetes between December 2014 and June 2016 at the time of initiation of a second-line glucose-lowering medication (GLM). Demographic, anthropometric, and quality-of-life data were collected at baseline, and after 6, 12, 24 and 36 months of follow-up. Using a hierarchical, repeated-measures linear regression model, we examined factors associated with weight change over time. RESULTS: Of 10 675 participants with type 2 diabetes who were overweight/obese (mean age 57.1 ± 11.1 years, 46% women), 21% lost ≥5% weight over 3 years, which was associated with modestly improved physical and mental health. Advancing age, female sex, and higher baseline weight were associated with weight loss. Most importantly, the type of GLM prescribed at previous visit had the strongest impact on weight change over time independent of participant factors, with use of a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist associated with 1.0% weight loss versus a 0.6% weight gain with sulphonylureas, thiazolidinediones, meglitinides or insulin. CONCLUSION: In this large contemporary prospective study, approximately one in five participants with early-stage type 2 diabetes and overweight/obesity lost ≥5% weight over 3 years. The type of GLM has the most impact on weight loss over time, highlighting the need for a careful selection of agents that takes baseline weight into consideration.

Switching between GLP-1 receptor agonists in clinical practice: Expert consensus and practical guidance.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an established treatment for patients with type 2 diabetes (T2D). Differences between GLP-1RAs in pharmacokinetics, dosing regimens and clinical effects, including cardiovascular (CV) outcomes, mean there may be benefits to switching from one to another. However, clinical guidance on switching is lacking and data from clinical trials are limited. This article provides a clinical perspective and consensus on the benefits of switching between GLP-1RAs, the triggers for switching and how best to manage this in clinical practice. Once weekly (OW) semaglutide is used as an example to illustrate how the authors might switch to a different GLP-1RA in clinical practice. METHODS: Literature was searched and perspectives from 10 healthcare professionals with experience in switching patients with T2D to OW semaglutide from another GLP-1RA were collated. RESULTS: Medical triggers for switching to another GLP-1RA included HbA1c targets not being met, a desire for additional weight loss, poor adherence, patients moving to increased CV risk status and adverse effects with the current GLP-1RA. Non-medical triggers for switching included patient preference, cost, formulary changes and insurance mandates. Once the decision to switch is made, an individualised approach is recommended, based on considerations that include reimbursement requirements, treatment duration with (and dose of) previous GLP-1RA, the patient's experience initiating the prior GLP-1RA, any concomitant treatment and clinical characteristics. When switching, it is important to emphasise that treatment burden will not increase and that if gastrointestinal adverse effects occur, they are typically transient. Any transient gastrointestinal adverse effects that may occur (or recur) when switching to another GLP-1RA can be reduced by slow up-titration and advising patients to reduce food portion sizes and fat intake. CONCLUSION: Switching from one GLP-1RA to another, such as OW semaglutide, can provide clinical benefits and may delay the need for treatment intensification.

Effectiveness and tolerability of orlistat and liraglutide in patients with obesity in a real-world setting: The XENSOR Study.

AIMS: To evaluate in a real-world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. METHODS: Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with at least a weight-related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification. The co-primary end-points, assessed at 3-6 months and at the end of the follow-up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs. RESULTS: Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included. Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low-density lipoprotein-cholesterol and alanine transaminase over a median follow-up period of 7 months. WL with liraglutide (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. CONCLUSIONS: In this real-world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.

Immunity against the Obligate Intracellular Bacterial Pathogen Rickettsia australis Requires a Functional Complement System.

The complement system has a well-defined role in deterring blood-borne infections. However, complement is not entirely efficacious, as several bacterial pathogens, including some obligate intracellular pathogens, have evolved mechanisms for resistance. It is presumed that obligate intracellular bacteria evade complement attack by residing within a host cell; however, recent studies have challenged this presumption. Here, we demonstrate that the complement system is activated during infection with the obligate intracellular bacterium Rickettsia australis and that genetic ablation of complement increases susceptibility to infection. Interaction of Rickettsia australis with serum-borne complement leads to activation of the complement cascade, producing three effector mechanisms that could negatively influence R. australis. The C9-dependent membrane attack complex can lead to deposition of a bacteriolytic membrane pore on the bacteria, but this system does not contribute to control of rickettsial infection. Similarly, complement receptor (CR1/2)-dependent opsonophagocytosis may lead to engulfment and killing of the bacteria, but this system is also dispensable for immunity. Nevertheless, intact complement is essential for naturally acquired and antibody-mediated immunity to Rickettsia infection. Comparison of infection in mice lacking the central complement protein C3 with infection in their wild-type counterparts demonstrated decreases in gamma interferon (IFN-γ) production, IgG secretion, and spleen hyperplasia in animals lacking complement. The correlation between loss of secondary immune functions and loss of complement indicates that the proinflammatory signaling components of the complement system, and not membrane attack complex or opsonophagocytosis, contribute to the immune response to this pathogen.

Nonselective Persistence of a Rickettsia conorii Extrachromosomal Plasmid during Mammalian Infection.

Scientific analysis of the genus Rickettsia is undergoing a rapid period of change with the emergence of viable genetic tools. The development of these tools for the mutagenesis of pathogenic bacteria will permit forward genetic analysis of Rickettsia pathogenesis. Despite these advances, uncertainty still remains regarding the use of plasmids to study these bacteria in in vivo mammalian models of infection, namely, the potential for virulence changes associated with the presence of extrachromosomal DNA and nonselective persistence of plasmids in mammalian models of infection. Here, we describe the transformation of Rickettsia conorii Malish 7 with the plasmid pRam18dRGA[AmTrCh]. Transformed R. conorii stably maintains this plasmid in infected cell cultures, expresses the encoded fluorescent proteins, and exhibits growth kinetics in cell culture similar to those of nontransformed R. conorii. Using a well-established murine model of fatal Mediterranean spotted fever, we demonstrate that R. conorii(pRam18dRGA[AmTrCh]) elicits the same fatal outcomes in animals as its untransformed counterpart and, importantly, maintains the plasmid throughout infection in the absence of selective antibiotic pressure. Interestingly, plasmid-transformed R. conorii was readily observed both in endothelial cells and within circulating leukocytes. Together, our data demonstrate that the presence of an extrachromosomal DNA element in a pathogenic rickettsial species does not affect either in vitro proliferation or in vivo infectivity in models of disease and that plasmids such as pRam18dRGA[AmTrCh] are valuable tools for the further genetic manipulation of pathogenic rickettsiae.

RC1339/APRc from Rickettsia conorii is a novel aspartic protease with properties of retropepsin-like enzymes.

Members of the species Rickettsia are obligate intracellular, gram-negative, arthropod-borne pathogens of humans and other mammals. The life-threatening character of diseases caused by many Rickettsia species and the lack of reliable protective vaccine against rickettsioses strengthens the importance of identifying new protein factors for the potential development of innovative therapeutic tools. Herein, we report the identification and characterization of a novel membrane-embedded retropepsin-like homologue, highly conserved in 55 Rickettsia genomes. Using R. conorii gene homologue RC1339 as our working model, we demonstrate that, despite the low overall sequence similarity to retropepsins, the gene product of rc1339 APRc (for Aspartic Protease from Rickettsia conorii) is an active enzyme with features highly reminiscent of this family of aspartic proteases, such as autolytic activity impaired by mutation of the catalytic aspartate, accumulation in the dimeric form, optimal activity at pH 6, and inhibition by specific HIV-1 protease inhibitors. Moreover, specificity preferences determined by a high-throughput profiling approach confirmed common preferences between this novel rickettsial enzyme and other aspartic proteases, both retropepsins and pepsin-like. This is the first report on a retropepsin-like protease in gram-negative intracellular bacteria such as Rickettsia, contributing to the analysis of the evolutionary relationships between the two types of aspartic proteases. Additionally, we have also shown that APRc is transcribed and translated in R. conorii and R. rickettsii and is integrated into the outer membrane of both species. Finally, we demonstrated that APRc is sufficient to catalyze the in vitro processing of two conserved high molecular weight autotransporter adhesin/invasion proteins, Sca5/OmpB and Sca0/OmpA, thereby suggesting the participation of this enzyme in a relevant proteolytic pathway in rickettsial life-cycle. As a novel bona fide member of the retropepsin family of aspartic proteases, APRc emerges as an intriguing target for therapeutic intervention against fatal rickettsioses.

Pathogenic Rickettsia species acquire vitronectin from human serum to promote resistance to complement-mediated killing.

Bacteria of the genus Rickettsia are transmitted from arthropod vectors and primarily infect cells of the mammalian endothelial system. Throughout this infectious cycle, the bacteria are exposed to the deleterious effects of serum complement. Using Rickettsia conorii, the etiologic agent of Mediterranean spotted fever (MSF), as a model rickettsial species, we have previously demonstrated that this class of pathogen interacts with human factor H to mediate partial survival in human serum. Herein, we demonstrate that R. conorii also interacts with the terminal complement complex inhibitor vitronectin (Vn). We further demonstrate that an evolutionarily conserved rickettsial antigen, Adr1/RC1281, interacts with human vitronectin and is sufficient to mediate resistance to serum killing when expressed at the outer-membrane of serum sensitive Escherichia coli. Adr1 is an integral outer-membrane protein whose structure is predicted to contain eight membrane-embedded ß-strands and four 'loop' regions that are exposed to extracellular milieu. Site-directed mutagenesis of Adr1 revealed that at least two predicted 'loop' regions are required to mediate resistance to complement-mediatedkilling and vitronectin acquisition. These results demonstrate that rickettsial species have evolved multiple mechanisms to evade complement deposition and that evasion of killing in serum is an evolutionarily conserved virulence attribute for this genus of obligate intracellular pathogens.

OmpA-mediated rickettsial adherence to and invasion of human endothelial cells is dependent upon interaction with α2ß1 integrin.

Rickettsia conorii, a member of the spotted fever group (SFG) of the genus Rickettsia and causative agent of Mediterranean spotted fever, is an obligate intracellular pathogen capable of infecting various mammalian cell types. SFG rickettsiae express two major immunodominant surface cell antigen (Sca) proteins, OmpB (Sca5) and OmpA (Sca0). While OmpB-mediated entry has been characterized, the contribution of OmpA has not been well defined. Here we show OmpA expression in Escherichia coli is sufficient to mediate adherence to and invasion of non-phagocytic human endothelial cells. A recombinant soluble C-terminal OmpA protein domain (954-1735) with predicted structural homology to the Bordetella pertussis pertactin protein binds mammalian cells and perturbs R. conorii invasion by interacting with several mammalian proteins including ß1 integrin. Using functional blocking antibodies, small interfering RNA transfection, and mouse embryonic fibroblast cell lines, we illustrate the contribution of α2ß1 integrin as a mammalian ligand involved in R. conorii invasion of primary endothelial cells. We further demonstrate that OmpA-mediated attachment to mammalian cells is in part dependent on a conserved non-continuous RGD motif present in a predicted C-terminal 'pertactin' domain in OmpA.Our results demonstrate that multiple adhesin-receptor pairs are sufficient in mediating efficient bacterial invasion of R. conorii.

Relatedness dynamics and sex-biased dispersal in a seasonal cycle of corn mice from intensively managed agroecosystems.

The sex-biased dispersal and kinship dynamics are important factors shaping the spatial distribution of individuals and are key parameters affecting a variety of ecological and evolutionary processes. Here, we studied the spatial distribution of related individuals within a population of corn mice Calomys musculinus in a seasonal cycle to infer dispersal patterns. The sampling was carried out from spring 2005 to winter 2006 in field borders of intensively managed agroecosystems. Genotyping data from 346 individuals with 9 microsatellites showed spatial genetic structure was weak for males, but not for females. The results indicate a complex spatial kinship dynamic of related females across all seasons. Which, contrary to our expectations, dispersal distances decrease with the increase of the population abundance. Meanwhile, male dispersal distances were greater when population abundance increased and thus the availability of active females. Males disperse greater distances to mate and sire offspring with distant females as a possible inbreeding avoidance mechanism. This study shows that C. musculinus is capable of much greater scattering distances than previously reported and that dispersal occurs fluidly and without barriers across the agroecosystem. The indirect benefit of dispersal on individual fitness could be related to relaxing the competition in the natal area and increasing the mating rate. Our study highlights the value of combining genetic relatedness, fieldwork observations, and behavioral data to estimate dispersal at a fine geographical scale.

Epidural Hematoma Associated with Red Clover Use After Epidural Injection: A Case Report.

An epidural hematoma is a rare but devastating complication after interventional pain procedures. The etiology is multifactorial, including anatomical variations, inherited coagulation disorders, and consumption of anticoagulants or antiplatelet substances. Specifically, in regard to platelet aggregation, the consumption of herbal medicine is often forgotten as a potential cause for coagulation profile disorders, potentially leading to an epidural hematoma. We present the case of a patient who developed an epidural hematoma after a cervical epidural block, most likely associated with daily "red clover" consumption.

Identification and characterization of the mammalian association and actin-nucleating domains in the Rickettsia conorii autotransporter protein, Sca2.

Establishment of infection by spotted fever group rickettsial species is dependent on the ability of these bacteria to adhere to and invade the host endothelium. Recent studies have attributed these processes to a handful of rickettsial surface proteins from the surface cell antigen (sca) family of autotransporters. A rickettsial autotransporter from Rickettsia conorii, Sca2, has been shown to be sufficient to mediate both adherence and invasion of human endothelial cells and to participate in intracellular actin-based motility. Here we identify a region of Sca2 capable of interacting with the mammalian cell surface and show that this function of Sca2 is independent and separable from its actin nucleation activity. Furthermore, pre-incubation of mammalian cells with the Sca2 mammalian association region prior to R. conorii infection can competitively inhibit rickettsial invasion, suggesting that Sca2 plays an important role in the initial interaction with mammalian cells. Together, our results demonstrate that the Sca2 autotransporter protein in R. conorii contains distinct functional domains that likely are involved in mediating cellular interactions at the plasma membrane and the host cytosol.

Effects of Aspergillus oryzae prebiotic on animal performance, nutrients digestibility, and feeding behavior of backgrounding beef heifers fed with either a sorghum silage- or a byproducts-based diet.

Eighty-four Angus crossbred heifers (13 ± 1 mo of age, 329.5 ± 61.92 kg of body weight [BW]) were used in a generalized randomized block design with a 2 × 2 factorial arrangement of treatments. The factors evaluated were: 1) diet type (whole plant sorghum silage [SS] vs. byproducts-based [BP]), and 2) feed additive: Aspergillus oryzae prebiotic (AOP; 2 g/d) vs. Negative control (CTL; 0 g/d), resulting in four treatments: sorghum silage-control (SC), sorghum silage-AOP (SA), byproducts-control (BC), and byproducts-AOP (BA). Heifers were stratified by body weight (BW), randomly assigned to treatments (21 heifers per treatment) and housed in 12 pens equipped with two GrowSafe feed bunks each to measure individual dry matter intake (DMI). After a 14-d adaptation, BW was measured every 14 d for 56 d. Chewing activity was monitored through collar-mounted HR-Tags (heat-related tags). Following the performance period, apparent total tract digestibility was measured in 40 heifers, using indigestible neutral detergent fiber as a marker. Heifers fed with the BP diets had greater DMI (2.92% vs. 2.59% of BW, P < 0.01) and average daily gain (ADG; 1.16 vs. 0.68 kg, P ≤ 0.01) than heifers fed with SS diets. Compared with BP-fed animals, heifers consuming the SS diets had 23 more visits/d to the feed bunks (P ≤ 0.01), consumed 53% less dry matter on each visit (P ≤ 0.01), and spent 39% more min chewing/d and 63% more min chewing/kg of DMI (P ≤ 0.01). However, chewing measured in min/kg of neutral detergent fiber intake was not affected by treatment (average 111.3 min/kg of NDF intake). Feeding AOP improved gain:feed (GF) by 15% in BP-fed heifers (0.120 vs. 0.104 kg/kg; P < 0.05). Inclusion of AOP increased organic matter digestibility (OMD) in SS diets (55.88% vs. 49.83%; P < 0.01), whereas it decreased OMD in BP diets (61.67% vs. 65.77%; P < 0.05). In conclusion, ADG and GF of BP-fed heifers was greater than SS-fed heifers, and GF was greater with AOP supplementation in BP-fed heifers. Improvement in GF in BP-fed heifers was likely not related to differences in nutrient digestibility as AOP inclusion did not enhance digestibility in the BP diet. Additionally, the effects of the AOP inclusion appear to be diet-dependent, where the 15% improvement in GF by AOP occurred in heifers fed with the more fermentable diet. Therefore, further research should explore the mechanisms responsible for the observed improvements in growth performance when feeding AOP to BP-fed heifers.

This experiment evaluated the effects of the dietary inclusion or not of Aspergillus oryzae prebiotic (AOP; 2 g/d) in two contrasting diets: sorghum silage-based (SS) vs. byproducts-based (BP), on growth performance, nutrient digestibility, and feeding behavior of growing heifers. A total of 84 Angus crossbred heifers were used in the study. Heifers fed with the BP diets had greater feed intake, average daily gain, and final body weight. In addition, heifers fed with the BP diets had reduced number of visits to the feed bunk but consumed more in each visit than heifers fed with the SS diets. Additionally, heifers fed with the BP diets had lesser chewing activity measured in total min/d and in min/kg of dry matter intake; however, chewing activity measured in min/kg of neutral detergent fiber was not influenced by treatments. The inclusion of AOP increased the gain:feed ratio by 15% in heifers fed with the BP diet but did not influence this variable in the SS diet. The inclusion of AOP increased nutrient digestibility in heifers fed with the SS diet and decreased nutrient digestibility in heifers fed with the BP diet. These results show that feeding AOP can enhance growth performance in beef heifers in a diet-dependent manner.

Effectiveness and Tolerability of the Intensification of Canagliflozin Dose from 100 mg to 300 mg Daily in Patients with Type 2 Diabetes in Real Life: The INTENSIFY Study.

Aim: This study aimed to evaluate the effectiveness and tolerability of intensifying the dose of canagliflozin from 100 mg/day (CANA100) to 300 mg/day (CANA300) in patients with type 2 diabetes (T2DM) and suboptimal metabolic control in a real-world setting. Methods: A multicenter observational study was conducted on adult patients with T2DM who initiated treatment with CANA100 and subsequently required intensification to CANA300. The primary outcome measures were changes in HbA1c and weight at 6 months after the switch and at the end of the follow-up period. Results: A total of 317 patients met the inclusion criteria (59.6% male, mean age 62.2 years, baseline HbA1c 7.55%, weight 88.6 kg, median duration of treatment with CANA100 9.9 months). Switching to CANA300 resulted in a significant reduction in HbA1c (6 months: -0.33%; last visit: -0.47%, both p < 0.0001) and weight (6 months: -1.8 kg; last visit: -2.9 kg, both p < 0.0001) over a median follow-up period of 20.8 months. The proportion of patients that achieved HbA1c < 7% increased from 26.7% with CANA100 to 51.6% with CANA300 (p < 0.0001). Among individuals with poor baseline glycemic control (HbA1c > 8%, mean 9.0%), HbA1c was significantly reduced by -1.24% (p < 0.0001). Furthermore, significant improvements were observed in fasting plasma glucose (FPG), blood pressure (BP), liver enzymes, and albuminuria. No unexpected adverse events were reported. Conclusions: Intensifying the treatment to CANA300 in a real-world setting resulted in further significant and clinically relevant reductions in FPG, HbA1c, weight, and BP in patients with T2DM. The switch was particularly effective in patients with higher baseline HbA1c levels.

Comprehensive Cardiovascular and Renal Protection in Patients with Type 2 Diabetes.

Type 2 diabetes (T2DM) is one of the main public health care problems worldwide. It is associated with a marked increased risk of developing atherosclerotic vascular disease, heart failure, chronic kidney disease and death. It is essential to act during the early phases of the disease, through the intensification of lifestyle changes and the prescription of those drugs that have been shown to reduce these complications, with the aim not only of achieving an adequate metabolic control, but also a comprehensive vascular risk control. In this consensus document, developed by the different specialists that treat these patients (endocrinologists, primary care physicians, internists, nephrologists and cardiologists), a more appropriate approach in the management of patients with T2DM or its complications is provided. A particular focus is given to the global control of cardiovascular risk factors, the inclusion of weight within the therapeutic objectives, the education of patients, the deprescription of those drugs without cardiovascular benefit, and the inclusion of GLP-1 receptor agonists and SGLT2 inhibitors as cardiovascular protective drugs, at the same level as statins, acetylsalicylic acid, or renin angiotensin system inhibitors.

Factores asociados a sobrevida a un año en pacientes postoperados de glioblastoma.

OBJECTIVE: To identify factors associated with one-year survival in postoperative glioblastoma patients at a hospital in northeastern Mexico. MATERIAL AND METHODS: Nested case-control study. Patients operated on for glioblastoma between 2016-2019 were included. Information about clinical and surgical factors was obtained, survival was calculated by Kaplan-Meier analysis. Descriptive analysis was performed with medians and ranges, and inferential analysis with χ2, Fisher and Student t test, odds ratio and 95% confidence interval. A value of p < 0.05 was considered significant. RESULTS: Sixty-two patients with glioblastoma were included, 27 (43.5%) women and 35 (56.5%) men, median age 56 years (range: 6-83). Median survival was 3.6 months (1-52), 45 (72.6%) survived less than 12 months. The factors associated with a higher survival were administration of adjuvant treatment (p < 0.001), better functional status (p = 0.001), and absence of post-surgical complications (p = 0.034). CONCLUSIONS: Most patients with glioblastoma survive less than 12 months and the factors most strongly associated with longer survival are administration of adjuvant treatment, better functional status of the patient and absence of post-surgical complications.

OBJETIVO: Identificar los factores asociados a la sobrevida a un año en pacientes postoperados de glioblastoma en un hospital del noreste de México. MATERIAL Y MÉTODOS: Estudio de casos y controles anidado en una cohorte. Se incluyeron pacientes operados de glioblastoma entre 2016 y 2019. Se obtuvo la información sobre factores clínicos y quirúrgicos, se calculó la sobrevida mediante análisis de Kaplan-Meier. El análisis descriptivo se realizó con medianas y rangos, y el inferencial con prueba de χ2, Fisher, t de Student, razón de momios e intervalo de confianza al 95%. Se consideró significativo un valor de p < 0.05. RESULTADOS: Se incluyeron 62 pacientes con glioblastoma, 27 (43.5%) mujeres y 35 (56.5%) hombres, mediana de edad de 56 años (rango: 6-83). La mediana de sobrevida fue de 3.6 meses (1-52), 45 (72.6%) sobrevivieron menos de 12 meses. Los factores asociados a mayor sobrevida fueron: administración de tratamiento adyuvante (p < 0.001), mejor estado funcional (p = 0.001) y ausencia de complicaciones posquirúrgicas (p = 0.034). CONCLUSIONES: La mayoría de los pacientes con glioblastoma sobreviven menos de 12 meses y los factores más fuertemente asociados a mayor sobrevida son administración de tratamiento adyuvante, mejor estado funcional del paciente y ausencia de complicaciones posquirúrgicas.

The rickettsial OmpB ß-peptide of Rickettsia conorii is sufficient to facilitate factor H-mediated serum resistance.

Pathogenic species of the spotted fever group Rickettsia are subjected to repeated exposures to the host complement system through cyclic infections of mammalian and tick hosts. The serum complement machinery is a formidable obstacle for bacteria to overcome if they endeavor to endure this endozoonotic cycle. We have previously demonstrated that that the etiologic agent of Mediterranean spotted fever, Rickettsia conorii, is susceptible to complement-mediated killing only in the presence of specific monoclonal antibodies. We have also shown that in the absence of particular neutralizing antibody, R. conorii is resistant to the effects of serum complement. We therefore hypothesized that the interactions between fluid-phase complement regulators and conserved rickettsial outer membrane-associated proteins are critical to mediate serum resistance. We demonstrate here that R. conorii specifically interacts with the soluble host complement inhibitor, factor H. Depletion of factor H from normal human serum renders R. conorii more susceptible to C3 and membrane attack complex deposition and to complement-mediated killing. We identified the autotransporter protein rickettsial OmpB (rOmpB) as a factor H ligand and further demonstrate that the rOmpB ß-peptide is sufficient to mediate resistance to the bactericidal properties of human serum. Taken together, these data reveal an additional function for the highly conserved rickettsial surface cell antigen, rOmpB, and suggest that the ability to evade complement-mediated clearance from the hematogenous circulation is a novel virulence attribute for this class of pathogens.

Beyond the Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy.

Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure with reduced ejection fraction and chronic kidney disease. In all indications, treatment can be initiated in adults with estimated glomerular filtration rate of at least 25 mL/min/1.73 m2. As monotherapy or as an additive therapy, dapagliflozin has been shown to promote better glycaemic control, associated with a reduction in body weight and blood pressure in a wide range of patients. In addition, dapagliflozin has a positive impact on arterial stiffness, helps to control the lipid profile and contributes to a reduced risk of cardiovascular complications. This article reviews the current scientific evidence on the role of dapagliflozin in cardiovascular risk factors including arterial stiffness, cardiovascular disease and heart failure in patients with T2DM, with the aim of helping to translate this evidence into clinical practice. The underuse of SGLT2i in actual clinical practice is also discussed.

Predictive Factors of Renal Function Decline in Patients with Type 2 Diabetes Treated with Canagliflozin in the Real-Wecan Study.

The Real-WECAN study evaluated the real-life effectiveness and safety of canagliflozin 100 mg daily (initiated in SGLT-2 inhibitors naïve patients) and canagliflozin 300 mg daily (switching from canagliflozin 100 mg or other SGLT-2 inhibitors) in individuals with type 2 diabetes. The objectives of this sub-analysis were to estimate the eGFR slope over the follow-up period and to identify predictive factors of eGFR decline in a multiple linear regression analysis. A total of 583 patients (279 on canagliflozin 100 mg and 304 on canagliflozin 300 mg) were included, with median follow-up at 13 months. The patients had a mean age of 60.4 years, HbA1c of 7.76%, BMI of 34.7 kg/m2, eGFR below 60 mL/min/1.73 m2 8.6%, and urine albumin-to-creatinine ratio (UACR) above 30 mg/g 22.8%. eGFR decreased by −1.9 mL/min/1.73 m2 (p < 0.0001) by the end of the study. The mean eGFR slope during the maintenance phase was −0.16 mL/min/1.73 m2 per year. There were no significant differences between both doses of canagliflozin in the eGFR reduction or in the eGFR slope. The best predictive multivariate model of eGFR decline after canagliflozin therapy included age, hypertension, combined hyperlipidemia, heart failure, eGFR and severely increased albuminuria. All these variables except hypertension were independently associated with the outcome. In conclusion, in this real-world study, individuals with older age, combined hyperlipidemia, heart failure, higher eGFR and UACR > 300 mg/g showed a greater decline in their eGFR after canagliflozin treatment.