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.

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.

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.

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.

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.

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.

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.

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.

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.

Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated in type 2 diabetes and obesity for their high efficacy in controlling glycaemia and inducing body weight loss, respectively. Patients may develop gastrointestinal adverse events (GI AEs), namely nausea, vomiting, diarrhoea and/or constipation. To minimize their severity and duration, healthcare providers (HCPs) and patients must be aware of appropriate measures to follow while undergoing treatment. An expert panel comprising endocrinologists, nephrologists, primary care physicians, cardiologists, internists and diabetes nurse educators convened across virtual meetings to reach a consensus regarding these compelling recommendations. Firstly, specific guidelines are provided about how to reach the maintenance dose and how to proceed if GI AEs develop during dose-escalation. Secondly, specific directions are set about how to avoid/minimize nausea, vomiting, diarrhoea and constipation symptoms. Clinical scenarios representing common situations in daily practice, and infographics useful to guide both HCPs and patients, are included. These recommendations may prevent people with T2D and/or obesity from withdrawing from GLP-1 RAs treatment, thus benefitting from their superior effect on glycaemic control and weight loss.

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.

Real-World Use of Insulin Glargine U100 and U300 in Insulin-Naïve Patients with Type 2 Diabetes Mellitus: DosInGlar Study.

INTRODUCTION: In the EDITION clinical trial programme, patients with type 2 diabetes mellitus (T2DM) receiving insulin glargine (IGlar) U300 required 10-15% more insulin than those receiving IGlar U100. This study sought to determine whether this difference was apparent in real-world practice. METHODS: In this observational, retrospective cohort study, electronic medical records in the Big-Pac® database (Real Life Data) relating to adult insulin-naïve patients with T2DM who initiated IGlar U100 or U300 treatment in Spain in 2016-2017 and remained on treatment for 18 months were selected. IGlar U100- and U300-treated patients were matched 1:1 (propensity score matching). The primary analysis compared changes from baseline in mean daily IGlar dose (U and U/kg) at 6 (± 2), 12 (± 2) and 18 (± 2) months between cohorts (paired t tests). Changes in glycated haemoglobin (HbA1c) and weight were analysed descriptively. RESULTS: The IGlar U100 and U300 cohorts included 556 matched pairs (46.9% female) with the following mean (standard deviation) values at baseline, respectively: age 63.6 (12.8) versus 63.7 (11.9) years; years since diagnosis 9.5 (1.4) versus 9.5 (1.3); HbA1c 8.8 (1.3) versus 8.7 (1.5) %; weight 84.6 (16.9) versus 84.7 (17.1) kg. Mean IGlar dose at baseline was 0.19 U/kg/day (both cohorts). Patients receiving IGlar U300 showed a greater increase from baseline in IGlar dose at 6, 12 and 18 months [mean dose (U/kg/day) 5.1%, 10.3% and 12.8% greater, respectively, in IGlar U300-treated patients]. Mean HbA1c was 8.1% in both cohorts at 18 months. Mean (SD) weight at 18 months with IGlar U100 and IGlar300 was 86.8 (17.0) kg and 85.0 (17.1) kg, respectively. CONCLUSION: In real-world practice, insulin dose was significantly higher in IGlar U300-treated than U100-treated patients at 6, 12 and 18 months, with similar reductions in HbA1c. At equal IGlar price/unit in Spain, the increased dose requirements of IGlar U300 would result in higher costs.

Significant Growth by Rickettsia Species within Human Macrophage-Like Cells Is a Phenotype Correlated with the Ability to Cause Disease in Mammals.

Rickettsia are significant sources of tick-borne diseases in humans worldwide. In North America, two species in the spotted fever group of Rickettsia have been conclusively associated with disease of humans: Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, and Rickettsia parkeri, the cause of R. parkeri rickettsiosis. Previous work in our lab demonstrated non-endothelial parasitism by another pathogenic SFG Rickettsia species, Rickettsia conorii, within THP-1-derived macrophages, and we have hypothesized that this growth characteristic may be an underappreciated aspect of rickettsial pathogenesis in mammalian hosts. In this work, we demonstrated that multiple other recognized human pathogenic species of Rickettsia, including R. rickettsii, R. parkeri, Rickettsia africae, and Rickettsiaakari can grow within target endothelial cells as well as within PMA-differentiated THP-1 cells. In contrast, Rickettsia bellii, a Rickettsia species not associated with disease of humans, and R. rickettsii strain Iowa, an avirulent derivative of pathogenic R. rickettsii, could invade both cell types but proliferate only within endothelial cells. Further analysis revealed that similar to previous studies on R. conorii, other recognized pathogenic Rickettsia species could grow within the cytosol of THP-1-derived macrophages and avoided localization with two different markers of lysosomal compartments; LAMP-2 and cathepsin D. R. bellii, on the other hand, demonstrated significant co-localization with lysosomal compartments. Collectively, these findings suggest that the ability of pathogenic rickettsial species to establish a niche within macrophage-like cells could be an important factor in their ability to cause disease in mammals. These findings also suggest that analysis of growth within mammalian phagocytic cells may be useful to predict the pathogenic potential of newly isolated and identified Rickettsia species.

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.

Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria.

Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell lipid functions that intracellular bacteria exploit for infection are the modulation of host plasma membrane microdomains (lipid rafts) required for efficient bacterial entry; the recruitment of specific lipids for membrane integrity of intracellular vacuoles; and the utilization of host lipid droplets for the regulation of immune responses and for energy production through fatty acid ß-oxidation and oxidative phosphorylation. The majority of published studies on the utilization of these host lipid pathways during infection have focused on intracellular bacterial pathogens that reside within a vacuole during infection and, thus, have vastly different requirements for host lipid metabolites when compared to those intracellular pathogens that are released into the host cytosol upon infection. Here we summarize the mechanisms by which intracellular bacteria sequester host lipid species and compare the modulation of host lipid pathways and metabolites during host cell infection by intracellular pathogens residing in either a vacuole or within the cytosol of infected mammalian cells. This review will also highlight common and unique host pathways necessary for intracellular bacterial growth that could potentially be targeted for therapeutic intervention.

Real-World Clinical Outcomes Associated with Canagliflozin in Patients with Type 2 Diabetes Mellitus in Spain: The Real-Wecan Study.

The aims of this multicentric retrospective study were to assess in a real-world setting the effectiveness and safety of canagliflozin 100 mg/d (CANA100) as an add-on to the background antihyperglycemic therapy, and to evaluate the intensification of prior sodium-glucose co-transporter type 2 inhibitor (SGLT-2i) therapy by switching to canagliflozin 300 mg/d (CANA300) in patients with T2DM. One cohort of SGLT2i-naïve patients with T2DM who were initiated on CANA100 and a second cohort of patients with prior background SGLT-2i therapy who switched to CANA300 were included in the study. The primary outcome of the study was the mean change in HbA1c over the follow-up time. In total, 583 patients were included-279 in the cohort of CANA100 (HbA1c 8.05%, weight 94.9 kg) and 304 in the cohort of CANA300 (HbA1c 7.51%, weight 92.0 kg). Median follow-up periods in both cohorts were 9.1 and 15.4 months respectively. CANA100 was associated to significant reductions in HbA1c (-0.90%) and weight (-4.1 kg) at the end of the follow-up. In those patients with baseline HbA1c > 8% (mean 9.25%), CANA100 lowered HbA1c levels by 1.51%. In the second cohort, patients switching to CANA300 experienced a significant decrease in HbA1c (-0.35%) and weight (-2.1 kg). In those patients with baseline HbA1c > 8% (mean 8.94%), CANA300 lowered HbA1c levels by 1.12%. There were significant improvements in blood pressure in both cohorts. No unexpected adverse events were reported. In summary, CANA100 (as an add-on therapy) and CANA300 (switching from prior SGLT-2i therapy) significantly improved several cardiometabolic parameters in patients with T2DM.

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.

Macrophages Infected by a Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Reveal Differential Reprogramming Signatures Early in Infection.

Despite their high degree of genomic similarity, different spotted fever group (SFG) Rickettsia are often associated with very different clinical presentations. For example, Rickettsia conorii causes Mediterranean spotted fever, a life-threatening disease for humans, whereas Rickettsia montanensis is associated with limited or no pathogenicity to humans. However, the molecular basis responsible for the different pathogenicity attributes are still not understood. Although killing microbes is a critical function of macrophages, the ability to survive and/or proliferate within phagocytic cells seems to be a phenotypic feature of several intracellular pathogens. We have previously shown that R. conorii and R. montanensis exhibit different intracellular fates within macrophage-like cells. By evaluating early macrophage responses upon insult with each of these rickettsial species, herein we demonstrate that infection with R. conorii results in a profound reprogramming of host gene expression profiles. Transcriptional programs generated upon infection with this pathogenic bacteria point toward a sophisticated ability to evade innate immune signals, by modulating the expression of several anti-inflammatory molecules. Moreover, R. conorii induce the expression of several pro-survival genes, which may result in the ability to prolong host cell survival, thus protecting its replicative niche. Remarkably, R. conorii-infection promoted a robust modulation of different transcription factors, suggesting that an early manipulation of the host gene expression machinery may be key to R. conorii proliferation in THP-1 macrophages. This work provides new insights into the early molecular processes hijacked by a pathogenic SFG Rickettsia to establish a replicative niche in macrophages, opening several avenues of research in host-rickettsiae interactions.

A Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Trigger Differential Proteome Signatures in Macrophages.

We have previously reported that Rickettsia conorii and Rickettsia montanensis have distinct intracellular fates within THP-1 macrophages, suggesting that the ability to proliferate within macrophages may be a distinguishable factor between pathogenic and non-pathogenic Spotted fever group (SFG) members. To start unraveling the molecular mechanisms underlying the capacity (or not) of SFG Rickettsia to establish their replicative niche in macrophages, we have herein used quantitative proteomics by SWATH-MS to profile the alterations resulted by the challenge of THP-1 macrophages with R. conorii and R. montanensis. We show that the pathogenic, R. conorii, and the non-pathogenic, R. montanensis, member of SFG Rickettsia trigger differential proteomic signatures in macrophage-like cells upon infection. R. conorii specifically induced the accumulation of several enzymes of the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid ß-oxidation, and glutaminolysis, as well as of several inner and outer membrane mitochondrial transporters. These results suggest a profound metabolic rewriting of macrophages by R. conorii toward a metabolic signature of an M2-like, anti-inflammatory activation program. Moreover, several subunits forming the proteasome and immunoproteasome are found in lower abundance upon infection with both rickettsial species, which may help bacteria to escape immune surveillance. R. conorii-infection specifically induced the accumulation of several host proteins implicated in protein processing and quality control in ER, suggesting that this pathogenic Rickettsia may be able to increase the ER protein folding capacity. This work reveals novel aspects of macrophage-Rickettsia interactions, expanding our knowledge of how pathogenic rickettsiae explore host cells to their advantage.