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Background In the strained actual economic context, all clinical pharmacy activities cannot be achieved for all patients of all care pathways. So finding a way to prioritize moments and patients needing those activities is essential. This is the challenge of the “5P project” (Patient personalized clinical pharmacy program integrated into care pathway). Objective To present adverse event (AE) risk management approach applied to develop clinical pharmacy programs integrated into care pathway, using two methods. Method Used as a priori AE risk management approach, the Delphi method and inductive approach analysis of semi-directed interviews were realized from April 1st to October 3rd, 2019, respectively in orthogeriatric (OG) and pediatric kidney transplantation (PKT) care pathways. Complementarily to bibliographic research, participants were medical and paramedical healthcare providers involved in the concerned care pathway. They have been interrogated regarding AE risks to identify the clinical pharmacy activities required, the patients who need them, and the appropriate steps of the care pathway. Results The Delphi method for OG care pathway has revealed: 1/. Patients were prioritized by the presence of at least 2 among the following 4 criteria: age ≥90 years old, cardiovascular diseases, prescribed potentially inappropriate medication for elderly patients, obesity or diabetes; priority steps were the post-operative and rehabilitation care steps. 2/. Prescription reviews, medication reconciliation and targeted pharmaceutical informative interview about oral anticoagulants were required. Nine semi-directed interviews used for PKT care pathway has revealed: 1/. Clinical pharmacy activities were carried out for all patients. Priority steps were pre-transplantation, immediate post-operative, and post-transplantation. 2/. Prescription reviews and educative interviews were required. Conclusions The two presented methods can be used to both develop patient prioritization and targeting steps for clinical pharmacy activities, and integrate it into care pathway. Today, those two developed programs have been executed in our teaching hospital.

Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19), the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. We aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of patients with and without diabetes hospitalized for COVID-19. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of the SARS-CoV-2 main receptor system (ACE2/TMPRSS2), and for the main molecule of the leukotriene B4 (LTB4) pathway (ALOX5). We found that diabetes activates the LTB4 pathway and that during COVID-19 it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19–related disorders, such as reduced oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (FiO2) and arterial partial pressure of oxygen/FiO2 levels, and increased disease duration. In addition, the expressions of ACE2 and ALOX5 are positively correlated, with increased expression in patients with diabetes and COVID-19 requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB4 is significantly increased in individuals with diabetes. In addition, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB4 and IL-6 systemic levels, as well as ACE2/ALOX5 blood expression, could be early markers of severe COVID-19 in individuals with diabetes.

Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological processes. Historically, the observation of acquired manganism in miners and people who misuse drugs provided early evidence of brain toxicity related to manganese exposure. The identification of inherited manganese transportopathies, which cause neurodevelopmental and neurodegenerative syndromes, further corroborates the neurotoxic potential of this element. Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders.

Background The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. Methods A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. Results The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. Conclusions Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. Clinical Trials Registration NCT03023111., This was a randomized, double-blind trial to evaluate the efficacy of oral miltefosine combined with topical granulocyte macrophage colony-stimulating factor compared with monotherapy with miltefosine and standard pentavalent antimony in treating cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil.

Context Pain is a therapeutic challenge after total knee arthroplasty (TKA), and it could lead to the overuse of opioids. Few methodologically robust clinical studies have been performed to assess the effectiveness of osteopathic manipulative therapy (OMTh; manipulative care performed by non–US-trained osteopaths) for postsurgical pain. Objective To evaluate the effectiveness of standardized preoperative OMTh on early postoperative pain and opioid consumption after TKA. Methods This comparative, nonrandomized study took place from 2013 to 2015 and included patients who had primary unilateral TKA for osteoarthritis in a knee that had not undergone any previous surgery. Patients were divided into 2 consecutive groups: 1 group received traditional preoperative management, and the other group received associated preoperative OMTh (general OMTh [rhythmic mobilization of all the body joints, from the ankles to the skull, using long-lever manipulation] and myofascial relaxation). The primary evaluation criterion was knee pain at rest 1 month after surgery: 0 (no pain) to 100 (the worst imaginable pain). The secondary evaluation criteria were: (1) knee pain while walking 1 month after surgery, (2) average weekly knee pain during the first month after surgery, (3) the presence of night pain and the consumption of sleeping pills and opioids or morphine at least once per week, (4) the International Knee Society scores and the Western Ontario and McMaster University Osteoarthritis index at postoperative 6 months and 1 year. The number of patients needed for a superiority trial was determined. Results No eligible patient refused OMTh when proposed. Seventy patients were evaluated (mean [SD] age, 75 [8] years; 47 women and 23 men). The 2 treatment groups contained 35 patients each. At postoperative month 1, the OMTh group had significantly less pain at rest (mean [SD], 6.8 [6] vs 20.9 [17.3]; P=.00001) and while walking (7.9 [9.4] vs 23.5 [20.6]; P=.0001) compared with the group that received traditional preoperative management. The consumption of opioids during the first postoperative week was significantly lower in the OMTh group (P=.0001). No statistically significant difference was found in the International Knee Society or Western Ontario and McMaster University Osteoarthritis scores between the 2 groups at 6 months and 1 year of follow-up. Conclusion Standardized preoperative OMTh was found to be effective in reducing pain in the first month after TKA for osteoarthritis and significantly reduced opioid consumption during the first postoperative week.

This article belongs to the Special Issue Three-Dimensional Culture Systems in Cancer Research., [Simple Summary]: Colorectal cancer is one of the most frequent and lethal types of cancer. Despite advances in recent decades, our knowledge of this disease is still limited, and novel and better therapies are needed. Organoids were recently developed as a new system to culture normal and tumor cells obtained from patients subjected to surgery or endoscopic tests. Organoids are being used to dissect the molecular and genetic bases of colorectal cancer initiation and progression. In this review, we describe how patient-derived organoids can be generated, and their use to investigate in depth the tumorigenic process. We show how this system has allowed the study of colorectal tumorigenesis features for the first time, including immunotherapy, interplay with microorganisms and, more importantly, assays of drug treatments at an individualized level. Additionally, we summarize the most recent developments of what is known as organoid technology directed towards personalized medicine., [Abstract]: Organoids were first established as a three-dimensional cell culture system from mouse small intestine. Subsequent development has made organoids a key system to study many human physiological and pathological processes that affect a variety of tissues and organs. In particular, organoids are becoming very useful tools to dissect colorectal cancer (CRC) by allowing the circumvention of classical problems and limitations, such as the impossibility of long-term culture of normal intestinal epithelial cells and the lack of good animal models for CRC. In this review, we describe the features and current knowledge of intestinal organoids and how they are largely contributing to our better understanding of intestinal cell biology and CRC genetics. Moreover, recent data show that organoids are appropriate systems for antitumoral drug testing and for the personalized treatment of CRC patients., The work in the authors’ laboratory is funded by the Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033), the Ministerio de Ciencia e Innovación (SAF2017-90604-REDT/NuRCaMeIn), and the Instituto de Salud Carlos III—Fondo Europeo de Desarrollo Regional (CIBERONC/CB16/12/00273, CIBERONC/CB16/12/00398 and ICI20/00057).

BackgroundVisceral leishmaniasis is an opportunistic disease in HIV-1 infected individuals, although not yet recognized as a determining factor for AIDS diagnosis. The growing geographical overlap of HIV-1 and Leishmania infections is an emerging challenge worldwide, as co-infection increases morbidity and mortality for both. Here, we determined the prevalence of people living with HIV (PWH) with a previous or ongoing infection by Leishmania infantum in Bahia, Brazil and investigated the virological and immunological factors associated with co-infection.Methodology and Principal FindingsWe adopted a two-stage cross-sectional cohort (CSC) design (CSC-I, n=5,346 and CSC-II, n=317) of treatment-naïve HIV-1-infected individuals in Bahia, Brazil. In CSC-I, samples collected at the time of HIV-1 diagnosis between 1998 and 2013 were used for serological screening for leishmaniasis by an in-house immunoassay (ELISA) with SLA (Soluble Leishmania Antigen), resulting in a prevalence of previous or ongoing infection of 16.27%. Next, 317 PWH were prospectively recruited from July 2014 to December 2015 with collection of sociodemographic and clinical data. Serological validation by two different immunoassays confirmed a prevalence of 15.46% and 8.20% by anti-SLA, and anti-HSP70 serology, respectively, whereas 4.73% were double-positive (DP). Stratification of these 317 individuals in DP and double-negative (DN) revealed a significant reduction of CD4+ counts and CD4+/CD8+ ratios and a tendency of increased viral load in the DP group, as compared to DN. No statistical differences in HIV-1 subtype distribution were observed between the two groups. However, we found a significant increase of CXCL10/IP-10 (p=0.0076) and a tendency of increased CXCL9/MIG (p=0.061) in individuals with DP serology for L. infantum, demonstrating intensified immune activation in this group. These findings were corroborated at the transcriptome level in independent Leishmania- and HIV-1-infected cohorts (Swiss HIV Cohort and Piaui Northeast Brazil Cohort), indicating that CXCL10 transcripts are shared by the IFN-dominated immune activation gene signatures of both pathogens and positively correlated to viral load in untreated PWH.Conclusions/SignificanceThis study demonstrated a high prevalence of PWH with L. infantum seropositivity in Bahia, Brazil, linked to IFN-mediated immune activation and a significant decrease in CD4+ levels. Our results highlight the urgent need to increase awareness and define public health strategies for the management and prevention of HIV-1 and L. infantum co-infection.AUTHOR SUMMARYMore than 1 billion people live in areas endemic for leishmaniasis and are at risk of infection, which includes one third of the 38 million people living with HIV (PWH) worldwide. Leishmaniasis is a neglected tropical disease caused by infection with Leishmania parasites, transmitted by bites from infected sand flies. HIV/Leishmania co-infection is increasing worldwide, especially in Southern Europe and Brazil, due to both human and ecological factors (migration, climate change, deforestation). This study demonstrates that a worryingly high number (one out of 6) of PWH in Bahia (Northeast Brazil) show previous or ongoing infection with the parasite Leishmania infantum, determined by antibodies detection against this parasite in PWH. Using a rigorous study design with data collection over 18 years in >5500 PWH, we found similarly high numbers (16.3% and 15.5%) of PWH with antibodies against Leishmania infantum in two consecutive cohorts. Moreover, PWH with antibodies against Leishmania infantum in Bahia, Brazil displayed a worse immune profile, with lower CD4 immune cells numbers and immune activation mediated by interferon, which we confirmed in independent HIV- and Leishmania-infected cohorts from other geographic areas. Our results underscore the need to raise awareness and define public health strategies to prevent HIV/Leishmania co-infection, since therapeutic failure and mortality are strongly increased in co-infected PWH, even with antiretroviral therapy as standard of care.

1Instituto Goncalo Moniz, Fundacao Oswaldo Cruz (FIOCRUZ), Salvador, Brazil; 2Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium; 3Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, Brazil; 4Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil; 5Laborato´rio de Anatomia Patolo´gica, Feira de Santana, Brazil; and 6Instituto de Investigacao em Imunologia (iii-INCT), Sao Paulo, Brazil 7These authors contributed equally to this work. 8These authors contributed equally as senior authors.

There is limited evidence on the impact of bariatric surgery (BS) on reproductive outcomes in the general population and specifically in patients with polycystic ovarian syndrome (PCOS) or the effect of different BS techniques. The study aims to investigate the impact of BS on fertility, pregnancy, and newborn outcomes in reproductive age women who have undergone BS and the outcomes according to surgical procedure and PCOS diagnosis. This was a retrospective, descriptive, cross-sectional study performed in women from 18–39 years undergoing BS in our centre from January 2005 to December 2010. We performed a telephone interview including a structured reproductive health survey on fertility, pregnancy, and offspring outcomes before and after BS. Of the women, 872 underwent BS during the study period, 298 were 18–39 years old, and reproductive data was obtained from 217. Women with regular menstrual cycles increased from 52.9% before BS to 72.9% 1 year after surgery. The percentage of patients with a time-to-pregnancy longer than 12 months was higher after laparoscopic sleeve gastrectomy (LSG) (17.8%) compared to laparoscopic Roux-en-Y gastric bypass (7.1%; p = 0.02). Menstrual regularity was less frequent in PCOS (n = 43) (26.0%) compared to non-PCOS women before BS (60.1%; p = 0.01), with no differences after surgery. Several perinatal results showed an improvement after BS, with a reduction in macrosomia rate and birth weight. BS was associated with an improvement in several reproductive outcomes. Menstrual regularity was especially improved in PCOS women. Further research may clarify the impact of LSG on fertility.

International audience; Purpose Hybrid aortic arch repair in patients with chronic residual aortic dissection (RAD) is a less invasive alternative to conventional surgical treatment. The aim of this study was to describe the short-term and long-term results of hybrid treatment for RAD after type A repair. Methods In this retrospective single-center cohort study, all patients treated for chronic RAD with hybrid aortic arch repair were included. Indications for treatment were rapid aortic growth, aortic diameter > 55 mm, or aortic rupture. Results Between 2009 and 2020, we performed 29 hybrid treatments for chronic RAD. Twenty-four patients were treated for complete supra-aortic debranching in zones 0 and 5 with left subclavian artery debranching alone in zone 2. There was 1 perioperative death (3.4%): The patient was treated for an aortic rupture. There was no spinal cord ischemia and 1 minor stroke (3.4%). After a median follow-up of 25.4 months (range 3-97 months), the long-term mortality was 10.3% (3/29) with no late aortic-related deaths. Twenty-seven patients (93.1%) developed FL thrombosis of the descending thoracic aorta; the rate of aneurysmal progression on thoraco-abdominal aorta was 41.4% (12/29), and the rate of aortic reintervention was 34.5% (10/29). Conclusion In a high-volume aortic center, hybrid repair of RAD is associated with good anatomical results and a low risk of perioperative morbidity and mortality, including that of patients treated in zone 0. A redo replacement of the ascending aortic segment is sometimes necessary to provide a safer proximal landing zone and reduce the risk of type 1 endoleak after TEVAR.

Objectives To compare topical granulocyte and macrophage colony-stimulating factor (GM-CSF) and miltefosine (G + M) versus placebo and miltefosine (P + M) or parenteral meglumine antimoniate (MA) in the treatment of 150 patients with cutaneous leishmaniasis (CL) caused by Leishmania guyanensis in the Amazon. Design A randomized and double-blinded clinical trial. Results At 90 days after the initiation of therapy, the cure rates were 66%, 58%, and 52% for the groups P + M, G + M, and MA, respectively (p > 0.05). Cure rates at 180 days did not differ. Healing time was similar in the 3 groups, but faster in the MA group as compared to the G + M group (p = 0.04). Mild and transitory systemic adverse events were frequent in all groups (above 85%). Nausea (85%) and vomiting (39%) predominated in the miltefosine groups and arthralgia (51%) and myalgia (48%) in the MA group. One patient (group MA) stopped treatment after presenting with fever, exanthema, and severe arthralgia. Conclusions Miltefosine did not present a higher cure rate than MA, and the association of GM-CSF did not improve the therapeutic response. Nevertheless, because of its less toxicity, easier administration, and a similar cure rate when compared with MA, miltefosine should remain as one of the main drugs for treating CL due to L. guyanensis. (Clinicaltrials.gov Identifier NCT03023111).

To evaluate the feasibility and safety of percutaneous transpedicular fixation by PEEK polymer implants and cementoplasty for vertebral compression fracture (VCF). From February 2019 to December 2019, 6 consecutive patients (3 men and 3 women; mean age 55 ± 8 years; range 40–64 years) who had percutaneous transpedicular fixation with cementoplasty for the treatment of VCF (5 tumor lesions, 1 traumatic) were included. The procedure duration, length of hospital stay, and complications were reported. Visual analog scale (VAS) and the Oswestry disability index (ODI) for pain and disability were assessed before and 2 months after the procedure. The mean procedure duration was 74 ± 47 min (range 20–140 min). The median length of hospital stay was 3 days (range 2–63) after the procedure. Only minor adverse events were reported (4 asymptomatic cement leakages) but no severe complications. No cases of procedural site fracture during follow-up were noted (median 198 days; range 78–238 days). The mean VAS score decreased from 6.2 ± 1.8 mm (median 6 mm; range 4–9 mm) before the procedure to 1.7 ± 2.1 mm (median 1; range 0–5 mm) after the procedure. The ODI decreased from 36 ± 14% (range 18–54%) before the procedure to 23 ± 10% (range 11–30%) at 2-months follow-up. Percutaneous transpedicular fixation of VCF by PEEK implants with cementoplasty appears feasible and safe.

The peptide hormone endothelin-1 and its receptors are linked to several disease states. Pharmacological inhibition of this pathway has proven beneficial in pulmonary hypertension, yet its potential in other disease states remains to be realized. This review considers an often understudied aspect of endothelin biology, circadian rhythm regulation and how understanding the intersection between endothelin signaling and the circadian clock may be leveraged to realize the potential of endothelin-based therapeutics.

Lupus anticoagulant (LA) can be a cause of thrombosis and/or pregnancy morbidities, producing antiphospholipid syndrome (APS). An increase in thrombin generation (TG) is correlated with prothrombotic status. Several changes in TG-derived parameters have been reported in APS patients.Evaluate whether the TG phenotype of APS can also be described in LA subjects without clinical manifestations of APS, and to investigate the possible influence of both LA potency and antiphospholipid (aPL) profile on it.TG was analyzed in 153 cases of LA and 41 healthy controls. We have observed prolongation of both lag time (3.7 min vs 2.32 min, p 0.001) and time to peak (6.48 min vs 5.27 min, p 0.001), increased peak height (221.7 nM vs 182.7 nM, p 0.001), slightly higher ETP (221.7 nM·min vs 182.7 nM·min, p = 0.041), and higher velocity index (100.7 nM/min vs 74.53 nM/min, p = 0.001) in LA subjects compared to controls. After adding thrombomodulin (TM), ETP%inh was significantly lower in LA group (37.90% vs 59.90%, p 0.001) showing resistance to TM/activated protein C (APC). Significant differences were found in lag time, time to peak and ETP%inh according to the potency and aPL profile.Previously described differences in TG-derived parameters in APS patients have been confirmed in incidental LA subjects: prolonged lag time and time to peak, slightly higher ETP, higher peak height, and less sensitivity to TM/APC. High LA potency and triple-positive aPL profile enhance differences in lag time, time to peak and, especially, increase APC resistance, but no effect in ETP was observed.

This article belongs to the Special Issue Stemness and Differentiation in Cancer., Colon and rectal tumors, often referred to as colorectal cancer, show different gene expression patterns in studies that analyze whole tissue biopsies containing a mix of tumor and non-tumor cells. To better characterize colon and rectal tumors, we investigated the gene expression profile of organoids generated from endoscopic biopsies of rectal tumors and adjacent normal colon and rectum mucosa from therapy-naive rectal cancer patients. We also studied the effect of vitamin D on these organoid types. Gene profiling was performed by RNA-sequencing. Organoids from a normal colon and rectum had a shared gene expression profile that profoundly differed from that of rectal tumor organoids. We identified a group of genes of the biosynthetic machinery as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3/calcitriol upregulated stemness-related genes (LGR5, LRIG1, SMOC2, and MSI1) in normal rectum organoids, while it downregulated differentiation marker genes (TFF2 and MUC2). Normal colon and rectum organoids share similar gene expression patterns and respond similarly to calcitriol. Rectal tumor organoids display distinct and heterogeneous gene expression profiles, with differences with respect to those of colon tumor organoids, and respond differently to calcitriol than normal rectum organoids., This research was founded by Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033), Agencia Estatal de Investigación-Fondo Europeo de Desarrollo Regional (SAF2016-76377-R, MINECO/AEI/FEDER, UE), Ministerio de Economía y Competitividad (SAF2017-90604-REDT), Instituto de Salud Carlos III—Fondo Europeo de Desarrollo Regional (CIBERONC, CB16/12/00273; CIBERES, CB15/00037), and Mutua Madrileña.

This article belongs to the Special Issue Stemness and Differentiation in Cancer., Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types., The work in the authors’ laboratory is funded by the Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033), the Agencia Estatal de Investigación-Fondo Europeo de Desarrollo Regional (SAF2016-76377-R, MINECO/AEI/FEDER, EU), the Ministerio de Economía y Competitividad (SAF2017-90604-REDT/NuRCaMeIn), and the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (CIBERONC; CB16/12/00273).

AIM To compare the systemic cytokines/chemokines levels over time during the evolution of children hospitalized with community-acquired pneumonia (CAP) with and without pneumococcal infection. METHODS Children less than 5-years-old hospitalized with CAP were prospectively investigated in Salvador, Brazil. Clinical data and biological samples were collected to investigate 20 etiological agents and to determine serum cytokines/chemokines levels on admission and 2 to 4 weeks later. Cases with pneumococcal infection received this diagnosis irrespective of also having other etiologies. RESULTS A total of 277 patients were enrolled, however, serum sample was unavailable for cytokine measurement upon admission (n = 61) or upon follow-up visit (n = 36), etiology was undetected (n = 50) and one patient did not attend the follow-up visit. Therefore, this study group comprised of 129 cases with established etiology. The median (interquartile range) age and sampling interval was 18 (9-27) months and 18 (16-21) days, respectively. Established etiology was viral (52.0%), viral-bacterial (30.2%), and bacterial (17.8%). Pneumococcal infection was found in 31 (24.0%) patients. Overall, median interleukin-6 (IL-6; 10.6 [4.7-30.6] vs 21.0 [20.2-21.7]; P = .03), IL-10 (3.5 [3.1-4.5] vs 20.1 [19.8-20.4]; P

Elderly patients hospitalized in acute care service very often have a weakened venous tissue which, in the case of medium-term intravenous treatment, leads to multiple painful punctures. In order to alleviate this major inconvenience, within the framework of a cooperation protocol, a catheter team was trained in the ultrasound-guided insertion of the appropriate catheter for the management of geriatric patients.

Cysteine proteinases are well-known virulence factors of Leishmania spp. with demonstrated actions in both experimental mouse infection and human infection. However, studies on these enzymes in canine leishmaniasis are scarce. Here, we show, for the first time, the reactivity of sera from dogs living in an endemic area to a recombinant protein from the COOH-terminal region of cysteine B protease. In this work, enzyme-linked immunosorbent assays were performed using a 14 kDa rcyspep protein obtained through a pET28-a expression system in Escherichia coli. First, 96-well plates were coated with rcyspep (500 ng/well) and incubated with sera from dogs (1:100). Subsequently, IgG antibody detection was performed using rabbit anti-dog IgG antibodies conjugated with peroxidase. Sera from dogs (n = 114), including suspect (n = 30) and positive (n = 50) dogs from a leishmaniasis-endemic area and dogs from a nonendemic area, (n = 34), negative for leishmaniasis, were assessed. The results showed that sera from the suspect (42%) and positive (68%) groups responded differently to the antigen titers tested above the cut-off (Optical Density = 0.166). This finding suggests that the immune response detected against cyspep may be related to clinical disorders present in these animals. Collectively, the data gathered here suggest that cyspep can sensitize the immune systems of dogs from a leishmaniasis-endemic area to elicit a humoral response, an immunological parameter indicating the contribution of this protein in host-parasite interaction.

International audience; Background: The natural history of type B intramural hematomas is little-known. Aneurysmal progression or an aortic dissection occurs in 15 to 20% of the cases. The study of the natural anatomical evolution could help identify the patients at risk of unfavorable evolution.Methods: All the patients monitored for a type B intramural hematoma between 2009 and 2018 were included in this monocentric retrospective study. Computed tomography angiography centerline measurement of diameters was obtained in various points of aortic segmentation on day (D) 0 and at one month (M1). Aortic volumes (lumen, intramural hematoma, and total volume) were calculated. The circulating volume was calculated using the volume rendering method. The volume of the intramural hematoma was measured using a manual section-by-section segmentation tool, and the total volume was obtained by summing up the two preceding volumes. Two groups of patients were compared: group 1 (favorable anatomical evolution) and group 2 (unfavorable anatomical evolution).Results: Between January 2008 and August 2018, 25 patients were managed for a type B intramural hematoma in our center. After an average follow-up of 15.5 months (1-52), 13 patients (52%) presented a favorable evolution and 12 (48%) an unfavorable evolution. At M1, a significant increase of the luminal diameters (37 mm vs. 32 mm; P < 0.01) and a significant reduction in the longitudinal extension (19 mm vs. 26 mm; P < 0.01) were observed. The maximum aortic diameter evolved significantly between D0 and M1 in the unfavorable evolution group (49 mm vs. 44 mm, respectively; P = 0.038). Such a difference was not found in the favorable evolution group (37.4 vs. 37.1, respectively; P = 0.552). An overall significant reduction in the total aortic volume (166 cm3 vs. 219 cm3; P < 0.01), the circulating volume (124 cm3 vs. 145 cm3; P = 0,026), and the volume of the hematoma (42 cm3 vs. 39 cm3; P < 0.01) was observed. The circulating volume decreased significantly between D0 and M1 in the favorable evolution group (110 cm3 vs. 135 cm3; P = 0.05), whereas no difference was noted in the unfavorable group (142 cm3 vs, 157 cm3; P = 0.24).Conclusions: The progression of the maximum aortic diameter and of the circulating volume after one month of follow-up could be predictive factors of the poor long-term evolution of type B intramural hematomas.

Introduction: Methotrexate (MTX) is the drug of choice for juvenile idiopathic arthritis. Its clinical efficacy is limited due to the development of adverse effects (AEs). Patients and methods: A retrospective observational study was conducted on the AEs associated with MTX therapy in children diagnosed with juvenile idiopathic arthritis followed-up in a tertiary hospital between 2008 and 2016. Results: The study included a total of 107 patients, of whom 71 (66.3%) were girls (66.3%). The median age at diagnosis was 6.4 years (IQR 3.1–12.4), with a median follow-up of 45.7 months (IQR 28.8–92.4). There were 48 patients (44.9%) with oligo arthritis, and 26 children (24.3%) with rheumatoid-factor negative polyarthritis. Of these, 52/107 (48.6%) developed AEs, with the most frequent being gastrointestinal symptoms (35.6%) and behavioural problems (35.6%). An age older than 6 years at the beginning of therapy increased the risk of developing AEs, both in the univariate (OR = 3.5; 95% CI: 1.5–7.3) and multivariate (12% increase per year) analyses. The doses used, administration route, or clinical form according to International League of Associations for Rheumatology (ILAR) clasiification, were not associated with the development of AEs. Twenty children required a dosage or route of administration modification, which resolved the AE in 11 (55%) cases. MTX was interrupted due to the development of AEs in 37/107patients (34.6%), mainly due to increased plasma transaminases (n = 14, 37.8%), gastrointestinal symptoms (n = 9, 24.3%) and behavioural problems (n = 6, 16.3%). Conclusions: MTX is the therapy of choice for patients with juvenile idiopathic arthritis, but50% of the children develop some form of AE. Although the AEs are not severe, they lead to interruption of therapy in 35% of the children. Resumen: Introducción: El metotrexato (MTX) es el fármaco sistémico más utilizado en el tratamiento de pacientes con artritis idiopática juvenil. Su efectividad viene limitada por el desarrollo deefectos adversos (EA). Pacientes y métodos: Estudio observacional descriptivo retrospectivo de la frecuencia y tipo de EA asociados a MTX en pacientes con artritis idiopática juvenil seguidos en un hospital terciario en el periodo 2008-2016. Resultados: Se estudió a 107 pacientes, 71/107 mujeres (66.3%) con edad al diagnóstico de 6,4 años (RIC 3,1-12,4) durante una mediana de seguimiento de 45,7 meses (RIC 28,8-92,4). El 44.9% (48 pacientes) tenía oligoartritis y el 24.3% (n = 26) poliartritis factor-reumatoide negativo. El 48.6% (52/107) desarrolló EA, siendo los más frecuentes los síntomas gastrointestinales y los trastornos conductuales (35.6% cada uno). La edad mayor de 6 años al inicio del tratamiento aumentaba el riesgo de desarrollar EA, tanto en el estudio univariable (OR = 3,5; IC95% 1,5-7,3) como en el multivariable (aumento del riesgo del 12% por año). La dosis, vía de administración o forma clínica según la clasificación de la Liga Internacional de Asociaciones de Reumatología (ILAR) no presentaban relación con el desarrollo de EA. Veinte niños precisaron cambio de dosis o vía de administración, resolviéndose el EA en 11 (55%). MTX se suspendió en 37/107 pacientes (34.6%) por EA, principalmente por hipertransaminasemia (n = 14; 37.8%), síntomas gastrointestinales (n = 9; 24.3%) y trastornos conductuales (n = 6; 16.3%). Conclusiones: MTX es el tratamiento de elección de niños con artritis idiopática juvenil pero produce EA en prácticamente el 50% de los pacientes. Aunque estos EA no son graves, obligan a interrumpir el tratamiento en el 35%.

Traumatic tracheobronchial injuries occur in 1% of patients with thoracic trauma, most of them dying at the site of the trauma. In this case report, we present a 26-year-old female patient admitted to the ICU due to a blunt chest trauma causing life threatening hypoxaemia and acidosis; deciding to implant percutaneous venovenous extracorporeal membrane oxygenation. The use of percutaneous venovenous extracorporeal membrane oxygenation, implemented with a lower anticoagulation target, allowed the diagnosis and treatment of a bronchopleural fistula under conditions of respiratory and hemodynamic stability without haemorrhagic complications, obtaining a fast and adequate assistance achieving the survival of the patient.

International audience; The Rhône-Loire metropolitan areas’ 2020/21 respiratory syncytial virus (RSV) epidemic was delayed following the implementation of non-pharmaceutical interventions (NPI), compared with previous seasons. Very severe lower respiratory tract infection incidence among infants ≤ 3 months decreased twofold, the proportion of cases among children aged > 3 months to 5 years increased, and cases among adults > 65 years were markedly reduced. NPI appeared to reduce the RSV burden among at-risk groups, and should be promoted to minimise impact of future RSV outbreaks.

Supplemental Digital Content is available in the text., IMPORTANCE: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking. OBJECTIVES: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome. DESIGN: Data from two prospective cohort studies. SETTING AND PARTICIPANTS: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission). MAIN OUTCOMES AND MEASURES: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay. RESULTS: In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis. CONCLUSIONS AND RELEVANCE: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with death, particularly in meningococcal sepsis. Future studies should confirm the prognostic value of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 and should study pathophysiologic mechanisms.

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in newly obtained biopsies. Surprisingly, we found a strong labeling of TREM-1 in keratinocytes, prompting the hypothesis that increased TREM-1 activation may be the result of tissue damage. However, increased TREM-1 expression was only seen in human lineage keratinocytes following parasite stimulation. Moreover, no up-regulation of TREM-1 expression was observed in the skin lesions caused by other non-infectious inflammatory diseases. Together, these findings indicate that L. braziliensis (Lb) induces the expression of the TREM-1 receptor in tissue keratinocytes regardless of tissue damage, suggesting that non-immune skin cells may play a role in the inflammatory response of CL.

Multi-host pathogens emerging and re-emerging at the wildlife–domestic animal interface affect wildlife management and conservation. This is the case of canine distemper virus (CDV), a paramyxovirus closely related to human measles virus and rinderpest virus of cattle. With an area of 10,603 km2, Asturias region in Atlantic Spain is a hotspot of carnivore diversity, which includes the largest Eurasian brown bear (Ursus arctos arctos) population and one of the largest wolf (Canis lupus) populations in south-western Europe. In 2020–2021, we recorded mortality due to distemper in four carnivore species including three mustelids (Eurasian badger Meles meles, European marten Martes martes and European polecat Mustela putorius) and one canid (red fox, Vulpes vulpes). Clinical signs and pathology were similar across species and consistent with the emergence of a highly pathogenic viral strain, with CDV antigen mainly located in the central nervous system, lungs, spleen and lymph nodes. A molecular study in eight wild carnivore species, also including the Iberian wolf, Eurasian brown bear, American mink (Neovison vison) and stone marten (Martes foina), revealed 19.51% (16/82) of positivity. Phylogenetic analysis demonstrated that CDV belonged to the previously described European lineage. A retrospective serosurvey (2008–2020) showed a high seroprevalence of CDV antibodies (43.4%) in 684 analyzed badgers, indicating a long-term though not stable viral circulation in this multi-host community. The possible triggers of the 2020–2021 outbreak and the implications for carnivore management and conservation are discussed., This work has been funded by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) and the Agencia Estatal de Investigación (AEI) reference project RTI2018-096010-B-C21 (FEDER co-funded) and, by PCTI 2018−2020 (GRUPIN: IDI2018-000237) and FEDER. C.B.V. was supported by a grant from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Spain. T.D.B. was supported by a fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; process number 88887.511077/2020-00). D.B. was supported by an ERASMUS Practices Grant 2021.

1Instituto Goncalo Moniz, FIOCRUZ, Salvador, Brazil, 2Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil, 3Division of Infectious Diseases and Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, CA, USA, 4Instituto Aggeu Magalhaes, FIOCRUZ, Recife, Brazil, 5Faculdade de Ceilândia, Universidade de Brasilia, (FCE-UnB), Brasilia, Brazil and 6Hospital Geral Roberto Santos, Salvador, Brazil

BACKGROUND Visceral leishmaniasis (VL) is a tropical neglected disease with high associated rates of mortality. Several studies have highlighted the importance of the intestinal tract (IT) and gut microbiota (GM) in the host immunological defense. Data in the literature on parasite life cycle and host immune defense against VL are scarce regarding the effects of infection on the IT and GM. OBJECTIVES This study aimed to investigate changes observed in the colon of Leishmania infantum-infected hamsters, including alterations in the enteric nervous system (ENS) and GM (specifically, levels of bifidobacteria and lactobacilli). METHODS Male hamsters were inoculated with L. infantum and euthanised at four or eight months post-infection. Intestines were processed for histological analysis and GM analysis. Quantitative polymerase chain reaction (qPCR) was performed to quantify each group of bacteria: Bifidobacterium spp. (Bf) and Lactobacillus spp (LacB). FINDINGS Infected hamsters showed histoarchitectural loss in the colon wall, with increased thickness in the submucosa and the mucosa layer, as well as greater numbers of intraepithelial lymphocytes. Forms suggestive of amastigotes were seen inside mononuclear cells. L. infantum infection induced changes in ENS, as evidenced by increases in the area of colonic enteric ganglia. Despite the absence of changes in the levels of Bf and LacB during the course of infection, the relative abundance of these bacteria was associated with parasite load and histological alterations. MAIN CONCLUSIONS Our results indicate that L. infantum infection leads to important changes in the colon and suggest that bacteria in the GM play a protective role.

Objective:To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population.Method:Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease.Results:The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively).Conclusions:Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype.

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Results: A significant survival benefit of 25 months ( p = 0.037) and 47% reduced risk of death ( p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib ( n = 45) versus placebo ( n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality. This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

ObjectiveTo describe persistent symptoms after acute COVID-19 in different spectrum of disease severity in a population from an upper/middle income country, and identify the main clinical features impacting the quality of life.DesignCross-sectional study.SettingOutpatient clinic from a public post-COVID-19 health center (CPC) at Bahia-Brazil, a state where 80% are black or mixed race.ParticipantsPatients admitted between August 2020 and February 2021 with symptoms at least one month after the onset of COVID-19.Main outcome measuresPACS and related disorders such as hospitalization one month or later after disease onset, biochemical dysregulation and reduced quality of life (EQ-5D-5L questionnaire).ResultsAmong 683 individuals assisted at CPC in this period, 602 were recruited. Patients had average of 52 (±14.6) years, 355 (59%) were female, 528 (88%) black/brown. Individuals were classified as mild (39.9%), moderate (27.9%) or severe (32.2%) during acute illness if outpatient, hospitalized non-UCI or UCI, respectively. Most patients reported a polysymptomatic profile, in median eight (IQR=6-9) acute symptoms. The most frequent residual symptoms were dyspnea (66%), fatigue (62%) and chest pain (43%). Women were more affected regardless disease severity at acute stage: presented more residual symptoms [4 (2-6) vs 3 (2-4)] and a higher impact in quality of life. Altered HbA1c [(184/275 (66.9%)], high CRP levels [195/484 (40.3%)] and anemia [143/545 (26.2%)] were the most common abnormalities in laboratory exams. 76 patients presented HbA1c above 6.4% although only 42 referred previous diagnosis of diabetes mellitus. After one month of disease onset, 30 patients required hospitalization, including seven cases with mild acute illness. Hospital admission after acute disease was required on 30 patients, seven (23%) were mild. Quality of life had been affected for 357/404 (88.4%) patients according to EuroQoL (EQ-5D-5L), mainly the domains of anxiety/depression [severe or extreme anxiety for 79/401 (19.7%)] and pain/discomfort [severe or extreme pain for 71/403 (17.6%)]. The median EuroQoL Global Score was 70 [IQR 50-80]. PACS symptoms such as dyspnea, chest pain, and fatigue, was associated with decreased quality of life.ConclusionsPACS, such as dyspnea, chest pain and fatigue, occurred after variable degree of disease severity. Among this majority black/mixed-race patients, woman seemed to be more affected. Other consequences included post-acute hospitalization, and abnormal glucose metabolism and reduced quality of life.Summary BoxSection 1: What is already known on this topic:✓ Post-Acute COVID Syndrome (PACS) comprises a set of persistent or new-onset symptoms after illness onset.✓ As far as we know, there are no studies describing PACS in a population principally black and mixed-race. Additionally, few studies have addressed PACS among outpatients.Section 2: What this study adds:✓ Similar PACS were reported after mild, moderate and severe illness. Dyspnea, fatigue and chest pain were the most prevalent symptoms in this population presenting majority of black/mixed-race patients.✓ Women presented more residual symptoms, a higher frequency of myalgia and worse score for mobility, usual activities, anxiety/depression, and pain.✓ Hospitalization may occur one month or later after mild or moderate/severe acute infection due to respiratory and vascular disorders. Abnormal glucose metabolism was detected in the absence of previous diagnosis of diabetes mellitus.

Summary Caseous lymphadenitis (CLA) is a small ruminant disease characterized by the development of granulomatous lesions in superficial and internal lymph nodes, as well as in some organs, and causes significant economic losses worldwide. The aetiological agent of CLA is the bacterium Corynebacterium pseudotuberculosis; however, the commercially available diagnostic tools present problems with regard to specificity, which can lead to false‐negative results. This study aimed to develop an indirect enzyme‐linked immunosorbent assay (ELISA) for the detection of specific immunoglobulins in goats and sheep using recombinant C. pseudotuberculosis PLD, CP40, PknG, DtxR and Grx proteins. For validation of the ELISAs, 130 goat serum samples and 160 sheep serum samples were used. The best ELISA for goats was developed using a combination of PLD and CP40 as antigens at a 1:1 ratio, which presented 96.9% sensitivity and 98.4% specificity. The most effective ELISA for sheep presented 91% sensitivity and 98.7% specificity when recombinant PLD alone was used as the antigen. These ELISAs can be used as highly accurate tools in epidemiological surveys and for the serodiagnosis of C. pseudotuberculosis infection in goats and sheep.

Background Dyslipidemias induce angiogenesis and accelerate the development and in vitro growth of breast tumors. The aim of this study was to assess the lipid and metabolic profile of female dogs with mammary carcinomas and their correlations with body condition score and degree of tumor malignancy, as well as to study the effect of dietary fish oil supplementation on these animals. Results Overweight or obese dogs had more aggressive carcinomas and higher triglyceride (p = 0.0363), VLDL (p = 0.0181), albumin (p = 0.0188), globulin (p = 0.0145) and lactate (p = 0.0255) concentrations. There was no change in the lipid profile after supplementation with fish oil at any concentration. However, in relation to the metabolic profile, glucose (p = 0.0067), total protein (p = 0.0002) and globulin (p = 0.0002) concentrations were increased when 90% omega-3 fish oil was used as a dietary supplement. Conclusion Obese dogs showed altered lipid and metabolic profiles and more aggressive tumors, suggesting an important relationship between dyslipidemia and tumor aggressiveness. Supplementation with fish oil, rich in omega-3 fatty acids, may alter metabolic parameters in cancer patients.

Introduction Male Chronic Pelvic Pain Syndrome (MCPPS) is a complex condition and difficult to decipher due to the multifactorial etiologies and system interrelationships. No studies to date have described a movement-based, multisystem assessment including the musculoskeletal, visceral, nervous, lymphatic and vascular systems, as well as manual prostate mobility testing. The purpose of this paper is to demonstrate the importance of a comprehensive physical therapy evaluation to identify predominant mechanical and movement-based dysfunctions related to multiple anatomical structures and their interrelationships. Furthermore, symptoms and potentially confounding psychosocial, and environmental factors linked to MCPPS will be presented, and an overview of prospective treatment will be provided. Method A retrospective analysis of evaluative findings for ten men was performed. The men, with an average age 35 (range 24–46) were referred to physical therapy for MCPPS. Results This retrospective analysis of ten patients identifies potential contributing pain factors associated with MCPPS. Similarities in clinical presentation among men suffering from MCPPS were identified to include predominant mechanical dysfunctions of the thoraco-lumbar spine, the liver, the kidney, the femoral nerve, the bladder, the prostate, and the pelvic floor. Conclusion The observations in this retrospective study demonstrate that the use of a multisystem assessment approach in patients with MCPPS is critical for their more effective treatment. On the basis of these findings, and the close mechanical interrelationships of the anatomical elements involved and multisystem MCPPS etiologies, larger-scale research is warranted.

Introduction: Synovial fluid (SF) analysis is an important tool for the diagnosis of patients with juvenile idiopathic arthritis (JIA). Patients and methods: A retrospective analysis was carried out of cytological features of SF samples obtained from patients with JIA during the period 2008–2016. Results: A total of 102 SF samples from 59 patients were analysed. JIA was more common in females (66%). The most frequent form was persistent oligoarticular JIA (52.5%). The median age at onset was 5 years (IQR 2.4–11.8). SF usually showed an inflammatory pattern (median white blood cells count 11,757/mm3; IQR 4,543–18,800), with a predominance of polymorphonuclear (PMN) cells (61%; IQR 30–75). Eight patients (14%) had white blood cells counts of less than 2000 cells/mm3, with predominance of mononuclear cells (80%), whereas 3 patients (5%) had white blood cells counts higher than 50,000 cells/mm3, with a predominance of PMN cells (90%). Synovial white blood cells count did not show significant differences among the different forms of JIA. The median synovial white blood cells count in ANA-positive patients was 20% lower than in ANA-negative (9,340 vs. 11,600/mm3; P = .23). The proportion of PMN increased with increasing levels of ESR (P

Current treatment of cutaneous leishmaniasis includes pentavalent antimonials as first-line drugs, but this therapy has shown severe adverse effects. An alternative to minimize this issue is based on combination therapy scheme with other drugs. In this study we analyzed the potential of the association of meglumine antimoniate (MA) with the oxiranes epoxy-α-lapachone (LAP) or epoxymethyl-lawsone (LAW). Results demonstrated that association between these drugs enhanced leishmanicidal activity on Leishmania (Leishmania) amazonensis infection. The compounds were tested in monotherapy or in combinations (3:1; 1:1 and 1:3) and reduced intracellular parasite numbers, measured by the endocytic index, in all tested conditions. The most effective combination regimens were MA/LAP or MA/LAW in 3:1 ratio, which achieved a reduction of 98.3% and 93.6% in the endocytic index, respectively. BALB/c mice challenged with L. (L.) amazonensis showed significant reduction in lesion size and parasite load in both footpad and lymph nodes, after four weeks of treatment. Although, MA, LAP or LAW monotherapy were able to control the evolution of lesions when compared to untreated animals (30%, 40% and 40% of reduction, respectively), the combination of MA/LAP and LAW in 3:1 ratio showed better results reducing 61.7 and 54.4%, respectively. The results indicate that the association of meglumine antimoniate to oxiranes lead to an increment in the antileishmanial activity and represent a promising approach for the cutaneous leishmaniasis treatment., Graphical abstract Image 1, Highlights • Meglumine antimoniate with oxiranes enhanced effect against Leishmania infection. • The most effective treatment in vitro infection was observed in a 3:1 ratio. • Mice treatment with drugs caused reductions in lesion size and parasite load. • Antimony-based combination has the potential for leishmaniasis treatment.

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient’s marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P

Purpose To evaluate the safety and efficacy of percutaneous transarterial embolization (PTAE) for the treatment of spontaneous soft-tissue hematomas (SSTHs) and identify variables predictive of short-term outcome. Materials and Methods Between 2011 and 2017, the outcome was retrospectively analyzed for 112 patients (mean age ± standard deviation, 72 years ± 14; range, 28-92 years), including 65 women (mean age, 73 years ± 12.7; range, 39-92 years) and 47 men (mean age, 70 years ± 14.9; range, 28-91 years), with SSTH treated with PTAE. Thirty-day mortality, technical and clinical success, simplified acute physiology score (SAPS) II, anticoagulation, embolic agent, hematoma volume and location, serum hemoglobin level, hemodynamic instability, and presence of active bleeding at CT and/or angiography were recorded. Clinical success was defined as cessation of bleeding as determined by hemodynamic stability and/or serum hemoglobin level stabilization after PTAE. Univariable and multivariable analyses were performed by using a Cox model to identify variables associated with time to death. Results Mortality rate was 26.8% (30 of 112 patients), angiographic success rate was 95.5% (107 of 112 patients), and clinical success rate was 83% (93 of 112 patients). For surviving patients, mean SAPS II was 19.6 ± 7.1 (range, 13-31) and mean hematoma volume was 862 cm3 ± 618 (range, 238-1887 cm3). For deceased patients, mean SAPS II was 42 ± 13.2 (range, 18-63) and mean hematoma volume was 1419 cm3 ± 788 (range, 251-3492 cm3). SAPS II (P < .001), hematoma volume (P = .01), and retroperitoneal location (P = .01) were independently associated with fatal outcome. Conclusion Percutaneous transarterial embolization is effective for the emergency treatment of spontaneous soft-tissue hematomas. Simplified acute physiology score II, hematoma volume, and retroperitoneal location are predictors of short-term outcome. © RSNA, 2019 Online supplemental material is available for this article.

14 páginas, 6 figuras., The present work investigated the prevalence, spatial distribution, and temporal distribution of tuberculosis (TB) in free-ranging Eurasian badgers (Meles meles) and cattle in Asturias (Atlantic Spain) during a 13-year follow-up. The study objective was to assess the role of badgers as a TB reservoir for cattle and other sympatric wild species in the region. Between 2008 and 2020, 673 badgers (98 trapped and 575 killed in road traffic accidents) in Asturias were necropsied, and their tissue samples were cultured for the Mycobacterium tuberculosis complex (MTC) isolation. Serum samples were tested in an in-house indirect P22 ELISA to detect antibodies against the MTC. In parallel, data on MTC isolation and single intradermal tuberculin test results were extracted for cattle that were tested and culled as part of the Spanish National Program for the Eradication of Bovine TB. A total of 27/639 badgers (4.23%) were positive for MTC based on bacterial isolation, while 160/673 badgers (23.77%) were found to be positive with the P22 ELISA. The rate of seropositivity was higher among adult badgers than subadults. Badger TB status was spatially and temporally associated with cattle TB status. Our results cannot determine the direction of possible interspecies transmission, but they are consistent with the idea that the two hosts may exert infection pressure on each other. This study highlights the importance of the wildlife monitoring of infection and disease during epidemiological interventions in order to optimize outcomes., This work was funded by the Ministerio de Ciencia, Innovación y Universidades (MCIU), the Agencia Estatal de Investigación (AEI) reference project RTI2018-096010-B-C21 (FEDER co-funded), PCTI 2018–2020 (GRUPIN: IDI2018-000237), and FEDER and Ministerio de Agricultura, Pesca y Alimentación. C.B.V. was supported by a grant from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Spain. Publication costs were covered with funds from RTI2018- 096010-B-C21 (FEDER co-funded). T.D.B. was supported by a fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; process number 88887.511077/2020-00).

The relevance of wild hosts in the maintenance and transmission of animal tuberculosis may increase as the prevalence in livestock decreases. However, studies on wild mammals in low bovine tuberculosis prevalence scenarios are scarce. The Basque Country is an understudied region from the Atlantic Iberian Peninsula with low bovine tuberculosis prevalence. In this 10-year survey, we searched for Mycobacterium tuberculosis complex (MTC) infection in wildlife and studied the spatial and temporal distribution of the spoligotypes circulating among these wild species and cohabiting livestock. For these purposes, lymph nodes from 1472 wild mammals were cultured and isolates spoligotyped. Information on domestic tuberculosis cases was obtained from the Spanish Database of Animal Mycobacteriosis. Infection was confirmed in ten wild boar (1.12%; 95% CI 0.61–2.05) and four red deer (2.40%; 95% CI 0.94–6.00). MTC was not isolated from badgers or other wild species. The general spoligotype diversity in the region was high. Five distinct spoligotypes belonging to M. bovis (SB0121, SB0134, SB0881, SB2354, SB1086) and one to M. caprae (SB0415) were detected in wildlife. Wild ungulates harboured most of the M. bovis spoligotypes that were commonly found in cattle, being SB0121 and SB0134 geographically associated between wild boar and cattle. M. caprae SB0415 was also found in both wild species as well as in cattle and goats. Despite the absence of MTC-infected badgers and the overall low prevalence observed in wildlife, potential epidemiological links between cattle and wild boar have been revealed. No competent hosts should be ignored when developing global control strategies aimed at eradicating tuberculosis.

This study evaluated the impact of the TLR7 Gln11Leu (rs179008) and TLR9 -1237 T/C (rs5743836) single nucleotide polymorphisms (SNPs) on susceptibility to placental infections and pregnancy complications in 455 Brazilian women. Demographic, socioeconomic, gynecological, and clinical characteristics of the women were collected. Placental tissues were sampled from pregnant women and human and viral DNA was extracted. Human alphaherpesvirus 1 (Herpes simplex virus type 1, HSV-1), Human alphaherpesvirus 2 (Herpes simplex virus type 2, HSV-2) and Human betaherpesvirus 5 (Human cytomegalovirus, HCMV) were detected by nested PCR. TLR9 and TLR7 SNPs were genotyped by PCR amplification of bi-directional specific alleles (Bi-PASA) and restriction fragment length polymorphism (RFLP), respectively. Infections at the time of birth were detected in 45.71 % of women. The presence of the TT genotype (recessive model) of the TLR7 SNP was associated with increased susceptibility to HSV-1 infection (O.R. = 2.23, p = 0.05). The presence of the C allele of the TLR9 SNP, in heterozygosis or homozygosis (dominant model), decreased the infection risk by HCMV (O.R. = 0.31, p-mod0.05). The TT genotype (recessive model) of the TLR7 SNP was significantly associated (p 0.05) with increased occurrence of pre-treated hypertension. The codominant model of the TLR9 SNP was significantly associated (p 0.05) with reduced risk of hospitalization during pregnancy. In combination, the AA/CT (TLR7-TLR9) genotypes significantly decreased the risk of placental infection by HSV-1 and/or HSV-2 (O.R. = 0.47, p = 0.02), the susceptibility to all infectious agents considered in combination (O.R. = 0.4, p = 0.00), and the need of hospitalization (O.R. = 0.48, p = 0.02). In conclusion, TLR7 and TLR9 SNPs are potential modulating factors for the risk of placental infections and pregnancy complications.

Lipophosphoglycan (LPG), when used as an ELISA target, confers high specificity and sensitivity to the detection of Leishmania infantum antibodies in dogs. Glycoconjugates are economically viable because the yield is very high after extraction/purification. In addition, they are very stable, which allows their use in point-of-care testing without special storage conditions. During the glycoconjugate extraction, a glycoinositolphospholipid (GIPL)-enriched fraction is obtained in similar quantities as LPG. Since GIPLs can be extracted from the same parasite pellet as LPGs, this work aimed to evaluate the immune recognition of GIPLs by Leishmania infantum-infected dogs and its use for canine leishmaniasis (CanL) immunodiagnosis. Like LPG, GIPLs were recognized by sera from L. infantum-infected dogs, but with less sensitivity (83.8%). However, 80% (16/20) of subclinically infected dogs were detected as positive in the assay. Different from LPG, the GIPL-based assay achieved a lower specificity (73.7%) and cross-reactions occurred with T. cruzi and L. braziliensis-infected dogs. Although GIPLs exhibited a similar performance to LPG for subclinically L. infantum-infected dogs, the occurrence of cross-reactivities with other protozoa and a lower sensitivity hinders its use for an immunodiagnostic test. In places where those diseases do not co-exist such as in the Mediterranean region, its use for subclinically dogs could be an alternative.

Homeostatic perturbation caused by infection fosters two major defense stratagems, resistance and tolerance, which promote the host’s survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n=108) or symptomatic (n=134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n=128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. The findings mapped the relationships between the systemic degree of inflammatory perturbation and parasitemia values to define the disease tolerance in vivax malaria.Author SummaryPlasmodium vivax infection can result in a broad spectrum of disease manifestations, ranging from asymptomatic malaria to severe life-threatening disease. Despite significant advances in the current understanding of the critical factors associated with the disease outcomes in vivax malaria, the immunopathological events responsible for the diversity of severe manifestations in the disease remain deeply unknown. Here, a large panel of cytokines/chemokines were assessed in plasma samples from a Brazilian cohort of P. vivax patients presenting with asymptomatic infection or symptomatic malaria at the time of diagnosis, as well as from uninfected endemic controls, to define the relationships between systemic inflammation, disease presentation, parasitemia, and epidemiologic characteristics. In-depth analyses using the molecular degree of perturbation were employed to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity. Moreover, the discoveries diagrammed the occurrence of disease tolerance by narrowing down the interactions between the systemic degree of inflammatory perturbation and parasitemia values in vivax malaria patients.

Following publication of the original article at https://doi.org/10.1186/s13054-021-03727-x the authors identified an error in the Funding section that has been corrected (https://doi.org/10.1186/s13054-021-03849-2), Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

Fundac¸a˜o de Apoio a Pesquisa do Estado da Bahia (FAPESB), Bahia, Brazil, grant number 05/2015 and Conselho Nacional de Pesquisa (CNPq) grant number 401379/2014-0. DF received a CNPq fellowship (BJT_2014), and HA received a CNPq fellowship for undergraduate students. AB, VMB, EMC, LPC, DSZ, and CB are senior investigators of CNPq.

OBJECTIVE: There are no recommendations for screening for thoracic aortic aneurysms (TAAs), even in patients with infrarenal abdominal aortic aneurysms (AAAs). The aims of this study were to determine the prevalence of TAAs in patients with AAAs and to analyse the risk factors for this association. METHODS: This was a multicentre prospective study. The Aortic Concomitant Thoracic and Abdominal Aneurysm (ACTA) study included 331 patients with infrarenal AAAs > 40 mm between September 2012 and May 2016. These patients were prospectively enrolled in three French academic hospitals. RESULTS: Patients were classified as having a normal, aneurysmal, or ectatic (non-normal, non-aneurysmal) thoracic aorta according to their maximum aortic diameter indexed by sex, age, and body surface area. Thoracic aortic ectasia (TAE) was defined as above or equal to the 90th percentile of normal aortic diameters according to gender and body surface area. Descending TAA was defined as ≥q 150% of the mean normal value, and ascending TAA as > 47 mm in men and 42 mm in women; 7.6% (n~= 25) had either an ascending (seven cases; 2.2%) or descending aortic TAA (18 cases; 5.4%), and 54.6% (n~= 181) had a TAE. Among the 25 patients with TAAs, five required surgery; two patients had TAAs related to penetrating aortic ulcers < 60 mm in diameter, and three had a TAA > 60 mm. In the multinomial regression analysis, atrial fibrillation (AF) (odds ratio [OR] 11.36, 95% confidence interval [CI] 2.18 - 59.13; p~= .004) and mild aortic valvulopathy (OR 2.89, 1.04-8.05; p~= .042) were independent factors associated with TAAs. Age (OR 1.06, CI 1.02 - 1.09; p~= .003) and AF (OR 4.36, 1.21 - 15.61; p~= .024) were independently associated with ectasia. CONCLUSION: This study confirmed that TAAs coexisting with AAAs are not rare, and one fifth of these TAAs are treated surgically. Systematic screening by imaging the whole aorta in patients with AAAs is clinically relevant and should lead to an effective prevention policy.

We report the case of a 57-year-old woman diagnosed with an asymptomatic chronic type B aortic dissection. The maximum aortic diameter was 70 mm in the proximal descending thoracic aorta. The entry tear was located at the aortic isthmus, and the proximal neck included all of the supra-aortic trunks. The targeted proximal neck was ≥q 25 mm. The dissection extended to the infrarenal aorta. The patient was treated with a custom branched aortic graft with two branches, one for the innominate trunk and one for the left common carotid artery, combined with the stent-assisted balloon-induced intimal disruption and relamination technique. This combined technique seemed to provide a proximal seal zone in the arch and allow remodeling of the distal aorta in this patient with aneurysmal type B aortic dissection.