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BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the β-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations.METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment.FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness).INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified.FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.

Background West Nile Disease (WND) is a zoonotic mosquito‐borne infection involving viral pathogens, human and animal hosts, vectors and environment. Cooperation among medical, veterinary and entomological fields has been promoted by the Italian Public Health Authorities, and an integrated West Nile Virus (WNV) Surveillance Plan has been in force in Italy since 2016 to prevent the transmission risk of WND to humans through an early detection of viral circulation by animal and entomological surveillance. This managing model is unique in Europe. Objectives This survey aimed at presenting the ‘One Health’ approach applied in 2016 to the first autochthonous human case of West Nile Neuroinvasive Disease (WNND) in Sicily (Southern Italy). Methods Serological (anti‐WNV IgM and IgG ELISA, anti‐WNV neutralizing antibodies) and molecular tests were conducted on blood, liquor and urine of a 38‐year‐old man with encephalitis and meningitis. Overall, 2704 adult culicides from 160 mosquito catches were morphologically identified. Female mosquitoes were analysed in pools for WNV RNA detection. Serological (anti‐WNV IgM and IgG ELISA) and molecular analyses for WNV were carried out in 11 horses, 271 chickens and two dogs sampled in farms around the man's residence. Results and conclusions WNND was confirmed by serological analysis on patient's liquor and serum. Collected mosquito species included Culex pipiens (93.56%, CI95% 92.64%–94.49%), Aedes albopictus (5.25%, CI95% 4.41%–6.09%), Culex hortensis (0.59%, CI95% 0.30%–0.88%), Culiseta longiareolata (0.55%, CI95% 0.27%–0.83%) and Anopheles maculipennis s.l. (0.04%, CI95% –0.04% to 0.11%). Mosquito pools were negative for WNV RNA. Two dogs (100%) and two horses (18.18%, CI95% –4.61 to 40.97%) resulted positive for anti‐WNV specific antibodies. The ‘One Health’ approach allowed to report the first human neuroinvasive WND in Sicily and to confirm the local circulation of WNV in animals of the same area where the clinical case occurred, defining the autochthonous origin of the infection., Description of the first neuroinvasive human case of West Nile disease in Sicily.Detection of West Nile Virus antibodies in dogs and horses in the surrounding area.Presence of the main West Nile Virus vector Culex pipiens in the investigated area.

The gut microbiota exerts a variety of positive effects on the intestinal homeostasis, including the production of beneficial molecules, control of the epithelial barrier integrity and the regulation of the balance between host’s cell death and proliferation. The interactions between commensal bacteria and intestinal cells are still under-investigated and is then of paramount importance to address such interactions at the molecular and cellular levels. We report an in vitro analysis of the effects of molecules secreted by Lactobacillus gasseri SF1183 on HCT116 cells, selected as a model of intestinal epithelial cells. SF1183 is a L. gasseri strain isolated from an ileal biopsy of a human healthy volunteer, able to prevent colitis symptoms in vivo. Expanding previous findings, we show that bioactive molecules secreted by SF1183 reduce the proliferation of HCT116 cells in a reversible manner determining a variation in cell cycle markers (p21WAF, p53, cyclin D1) and resulting in the protection of HCT116 cells from TNF-alfa induced apoptosis, an effect potentially relevant for the protection of the epithelial barrier integrity and reconstitution of tissue homeostasis. Consistently, SF1183 secreted molecules increase the recruitment of occludin, a major component of TJ, at the cell–cell contacts, suggesting a reinforcement of the barrier function.

Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability can be problematic, whereas epitope tagging can be impractical in many cases. To address these limitations, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. Eight hundred eighty-seven unique antibodies against 681 unique human transcription factors (TFs) were assayed by ultra-high-resolution ChIP-exo/seq, generating approximately 1200 ChIP-exo data sets, primarily in a single pass in one cell type (K562). Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed high-confidence target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that were distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We show and discuss the metrics and challenges to antibody validation in chromatin-based assays.

Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form. This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described. Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock., This research was funded by the Italian Ministry of Health with grants RC IZSSI 08/19 and RC IZSSI 01/20.

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015-2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015-2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.

Summary: The established impact of gut microbiota- and probiotic-derived metabolites on immune-checkpoint blockade (ICB) has spurred extensive efforts to identify strains and druggable bioactive molecules of microbial origin that can improve tumor immune therapy. In this issue, Kawanabe-Matsuda and colleagues show that the exopolysaccharide EPS-R1 produced by the probiotic strain Lactobacillus delbrueckii subsp. bulgaricus augments the response to ICB therapy by expanding the population of Peyer's patches CCR6+ CD8+ T cells, which can subsequently migrate from the gut into CCL20-expressing tumors to enhance antitumor activity. See related article by Kawanabe-Matsuda et al., p. 1336 (10).

Background Cardiovascular complications of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV2) are known to be associated with poor outcome. A small number of case series and reports have described cases of myocarditis and ischaemic events, however, knowledge on the aetiology of acute cardiac failure in SARS-CoV2 remains limited. We describe the occurrence and risk stratification imaging correlates of ‘takotsubo’ stress cardiomyopathy presenting in a patient with Coronavirus Disease 2019 (COVID-19) in the intensive care unit. Case summary An intubated 53-year old patient with COVID19 suffered acute haemodynamic collapse in the intensive care unit, and was thus investigated with transthoracic echocardiography (TTE), 12-lead electrocardiograms (ECG) and serial troponins and blood tests, and eventually coronary angiography due to clinical suspicion of ischaemic aetiology. Echocardiography revealed a reduced ejection fraction, with evident extensive apical akinesia spanning multiple coronary territories. Troponins and NT-proBNP were elevated, and ECG revealed ST elevation: coronary angiography was thus performed. This revealed no significant coronary stenosis. Repeat echocardiography performed within the following week revealed a substantial recovery of ejection fraction and wall motion abnormalities. Despite requirement of a prolonged ICU stay, the patient now remains clinically stable, and is on spontaneous breathing. Conclusion This case report presents a case of takotsubo stress cardiomyopathy occurring in a critically unwell patient with COVID19 in the intensive care setting. Stress cardiomyopathy may be an acute cardiovascular complication of COVID-19 infection. In the COVID19 critical care setting, urgent bedside echocardiography is an important tool for initial clinical assessment of patients suffering haemodynamic compromise.

This article belongs to the Special Issue Inflammasome., Many pathogens are transmitted by tick bites, including Anaplasma spp., Ehrlichia spp., Rickettsia spp., Babesia and Theileria sensu stricto species. These pathogens cause infectious diseases both in animals and humans. Different types of immune effector mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. The components of innate immunity, such as natural killer cells, complement proteins, macrophages, dendritic cells and tumor necrosis factor alpha, cause a rapid and intense protection for the acute phase of infectious diseases. Moreover, the onset of a pro-inflammatory state occurs upon the activation of the inflammasome, a protein scaffold with a key-role in host defense mechanism, regulating the action of caspase-1 and the maturation of interleukin-1β and IL-18 into bioactive molecules. During the infection caused by different microbial agents, very similar profiles of the human innate immune response are observed including secretion of IL-1α, IL-8, and IFN-α, and suppression of superoxide dismutase, IL-1Ra and IL-17A release. Innate immunity is activated immediately after the infection and inflammasome-mediated changes in the pro-inflammatory cytokines at systemic and intracellular levels can be detected as early as on days 2–5 after tick bite. The ongoing research field of “inflammasome biology” focuses on the interactions among molecules and cells of innate immune response that could be responsible for triggering a protective adaptive immunity. The knowledge of the innate immunity mechanisms, as well as the new targets of investigation arising by bioinformatics analysis, could lead to the development of new methods of emergency diagnosis and prevention of tick-borne infections., This research was funded by Italian Ministry of Health RC IZSSI 07/18 and RC IZSSI 08/19.

This article belongs to the Section Molecular Immunology., Tick-transmitted pathogens cause infectious diseases in both humans and animals. Different types of adaptive immune mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen antigens or indirectly through soluble factors, such as cytokines and/or chemokines, secreted by host cells as response. Adaptive immunity effectors, such as antibody secretion and cytotoxic and/or T helper cell responses, are mainly involved in the late and long-lasting protective immune response. Proteins and/or epitopes derived from pathogens and tick vectors have been isolated and characterized for the immune response induced in different hosts. This review was focused on the interactions between tick-borne pathogenic hemoparasites and different host effector mechanisms of T- and/or B cell-mediated adaptive immunity, describing the efforts to define immunodominant proteins or epitopes for vaccine development and/or immunotherapeutic purposes. A better understanding of these mechanisms of host immunity could lead to the assessment of possible new immunotherapies for these pathogens as well as to the prediction of possible new candidate vaccine antigens., This research was funded by the Italian Ministry of Health with grants RC IZSSI 07/18 and RC IZSSI 08/19.

The COVID-19 pandemic has rapidly spread around the world. The rapid transmission of the virus is a threat that hinders the ability to contain the disease propagation. The pandemic forced widespread conversion of in-person to virtual care delivery through telemedicine. Given this gap, this article aims at providing a literature review of machine learning-based telemedicine applications to mitigate COVID-19. A rapid review of the literature was conducted in six electronic databases published from 2015 through 2020. The process of data extraction was documented using a PRISMA flowchart for inclusion and exclusion of studies. As a result, the literature search identified 1.733 articles, from which 16 articles were included in the review. We developed an updated taxonomy and identified challenges, open questions, and current data types. Our taxonomy and discussion contribute with a significant degree of coverage from subjects related to the use of machine learning to improve telemedicine in response to the COVID-19 pandemic. The evidence identified by this rapid review suggests that machine learning, in combination with telemedicine, can provide a strategy to control outbreaks by providing smart triage of patients and remote monitoring. Also, the use of telemedicine during future outbreaks could be further explored and refined.

Background Tick-borne diseases are common throughout Europe. Ticks transmit pathogens to the host while feeding and together with mosquitoes, they are major vectors of infectious agents worldwide. In recent years, there has been a marked increase in the incidence of tick-bite events and tick-borne disease in northwest Italy, but information on the prevalence of tick-borne pathogens in ticks removed from humans remains scarce. To fill this gap, we report here the prevalence of tick bites and tick-borne pathogens documented for humans in Piedmont, northwest Italy, in the 3-year period 2017–2019. Methods Ticks attached to humans during 2017–2019 were collected from residents of urban and rural area by physicians and veterinarians working with local veterinary agencies. All ticks (n = 1290) were morphologically identified to the species level. A subset of ticks removed from children (age 0–18 years) and the elderly (> 70 years), both age groups considered to be at-risk populations, was screened by biomolecular analysis to detect pathogens (e.g. Rickettsia spp., Borrelia spp., Anaplasma spp.). Pathogen identity was confirmed by Sanger sequencing. Results Ticks were taxonomically assigned to ten species of six genera (Amblyomma, Dermacentor, Haemaphysalis, Hyalomma, Ixodes and Rhipicephalus). Most belonged to the genus Ixodes: 1009 ticks (78.22%) were classified as Ixodes ricinus. A subset of 500 ticks collected from the two at-risk populations were subjected to PCR assay to determine the presence of Rickettsia spp., Borrelia spp., and Anaplasma spp. The overall prevalence of infection was 22.8% (n = 114; 95% confidence interval [CI]: 19.19–26.73%), meaning that at least one pathogen was detected: Rickettsia spp. (prevalence 15%, n = 76; 95% CI 12.17–18.65%); Borrelia spp. (prevalence 6.4%, n = 32; 95% CI 4.42–8.92%); and Anaplasma spp. (prevalence 1.2%, n = 6; 95% CI 0.44–2.6%). Conclusions Our data underline the importance of surveillance in the epidemiology of tick-borne diseases and the implementation of strategies to control tick infestation and associated pathogens. Graphical Abstract

Ceramides are sphingolipids that play roles as structural lipids and as second messengers in biological processes. Circulating ceramides are influenced by diet/food and predict major cardiovascular (CV) events, such as atrial fibrillation (AF). In 1227 patients with symptomatic chronic heart failure (HF), an association between diet and ceramides was found for coffee consumption of ≥3 cups and Cer(d18:1/24:0). Increased Cer(d18:1/24:0) was associated with lower incident AF (24.3% vs 15.4% tertile 1 vs 3, P = 0.016) and lower CV mortality (28.4% vs 12.0% tertile 1 vs 3, P < 0.0001). For coffee consumption, only an association with incident AF was found (24.5% never, 5.2% ≥3 cups). These inverse associations with AF were confirmed in survival analyses corrected for biomarkers (Cer(d18:1/24:0) HR: 0.79, P = 0.018; coffee consumption HR: 0.22, P = 0.001). In conclusion, higher coffee intake was associated with a lower risk of incident AF and with higher concentrations of Cer(d18:1/24:0). Cer(d18:1/24:0) was inversely associated to risk of AF.

Crohn’s disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets., Crohn’s disease results from transmural inflammation in the gut, but analyses of local immune populations are still lacking. Here, the authors show, by combining multiple single-cell approaches, that intraepithelial and lamina propria T cells are heterogenous, show unique phenotypes, and exhibit altered subsets upon inflammation.

Rickettsia species are an important cause of emerging infectious diseases in people and animals, and rickettsiosis is one of the oldest known vector-borne diseases. Laboratory diagnosis of Rickettsia is complex and time-consuming. This study was aimed at developing two quantitative real-time PCRs targeting ompB and ompA genes for the detection, respectively, of Rickettsia spp. and R. conorii DNA. Primers were designed following an analysis of Rickettsia gene sequences. The assays were optimized using SYBR Green and TaqMan methods and tested for sensitivity and specificity. This study allowed the development of powerful diagnostic methods, able to detect and quantify Rickettsia spp. DNA and differentiate R. conorii species.

Undernourished children in low-income countries often exhibit poor responses to oral vaccination. Perturbed microbiota development is linked to undernutrition but whether and how microbiota changes affect vaccine responsiveness remain unclear. Here, we show that gnotobiotic mice colonized with microbiota from undernourished Bangladeshi children and fed a Bangladeshi diet exhibited microbiota-dependent differences in mucosal IgA responses to oral vaccination with cholera toxin (CT). Supplementation with a nutrient-rich diet consisting of spirulina, amaranth, flaxseed and micronutrients augmented CT-IgA production. Mice initially colonized with a microbiota associated with poor CT responses exhibited improved immunogenicity upon invasion of bacterial taxa from cagemates colonized with a more ‘responsive’ microbiota. Additionally, a consortium of five cultured bacterial invaders conferred augmented CT-IgA responses in mice fed the supplemented diet and colonized with the ‘hypo-responsive’ community. These results provide preclinical proof-of-concept that diet and microbiota influence mucosal immune responses to CT vaccination and identify a candidate synbiotic formulation.

Insecticide resistance is an increasing problem worldwide that limits the efficacy of control methods against several pests of health interest. Among them,Aedes albopictusmosquitoes are efficient vectors of relevant pathogens causing animal and human diseases worldwide, including yellow fever, chikungunya, dengue, and Zika. Different mechanisms are associated in conferring resistance to chemical insecticides. One of the most widespread and analysed mechanisms is the knockdown resistance (kdr) causing resistance to DDT and pyrethroids. The mechanism is associated with mutations in the voltage sensitive sodium channel, which is involved in beginning and propagation of action potentials in nervous cells. The mechanism was originally discovered in the housefly and then it was found in a large number of arthropods. In 2011, akdrassociated mutation was evidenced for the first time inA. albopictusand afterward several evidences were reported in the different areas of the world, including China, USA, Brazil, India, and Mediterranean Countries. This review aims to update and summarize current evidences onkdrinA. albopictus, in order to stimulate further researches to analyse in depthA. albopictusresistance status across the world, especially in countries where the presence of this vector is still an emerging issue. Such information is currently needed given the well-known vector role ofA. albopictusin the transmission of severe infectious diseases. Furthermore, the widespread use of chemical insecticides for control strategies againstA. albopictusprogressively lead to pressure selection inducing the rise of insecticide resistance-related mutations in the species. Such event is especially evident in some countries as China, often related to a history of uncontrolled use of chemical insecticides. Thus, a careful picture on the diffusion ofkdrmutations worldwide represents a milestone for the implementation of control plans and the triggering of novel research on alternative strategies for mosquito-borne infections.

Galectin-3 (Gal-3) is a β-galactoside-binding protein belonging to the lectin family with pleiotropic regulatory activities and several physiological cellular functions, such as cellular growth, proliferation, apoptosis, differentiation, cellular adhesion, and tissue repair. Inflammation, tissue fibrosis and angiogenesis are the main processes in which Gal-3 is involved. It is implicated in the pathogenesis of several diseases, including organ fibrosis, chronic inflammation, cancer, atherosclerosis and other cardiovascular diseases (CVDs). This review aims to explore the connections of Gal-3 with cardiovascular diseases since they represent a major cause of morbidity and mortality. We herein discuss the evidence on the pro-inflammatory role of Gal-3 in the atherogenic process as well as the association with plaque features linked to lesion stability. We report the biological role and molecular mechanisms of Gal-3 in other CVDs, highlighting its involvement in the development of cardiac fibrosis and impaired myocardium remodelling, resulting in heart failure and atrial fibrillation. The role of Gal-3 as a prognostic marker of heart failure is described together with possible diagnostic applications to other CVDs. Finally, we report the tentative use of Gal-3 inhibition as a therapeutic approach to prevent cardiac inflammation and fibrosis.

Primary malignant brain and other central nervous system tumors (BT) are a rare cancer that causes morbidity and mortality disproportionate to their incidence. This study presents the most up-to-date mortality data for malignant BT in the United States (US) by histology groupings, age, race, and sex. Mortality rates for malignant BT were generated using the Center for Disease Control's National Vital Statistics Systems (NVSS, ~100% of US) data from 1975 to 2012. Histology-specific incidence-based mortality rates were calculated using the National Cancer Institute's Surveillance, Epidemiology, and End-Results 9 (SEER9, ~9.4% of US) data from 1975 to 2012. Joinpoint modeling was used to estimate trends. Mortality was similar in both the NVSS and SEER9 datasets. Overall, mortality from 1975 to 2012 was higher among men, higher in older individuals, and higher in Whites compared to other races. Persons age 65+ years had significant increases in mortality for all malignant tumors overall and for glioma histologies, while persons age

General population-based survival statistics for primary malignant brain or other central nervous system (CNS) tumors do not provide accurate estimations of prognosis for individuals who have survived for a significant period of time. For these persons, the use of conditional survival percentages provides more accurate information to estimate potential outcomes. Using information from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program from 1995 to 2012, conditional survival percentages were calculated for 1 or 5 years of additional survival for all primary malignant brain and CNS tumors overall and by gender, race, ethnicity and age. Rates were calculated to include 1, 2, 3, 4, 5, 10 and 15 years post diagnosis. Conditional survival was also calculated in intervals from 1995–2004 to 2005–2012, to examine the potential effect that the introduction of new treatment protocols may have had on survival rates. The percentage of patients surviving one or five additional years varied by histology, age at diagnosis, gender, race and ethnicity. Younger persons (age

Biting midges of the genus Culicoides are known vectors of arboviruses affecting human and animal health. However, little is known about Culicoides imicola microbiota and its influence on this insect's biology. In this study, the impact of biotic and abiotic factors on C. imicola microbiota was characterized using shotgun-metagenomic sequencing of whole-body DNA samples. Wild-caught C. imicola adult nulliparous females were sampled in two locations from Sicily, Italy. The climatic variables of temperature and soil moisture from both localities were recorded together with potential host bloodmeal sources. Shared core microbiome among C. imicola populations included Pseudomonas, Escherichia, Halomonas, Candidatus Zinderia, Propionibacterium, and Schizosaccharomyces. Specific and unique taxa were also found in C. imicola from each location, highlighting similarities and differences in microbiome composition between the two populations. DNA and protein identification showed differences in host preferences between the two populations, with Homo sapiens and Canis lupus familiaris L. being the preferred bloodmeal source in both locations. A principal component analysis showed that the combined effect of host preferences (H. sapiens) and local soil moisture factors shape the microbiome composition of wild-caught populations of C. imicola. These results contribute to characterizing the role of the microbiome in insect adaptation and its utility in predicting geographic expansion of Culicoides species with potential implications for the control of vector-borne diseases.

OBJECTIVETo evaluate hospital administrative data to identify potential surgical site infections (SSIs) following primary elective total hip or knee arthroplasty.DESIGNRetrospective cohort study.SETTINGAll acute care facilities in Alberta, Canada.METHODSDiagnosis and procedure codes for 6 months following total hip or knee arthroplasty were used to identify potential SSI cases. Medical charts of patients with potential SSIs were reviewed by an infection control professional at the acute care facility where the patient was identified with a diagnosis or procedure code. For SSI decision, infection control professionals used the National Healthcare Safety Network SSI definition. The performance of traditional surveillance methods and administrative data–triggered medical chart review was assessed.RESULTSOf the 162 patients identified by diagnosis or procedure code, 46 (28%) were confirmed as an SSI by an infection control professional. More SSIs were identified following total hip vs total knee arthroplasty (42% vs16%). Of 46 confirmed SSI cases, 20 (43%) were identified at an acute care facility different than their procedure facility. Administrative data–triggered medical chart review with infection control professional confirmation resulted in a 1.1- to 1.7-fold increase in SSI rate compared with traditional surveillance. SSIs identified by administrative data resulted in sensitivity of 90% and specificity of 99%.CONCLUSIONMedical chart review for cases identified through administrative data is an efficient supplemental SSI surveillance strategy. It improves case-finding by increasing SSI identification and making identification consistent across facilities, and in a provincial surveillance network it identifies SSIs presenting at nonprocedure facilities.Infect Control Hosp Epidemiol 2016;37:699–703

Rickettsiae (family Rickettsiaceae, order Rickettsiales) are obligate intracellular bacteria transmitted by arthropod vectors. Several Rickettsia species causing vector-borne rickettsioses belong to the spotted fever group (SFG). Traditionally, Rickettsia conorii has been considered as the main etiologic agent of Mediterranean spotted fever. However, the molecular characterization of rickettsiae allowed identifying other species involved in spotted fever in the Mediterranean region. In this study, 42 ticks collected from humans were subjected to morphological identification and molecular characterization of Rickettsia species potentially involved in human rickettsiosis in Sicily. Fourteen ticks positive to at least two Rickettsia spp. molecular markers were used in the study. Identified Rickettsia spp. included R. conorii, found in Rhipicephalus sanguineus sensu lato and Rhipicephalus turanicus, Rickettsia aeschlimannii found in Hyalomma marginatum, Hyalomma lusitanicum, Dermacentor marginatus and Ixodes ricinus, Rickettsia massiliae found in R. turanicus and R. sanguineus s.l., and Rickettsia slovaca found in D. marginatus and R. sanguineus s.l. Our results showed a great variety of zoonotic Rickettsia spp. in ticks collected from humans in Sicily. The Rickettsia spp. reported in this study were identified in previously recognized or new potential tick vectors in Europe, highlighting the risk of infection by different Rickettsia spp. for humans bitten by ticks in Sicily., This work was supported by Italian Ministry of Health (grant numbers IZS SI RC 02/13 and IZS SI RC 10/14).

Ticks (Acari: Ixodidae) are ectoparasites infesting livestock in every geographic area in the world and they are vectors of several viral, bacterial, and protozoan pathogens to animals and humans worldwide. A deep knowledge of the geographical distribution of these arthropods would have a key role in the control of tick-borne diseases. Few data are available about tick presence in domestic ruminants in Lebanon. The study aimed at providing an analysis of tick presence and distribution in Lebanon. Ticks were collected from cattle, sheep, and goats farms distributed in 6 Lebanese provinces between June and September 2014. A total of 272 adult hard ticks were randomly collected from domestic ruminants (cattle, sheep, and goats) located at 37 Lebanese farms, distributed among 30 villages. Ticks belonged to 4 Ixodidae genera: Rhipicephalus (72.4%), Haemaphysalis (11.4%), Dermacentor (8.1%), and Hyalomma (8.1%). They included the following species: Rhipicephalus annulatus (50.7%), Rhipicephalus turanicus (18.8%), Hyalomma anatolicum (8.1%), Haemaphylasis punctata (11.4%), Dermacentor marginatus (8.1%), Rhipicephalus sanguineus (2.5%), and Rhipicephalus bursa (0.4%). Rhipicephalus turanicus and H. anatolicum were found on cattle, sheep, and goats, R. annulatus on cattle and sheep, R. sanguineus, D. marginatus and Hea. punctata on sheep and goats, while R. bursa was collected only on sheep. Tick species involved in pathogen transmission were found and some of the identi ed species were recorded in Lebanon for the rst time.

Letter to the Editor.-- et al., This research was supported by the Italian Ministry of Health, project IZSSI 08/08.

A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

Recent data are lacking about the number of patients with angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes also are not known.To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED.We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the Emergency Medicine Network. A structured data abstraction form was used to collect each patient's demographic factors, medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on treatment provided in the ED and subsequent need for hospitalization.We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%-34%). The annual rate of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12% were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status (24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length of stay.ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway angioedema.

To the Editor: Scalp eschar and neck lymphadenopathy is a common clinical entity that most frequently affects women and children during spring and fall. It is usually caused by Rickettsia slovaca and R. raoultii. Typical clinical signs are a scalp lesion at the tick bite site and regional, often painful, lymphadenopathy. Acute disease can be followed by residual alopecia at the bite site (1,2). Two designations have been proposed for this syndrome: tick-borne lymphadenopathy and Dermacentor-borne necrosis-erythema-lymphadenopathy (both have been associated with R. slovaca); however, the most generic and all-inclusive term is scalp eschar and neck lymphadenopathy. R. massiliae belongs to the spotted fever group rickettsiae, is distributed worldwide, and is transmitted by ticks of the genus Rhipicephalus (3). To our knowledge, only 3 cases of R. massiliae infection in humans have been documented and confirmed by molecular methods. The first case was detected in a blood sample from a patient in Italy who had Mediterranean spotted fever (4); the second case was in a patient in southern France who had spotted fever and acute loss of vision (5); and the third case was in a woman in Argentina who had fever, a palpable purpuric rash, and tache noire (3). We report a case of R. massiliae infection that resulted in scalp eschar and neck lymphadenopathy. On May, 10, 2012, a 13-year-old boy was examined for headache, high fever, and right painful neck and occipital swelling. Six days earlier, a tick had been removed from the top of his scalp, after which signs and symptoms arose and gradually worsened. Physical examination revealed temperature 39.5°C, pulse rate 70 beats/min, and respiratory rate 20 breaths/min. The boy appeared to be in good condition. An ≈1-cm black eschar was noted at the site of the tick bite. Palpation of the neck revealed painful bilateral adenopathies. Other lymph nodes in the occipital region were enlarged. No exanthema was noted, the liver was palpable 1 cm under the costal margins, and the spleen was not enlarged. Laboratory evaluation indicated blood cell counts and liver and kidney function within reference limits, mild elevation of inflammatory markers (C-reactive protein 1.2 mg/dL [reference

The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.

Background: Periodic surveys of research directors (RDs) in emergency medicine (EM) are useful to assess the specialty’s development and evolution of the RD role. Objectives: To assess associations between characteristics and research productivity of RDs and EM programs. Methods: A survey of EM RDs was developed using the nominal group technique and pilot tested. RDs or surrogate respondents at programs certified by the Accreditation Council for Graduate Medical Education were contacted by e-mail in early 2005. The survey assessed programs’ research infrastructure and productivity, as well as RD characteristics, responsibilities, and career satisfaction. Three measures of research productivity were empirically defined: research publications, grant awards, and grant revenue. Results: Responses were received from 86% of 123 EM programs. Productivity was associated with the presence of nonclinical faculty, dedicated research coordinators, and reduced clinical hours for research faculty. Programs with an RD did not have greater research productivity, using any measure, than those without an RD. The majority of RDs cited pursuing their own studies, obtaining funding, research mentoring, and research administration to be major responsibilities. The majority characterized internal research funding, grant development support, and support from other faculty as inadequate. Most RDs are satisfied with their careers and expect to remain in the position for three or more years. Conclusions: Research productivity of EM residency programs is associated with the presence of dedicated research faculty and staff and with reduced clinical demands for research faculty. Despite perceiving deficiencies in important resources, most RDs are professionally satisfied. ACADEMIC EMERGENCY MEDICINE 2006; 13:637–644 a 2006 by the Society for Academic Emergency

The geriatric emergency care model emphasizes older emergency patients be considered a special population, analogous to pediatric patients [1]. This concept is especially relevant to pharmacologic issues in the elderly. The need for practitioners to create a balance between using medications with adverse effects while providing access to therapies that may have a beneficial effect on morbidity, mortality, function, and quality of life is challenging. Variables affecting this challenge in the elderly population include comorbidities, limited evidence for efficacy, increased risk of adverse drug reactions, polypharmacy, and altered pharmokinetics. Elderly patients become involved in a vicious cycle described by Rochan as the ‘‘prescribing cascade’’ [2,3]. This cascade begins when an adverse drug reaction is misinterpreted as a new medical condition. A drug is prescribed to treat this new ‘‘medical condition’’ and another adverse drug effect occurs. Again, this is interpreted as a new condition and the patient is again subjected to unnecessary treatment and additional adverse effects of the drug. Because elderly patients have multiple medical problems they are prescribed multiple medications that lead to increased risk of adverse effects. Many of these adverse effects go unrecognized as such and lead to new drugs being added. This perpetuates the continued cycle of adverse effects. This article describes the scope of the problem of drug prescribing in the elderly. It looks at the concept of adverse drug reactions and events, principles underlying clinical geriatric pharmacology, and reviews drugs that commonly cause adverse drug reactions. It includes recommendations about drugs to be avoided and substitutes and approaches to evaluate the evidence for risk and benefits when selecting drugs for an elderly person.

It is now commonly accepted that the intestinal microbiota plays a crucial role in the gut physiology and homeostasis, and that both qualitative and quantitative alterations in the compositions of the gut flora exert profound effects on the host’s intestinal cells. In spite of this, the details of the interaction between commensal bacteria and intestinal cells are still largely unknown and only in few cases the molecular mechanisms have been elucidated. Here we analyze the effects of molecules produced and secreted by Lactobacillus gasseri SF1183 on human intestinal HCT116 cells. L. gasseri is a well known species of lactic acid bacteria, commonly associated to the human intestine and SF1183 is a human strain previously isolated from an ileal biopsy of an healthy volunteer. SF1183 produces and secretes, in a growth phase-dependent way, molecule(s) able to drastically interfere with HCT116 cell proliferation. Although several attempts to purify and identify the bioactive molecule(s) have been so far unsuccessful, a partial characterization has indicated that it is smaller than 3 kDa, thermostable and of proteinaceous nature. L. gasseri molecule(s) stimulate a G1-phase arrest of the cell cycle by up-regulation of p21WAF1 rendering cells protected from intrinsic and extrinsic apoptosis. A L. gasseri-mediated reduction of apoptosis and of cell proliferation could be relevant in protecting epithelial barrier integrity and helping in reconstituting tissutal homeostasis.

Objectives: Pain related to the gurney is a frequent complaint of older emergency department (ED) patients. The authors hypothesized that these patients may have less pain and higher satisfaction if allowed to sit in a reclining hospital chair. Methods: A single-blind, randomized controlled trial was performed. Patients 65 years old or older who were able to sit upright, transfer, and engage in normal conversation were eligible. Severely ill or cognitively impaired patients were excluded. Patients were randomized to either remain on the gurney or transfer to the chair after initial evaluation. Patients reported pain at arrival (t0), at one hour (t1), and at two hours (t2) using a 0–10 pain scale, and satisfaction at study completion on a 0–10 scale. The primary outcome was a decrease in pain between t0 and t1 or no pain at both t0 and t1. This outcome was analyzed using a 95% confidence interval for the difference between proportions; exclusion of zero was considered significant. Results: Sixty-six patients in each group were enrolled. There was no difference in demographics between groups, but the chair patients were more likely to have pain at t0 than the gurney patients. More chair patients than gurney patients had a successful primary outcome (97% vs. 76%, 21% difference, 95% CI=10% to 32%). The mean satisfaction score was higher in the chair group than in the gurney group (8.1 vs. 6.0, 2.1 difference, 95% CI=1.4% to 2.8%). Conclusions: The simple modification of allowing older ED patients to sit in reclining chairs resulted in less pain and higher satisfaction.

Airway control is one of the most critical interventions required for saving a life. It is essential that practitioners be as well trained as possible in the numerous techniques available to establish airway control. This article reviews some of the available techniques, though other techniques that are not discussed (such as fiberoptic-assisted endotracheal intubation) may also be useful. Perhaps the most important aspect of advanced airway management is the ability to anticipate and prepare for the difficult airway. This article gives numerous options for the difficult airway situation.

Study Objective: Glucagon is a rapid-acting smooth muscle relaxant with a short half-life. Previous studies suggested glucagon may have bronchodilator effects. We sought to determine whether intravenous glucagon produces clinically important immediate bronchodilation in emergency department patients with asthma exacerbation. Methods: We conducted a randomized, double-blind, placebo-controlled study at 2 university-affiliated community teaching hospital EDs (annual census 90,000). ED patients 18 to 50 years old with asthma exacerbation and peak expiratory flow rate (PEFR) less than 350 L/min were eligible. Exclusion criteria were need for intubation, chronic obstructive pulmonary disease, diabetes mellitus, insulinoma, pheochromocytoma, pregnancy, lactation, or current oral steroid treatment. Patients were randomly assigned to receive glucagon 0.03 mg/kg or an equivalent volume of saline solution intravenously. At 10 minutes, PEFR was measured and all patients began standardized albuterol therapy. Successful bronchodilation was a PEFR increase of 60 L/min at 10 minutes. Results: Success occurred in 2 (9.5%) of 21 glucagon-treated patients and 3 (12%) of 25 placebo-treated patients (95% confidence interval [CI] for difference of –2.5% [–20.4% to 15.4%]). Mean PEFR improvement for glucagon was 2 L/min versus 9 L/min for placebo (95% CI for difference of –7 L/min [–36 L/min to 23 L/min]). Conclusion: Glucagon alone provided no clinically important immediate bronchodilation in ED patients with asthma exacerbation. [Wilber ST, Wilson JE, Blanda M, Gerson LW, Meerbaum SO, Janas G. The bronchodilator effect of intravenous glucagon in asthma exacerbation: a randomized, controlled trial. Ann Emerg Med. November 2000;36:427-431.]

To describe EMTs' knowledge of CDC universal precaution guidelines and transmission routes for human immunodeficiency virus (HIV), hepatitis, meningitis, and tuberculosis (TB) and their perceived exposures to and concerns about these diseases.A convenience sample of EMTs were surveyed at mandatory continuing education meetings in a midwest community (pop. 523,191) between October 1 and November 30, 1996. The survey contained 101 questions about knowledge of universal precautions, transmission routes, postexposure actions, personal and family concerns, and demographics. Correct responses were based on CDC guidelines, and incorrect answers were added.Four hundred of 425 surveys (94%) were returned. Eighty-one percent of the EMTs were full-time paramedics with 9.4 (95% CI 8.7-10.0%) years of experience. Seventy-five percent reported HIV, hepatitis, and TB education, while 57% reported meningitis education within the preceding year. Ninety-one percent knew universal precautions should be used with every patient. Needlestick was correctly reported as a transmission route for HIV (98%) and hepatitis (92%), but incorrectly reported for TB (37%) and meningitis (60%). Tuberculosis (94%) and meningitis (64%) were correctly identified as airborne. Thirty-four percent of the EMTs reported inadequate knowledge of infectious diseases (IDs) to protect themselves. Their perceived exposure for all four diseases ranged from 65% to 73%, but only 10-40% reported follow-up testing. Families' concern about EMTs' exposure was reported as moderate to high by 63% of the respondents.There appears to be a need for continuing education for EMTs focusing on the routes of transmission of IDs, their chance of exposure, appropriate use of protective equipment, and the need for follow-up testing. This may allow more effective use of protective equipment and allay fears of EMTs and their families.

Background: Older patients may visit the emergency department (ED) when their illness affects their function. Objectives: To quantify the function of older ED patients, to assess whether functional decline (FD) had occurred, and to determine whether function contributes to the ED visit and hospital admission. Methods: The authors performed an institutional review board–approved, prospective, cross-sectional study in a community teaching hospital ED. Eligible patients were older than 74 years of age, with an illness at least 48 hours old. Patients from a nursing facility and those without a proxy who were unable or unwilling to complete the questions were excluded. The Older Americans Resources and Services Questionnaire, which tests seven instrumental activities of daily living (IADL) and seven physical ADLs (PADL), was used. Data are presented as means or proportions with 95% confidence intervals (95% CI), and comparisons as 95% CI for the difference between proportions. Results: The authors enrolled 90 patients (mean age, 81.6 yr [SD ± 4.9], 40% male). Dependence in at least one IADL was reported by 68% (95% CI = 57% to 77%), and in at least one PADL by 61% (95% CI = 50% to 71%). Functional decline was reported by 74% (95% CI = 64% to 83%). Two thirds of those with IADL decline and three quarters of those with PADL decline said that this contributed to their ED visit. Seventy-seven percent with, and 63% without, IADL decline were admitted (14% difference, 95% CI =−6.1% to 33%). Seventy-nine percent with and 61% without PADL decline were admitted (18% difference, 95% CI =−1.4% to 38%). Conclusions: Functional decline is common in older ED patients and contributes to ED visits in older patients; its role in admission is unclear.

BACKGROUND Donor exposure risk and cost in platelet transfusion practice can be limited by increasing the recovery of platelets from donor units. STUDY DESIGN AND METHODS This study presents results of continuous quality improvement efforts in platelet production and compares the in vivo therapeutic efficacy of currently produced platelet concentrates (PCs) with that of apheresis platelets. Production quality improvement measures included optimization of instrument performance (rotor speed trials), process (massaging whole-blood units, using cup liners, limiting spin-expression time, and refining plasma expression technique), and staff (intensive training with observation and ongoing quality control data feedback). Corrected count increments and increments per kg were calculated for transfusions of 4 pooled PCs and apheresis platelets over a 30-day period. RESULTS The mean number of platelets per PC increased from 5.5 x 10(10) in 1975 to 9.69 x 10(10) in 1994. The mean platelet dose was 3.78 x 10(11) for 4 PCs and 4.17 x 10(11) for apheresis platelets. A total of 34 pooled PCs and 17 apheresis platelets was transfused to 21 patients. The mean increment, the increment per kg, and the corrected count increment were, respectively, 31 x 10(3) per microL, 4.8 x 10(2) per microL, and 14,700 for 4 PCs and 35.4 x 10(3) per microL, 5.4 x 10(2) per microL, and 14,700 for apheresis platelets. Differences were not significant. CONCLUSION Therapeutic efficacy comparable to that of apheresis platelets can be obtained with 4 high-yield PCs.

The current standard of care for hepatitis C virus (HCV)-infected patients consists of lengthy treatment with interferon and ribavirin. To increase the effectiveness of HCV therapy, future regimens will incorporate multiple direct-acting antiviral (DAA) drugs. Recently, the HCV-encoded NS5A protein has emerged as a promising DAA target. Compounds targeting NS5A exhibit remarkable potency in vitro and demonstrate early clinical promise, suggesting that NS5A inhibitors could feature in future DAA combination therapies. Since the mechanisms through which these molecules operate are unknown, we have used NS5A inhibitors as tools to investigate their modes of action. Analysis of replicon-containing cells revealed dramatic phenotypic alterations in NS5A localization following treatment with NS5A inhibitors; NS5A was redistributed from the endoplasmic reticulum to lipid droplets. The NS5A relocalization did not occur in cells treated with other classes of HCV inhibitors, and NS5A-targeting molecules did not cause similar alterations in the localization of other HCV-encoded proteins. Time course analysis of the redistribution of NS5A revealed that the transfer of protein to lipid droplets was concomitant with the onset of inhibition, as judged by the kinetic profiles for these compounds. Furthermore, analysis of the kinetic profile of inhibition for a panel of test molecules permitted the separation of compounds into different kinetic classes based on their modes of action. Results from this approach suggested that NS5A inhibitors perturbed the function of new replication complexes, rather than acting on preformed complexes. Taken together, our data reveal novel biological consequences of NS5A inhibition, which may help enable the development of future assay platforms for the identification of new and/or different NS5A inhibitors.

Summary Anterior cruciate ligament (ACL) reconstruction is often a painful operation. Fifty-eight patients who underwent ACL reconstruction using patellar tendon autograft received either a lumbar plexus block (LPB) or patient-controlled analgesia (PCA) for pain relief during the first 24 h after surgery. The average total dose of narcotic used was dramatically less for the LPB group (10.1 mg) than for the PCA group (91.9 mg). The common narcotic analgesic side effects of nausea, pruritus, sedation, and urinary retention were significantly less in the LPB group. The LPB is a safe and effective alternative analgesia after ACL reconstruction.

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

To describe acute asthma in younger versus older adults presenting to the emergency department (ED).Prospective cohort study. Asthmatic adults were divided into three age groups: 18 to 34, 35 to 54, and 55 and older. The analysis was restricted to never smokers and smokers with fewer than 10 pack-years.ED.Two thousand sixty-four patients aged 18 and older with a physician diagnosis of asthma.Medications and peak expiratory flow.There were 1,158 (56%) subjects aged 18 to 34; 777 (37%) aged 35 to 54; and 129 (6%) aged 55 and older. Older patients were most likely to have a primary care provider (65%, 74%, and 91%, respectively; P.001); most were not taking inhaled corticosteroids (39%, 55%, and 48%, respectively; P.001). Older patients reported fewer ED visits for asthma (2, 2, and 1, respectively; P=.001) but were more likely to report asthma hospitalization (24%, 31%, and 37%, respectively; P.001). All groups had severe exacerbations (initial percentage predicted peak flow: 47, 47, and 47, respectively; P=.50), but older patients were least likely to report severe symptoms (72%, 79%, and 67%, respectively; P=.001). Older patients did not respond as well to bronchodilators, even after controlling for other demographic factors, markers of asthma severity, and ED management (change between initial and final peak expiratory flow, using subjects aged 18 to 34 as reference: aged 35-54, beta=-0.7 (95% CI=-9.4-8.0); agedor = 55, beta=-18.4 (-31.9 to -4.9)). The smaller change in peak expiratory flow contributed most to older patients' greater likelihood of hospitalization.Older asthma patients were less responsive to emergency bronchodilation. This may reflect chronic undertreatment with inhaled corticosteroids.

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 μM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.