Heterogeneity of sensitization profiles and clinical phenotypes among patients with seasonal allergic rhinitis in Southern European countries-The @IT.2020 multicenter study.

BACKGROUND: Pollen allergy poses a significant health and economic burden in Europe. Disease patterns are relatively homogeneous within Central and Northern European countries. However, no study broadly assessed the features of seasonal allergic rhinitis (SAR) across different Southern European countries with a standardized approach. OBJECTIVE: To describe sensitization profiles and clinical phenotypes of pollen allergic patients in nine Southern European cities with a uniform methodological approach. METHODS: Within the @IT.2020 multicenter observational study, pediatric and adult patients suffering from SAR were recruited in nine urban study centers located in seven countries. Clinical questionnaires, skin prick tests (SPT) and specific IgE (sIgE) tests with a customized multiplex assay (Euroimmun Labordiagnostika, Lübeck, Germany) were performed. RESULTS: Three hundred forty-eight children (mean age 13.1 years, SD: 2.4 years) and 467 adults (mean age 35.7 years SD: 10.0 years) with a predominantly moderate to severe, persistent phenotype of SAR were recruited. Grass pollen major allergenic molecules (Phl p 1 and/or Phl p 5) ranged among the top three sensitizers in all study centers. Sensitization profiles were very heterogeneous, considering that patients in Rome were highly poly-sensitized (sIgE to 3.8 major allergenic molecules per patient), while mono-sensitization was prominent and heterogeneous in other cities, such as Marseille (sIgE to Cup a 1: n = 55/80, 68.8%) and Messina (sIgE to Par j 2: n = 47/82, 57.3%). Co-sensitization to perennial allergens, as well as allergic comorbidities also broadly varied between study centers. CONCLUSIONS: In Southern European countries, pollen allergy is heterogeneous in terms of sensitization profiles and clinical manifestations. Despite the complexity, a unique molecular, multiplex, and customized in-vitro IgE test detected relevant sensitization in all study centers. Nevertheless, this geographical diversity in pollen allergic patients imposes localized clinical guidelines and study protocols for clinical trials of SAR in this climatically complex region.

Treatment of aseptic osteonecrosis of the femoral head: Historical aspects.

The treatment of aseptic osteonecrosis (ON) of the femoral head has been the subject of numerous therapeutic and surgical proposals due to the absence of medical treatment with proven efficacy. For many years, the goal of surgical treatment was to avoid total hip replacement (THR) with uncertain survival in patients considered too young (30-50 years) for this procedure. Numerous conservative treatments were thus proposed: core decompression with numerous variants, non-vascularized and vascularized bone grafts, intertrochanteric and rotational transtrochanteric osteotomies, cementing. The lack of a common classification and a lack of knowledge of natural history complicated the interpretation of the results for a long time. Nevertheless, it appeared that these treatments were effective only in the very early stages and among these in the limited ONs, medial rather than central and especially lateral, with discrepancies according to etiologies apart from sickle cell disease recognized by all as being pejorative. For the same reason, partial arthroplasties have been attempted and abandoned in turn: femoral head total and partial resurfacing and femoral prosthesis. The most recent advances are stem-cell-enhanced core decompression and progress in total arthroplasty, whose reliability has made it possible to extend the indications to increasingly younger patients seeking treatment with guaranteed or near-guaranteed efficacy. Most of the other interventions have disappeared or almost disappeared because of their lack of effectiveness especially in extensive and post-fracture ONs, sometimes because of their complexity and the length of their post-operative management, and also because they complicate and penalize a future total arthroplasty. This argues for early detection of ON at an early stage where the "head can be saved" by stem cell augmented core decompression, a minimally invasive treatment that leaves the chances of success of a THR intact.

Clearsight™ use for haemodynamic monitoring during the third trimester of pregnancy - a validation study.

BACKGROUND: We assessed the validity of Clearsight™ as a non-invasive cardiac output and stroke volume monitoring device, comparing it with transthoracic echocardiography measurements during the third trimester of pregnancy. METHODS: Measurements obtained from Clearsight™ were compared with those from echocardiography as the gold standard. The precision and accuracy of the Clearsight™ was measured using the Bland and Altman method. Clinical agreement with echocardiography was assessed using the agreement tolerability index. RESULTS: Measurements were recorded from 44 pregnant women with a median [IQR range] gestational age of 33 [30-37] weeks. We found that Clearsight™ measurements presented a systematic overestimation of cardiac output, with mean bias [CI 95%] of 2.7 [2.3-3.0] L/min, with limits of agreement of  -0.1 to 5.4 L/min. It overestimated stroke volume, with a bias of 29.5 [25.0-33.4] mL and a limit of agreement of -1.6 to 60.1 mL. In addition, the analysis of cardiac output showed a percentage of error of 41% and intra-class correlation [CI 95%] of 0.37 [0.17 to 0.53, P <0.001]. For stroke volume, the percentage of error was 40% and intra-class correlation 0.16 [-0.1 to 0.34; P=0.27]. We found that agreement tolerability index scores were unacceptable. We evaluated the ability of the device to track changes in cardiac output by inducing a left lateral decubitus position, but the analysis was inconclusive. CONCLUSION: The agreement between Clearsight™ and the echocardiography measurements of cardiac output and stroke volume were not within an acceptable range in the third trimester of pregnancy.

Can point-of-care ultrasound predict spinal hypotension during caesarean section? A prospective observational study.

Spinal anaesthesia for elective caesarean section is associated with maternal hypotension, secondary to alteration of sympathetic tone and hypovolemia, in up to 70% of cases. Measurement of the subaortic variation in the velocity time integral (VTI) after passive leg raising allows prediction of fluid responsiveness. Our objective, in this prospective single-centre observational study, was to assess the ability of change in VTI after 45° passive leg raising to predict hypotension after spinal anaesthesia. Ultrasound measurements were performed just before elective caesarean section. Anaesthesia, intravenous coloading and prophylactic vasopressor treatment were standardised according to current guidelines. We studied 40 women. Hypotension occurred in 17 (45%) women. The area (95%CI) under the receiver operating characteristics (ROC) curve for the prediction of spinal hypotension was 0.8 (0.6-0.9; p = 0.0001). Seventeen women had a change in VTI with leg elevation ≤ 8%, which was predictive for not developing hypotension, and 11 had a change ≥ 21%, predictive for hypotension. The grey zone between 8% and 21%, with inconclusive values, included 12 women. We suggest that cardiac ultrasound provides characterisation of the risk of hypotension following spinal anaesthesia at elective caesarean section, and therefore may allow individualised strategies for prevention and management.

Lorentz Symmetry Violations from Matter-Gravity Couplings with Lunar Laser Ranging.

The standard-model extension (SME) is an effective field theory framework aiming at parametrizing any violation to the Lorentz symmetry (LS) in all sectors of physics. In this Letter, we report the first direct experimental measurement of SME coefficients performed simultaneously within two sectors of the SME framework using lunar laser ranging observations. We consider the pure gravitational sector and the classical point-mass limit in the matter sector of the minimal SME. We report no deviation from general relativity and put new realistic stringent constraints on LS violations improving up to 3 orders of magnitude previous estimations.

Testing Lorentz Symmetry with Lunar Laser Ranging.

Lorentz symmetry violations can be parametrized by an effective field theory framework that contains both general relativity and the standard model of particle physics called the standard-model extension (SME). We present new constraints on pure gravity SME coefficients obtained by analyzing lunar laser ranging (LLR) observations. We use a new numerical lunar ephemeris computed in the SME framework and we perform a LLR data analysis using a set of 20 721 normal points covering the period of August, 1969 to December, 2013. We emphasize that linear combination of SME coefficients to which LLR data are sensitive and not the same as those fitted in previous postfit residuals analysis using LLR observations and based on theoretical grounds. We found no evidence for Lorentz violation at the level of 10^{-8} for s[over ¯]^{TX}, 10^{-12} for s[over ¯]^{XY} and s[over ¯]^{XZ}, 10^{-11} for s[over ¯]^{XX}-s[over ¯]^{YY} and s[over ¯]^{XX}+s[over ¯]^{YY}-2s[over ¯]^{ZZ}-4.5s[over ¯]^{YZ}, and 10^{-9} for s[over ¯]^{TY}+0.43s[over ¯]^{TZ}. We improve previous constraints on SME coefficient by a factor up to 5 and 800 compared to postfit residuals analysis of respectively binary pulsars and LLR observations.

Ultrasonographic measurement of antral area for estimating gastric fluid volume in parturients.

BACKGROUND: The aim of this prospective observational study was to assess the performance of ultrasonographic gastric antral area (GAA) to predict gastric fluid volumes of >0.4, >0.8 and >1.5 ml kg(-1), in fasted women in established labour. METHODS: A first ultrasound examination of the antrum was performed, in order to confirm gastric vacuity by using a qualitative score. Baselines GAA measurements were obtained in both supine and right lateral decubitus positions. Thereafter, parturients were allowed to drink clear fluids only. Measurement of GAA was repeated 15 min after last fluid intake, in both supine and right lateral positions. Receiver operating characteristics (ROC) curves were constructed to determine the accuracy of GAA to diagnose ingested volumes of >0.4, >0.8 and >1.5 ml kg(-1). RESULTS: Data from forty parturients were analysed. The areas under the ROC curves ranged from 80% to 86%. The cut-off value for antral area measured in supine position, to detect a volume >0.4 ml kg(-1), was 387 mm(2), with a sensitivity of 87%, a specificity of 70% and a negative predictive value of 85%. A cut-off value of 608 mm(2) predicted a fluid volume >1.5 ml kg(-1), with a specificity of 94%, a sensitivity of 75% and a negative predictive value of 92%. CONCLUSIONS: This study provides cut-off values for GAA that could be used in addition to the qualitative assessment of the antrum to define a full stomach in labouring patients.

White paper: an outlook on U.S. biosimilar competition.

The pharmaceutical industry is experiencing change in ways it hasn't ever before. One topic at the center of all of these changes is the U.S. biosimilars market. This report will provide updates and changes associated with biosimilar regulations in the U.S. Additionally, the paper will identify requirements for success, and the likely early entrants in the U.S. market.

Business of biosimilars - 14th annual conference (October 15-17, 2013 - Boston, Massachusetts, USA).

Competition in the biological market offers a new set of opportunities and challenges within the healthcare industry. Biosimilars, like generic small-molecule drugs, can provide cost savings and increase patient access, while also promoting innovation. While large molecule manufacturers face many challenges unique to complex therapeutics, it is becoming clear that the commercialization of biosimilars shares many of the same hurdles as the generics market. The 14th Annual Business of Biosimilars Conference provided quality presentations from industry leaders regarding many commercial considerations for stakeholders interested in entering the biosimilars market. Opportunities to network with industry experts were offered, with over 120 attendees.

Lung ultrasound-guided management of acute breathlessness during pregnancy.

Lung ultrasonography is a standard tool in the intensive care unit and in emergency medicine, but has not been described in the particular setting of the labour ward. During pregnancy, acute respiratory failure and pulmonary oedema are not uncommon life-threatening events. We present two case reports outlining the potential of lung ultrasonography in parturients. In case 1, lung ultrasonography allowed early diagnosis and treatment of acute dyspnoea in a parturient admitted for suspected asthma exacerbation. Lung ultrasonography revealed a 'B-pattern' of vertical lines radiating into the lung tissue, indicating severe pulmonary oedema complicating previously undiagnosed pre-eclampsia. In case 2, a pre-eclamptic patient was managed with combined transthoracic echocardiography and lung ultrasonography. The accuracy of lung ultrasonography in detecting interstitial oedema at a pre-clinical stage allowed adequate fluid resuscitation in this patient who had a high risk of alveolar pulmonary oedema. We believe that these cases strongly support the prospective validation of lung ultrasound for management of lung disorders in pregnant women.

[The agents used for sedation in neurointensive care unit]. / Les agents utilisés pour la sédation en neuro-réanimation.

Sedation and analgesia can be routinely prescribed in head injury patients. The goals of such sedation are three: brain protection, prevention and treatment of intracranial hypertension and therapeutic facilitation. In such situation, the use of sedative and analgesic therapy should respect the rate of cerebral blood flow/cerebral oxygen consumption coupling while preserving cerebral perfusion pressure and decreasing the intracranial pressure. This treatment should have an analgesic and myorelaxing action with short and predictable time of action. The ideal sedation agent with all these properties does not exist. Only the combination of several different pharmacological classes of compounds may reach this goal. Benzodiazepines are the most frequently used agents. In most of the cases they are associated with analgesic agents such as opioid or ketamine. Opioids may be the basic analgesic agents because they do not produce brain haemodynamic modifications if arterial pressure is maintained. Among them, sufentanil, thanks to its pharmacokinetics properties, remains the most prescribed opioid. However, in the future, remifentanil that presents a fast elimination may be more frequently used for neurological follow up of patients. Ketamine whose use is subject of debate, has the main advantage of maintaining haemodynamic status. Ketamine has no side effects on brain haemodynamic when used with propofol or midazolam. Taking into account their deleting effect on haemodynamic status and immune system, barbituric are no longer used as long term sedative agents. However, their use is still recommended in the cases of refractory intracranial hypertension. Propofol remains the ideal sedative agent because of its short duration action but its use is limited by its cost. Its use may be recommended for short time sedations with or without an opioid drug. The curare use should be restrain to refractory intracranial hypertension to usual treatments and happening during stimulation.

Human papillomavirus infection of the cervix uteri in women attending a Health Examination Center of the French social security.

Since human papillomavirus (HPV) is the central causal factor in cervical cancer, understanding the epidemiology of this infection constitutes an important step towards development of strategies for prevention. Six hundred and fifty seven cervical samples were tested for HPV using PCR with consensus primers (MY09/MY11), by genotyping (restriction and sequencing analyses) and by cervical cytology, from women who attended a Health Examination Center of the French social security. Women with no cervical smear as well as women with cytological abnormalities within the last 3 years were recruited. HPV DNA was detected in 7.3% of the women (5.3% for high-risk, 2.4% for low-risk, and 0.5% for unknown risk types) including 6 (0.9%) mixed infections. Fifteen different genotypes were detected, of which genotypes 16 (22.2%), 58 (13.0%), 18 (11.1%), 30 (9.2%), and 33 (9.2%) were the most prevalent. In age group 17-25 years, we found the highest frequencies for both any (22.1%) and high-risk (14.7%) HPV, and prevalences gradually decreased with age. 5.2% of low-grade squamous intraepithelial lesion, 0.3% of high-grade squamous intraepithelial lesion, and 1.2% of atypical squamous cells of undetermined significance were found. The frequencies of high risk and all HPV types were significantly higher in squamous intraepithelial lesions than in those with normal and reactive/reparative changes (P < 0.0001). The prevalence of high-risk HPV in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion group (28.6%) was significantly higher than in the normal and reactive/reparative changes groups (3.4%) (P < 0.0001). HPV detection was associated with younger age, single marital and non-pregnant status (P < 0.0001), premenopausal status (P = 0.0004), and contraception (P = 0.0008). Marital status (OR 4.5; 95% CI = 2.3-9.0) and tobacco consumption (OR 3.0; 95% CI = 1.6-5.7) were predictive independent factors of HPV infection. The French system of Health Examination Centers might be of interest for following women regularly, especially those with a low socioeconomic status.

[Therapeutic management of peritonitis]. / Prise en charge thérapeutique des péritonites.

Antibiotherapy is a fundamental for the treatment of peritonitis. It may be used before surgery or as a complementary treatment after. Experimental models have demonstrated that infections are both aerobic and anaerobic. During the first stage, septicemic with a high death rate, the infection is due to enterobacteria, mostly Escherichia coli. Between D5 and D7 in surviving animals, there is a second stage with abscesses due to anaerobic bacteria, mostly Bacteroides fragilis. The antibiotic treatment must include these two types of bacteria in its spectrum. The role of Enterococcus faecalis is not clearly defined, but this bacterium must be taken into account in case of organ failure or associated septic shock. Treatment options for secondary peritonitis may be, according to severity, cefoxitin, an Augmentin + gentamycin combination, Tazocillin, or ertapenem. The reference treatment for nosocomial or tertiary peritonitis is the imipenem + amikacin combination. An antifungal treatment (fluconazole) is usually necessary, at least until the results of peritoneal fluid culture are available. The duration of treatment is quite variable, ranging from 48 h in less severe forms to 14 days.

[Which therapeutic prospects in the septic syndrome?]. / Quelles perspectives thérapeutiques dans le syndrome septique ?

OBJECTIVE: To evaluate recent data provided on new treatments of patients with septic shock. DATA EXTRACTION: A Medline search was performed to identify pertinent literature on the pathophysiology of septic shock and treatment strategies from 1990 to 2003. Keywords were "septic shock", "sepsis", "inflammation" and "management". DATA SYNTHESIS: Advances were performed in our current understanding of pathophysiology of sepsis. The loss of homeostatic balance among the systemic inflammatory response and the disturbance of coagulation with generalized coagulopathy lead to organ failures and death. The administration of activated protein C (drotrecogin alfa) reducing this coagulopathy can decrease the mortality of septic shock patients. The modulation of inflammation did not make it possible to improve survival of septic shock patients until now. The efficacy of low doses of steroid has been recently shown in septic shock patients. In addition, new data highlighted the interest of an early goal therapy in patients with sepsis who are admitted to emergency. CONCLUSION: The improvement of survival in septic syndrome patients is a difficult challenge. The uses of different new therapeutic options like protein C reactive, steroids, or early goal therapy in association should make it possible to reduce the mortality in septic patients.

The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats.

Although previous studies have established that cizolirtine (5-([(N,N-dimethylaminoethoxy)phenyl]methyl)-1-methyl-1H-pyrazol citrate) is a potent analgesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro and in vivo approaches were used to assess whether cizolirtine could affect the spinal release of two pain-related neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly reduced the K(+)-evoked overflow of both the SP-like material (SPLM; -25% at 0.1 microM--0.1 mM) and CGRPLM (-20% at 0.1--1.0 microM) from slices of the dorsal half of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine markedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but only marginally that of CGRPLM. Systemic administration of cizolirtine at an analgesic dose (80 mg/kg i.p.) also reduced spinal SPLM outflow (-50%) but not that of CGRPLM. Under both in vitro and in vivo conditions, idazoxan (10 microM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, suggesting their mediation through alpha(2) adrenoceptors.

Role of glycopeptides in the treatment of septic complications after cardiac surgery.

Agents like Staphylococcus epidermidis and Staphylococcus aureus are common agents in both early and late prosthetic valve endocarditis (PVE). Streptococci, especially vividans and enterococci are more apt to occur late. Diphtheroids and gram-negative bacteria are also frequent in early and late PVE. Fungi are found at a frequency of 5 to 8% and a variety of unusual organisms are found in individual case reports. Treatment is based on parenteral therapy with a bactericidal agent that can achieve trough serum levels in excess of 8-10 X MICs of the infecting organisms. Initially the antibiotic selection should be active against the most common isolates. Because most S. epidermidis are beta-lactam-resistant, vancomcyin must be part of the initial empiric regimen. Vancomycin should be combined with rifampin or an aminoglycoside (usually gentamicin) or both. When there is a high level of resistance to aminoglycoside, vancomycin may be used alone until susceptibility data are available and then rifampin can be given together with an aminoglycoside or a quinolone to which the organism is susceptible. The aminoglycoside should be given for a maximum of 2 weeks, to avoid nephrotoxicity, and vancomycin for 6 weeks. Surgery is required in case of major emboli, hemodynamic decompensation, and uncontrolled infection. The presence of bacteremia for more than 1 week may warrant surgical intervention but, if the patient appears to be well and without emboli or hemodynamic problems, serum levels of antibiotic, particularly vancomycin, should be evaluated. Dosage regimen should be modified to achieve trough levels of vancomycin between 15 to 20 microg/ml. Use of vancomycin by continuous infusion may be considered with a targeted blood concentration of 15 to 20 microg/ml.