X-ray-free protocol for pectus deformities based on magnetic resonance imaging and a low-cost portable three-dimensional scanning device: a preliminary study

 Open in a separate windowOBJECTIVESTo compare a standard protocol using chest computed tomography (CT) to a non-irradiant protocol involving a low-cost portable 3D scanner and magnetic resonance imaging (MRI) for all pectus deformities based on the Haller index (HI).METHODSFrom April 2019 to March 2020, all children treated for pectus excavatum or carinatum at our institution were evaluated by chest CT, 3D scanning (iPad with Structure Sensor and Captevia—Rodin4D) and MRI. The main objectives were to compare the HI determined by CT or MRI to a derived index evaluated with 3D scanning, the external Haller index (EHI). The secondary objectives were to assess the inter-rater variability and the concordance between CT and MRI for the HI and the correction index.RESULTSEleven patients were evaluated. We identified a strong correlation between the HI with MRI and the EHI (Pearson correlation coefficient = 0.900; P < 0.001), with a strong concordance between a radiologist and a non-radiologist using intra-class correlation for the HI with MRI (intra-class correlation coefficient = 0.995; [0.983; 0.999]) and the EHI (intra-class correlation coefficient = 0.978; [0.823; 0.995]). We also identified a marked correlation between the HI with CT and the EHI (Pearson coefficient = 0.855; P = 0.002), with a strong inter-rater concordance (intra-class correlation coefficient = 0.975; [0.901; 0.993]), a reliable concordance between CT and MRI for the HI and the correction index (Pearson coefficient = 0.886; P = 0.033).CONCLUSIONSNon-irradiant pectus deformity assessment is possible in clinical practice, replacing CT with MRI and 3D scanning as a possible readily-accessible monitoring tool.     

Bertolotti's syndrome in children: From low-back pain to surgery. A case report

Bertolotti's syndrome is a little-known and little-discussed pathology. We report the case of a 13-year-old child diagnosed with Bertolotti's syndrome after several years of functional complaints. Conventional radiography was used to diagnose the transverse mega-apophysis of L5, while sectional and functional imaging confirmed a lumbosacral-iliac impingement. In view of the transient efficacy of medical management, surgical resection of the transverse mega-apophysis was performed. The medium-term decline in symptoms was excellent and the patient resumed physical activities without limitation or pain.     

Laryngospasm as preceding symptom of amyotrophic lateral sclerosis

Journal of Neurology -     

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate,Mechanical Ventilation,and Reason for Admission

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients'' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.Ceftazidime is a broad-spectrum cephalosporin generally used in the treatment of severe Pseudomonas aeruginosa infections. Since ceftazidime exhibits time-dependent killing of gram-negative bacteria in vitro or in critically ill patients, studies involving continuous administration of cephalosporin confirm that the steady-state concentration in blood should be four to five times higher than the bacterial MIC (6, 27). When the MIC is not available, the European breakpoint is used to calculate the target concentration (8). In patients with sepsis syndrome, ceftazidime plasma concentrations after a 2-g dose of ceftazidime every 8 h or 4 g by continuous infusion may be inadequate (42).Intensive care unit (ICU) patients represent a highly heterogeneous population ranging from young trauma patients to elderly medical patients and postsurgical patients. This heterogeneity is well known to produce high variability in pharmacokinetic parameters, as was previously demonstrated for the clearance and the total volume of distribution (15, 26, 36). Ceftazidime pharmacokinetics in critically ill patients is altered by an increased volume of drug distribution and a longer elimination half-life (16).In order to determine interindividual pharmacokinetic variability and the influence of some patient characteristics on the pharmacokinetics of ceftazidime, we conducted a population pharmacokinetic study to develop and validate a model to enable an adequate individual dosing strategy to be put in place (3). We used rich data collected in a prospective study comparing continuous infusion versus intermittent administration of ceftazidime, along with the demographic, clinical, and biological characteristics of these ICU patients. This study used the nonlinear mixed-effect model as implemented in the NONMEM program for pharmacostatistical analysis (4).     

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients

The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8⁺ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8⁺ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1⁺ NY-ESO-1–specific CD8⁺ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3⁺PD-1⁺ NY-ESO-1–specific CD8⁺ T cells are more dysfunctional than Tim-3⁻PD-1⁺ and Tim-3⁻PD-1⁻ NY-ESO-1–specific CD8⁺ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8⁺ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8⁺ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.There is ample evidence that patients with melanoma can develop immune responses directed against antigens expressed by their own tumor (Boon et al., 2006). Among these antigens, cancer-germline antigens (CGAs) are expressed by tumors of many different histological types, including melanoma, but not by normal tissues, except testis. Because germ cells in testis do not express HLA molecules on their surface (Haas et al., 1988), CGAs represent strictly tumor-specific T cell targets (Boon et al., 2006). Among CGAs, NY-ESO-1 has been shown to stimulate spontaneous cellular and humoral responses that are detectable only in patients with advanced NY-ESO-1–expressing cancer (Stockert et al., 1998; Jäger et al., 2000; Mandic et al., 2005; Fourcade et al., 2008). Understanding the failure of spontaneous NY-ESO-1–specific T cell responses to promote regression of NY-ESO-1⁺ tumors is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape.We have previously shown that the large majority of spontaneous NY-ESO-1–specific CD8⁺ T cells up-regulates programmed death 1 (PD-1) expression (Fourcade et al., 2009), which appears to be associated with T cell exhaustion/dysfunction in chronic viral infections in animals and humans (Barber et al., 2006; Day et al., 2006; Petrovas et al., 2006; Trautmann et al., 2006). We observed that PD-1 up-regulation on spontaneous NY-ESO-1–specific CD8⁺ T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines ex vivo upon stimulation with cognate antigen. Blockade of the PD-1–programmed death ligand 1 (PD-L1) pathway in combination with prolonged antigen stimulation with PD-L1⁺ APCs or melanoma cells augmented the frequencies of cytokine-producing, proliferating, and total NY-ESO-1–specific CD8⁺ T cells. Our findings are in line with previous studies of PD-1 expression by HIV- and SIV-specific CD8⁺ T cells, demonstrating that PD-1 is a regulator of antigen-specific CD8⁺ T cell expansion in the context of chronic antigen exposure, although it does not exhibit a major impact upon their functionality on a cell-per-cell basis (Petrovas et al., 2006, 2007). To further determine whether other molecular pathways are involved in tumor antigen–specific T cell dysfunction, we studied T cell immunoglobulin and mucin-domain–containing molecule 3 (Tim-3) expression on spontaneous NY-ESO-1–specific CD8⁺ T cells from patients with advanced melanoma and investigated whether Tim-3 up-regulation defines a subgroup of dysfunctional tumor antigen–specific CD8⁺ T cells. Tim-3 is a transmembrane protein constitutively expressed on Th1/Tc1 cells in mice and humans (Monney et al., 2002). Several lines of evidence support the role of Tim-3 as an inhibitory molecule that down-regulates effector Th1/Tc1 cell responses. In mice, blocking the Tim-3–Tim-3L pathway resulted in hyperproliferation of Th1-type cells and abrogated the induction of peripheral and transplantation tolerance (Sabatos et al., 2003; Sánchez-Fueyo et al., 2003). Tim-3 interacts with its ligand galectin-9 to induce cell death in Th1 cells (Zhu et al., 2005). In humans, Tim-3 expression is defective in CD4⁺ T cells producing high levels of IFN-γ, as well as those isolated from cerebrospinal fluid of patients with multiple sclerosis (Koguchi et al., 2006). Recently, Tim-3 up-regulation has been reported in HIV-specific and HCV-specific CD8⁺ T cells in patients with progressive HIV infection and chronic hepatitis C, respectively (Jones et al., 2008; Golden-Mason et al., 2009). Tim-3⁺ HIV- and HCV-specific CD8⁺ T cells were distinct from the PD-1⁺ CD8⁺ T cells and exhibited T cell dysfunction. However, it is unknown whether tumor antigen–specific CD8⁺ T cells in patients with advanced cancers express Tim-3.In this study, we show that a fraction of PD-1⁺ NY-ESO-1–specific CD8⁺ T cells, which represents the large majority of circulating NY-ESO-1–specific CD8⁺ T cells in patients with advanced melanoma, up-regulates Tim-3 expression. Tim-3⁺PD-1⁺ NY-ESO-1–specific CD8⁺ T cells are highly dysfunctional compared with Tim-3⁻PD-1⁺ and Tim-3⁻PD-1⁻ NY-ESO-1–specific CD8⁺ T cells. Tim-3–Tim-3L pathway blockade alone or in combination with PD-1–PD-L1 pathway blockade enhanced NY-ESO-1–specific CD8⁺ T cell numbers and functions. Collectively, our findings support the use of Tim-3–Tim-3L blockade in association with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.     

Can simple tests performed in the primary care setting provide accurate and efficient diagnosis of benign prostatic hyperplasia? Rationale and design of the Diagnosis Improvement in Primary Care Trial

Effective treatment of benign prostatic hyperplasia (BPH) improves lower urinary tract symptoms (LUTS) and patient quality of life, and reduces the risk of complications arising from disease progression. However, treatment can only be initiated when men with BPH are identified by accurate diagnostic tests. Current evidence suggests that diagnostic procedures employed by primary care physicians vary widely across Europe. The expected increases in BPH prevalence accompanying the gradual aging of the population, coupled with greater use of medical therapy, mean that general practitioners (GPs) are likely to have an increasingly important role in managing the condition. The GP/primary care clinic is therefore an attractive target location for strategies designed to improve the accuracy of BPH diagnosis. The Diagnosis Improvement in Primary Care Trial (D‐IMPACT) is a prospective, multicentre, epidemiological study that aims to identify the optimal subset of simple tests applied by GPs in the primary care setting to diagnose BPH in men who spontaneously report obstructive (voiding) and/or irritative (storage) LUTS. These tests comprise medical history, symptom assessment with the International Prostate Symptom Score questionnaire, urinalysis, measurement of serum levels of prostate‐specific antigen and subjective GP diagnosis after completing all tests including digital rectal examination. GP diagnoses and all other tests will be compared with gold‐standard diagnoses provided by specialist urologists following completion of additional diagnostic tests. D‐IMPACT will establish the diagnostic performance using a non‐subjective and reproducible algorithm. An adjusted and multivariate analysis of the results of D‐IMPACT will allow identification of the most efficient combination of tests that facilitate accurate BPH diagnosis in the primary care setting. In addition, D‐IMPACT will estimate the prevalence of BPH in patients who present spontaneously to GPs with LUTS.     

Multiple gastrointestinal atresias result from disturbed morphogenesis

 Multiple gastrointestinal atresias (MGA) have been reported to account for 6% to 32% of all intestinal atresias. Controversy exists regarding the pathogenesis. Many investigators believe MGA to be the result of multiple ischemic infarctions of the intestinal tract. However, some have suggested that MGA results from a malformative process early in fetal life. Prenatal exposure to adriamycin in a rat model has been reported to lead to a spectrum of tracheoesophageal and associated malformations of the gastrointestinal tract, including intestinal atresias, identical to these observed in humans. The aim of this study was to determine the incidence and histopathologic findings of MGA in order to understand the pathogenesis. Timed-pregnant Sprague-Dawley rats were injected with adriamycin (1.75 mg/kg) in nine different gestational-day protocols. MGA was only seen in those rats who received adriamycin on gestational days 7, 8, and 9. The litters were recovered on day 21 by cesarean section. The digestive tracts (DT) of the fetuses were harvested for macroscopic and microscopic examination. Ten rats who received adriamycin on gestational days 7, 8, and 9 produced 87 newborns; 1 was damaged during dissection. DT anomalies occurred in 80 (93%) of the 86 newborns; 94% of these demonstrated MGA. There was a very high incidence of associated anomalies in newborns with MGA. Histologically, the blind-ending atresias showed different degrees of villous hyperplasia with or without intraluminal material. This is the first report demonstrating a high rate of occurrence of MGA in the adriamycin rat model. The injection of adriamycin early in gestation, the high incidence of associated malformations, and the anatomic and histologic findings in MGA indicate that MGA is a result of a malformative rather than an ischemic process. Accepted: 22 September 2000