Fractioned-pattern radiation mapping, Part II: assessment.

In Part I, the authors proposed a theoretical background for predicting the radiation distribution in any optical system based on decomposing the emitting source power. Here, we describe the validity of this decomposition through a practical example that uses a radiating source and a single surface optical system. This source is calibrated in a metrology testbed that guarantees its traceability to the candela (cd), the International System (SI) base unit for luminous intensity I v. A second example, this time numerical, shows the method's performance in a multisurface optical system.

A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults.

BACKGROUND: Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. METHODS: This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. RESULTS: BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose-proportionally. Mean half-life was short (2.4-4.9 h), and mean renal clearance was comparable in all doses (4.05-5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%-15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14-deoxypoststerone) were identified and quantified. CONCLUSIONS: BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

Humoral response after SARS-CoV-2 mRNA vaccines in dialysis patients: Integrating anti-SARS-CoV-2 Spike-Protein-RBD antibody monitoring to manage dialysis centers in pandemic times.

Dialysis patients are both the most likely to benefit from vaccine protection against SARS-CoV-2 and at the highest risk of not developing an immune response. Data from the medical field are thus mandatory. We report our experience with a BNT162b2-mRNA vaccine in a retrospective analysis of 241 dialysis patients including 193 who underwent anti-Spike-Protein-Receptor-Binding-Domain (RBD) IgG analysis. We show that a pro-active vaccine campaign is effective in convincing most patients to be vaccinated (95%) and frequently elicits a specific antibody response (94.3% after two doses and 98.4% after three doses). Only immunocompromised Status is associated with lack of seroconversion (OR 7.6 [1.5-38.2], p = 0.02). We also identify factors associated with low response (last quartile; IgG<500AU/mL): immunocompromised status, age, absence of RAAS inhibitors, low lymphocytes count, high C Reactive Protein; and with high response (high quartile; IgG>7000AU/mL): age; previous SARS-CoV-2 infection and active Cancer. From this experience, we propose a strategy integrating anti-spike IgG monitoring to guide revaccination and dialysis center management in pandemic times.

Epidemiology and antimicrobial resistance of Streptococcus pneumoniae in France in 2007: data from the pneumococcus surveillance network.

Antimicrobial resistance of Streptococcus pneumoniae in France is closely monitored by the pneumococcus surveillance network, founded in 1995, which collects data from regional observatories (Observatoire Régionaux du Pneumocoque [ORP]). In 2007, 23 ORPs analyzed the antibiotic susceptibility of 5,302 isolates of S. pneumoniae recovered in France from cerebrospinal fluid, blood, middle ear fluid, and pleural fluid, as well as from adult respiratory samples. The study showed that 38.2% of the strains were nonsusceptible to penicillin, 19.3% nonsusceptible to amoxicillin, and 10.5% nonsusceptible to cefotaxime. The percentage of pneumococcus nonsusceptible to penicillin varied according to both the sample and the age of the patient (child/adult): blood (27.8%/32.5%), cerebrospinal fluid (33.7%/34.6%), middle ear fluid (60.2%/27.5%), and pleural fluid (50.0%/31.0%). Between 2003 and 2007, the frequency of penicillin resistance in invasive pneumococcal disease gradually decreased from 46.4% to 29.0% in children and from 43.8% to 32.7% in adults. This decrease coincided with the introduction of a seven-valent pneumococcal conjugate vaccine into immunization programs and with a general reduction in levels of antibiotic consumption in France.

Serotype distribution and antibiotic resistance of Streptococcus pneumoniae strains isolated from adults in France: evolution between 2001 and 2003.

Antibiotic-resistant Streptococcus pneumoniae (Sp) are described around the world. The present national surveillance study report analyzes more than 6000 Sp strains, isolated from adults across France in 2001 and 2003, from blood cultures (3086 in 2001 and 3164 in 2003), cerebrospinal fluid (respectively, 238 and 240), or middle ear fluid (respectively, 110 and 100). The proportion of isolates with reduced susceptibility to penicillin fell significantly between 2001 and 2003 from 46.5% to 43.9%. The proportion of high-level resistant strains to penicillin minimal inhibitory concentrations (MIC > 1 mg/L), amoxicillin, and cefotaxime (MIC > 2 mg/L) slightly decreased but remained low: 10.6%, 1.2%, and 0.2% in 2003. Resistance to other antibiotics (erythromycin, cotrimoxazole, tetracycline, and chloramphenicol) also decreased. Decrease in prevalence of penicillin-resistant Sp varied according to specimen source. The proportion of penicillin nonsusceptible pneumococci decreased in blood cultures and middle ear fluids between 2001 and 2003 but increased in cerebrospinal fluid (43.4% and 46.5%, respectively). Serotypes covered by the heptavalent vaccine accounted for 42.4% of all isolates recovered in 2001 and 46.1% in 2003. Prevalence of antibiotic-resistant Sp decreased in 2003 in France.

Antimicrobial resistance data on 16,756 Streptococcus pneumoniae isolates in 1999: A Pan-Regional Multicenter Surveillance Study in France.

The rising prevalence of antibiotic-resistant Streptococcus pneumoniae is a phenomenon observed to different degrees around the world. The present national surveillance study report analyzes a total of 16,756 strains of S. pneumoniae collected across France in 1999. The overall prevalence of S. pneumoniae with decreased susceptibility to penicillin was 44%, to amoxicillin 26%, and to cefotaxime 17%. The proportion of high-level resistant strains to penicillin (MIC > 1 mg/L), amoxicillin and cefotaxime (MIC > 2 mg/L) remained low: 12.3%, 1.8%, and 0.4% respectively. Prevalence of resistance to other antibiotics was high: 53% to erythromycin, 41.7% to cotrimoxazole, 31.8% to tetracycline, and 24.6% to chloramphenicol. Prevalence of penicillin-resistant S. pneumoniae varied according to subject age and specimen source. It was higher in children (52.7%) than in adults (39.8%) and higher in strains isolated from middle ear fluid (63.6%) than from blood cultures (41.8%) in children. S. pneumoniae resistant to other antibiotics were more common in children than in adults, although figures showed geographical variations. Comparison with a previous study realized in 1997 in the same regions confirms a rising trend in the prevalence of resistant bacteria. Therefore, we conclude that prevalence of antibiotic-resistant S. pneumoniae in 1999 continued to rise in France, although strains with high-level resistance to penicillin remained stable.

Bacteriostatic and bactericidal activities of eight fluoroquinolones against MexAB-OprM-overproducing clinical strains of Pseudomonas aeruginosa.

OBJECTIVES: To assess the impact of stable overproduction of efflux system MexAB-OprM on the bacteriostatic and bactericidal activities of fluoroquinolones against clinical Pseudomonas aeruginosa strains. METHODS: The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) of eight fluoroquinolones (pefloxacin, norfloxacin, ofloxacin, moxifloxacin, levofloxacin, ciprofloxacin, trovafloxacin and grepafloxacin) were determined for nine post-therapy resistant isolates of P. aeruginosa overexpressing MexAB-OprM. Clinical significance of low-level resistance conferred by the efflux mechanism was evaluated with a Monte Carlo simulation. RESULTS: Compared with their pre-therapy susceptible counterparts, seven out of the nine post-therapy efflux mutants exhibited a modest two- to eight-fold increase in resistance to all the fluoroquinolones tested. Interestingly, stronger variations in resistance (up to 64-fold) were observed in two other mutants, one of which had acquired a GyrB target mutation in addition to efflux under chemotherapy. Time-kill experiments showed that MexAB-OprM up-regulation did not confer tolerance to fluoroquinolones as the ratio of MBC to MIC was less than 4 for most of the strains. To gain an insight into the clinical significance of resistance conferred by MexAB-OprM, a Monte Carlo simulation was conducted with various fluoroquinolone regimens. With this model, low levels of resistance to ciprofloxacin (MIC > or = 0.25 mg/L) or levofloxacin (MIC > or = 1 mg/L), such as those due to overproduced MexAB-OprM, were predicted to result in poor clinical outcomes. CONCLUSIONS: Altogether, these data strongly suggest that when derepressed, MexAB-OprM provides P. aeruginosa with a resistance that may be sufficient to impair the efficacy of single therapy with highly potent fluoroquinolones, such as ciprofloxacin and ofloxacin.

Contribution of the ATP binding site of ParE to susceptibility to novobiocin and quinolones in Streptococcus pneumoniae.

In Streptococcus pneumoniae, an H103Y substitution in the ATP binding site of the ParE subunit of topoisomerase IV was shown to confer quinolone resistance and hypersensitivity to novobiocin when associated with an S84F change in the A subunit of DNA gyrase. We reconstituted in vitro the wild-type topoisomerase IV and its ParE mutant. The ParE mutant enzyme showed a decreased activity for decatenation at subsaturating ATP levels and was more sensitive to inhibition by novobiocin but was as sensitive to quinolones. These results show that the ParE alteration H103Y alone is not responsible for quinolone resistance and agree with the assumption that it facilitates the open conformation of the ATP binding site that would lead to novobiocin hypersensitivity and to a higher requirement of ATP.

Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations.

Alcohol detoxification is accompanied by sustained difficulties in sleep initiation and maintenance. These difficulties are thought to be an important cause of relapse to alcohol use. However, the treatment of sleep problems with hypnotic drug is made difficult by cross-tolerance between benzodiazepines and alcohol. In this report, we evaluated the capacity of trazodone (TRZ), a second-generation antidepressant with anxiolytic and sedative properties, to increase the sleep efficiency in alcohol-dependent patients after detoxification. Sixteen patients completed the TRZ (n = 8) or the placebo (PL; n = 8) treatment arms. Polysomnographies were performed at baseline, after the 1st drug dose, and after 4 weeks of treatment. The main outcome was sleep efficiency. Secondary outcomes included changes in other sleep parameters, Hamilton Depression Rating and Clinical Global Impression scales. Sleep efficiency was increased in the TRZ group when it was computed after sleep onset, both immediately after 1st administration of the drug and after 4 weeks of treatment. No benefit was observed in the PL group. Sleep improvement under TRZ also included the number of awakenings, intermittent wake sleep time, and non-rapid eye movement sleep. Hamilton and Clinical Global scales were better for the TRZ group. TRZ is thus a potential option in the treatment of alcohol post-withdrawal insomnia.

Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin.

BACKGROUND: Within a period of three years, we identified 13 patients in whom pure red-cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We investigated whether there was an immunologic basis for the anemia in these patients. METHODS: Serum samples from the 13 patients with pure red-cell aplasia were tested for neutralizing antibodies that could inhibit erythroid-colony formation by normal bone marrow cells in vitro. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of radiolabeled intact, deglycosylated, or denatured epoetin. RESULTS: Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin. Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titer slowly decreased after the discontinuation of treatment with epoetin. CONCLUSIONS: Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.