Microwave Fluorescence Detection of Spin Echoes.

Counting the microwave photons emitted by an ensemble of electron spins when they relax radiatively has recently been proposed as a sensitive method for electron paramagnetic resonance spectroscopy, enabled by the development of operational single microwave photon detectors at millikelvin temperature. Here, we report the detection of spin echoes in the spin fluorescence signal. The echo manifests itself as a coherent modulation of the number of photons spontaneously emitted after a π/2_{X}-τ-π_{Y}-τ-π/2_{Φ} sequence, dependent on the relative phase Φ. We demonstrate experimentally this detection method using an ensemble of Er^{3+} ion spins in a scheelite crystal of CaWO_{4}. We use fluorescence-detected echoes to measure the erbium spin coherence time, as well as the echo envelope modulation due to the coupling to the ^{183}W nuclear spins surrounding each ion. We finally compare the signal-to-noise ratio of inductively detected and fluorescence-detected echoes, and show that it is larger with the fluorescence method.

Single-electron spin resonance detection by microwave photon counting.

Electron spin resonance spectroscopy is the method of choice for characterizing paramagnetic impurities, with applications ranging from chemistry to quantum computing1,2, but it gives access only to ensemble-averaged quantities owing to its limited signal-to-noise ratio. Single-electron spin sensitivity has, however, been reached using spin-dependent photoluminescence3-5, transport measurements6-9 and scanning-probe techniques10-12. These methods are system-specific or sensitive only in a small detection volume13,14, so that practical single-spin detection remains an open challenge. Here, we demonstrate single-electron magnetic resonance by spin fluorescence detection15, using a microwave photon counter at millikelvin temperatures16. We detect individual paramagnetic erbium ions in a scheelite crystal coupled to a high-quality-factor planar superconducting resonator to enhance their radiative decay rate17, with a signal-to-noise ratio of 1.9 in one second integration time. The fluorescence signal shows anti-bunching, proving that it comes from individual emitters. Coherence times up to 3 ms are measured, limited by the spin radiative lifetime. The method has the potential to be applied to arbitrary paramagnetic species with long enough non-radiative relaxation times, and allows single-spin detection in a volume as large as the resonator magnetic mode volume (approximately 10 µm3 in the present experiment), orders of magnitude larger than other single-spin detection techniques. As such, it may find applications in magnetic resonance and quantum computing.

Public health issues and health rendezvous for migrants from conflict zones in Ukraine: A French practice guideline.

Given the number of people leaving the war zone in Ukraine and arriving in France, the French high council for public health (HCSP) has drawn up a number of recommendations. The experts have taken into account the vulnerability of migrant populations, which is exacerbated by (a) promiscuity that increases the risk of exposure to infectious agents; (b) the psychological consequences of conflict, family separation and exile; (c) prevalence in Ukraine of communicable diseases such as (possibly multi-resistant) tuberculosis, HIV and HCV; (d) low vaccination coverage (risk of circulation of poliovirus) and (e) the risk of spreading infectious diseases (Covid-19, measles…). Consequently, experts recommend that priority be given to: (i) Initial (immediate) reception, which will help to provide emergency care and to assess immediate needs (psychological disorders, risk of medication breakdown and risk of infection); (ii) Other priority measures (vaccination catch-up, including vaccination against SARS-CoV-2 and mandatory vaccination for children's entry into school, screening for post-traumatic stress disorder and tuberculosis) must be implemented as soon as feasible. At this stage, it is imperative: To ensure coordination and access to information throughout the country, by providing medico-social support (opening of social rights and access to care); To digitize medical data for the purposes of traceability; To use professional interpreting and/or health facilitators, or else, if necessary, digital translation tools. (iii) Finally, experts stress the need for vigilance in terms of management, conservation of social rights and continuity of care after the initial period, and organization of a "health rendezvous" within four months of a migrant's entering the country.

Quantitation using HRMS: A new tool for rapid, specific and sensitive determination of catecholamines and deconjugated methanephrines metanephrines in urine.

Urinary catecholamines and their methylated metabolites are biochemical indicators of pheochromocytoma, paraganglioma and neuroblastoma. A rapid and precise analytical method based on solid-phase extraction (SPE) and liquid chromatography separation coupled to high-resolution mass spectrometry (LC-HRMS) was developed and validated to measure urinary catecholamines (epinephrine (E), norepinephrine (NorE), dopamine (D)) and total methylated metabolites (normetanephrine (NorMN), metanephrine(MN) and 3-methoxytyramine (3-MT)) in a clinical setting. Results of 51 urine specimens measured using this LC-HRMS method were compared with a liquid chromatography assay with electrochemical detection (LC-EC). Urine samples (200 µL) were spiked with an internal standard solution followed by SPE purification. In the case of total methylated metabolites, urine was hydrolyzed before SPE purification. Separation was achieved on an Acclaim Mixed Mode WCX column, with an 8.5 min runtime. All compounds were detected in electrospray positive ionization mode with a parallel reaction monitoring acquisition and quantified with a linear regression (r2 > 0.998) between 2 and 200 µg/L (10.9-1090; 11.8-1182 nmol/L) for E and NorE respectively and between 10 and 1000 µg/L for others (65.2-6520; 50.7-5070; 54.5-5450 ; 59.8-5980 nmol/L for D, M, NorMN and 3-MT, respectively). Overall imprecision and bias did not exceed 15%. No significant matrix effect was observed. Correlation between the two assays was good except for epinephrine. Epinephrine concentrations measured by LC-EC method were slightly higher than values obtained with LC-HRMS method but without impact on clinical decision. This LC-HRMS assay provides a new tool for simultaneous quantitative catecholamine determination and was successfully applied in routine for the screening or follow up of pheochromocytoma, paraganglioma and neuroblastoma. LC-HRMS method offers significant advantages compared to LC-EC with good sensitivity, an unambiguous analyte determination and high sample throughput.

[Phaeochromocytoma and paraganglioma]. / Phéochromocytome et paragangliome.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that arise from the adrenal medulla or sympathetic and parasympathetic ganglia. These tumors produce most often catecholamines in excess, causing hypertension and sometimes severe acute cardiovascular complications. The diagnosis is based on plasma or urines metanephrines measurements and on conventional and nuclear medicine imaging. Catecholamines-producing PPGL is very unlikely if levels are normal. The diagnosis of PPGL cannot be made without visualization of a tumor. Therapeutic management consists mostly of surgical excision, after drug preparation, and should be done in referral centers. About 40% of pheochromocytomas and paragangliomas occur in the context of an autosomal inherited syndrome, making genetic testing essential. The follow-up must be prolonged because a metastatic evolution or a recurrence can be observed in about 15% of the cases.

Switching from abacavir/lamivudine plus nevirapine to abacavir/lamivudine/dolutegravir in virologically controlled HIV-infected adults (SWAD study).

INTRODUCTION: The metabolic pathways of dolutegravir suggest a potential predator effect of nevirapine on dolutegravir pharmacokinetics and switching from a nevirapine- to a dolutegravir-containing regimen could lead to a lower and suboptimal exposure to dolutegravir several weeks after the switch in case of persistent inducer effect. PATIENTS AND METHOD: Prospective, pilot, single-arm, open-label, non-comparative, bicentric study to evaluate the pharmacokinetics, virologic outcomes, safety, and patient satisfaction of switching from abacavir/lamivudine and nevirapine to a single tablet of abacavir/lamivudine/dolutegravir. The primary endpoint was the maintenance of virologic suppression (HIV-1 RNA<50 copies/mL) at week 12. Secondary endpoints were virologic suppression at week 48, safety and tolerability, patient satisfaction, and pharmacokinetic interaction between nevirapine and dolutegravir. Fifty-three adults on stable abacavir/lamivudine and nevirapine regimen for a median duration of 6years and virologically suppressed for 9.6years were included. RESULTS: Dolutegravir reached steady state by week 4/week 12 when expected by day 5/day 10. All subjects maintained plasma HIV-RNA˂50 copies/mL at week 12 and week 48. Abacavir/lamivudine/dolutegravir was well-tolerated, with two cases of serious adverse events deemed unrelated to study drugs (coronary syndrome in both cases), and one discontinuation for renal impairment at week 24 with a slight improvement after dolutegravir discontinuation. Level of treatment satisfaction remained high after the switch. CONCLUSION: The transient predator effect of nevirapine on dolutegravir had no clinical consequences after switching from nevirapine to dolutegravir, neither on safety nor maintenance of virologic suppression. It also had no consequences on patient satisfaction.

Factors associated with deaths from suicide in a French nationwide HIV-infected cohort.

OBJECTIVES: People living with HIV (PLHIV) are at a higher risk of dying by suicide than the general population. Epidemiological data regarding determinants of suicide in PLHIV are scarce. The aim of this study was thus to study demographic, socio-economic, psychiatric history and immunovirological characteristics associated with death from suicide in the French multicenter Dat'AIDS cohort, from January 2000 to July 2013. METHODS: This was a nested case-control study. All deceased PLHIV during the study period who died by suicide and whose medical files could be checked were included as cases. Controls were selected using incidence density sampling. For each case, up to four controls were selected among all actively followed PLHIV at the index date (date of death of cases). Controls were matched for time from HIV diagnosis (5-year periods) and clinical centre. RESULTS: Seventy cases and 279 controls were included in the study. By multivariable analysis, the factors significantly associated with death from suicide were: not having children, active or substituted drug consumption, alcohol intake > 20 g/day or history of alcohol abuse, history of depressive disorder and/or of attempted suicide, and psychotropic drug intake. Conversely, age, gender, country of birth, positive HCV serology and HIV-related factors, such as AIDS status, use of combination antiretroviral therapy (cART), nadir and current CD4 counts and HIV viral load, were not significantly associated with the risk of death from suicide. CONCLUSIONS: In the cART era, HIV-related factors are not associated with a higher risk of suicide mortality. Suicide prevention measures should target PLHIV with the psychological morbidities observed in our cohort.

Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children.

BACKGROUND: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. OBJECTIVE: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. METHODS: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. RESULTS: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. CONCLUSION: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

A simple ultra-high-performance liquid chromatography-high resolution mass spectrometry assay for the simultaneous quantification of 15 antibiotics in plasma.

Antibiotic (ATB) treatment of critically ill patients with pathophysiological injuries remains a challenge due to the constant increase in antimicrobial resistance. Therapeutic drug monitoring (TDM) is advised for ATB dose adjustments to avoid suboptimal concentrations and dose-related adverse effects. Therefore, a single and reliable analytical method for a broad selection of ATBs was developed using a high-resolution mass spectrometry (HRMS) platform for frequent use in intensive care units. An UHPLC assay coupled to high resolution accurate mass acquisition has been developed for the quantification of penicillins (amoxicillin, oxacillin, piperacillin, and ticarcillin), cephalosporines (cefepime, cefotaxime, ceftazidime, and ceftriaxone), carbapenems (ertapenem, imipenem, and meropenem), lincosamide (clindamycin), quinolones (ofloxacin and ciprofloxacin) and tazobactam. Plasma samples (100µL) were spiked with an internal standard solution followed by protein precipitation. Separation was achieved on an Accucore C18 column, which enabled sample analysis every 9min. All compounds were detected in electrospray positive ion mode and quantified with a linear regression between 0.5 and 32mg/L (r2>0.998). Overall precision and accuracy did not exceed 15%. No significant matrix effect was observed for the studied ATBs. Stored stock solutions at -20°C were stable for 6 months, except for amoxicillin and imipenem. Analytes in plasma were stable for 24h under ambient conditions as well as in post-preparation in an autosampler, except for amoxicillin and imipenem. This HRMS assay provides the simultaneous quantification of 15 ATB; it fulfills the usual quality criteria and was successfully applied for routine TDM of ATBs. The method is based on a full scan acquisition, and it would be easy to add other compounds to the present panel in the future, as this assay has already been proven to be efficient for different classes of compounds.

Prevalence and Risk Factors of Sleep Disturbance in a Large HIV-Infected Adult Population.

This cross-sectional study evaluates the prevalence and factors associated with sleep disturbances in French adult HIV-infected outpatients. Patients fullfilled a self-administered questionnaire on their health behavior, sleep attitudes (Pittsburgh sleep quality index, PSQI), quality of life and depression; 1354 patients were enrolled. Median sleeping time was 7 h. Poor sleep quality was observed in 47 % of the patients, and moderate to serious depressive symptoms in 19.7 %. Factors significantly associated with sleep disturbances were depression, male gender, active employment, living single, tobacco-smoking, duration of HIV infection, nevirapine or efavirenz-including regimen. Prevalence of poor sleepers is high in this HIV adult outpatient population. Associated factors seem poorly specific to HIV infection and more related to social and psychological status. Taking care of these disturbances may prove to be an effective health management strategy.

Family physicians and HIV infection.

OBJECTIVE: We aimed to describe the current and desired involvement of family physicians (FPs) in the treatment of HIV patients (screening practices, potential training and patient follow-up) to reduce the duration and frequency of their hospital treatment. MATERIAL AND METHODS: We conducted a descriptive cross-sectional survey between 2011 and 2012 with the support of COREVIH (Regional Coordinating Committee on HIV). We sent a self-assessment questionnaire to all FPs of the Pays de la Loire region to enquire about their HIV screening practices and expectations for the management of HIV patients. RESULTS: A total of 871 FPs completed the questionnaire (response rate: 30.4%). A total of 54.2% said to provide care to HIV patients; the mean number of HIV patients per FP was estimated at 1.4. With regard to HIV screening, 12.2% systematically suggest an HIV serology to their patients and 72.7% always suggest it to pregnant women. About 45.4% of responding FPs said to be willing to manage HIV patients (clinical and biological monitoring, compliance checks and prescription renewal). FPs mainly reported the lack of training and the low number of HIV patients as a barrier to their further involvement in the management of HIV patients. CONCLUSION: The responding FPs provide care to very few HIV patients. They are, however, willing to be more involved in the routine care of these patients. Medical training provided by COREVIH would help improve HIV screening. The management of HIV patients could thus be handed over to willing FPs.

Switching from tenofovir/emtricitabine and nevirapine to a tenofovir/emtricitabine/rilpivirine single-tablet regimen in virologically suppressed, HIV-1-infected subjects.

OBJECTIVES: Nevirapine is an inducer of hepatic metabolism. After discontinuation, nevirapine has an inductive effect on cytochrome P450 3A4, which persists for a few weeks and which, after switching to rilpivirine, may reduce rilpivirine exposures and have a negative clinical impact. This study evaluates the virological outcome, pharmacokinetics and safety of switching virologically suppressed, HIV-1-infected patients from nevirapine to rilpivirine. PATIENTS AND METHODS: This 24 week open-label single-centre study included HIV-1-infected adults with HIV-1 RNA <50 copies/mL for >6 months on tenofovir/emtricitabine and nevirapine, who were willing to simplify their regimen to tenofovir/emtricitabine/rilpivirine. Virological suppression, safety and nevirapine and rilpivirine pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 32 subjects remained virologically suppressed. One subject discontinued at week 1 for rilpivirine-associated insomnia and two patients chose to resume tenofovir/emtricitabine and nevirapine after week 12 because of rilpivirine-associated food constraint. There was no grade 3/4 laboratory abnormality. Rilpivirine trough concentrations were above the mean trough concentrations observed in Phase 3 studies by 1 week post-switch. Twenty-seven out of 32 patients had no measurable levels of nevirapine by 2 weeks post-switch. The meal accompanying tenofovir/emtricitabine/rilpivirine intake satisfied food requirements in 81% of cases. Overall general satisfaction was improved in 90% of the subjects despite food constraints. CONCLUSION: Nevirapine has a short and limited inductive effect on rilpivirine metabolism, which is not clinically significant. Tenofovir/emtricitabine/rilpivirine is an efficacious and safe option for virologically suppressed HIV-infected patients on nevirapine wishing to simplify their regimen.

Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia.

PURPOSE: The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. PATIENTS AND METHODS: We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500ng/mL were considered as under dosed. RESULTS: Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003). CONCLUSION: This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML.

Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen.

OBJECTIVES: Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. PATIENTS AND METHODS: We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, ß2-microglobulin and α1-microglobulin were measured during a routine clinical visit. RESULTS: Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. CONCLUSIONS: Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited.

Pharmacokinetics of antifungal agents in neonates and young infants.

The prevention and treatment of pediatric fungal infections are limited by the fact that not all antifungal drugs are approved for the pediatric age and appropriate dosages have not been established for each age group. The management of neonates and infants with invasive fungal infection is becoming more complex with an increasing number of antifungal agents available. Dosing information, is not available for newer antifungals and is limited with older antifungal agents. Insufficient neonatal studies have been performed with newer agents and there are numerous differences between neonates, children and adults with invasive fungal infection. Kinetic parameters such as the half-life [t(½)], clearance [CL], and volume of distribution [Vd] change with development, therefore the kinetics of antifungals need to be studied in order to optimize therapy with these drugs. A reasonable aim of pediatric dosing is to ensure levels of drug exposure which are comparable to those achievable in adults and which approximate those for which antifungal efficacy has been established. Therefore it will be of clinical relevance to ascertain the dosages of antifungals which produce an equivalent magnitude of exposure to that observed in adults. Drug therapy, studies on prescription and dosing should consider differences between neonates, infants and toddlers, children and adolescents in terms of drug disposition: absorption, metabolism and elimination/excretion. Determining the safety and pharmacokinetics of antifungals in neonates addresses an unfulfilled medical need given that data are sparse in neonates; at present, reports of antifungal pharmacokinetics in the treatment of neonatal fungal infections are limited to case series. The aim of this article is to review the pharmacokinetics of old and new antifungal drugs in neonates and young infants in a single article in order to provide a critical analysis of the literature. It will be important to evaluate all newly developed antifungals in neonates and infants to assure their maximum efficacy and safety. More pharmacokinetic data are required to ensure that the dose recommended for the treatment of fungal infections in the neonate achieves evidence based medicine.

High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs.

OBJECTIVES: The aim of this study was to assess 25-hydroxyvitamin D (vitamin D) status in an HIV-infected adult population and to define HIV- and antiretroviral-related factors associated with vitamin D deficiency. METHODS: Using data from a prospective cohort of HIV-infected adult patients followed in five French centres (Dat'AIDS cohort), we evaluated the prevalence of vitamin D deficiency/insufficiency (<30 ng/mL). A multiple linear regression model was used to examine risk factors for vitamin D deficiency (≤10 ng/mL). RESULTS: Vitamin D deficiency/insufficiency was observed in 86.7% of the 2994 patients, including 55.6% with vitamin D insufficiency and 31.1% with vitamin D deficiency. In multivariate analysis, factors associated with vitamin D deficiency were current smoking [adjusted OR (aOR) 1.55], estimated glomerular filtration rate ≥90 mL/min/1.73 m(2) (aOR 1.51), vitamin D measurement not performed in summer (aOR 0.27), CD4 <350 cells/mm(3) (aOR 1.37 for CD4 200 to <350 and 1.62 for CD4 <200 cells/mm(3)) and antiretroviral therapy (aOR 2.61). Gender, body mass index, age, coinfection and previous AIDS were not associated factors. In the antiretroviral-treated population (n = 2660), besides the same factors found in the whole population, efavirenz was the only drug to be significantly associated with deficiency, with an aOR of 1.89 (95% CI 1.45-2.47). CONCLUSIONS: Vitamin D deficiency is frequent in this HIV-infected population. Patients on antiretroviral therapy are at higher risk of vitamin D deficiency than antiretroviral-naive patients, with an increased risk in patients receiving efavirenz. No effect of the other antiretrovirals, including the latest (etravirine, darunavir, raltegravir), was found.

Therapeutic drug monitoring in de novo kidney transplant receiving the modified-release once-daily tacrolimus.

INTRODUCTION: Advagraf (AVF) a new formulation of tacrolimus (TRL), allows once-daily administration while showing similar efficacy and safety to the conventional Prograf (PGF), which is prescribed twice daily. Our study sought to compare short-term therapeutic drug monitoring (TDM) of AVF and PGF in de novo kidney transplants. PATIENTS AND METHODS: We retrospectively collected results of TDM performed on blood trough samples (C0) using an LC- MS/MS assay to quantify TRL exposure in the two groups. Twelve subjects received initial immunosuppression with AVF associated with mycophenolic acid, steroids, and immunoglobulins. We compared median doses and C0 levels with those obtained in 18 cases receiving an equivalent dose of PGF during the same period. RESULTS AND DISCUSSION: Although both groups showed similar mean C0, the median dose in the AVF group tended to be higher than the PGF group-respectively, 9.8 and 7.9 mg/d-which may be attributed to the once-daily regimen, which inevitably results in lower C0 levels compared to the twice-a-day regimen, while overall exposure appeared similar in terms of area under the curve (AUC). This observation occurred especially during the first weeks despite the extended release formulation. In fact, one patient who showed a low C0 (5.9 ng/mL) while receiving high doses of AVF (0.28 mg/kg), the AUC of 356 and 211 ng.h/mL performed on days 12 and 18 respectively showed exposure consistent with efficacy. CONCLUSION: In conclusion, it seemed to be necessary to use higher doses (25%) of Advagraf to reach the targeted C0 levels during the first weeks posttransplant. For patients who do not reach the targeted C0 despite high doses, TRL exposure should be assessed by AUC or peak levels (C4h).