Investigating the potential of pyrazine dioxide based-compounds as organic electrodes for batteries.

Understanding structure-property relationship in redox-active molecular species is of central importance in various fields, including many medicinal and chemical applications. The quest for performant organic electrodes in the context of energy storage calls for pioneering studies to develop new and possibly optimal materials. Beyond modifying the molecular design of the existing compounds through functionalization, expansion of the search enabling the advent of efficient new backbones can potentially lead to breakthroughs in this research area. The number of already identified families able to constitute negative organic electrodes is much lower than that of their positive counterparts, which calls for finding ways to bridge this gap. To expand the dataset of known predicted redox potentials and in view of reaching an educated guess about the abilities of some eventual new redox active electrodes, we examined the properties of pyrazine N,N'-dioxide (PZDO) and its fully methylated functionalized derivative (TeMePzDO). The aspects and mechanisms driving the various features characteristic of these compounds were unraveled through molecular and periodic DFT calculations combined with accurate electronic structure analysis. The predicted molecular redox/crystalline intercalation potentials lead to the classification of PZDO and TeMePzDO systems within the class of negative electrodes, with features that are significantly appealing compared to those of some existing systems with backbones suited for such kind of application.

Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole.

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.

Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM.

ABSTRACT: Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, ß2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308µg/L vs 146µg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to ß2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Hereditary Alpha Tryptasemia: Validation of a Single-Well Multiplex Digital Droplet PCR Assay in a Cohort of Symptomatic Patients.

BACKGROUND: Hereditary alpha tryptasemia (HαT) has significant prevalence and potential morbidity in the general population. However, it remains largely undiagnosed in routine clinical diagnostics due to low availability of efficient assessment methods. To address this issue, we developed a reliable and efficient single-well multiplex digital droplet PCR assay. METHODS: The assay was based on the reconstruction of the TPSAB1 gene through quantification of the ratio of α- and ß-tryptase copy number variants (CNV) in a single-well measurement. We performed analytical validation by determining CNV measurement clustering around the expected copy numbers in 281 cases and determined the diagnostic accuracy of basal serum tryptase (BST) to predict HαT and HαT subtypes in 141 symptomatic patients. RESULTS: The assay determined α- and ß-tryptase CNVs with an overall accuracy, expressed as a 99% prediction interval, of 0.03 ± 0.27 copy numbers. The optimal BST cutoff level to predict HαT in symptomatic patients, who had no other explanation for relatively high tryptase levels (i.e., no diagnosis of systemic mastocytosis, myeloid neoplasm, or end-stage renal failure), was 9.2 ng/mL (sensitivity: 98.1%; specificity: 96.6%). HαT showed a linear gene-dose effect, with an average gene-dose increase of 7.5 ng/mL per extra α-tryptase gene. CONCLUSION: Our single-well multiplex digital droplet PCR assay accurately determined HαT and could be implemented as a state-of-the-art routine diagnostic test. The assay demonstrated a strong correlation with BST and the optimal threshold for identifying HαT in symptomatic patients with unexplained high tryptase concentrations was at a BST level of 9.2 ng/mL.

The effect of different abutment materials on peri-implant tissues-A systematic review and meta-analysis.

OBJECTIVES: In patients with dental implants, what is the effect of transmucosal components made of materials other than titanium (alloys) compared to titanium (alloys) on the surrounding peri-implant tissues after at least 1 year? MATERIALS AND METHODS: This systematic review included eligible randomized controlled trials identified through an electronic search (Medline, Embase and Web of Science) comparing alternative abutment materials versus titanium (alloy) abutments with a minimum follow-up of 1 year and including at least 10 patients/group. Primary outcomes were peri-implant marginal bone level (MBL) and probing depth (PD), these were evaluated based on meta-analyses. Abutment survival, biological and technical complications and aesthetic outcomes were the secondary outcomes. The risk of bias was assessed with the RoB2-tool. This review is registered in PROSPERO with the number (CRD42022376487). RESULTS: From 5129 titles, 580 abstracts were selected, and 111 full-text articles were screened. Finally, 12 articles could be included. Concerning the primary outcomes (MBL and PD), no differences could be seen between titanium abutment and zirconia or alumina abutments, not after 1 year (MBL: zirconia: MD = -0.24, 95% CI: -0.65 to 0.16, alumina: MD = -0.06, 95% CI: -0.29 to 0.17) (PD: zirconia: MD = -0.06, 95% CI: -0.41 to 0.30, alumina: MD = -0.29, 95% CI: -0.96 to 0.38), nor after 5 years. Additionally, no differences were found concerning the biological complications and aesthetic outcomes. The most important technical finding was abutment fracture in the ceramic group and chipping of the veneering material. CONCLUSIONS: Biologically, titanium and zirconia abutments seem to function equally up to 5 years after placement.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Effects of ultraviolet-filters on Daphnia magna development and endocrine-related gene expression.

Ultraviolet (UV) filters are emerging contaminants of concern that are widely spread throughout the aquatic environment. Many organic UV filters are endocrine disrupting compounds (EDCs) in vertebrates. However, few studies have assessed their effects on invertebrates. Molting, or the shedding of the exoskeleton, may be affected by exposure to these compounds in Arthropods (the largest phylum of invertebrates). Molting is necessary for growth and development and is regulated by an arthropod specific endocrine system, the ecdysteroid pathway. Alterations of this process by EDCs can result in improper development, reduced growth, and even death. We investigated the sublethal effects of chronic exposure to three organic UV filters (4-methylbenzylidene camphor (4MBC), octylmethoxycinnamate (OMC), and benzophenone-3 (BP3) in a crustacean, Daphnia magna, with particular emphasis on molting and development. We demonstrate that 4MBC, OMC, and BP3 affect development and long-term health in neonates of exposed parents at concentrations of 130 µg/L, 75 µg/L, and 166 µg/L, respectively. Additionally, the expression of endocrine-related genes (including ultraspiracle protein, usp) are significantly altered by 4MBC and BP3 exposure, which may relate to their developmental toxicity.

Ganciclovir therapeutic drug monitoring in transplant recipients.

BACKGROUND: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. OBJECTIVES: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. METHODS: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for. RESULTS: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline. CONCLUSIONS: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

[Heredity and cancer]. / Hérédité et cancer.

A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.

Une histoire personnelle ou familiale de cancer est aujourd'hui devenue la première cause de consultation en génétique. Au cours de ces dernières années, en effet, différents gènes associés à une prédisposition génétique plus ou moins marquée au développement de pathologies cancéreuses ont été identifiés. Le syndrome de prédisposition héréditaire au cancer du sein et de l'ovaire (HBOC : Hereditary Breast and/or Ovarian Cancer) et le syndrome de Lynch sont les plus fréquents. Mais il existe une multitude d'autres situations beaucoup moins fréquentes associées à un risque familial de cancer. Dans la plupart des cas, des recommandations claires existent quant à l'indication des tests génétiques et quant au suivi proposé au patient chez qui une prédisposition au cancer est identifiée. Au CHU de Liège, nous réalisons actuellement plus de 1.400 consultations d'oncogénétique par an et nous maintenons un taux de positivité des tests génétiques réalisés dans cette indication supérieur à 10 %. De cette façon, nous permettons une prise en charge multidisciplinaire des patients avec un haut risque oncologique et participons à une activité de prévention et de surveillance. Nous portons une attention croissante aux enfants et adolescents présentant un cancer, d'une part, et aux adultes ayant présenté de multiples cancers, d'autre part, particulièrement lorsque ceux-ci se développent à un âge précoce. Enfin, la consultation d'oncogénétique doit tenir compte des aspects psychologiques, éthiques et légaux, liés à un diagnostic qui implique le patient et son avenir, mais également l'ensemble de la famille.

The Added Value of [18F]FDG PET/CT in the Management of Invasive Fungal Infections.

Anatomy-based imaging methods are the usual imaging methods used in assessing invasive fungal infections (IFIs). [18F]FDG PET/CT has also been used in the evaluation of IFIs. We assessed the added value of [18F]FDG PET/CT when added to the most frequently used anatomy-based studies in the evaluation of IFIs. The study was conducted in two University Medical Centers in the Netherlands. Reports of [18F]FDG PET/CT and anatomy-based imaging performed within two weeks of the [18F]FDG PET/CT scan were retrieved, and the presence and sites of IFI lesions were documented for each procedure. We included 155 [18F]FDG PET/CT scans performed in 73 patients. A total of 216 anatomy-based studies including 80 chest X-rays, 89 computed tomography studies, 14 magnetic resonance imaging studies, and 33 ultrasound imaging studies were studied. The anatomy-based studies were concordant with the [18F]FDG PET/CT for 94.4% of the scans performed. [18F]FDG PET/CT detected IFI lesions outside of the areas imaged by the anatomy-based studies in 48.6% of the scans. In 74% of the patients, [18F]FDG PET/CT added value in the management of the IFIs.

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

BACKGROUND: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients. OBJECTIVE: To develop a risk score to predict SM in adults with MIS. METHODS: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves. RESULTS: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated. CONCLUSIONS: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.

Mineral dust increases the habitability of terrestrial planets but confounds biomarker detection.

Identification of habitable planets beyond our solar system is a key goal of current and future space missions. Yet habitability depends not only on the stellar irradiance, but equally on constituent parts of the planetary atmosphere. Here we show, for the first time, that radiatively active mineral dust will have a significant impact on the habitability of Earth-like exoplanets. On tidally-locked planets, dust cools the day-side and warms the night-side, significantly widening the habitable zone. Independent of orbital configuration, we suggest that airborne dust can postpone planetary water loss at the inner edge of the habitable zone, through a feedback involving decreasing ocean coverage and increased dust loading. The inclusion of dust significantly obscures key biomarker gases (e.g. ozone, methane) in simulated transmission spectra, implying an important influence on the interpretation of observations. We demonstrate that future observational and theoretical studies of terrestrial exoplanets must consider the effect of dust.

[A multidisciplinary approach for accelerated orthodontics]. / Une approche pluridisciplinaire pour l'accélération des traitements en orthodontie.

An increasing number of adult patients are seeking orthodontic treatment and several surgical and non-surgical methods have been developed to reduce the overall treatment time. Two randomized controlled clinical trials, performed in our University Hospital, demonstrated that the piezocision surgery - minimally invasive corticotomies - decreased the overall orthodontic treatment time by 43 % - effect during 4 to 6 months after the surgery - without any further clinical and radiological adverse effects. In addition, the use of a custom-made orthodontic system - brackets and arches - optimized the acceleration in the fine-tuning phase of orthodontic treatment. Finally, the combination of the two techniques is therefore relevant to maximize the reduction of the orthodontic treatment time. Fundamentally, our preclinical studies in rats have highlighted the biological phenomena underlying piezocision with an important bone demineralization and osteoclast recruitment associated with a predominant expression of the RANKL-OPG duo.

La demande des patients adultes pour entreprendre des traitements orthodontiques est en augmentation constante; cependant, la longueur des traitements reste souvent un frein. Dès lors, plusieurs techniques chirurgicales et non chirurgicales ont été mises au point afin de réduire le temps de traitement orthodontique. Deux études cliniques contrôlées randomisées, réalisées au sein de notre hôpital universitaire, ont démontré que la technique de piézocision - corticotomies minimalement invasives - permet de réduire jusqu'à 43 % le temps de traitement orthodontique - au cours des 4 à 6 mois après l'intervention - et ce, sans effets secondaires tant sur le plan clinique que radiologique. De plus, l'utilisation d'un système orthodontique customisé - employant des attaches et des arcs sur mesure - permet d'optimiser l'accélération du déplacement dentaire dans la phase de finition du traitement orthodontique. Finalement, la combinaison des deux techniques est donc pertinente pour maximaliser la réduction du temps de traitement en orthodontie. Par ailleurs, sur le plan fondamental, nous avons étudié, dans des essais précliniques chez le rat, les phénomènes biologiques sous-jacents à la piézocision à savoir une déminéralisation osseuse et un recrutement d'ostéoclastes plus important associés à une expression prédominante du duo RANKL-OPG.

Exploring failure of antimicrobial prophylaxis and pre-emptive therapy for transplant recipients: a systematic review.

OBJECTIVES: Infections remain a threat for solid organ and stem cell transplant recipients. Antimicrobial prophylaxis and pre-emptive therapy have improved survival of these patients; however, the failure rates of prophylaxis are not negligible. The aim of this systematic review is to explore the reasons behind failure of antimicrobial prophylaxis and pre-emptive therapy. SETTING: This systematic review included prospective randomised controlled trials and prospective single-arm studies. PARTICIPANTS: The studies included were on prophylaxis and pre-emptive therapy of opportunistic infections in transplant recipients. Studies were included from databases MEDLINE, CENTRAL and Embase published until October first 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures were breakthrough infections, adverse events leading to stopping of treatment, switching medication or dose reduction. Secondary outcome measures were acquired resistance to antimicrobials, antifungals or antivirals and death. RESULTS: From 3317 identified records, 30 records from 24 studies with 2851 patients were included in the systematic review. Seventeen focused on prophylactic and pre-emptive treatment of cytomegalovirus and seven studies on invasive fungal infection. The main reasons for failure of prophylaxis and pre-emptive therapy were adverse events and breakthrough infections, which were described in 54% (13 studies) and 38% (9 studies) of the included studies, respectively. In 25%, six of the studies, a detailed description of patients who experienced failure of prophylaxis or pre-emptive therapy was unclear or lacking. CONCLUSIONS: Our results show that although failure is reported in the studies, the level of detail prohibits a detailed analysis of failure of prophylaxis and pre-emptive therapy. Clearly reporting on patients with a negative outcome should be improved. We have provided guidance on how to detect failure early in a clinical setting in accordance to the results from this systematic review. PROSPERO REGISTRATION NUMBER: CRD42017077606.

A Novel Integrated and Labile eHealth System for Monitoring Dog Rabies Vaccination Campaigns.

The elimination of canine rabies through the implementation of high coverage mass dog vaccination campaigns is a complex task, particularly in the resource-limited countries of the rabies endemic world. Here we demonstrated the feasibility of applying targeted rabies vaccination campaigns to deliver more impactful intervention campaigns in resource-limited settings using evidence and lessons learnt from other diseases. With the use of strategic rabies intervention programs, we demonstrate the noteworthy reduction of rabies cases in two very different African settings. The strategic intervention was most significantly aided by the use of a custom-developed vaccination tracking device (the Global Alliance for Rabies Control (GARC) Data Logger) and an integrated rabies surveillance system (the Rabies Epidemiological Bulletin). Our first case study, an island-wide strategic dog vaccination on Tanzania's Unguja island, reduced the incidence of rabies by 71% in the first 16 months of implementation. In the second case study, a similar approach was applied in the metropolitan capital city of Zimbabwe and the incidence of rabies declined by 13% during the first 13 months of implementation. The methodologies and results presented here suggest that, in resource-limited settings, an optimal approach towards the elimination of dog rabies would revolve around strategic interventions, subject to the use of appropriate planning, surveillance, and vaccination tools.

Ruxolitinib in Myelofibrosis and Baseline Thrombocytopenia in Real Life: Results in Dutch Patients and Review of the Literature.

BACKGROUND: Ruxolitinib is an approved treatment for myelofibrosis patients, but data regarding patients with baseline thrombocytopenia are limited. The EXPAND study recently suggested tolerability of ruxolitinib, with a maximum starting dose of 10 mg 2 times a day (BID). However, the small sample size and vigorous follow-up in this trial hamper direct translation of these results to routine practice. PATIENTS AND METHODS: We report retrospective data on Dutch ruxolitinib-treated myelofibrosis patients, focusing on those with baseline thrombocytopenia. Additionally, we reviewed current literature regarding ruxolitinib treatment in this subgroup. RESULTS: In our cohort, 12 of 119 patients had a baseline platelet count of < 100 × 109/L. Spleen responses at a mean treatment duration of 25 weeks were documented in 1 of 6 and 15 of 47 patients with and without baseline thrombocytopenia, respectively. Despite a high rate of grade 3 or higher thrombocytopenia in thrombocytopenic versus nonthrombocytopenic patients (42% vs. 15%), no grade 3 or higher hemorrhage was reported. Median doses in thrombocytopenic patients were 15 and 10 mg BID at the start and after 12 weeks of treatment, respectively. Additionally, 238 thrombocytopenic patients were identified in the available literature, of whom 59 were treated in routine practice. Incidences of severe thrombocytopenia reported separately for patients with baseline thrombocytopenia were 30% to 59% (grade 3 or higher) and 4% to 60% (grade 4). Severe bleeding, pooled across our data and evaluable studies, occurred in 2.4%. CONCLUSION: Ruxolitinib treatment appears to be safe for patients with platelet counts of 50 to 100 × 109/L in real-life practice. We did not find any reason to discourage a starting dose of 10 mg BID in this subgroup.

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations.

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty-seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1-7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8-2.7) for prophylaxis and 1.76 mg/L (IQR 1.3-2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

Posaconazole trough concentrations are not influenced by inflammation: A prospective study.

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1-2.9 mg/L, range 0.1-7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5-75 mg/L, range 0-457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.