Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

BACKGROUND: Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. METHODS: We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. RESULTS: We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. CONCLUSIONS: In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

The stroke rate influences performance, technique and core stability during rowing ergometer.

The aim of this study is to determine the effect of stroke rate on performance, technique and core stability during rowing ergometer. Twenty-four high-level rowers performed maximal intensity one-minute bouts at 20, 28 and 34 spm on a RowPerfect3 ergometer. Power at the handle, legs, trunk and arms levels were determined, and core kinematics and neuromuscular activations were measured. The power at the handle was enhanced with a higher stroke rate in the first half of the drive phase due to higher segment's powers. This resulted in technical changes, as for instance greater mean to peak power ratio at each segment level. The higher trunk power preceded a delayed trunk extension but without significant increase in the erector spinae activation. This underlines the role of the core stability to transfer forces at a higher stroke rate. However, no co-activation parameters between trunk flexors and extensors helped further to understand this force transfer. Rowing at low stroke rate can be a training strategy to work on earlier trunk extension, while maintaining erectors spinae levels of activation. Training at higher stroke rate will induce a rowing technique closer to competition with greater neuromuscular activations, and maximise power production.

Characterizing the effects of an ergonomic handle on upper limbs kinematics and neuromuscular activity, comfort, and performance during ergometer rowing.

Articular stress and discomfort during repetitive movements may impact the risk of injuries of the upper limbs during ergometer rowing, especially when using a regular circular handle. Therefore, the purpose of the study was to propose and evaluate the influence of an ergonomic handle on upper limbs biomechanics, comfort and performance during ergometer rowing. An ergonomic irregular hexagon handle, with a 1:1.25 width/length diameters ratio, has been developed. Left upper limb kinematics and neuromuscular activity, perceived comfort and power production were monitored for 29 expert rowers. The ergonomic handle increased the perceived comfort while maintaining the overall articular stress and performance as the same level compared to the regular handle. We recommend using irregular hexagon handles with 1:1.25 ratio for ergometer rowing. Further improvements of the ergonomic handle such as an individualization based on the user's hand length may further enhance comfort and achieve better performance.

Prediction of rowing ergometer performance by technical and core stability parameters.

The purpose of this study was to evaluate the influence of technical and core stability parameters on rowing ergometer performance defined as mean power at the handle. Twenty-four high-level rowers were evaluated at their competitive stroke rate on an instrumented RowPerfect 3 ergometer to determine leg, trunk and arm power output, while trunk and pelvis 3D kinematics were measured. Linear mixed models revealed that mean power at the handle was predicted by the power output of legs, trunk and arms (r2 = 0.99), with trunk power being the best predictor. Time to peak power, work ratio and mean to peak power ratio were relevant technical parameters significantly predicting the different segments' power. In addition, a greater trunk range of motion significantly influenced the power produced by this segment. Accordingly, achieving an earlier peak power together with enhanced work production at the trunk and arm levels, as well as distributing the segments power over the whole drive phase, could serve as recommendations for technical training of rowers on dynamic ergometers in order to produce higher power output. Furthermore, the trunk appears to play a major role as a power producer within the kinetic chain from the legs to the arms.

Thiophenium Salts as New Oxidant for Redox Polymerization under Mild- and Low-Toxicity Conditions.

In mild conditions (under air, room temperature, no monomer purification and without any energy activation), redox free radical polymerization (RFRP) is considered as one of the most effective methods to polymerize (meth)acrylate monomers. In the past several years, there has been a growing interest in research on the development of new redox initiating systems (RISs), thanks mainly to the evolution of toxicity labeling and the stability issue of the current RIS based on peroxide and aromatic amine. In this study, a new, low-toxicity RIS based on thiophenium salt as the oxidant species is presented with various reductive species. The reactivity and the stability of the proposed RISs are investigated and the synthesis of new thiophenium salts reported.

Validation of a Gradient Diffusion Method (Etest) for Testing of Antimicrobial Susceptibility of Aerococcus urinae to Fluoroquinolones.

Aerococcus urinae is a urinary pathogen with well-described resistance to fluoroquinolones. This study aimed to validate the gradient diffusion (GD) method (Etest) on cation-adjusted Mueller-Hinton agar with 5% sheep blood for testing the susceptibilities of Aerococcus urinae to the antimicrobial agents ciprofloxacin and levofloxacin and to compare the Etest to the broth microdilution (BMD) method from CLSI document M45-A3. Agar dilution (AD), as recommended by EUCAST, was used as an alternative reference method to arbitrate discrepancies or address technical issues. Aerococcus urinae isolates from urinary specimens were prospectively collected between June 2016 and December 2017 from six hospitals in Quebec, Canada, and identifications were confirmed using Vitek MS with the IVD 3.0 database. Of the 207 isolates tested using BMD, 37 (17.9%) showed trailing and 19 (9.2%) showed insufficient growth; these were tested using AD. Also, 38 isolates (18.4%) for ciprofloxacin and 13 isolates (6.3%) for levofloxacin showed a lack of essential or categorical agreement between the Etest and BMD and were also tested by AD. By use of a combined reference method (BMD or AD), the susceptibility rates of Aerococcus urinae were 82.6% and 81.6% for ciprofloxacin and levofloxacin, respectively. Categorical agreement between GD and the combined reference methods was 95.2% for ciprofloxacin and 97.1% for levofloxacin, with no very major error identified. Major and minor error rates were 0.6% and 4.3% for ciprofloxacin and 1.2% and 1.9% for levofloxacin. Overall, antimicrobial susceptibility testing (AST) using the Etest on sheep blood agar showed good agreement with the reference methods and can be considered by clinical laboratories wishing to perform AST on Aerococcus urinae isolates.

UM171-Expanded Cord Blood Transplants Support Robust T Cell Reconstitution with Low Rates of Severe Infections.

Rapid T cell reconstitution following hematopoietic stem cell transplantation (HSCT) is essential for protection against infections and has been associated with lower incidence of chronic graft-versus-host disease (cGVHD), relapse, and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections, and TRM. Recently, results of a phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment (www.clinicaltrials.gov, NCT02668315). We assessed T cell reconstitution in patients who underwent transplantation with UM171-expanded CB grafts and retrospectively compared it to that of patients receiving unmanipulated CB transplants. While median T cell dose infused was at least 2 to 3 times lower than that of unmanipulated CB, numbers and phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the 2 cohorts. T cell receptor sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of clonotypes at 12 months post-transplant. This was associated with higher counts of naive T cells and recent thymic emigrants, suggesting active thymopoiesis and correlating with the demonstration that UM171 expands common lymphoid progenitors in vitro. UM171 patients also showed rapid virus-specific T cell reactivity and significantly reduced incidence of severe infections. These results suggest that UM171 patients benefit from rapid T cell reconstitution, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality, and late TRM observed in this cohort.

Hepatitis C virus genotyping based on Core and NS5B regions in Cameroonian patients.

BACKGROUND: Current HCV treatments are genotype specific although potential pan-genotype treatments have recently been described. Therefore, genotyping is an essential tool for the therapeutic management of HCV infection and a variety of technologies have been developed for HCV genotypes determination. Sequences analysis of HCV sub-genomic regions is considered as gold standard and is widely used for HCV genotyping. Here, we compared HCV genotyping using core and NS5B regions in routine practice in HCV-positive Cameroonian patients. METHODS: All plasma samples received at Centre Pasteur of Cameroon (CPC) in 2016 for HCV genotyping were included. Viral loads were determined using the Abbott Real Time assay. Further, genotyping was based on the amplification and sequencing of core and NS5B regions following by phylogenetic analysis of corresponding sequences. RESULTS: A total of 369 samples were received during the study period with high viral load values (median: 930,952 IU/ml; IQR: 281,833-2,861,179). Positive amplification was obtained in at least one genomic region (core or NS5B) for all the samples with similar amplification rate in the two genomic regions (p = 0.34). Phylogenetic analysis showed that among the 369 samples, 146 (39.6%) were classified as genotype 4, 132 (35.8%) as genotype 1, 89 (24.1%) as genotype 2, in both core and NS5B regions. Interestingly, for two samples (0.54%) discordant genotypes were obtained in both regions with the core region classified as genotype 4 while the NS5B was identified as genotype 1 indicating the presence of putative HCV recombinant virus or multiple infections in these samples. Discrimination of HCV subtypes was most likely possible with NS5B compared to core region. CONCLUSIONS: We found high amplification rates of HCV in both core and NS5B regions, and a good concordance was obtained at genotype level using both regions except for two samples where putative 1-4 recombinants/multiple infections were detected. Therefore, HCV genotyping based on at least two genomic regions could help to identify putative recombinants and improve therapeutic management of HCV infection.

High-Throughput Screening of the Alkoxide/Oxime-Based Library: An Alternative to Organotin Compounds for the Alkoxysilane Condensation in Adhesives and Sealants.

In this work, a high-throughput screening (HTS) method was used to discover new efficient catalysts to substitute organotin compounds (DBTDL) for the cross-linking of silyl-modified polymers (SMPs). We report here on the use of our HTS method to investigate a library of alkoxide/oxime systems with different metal/ligand (M/L) ratios. Among the 156 candidates tested, 40 interesting hits were detected. Then, the cross-linking times for the better hits were measured on the SMP. Some of these seem to be more efficient than DBTDL and exhibit a good stability during storage in cartridges. Thereby, a high efficiency of alkoxide/oxime systems was established that shows great potential for the generation of new ligands to provide new tin-free catalysts for the cross-linking of adhesives and sealants.

α,ω-Epoxide, Oxetane, and Dithiocarbonate Telechelic Copolyolefins: Access by Ring-Opening Metathesis/Cross-Metathesis Polymerization (ROMP/CM) of Cycloolefins in the Presence of Functional Symmetric Chain-Transfer Agents.

Epoxide- and oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(oxetane-2-ylmethyl) maleate (CTA 2), or bis(oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)s were isolated under mild operating conditions (40 or 60 °C, 24 h). The oxetane CTA 3 and the epoxide CTA 1 were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS2/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior.

Risk factors for the development of Clostridium difficile infection in adult allogeneic hematopoietic stem cell transplant recipients: A single-center study in Québec, Canada.

BACKGROUND: Clostridium difficile infection (CDI) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our primary objective was to determine risk factors for the development of CDI during the first year following allo-HSCT. METHODS: A matched case-control study nested in a cohort of allo-HSCT at a single hospital in Montréal, Québec, Canada, was conducted from 2002 through 2011. RESULTS: Sixty-five of 760 patients who underwent allo-HSCT between 2002 and 2011 developed CDI, representing an incidence of 8.6%. We selected 123 controls matched for year of transplant for risk factor analyses. In the multivariable analysis, receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prior to transplantation (adjusted odds ratio [aOR] 0.07, 95% confidence interval [CI] 0.02-0.27), mucositis (aOR 5.90, 95% CI 2.08-16.72), and reactivation of cytomegalovirus (CMV) (aOR 6.17, 95% CI 2.17-17.57) and of other Herpesviridae viruses (aOR 3.04, 95% CI 1.13-8.16) were the variables that remained statistically associated with CDI. High-risk antibiotic use in the late post-transplant period (aOR 7.63, 95% CI 2.14-27.22) was associated with development of late CDI. CONCLUSION: This study revealed reactivation of CMV and other Herpesviridae viruses as novel risk factors for CDI. Administration of TMP-SMX prior to transplantation was independently associated with a decreased risk of CDI. Early and late CDI after HSCT may have distinct risk factors.

External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Cloning of idiotype immunoglobulin genes in B cell lymphomas by anchored PCR and production of individual recombinant idiotype vaccines in Escherichia coli.

OBJECTIVES: Individual immunoglobulins expressed by B-cell lymphomas represent tumor-specific antigens ('idiotypes'). Immunization with idiotype in follicular lymphoma patients may induce specific immune responses, sustained progression-free survival, and disappearance of minimal residual disease. Manufacturing of idiotype vaccines has mostly relied on heterohybridomas established from viable lymphoma cells. This paper describes the feasibility of production of GMP-grade idiotype vaccines as recombinant Fab fragments in Escherichia coli. METHODS: IgH and IgL transcripts were analyzed by anchored PCR from 106 lymphoma and nine control biopsies. Lymphoma-derived V segments were inserted into prokaryotic expression plasmids. Recombinant idiotype Fab fragments were expressed in E. coli in a fermentation system. RESULTS: Idiotype IgH and IgL transcripts were identified in 95% of 106 lymphoma biopsies according to stringent clonality criteria. Large-scale idiotype expression was successful in 69 of 78 cases (89%) and yielded a median of 17 mg (range: 1.2-250 mg) recombinant Fab protein. After affinity chromatography, median vaccine purity was 99% heterodimeric Fab protein (range: 72-100%). Bacterial protein contamination was detectable in one vaccine only. Fab proteins with IgL lambda chains had a tendency for inferior yield and lesser purity than kappa-type Fabs. Among other structural idiotype features (isotype, V family usage, somatic hypermutation pattern, novel glycosylation sites, CDR III net charge), no consistent influences on Fab yield or purity were detected. CONCLUSIONS: Anchored PCR cloning and subsequent protein expression in E. coli provides a reliable technological basis for clinical idiotype vaccination trials.

Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture.

We created and studied new cybrid cell lines from sporadic Alzheimer's disease (SAD) or control (CTL) subjects to assess mitochondrial abnormalities just after metabolic selection ("early passage") and again six passages later ("late passage"). Cytochrome oxidase (CO) activities in early passage SAD cybrids created independently from the same platelet samples were highly correlated. Early passage SAD and CTL cybrids showed equivalent mitochondrial morphologies. Late passage SAD cybrids showed increased mitochondrial number, reduced mitochondrial size, and an approximately eightfold increase in morphologically abnormal mitochondria. Deficiency of SAD cybrid mitochondrial membrane potentials (DeltaPsi(M)) increased with passage. Mitochondrial bromodeoxyuridine (BrdU) uptake to estimate mitochondrial DNA (mtDNA) synthesis did not change with passage in CTL but increased in SAD cybrids. With time in culture, SAD mtDNA appears to replicate faster in cybrids, yielding cells with relative worsening of bioenergetic function. Metabolically deleterious SAD mitochondrial genes, like those in yeast, may have a replicative advantage over nondeleterious mitochondrial genes that assume dominance in CTL cybrids.