PCR‐based detection of Aspergillus fumigatus and absence of azole resistance due to TR34/L98H in a french multicenter cohort of 137 patients with fungal rhinosinusitis

Fungal rhinosinusitis (FRS) has a worldwide distribution, comprises distinct clinical entities but is mostly due to Aspergillus among which Aspergillus fumigatus plays a major role in European countries. Although, there is accumulating evidence for the emergence of environmentally acquired‐azole resistance in A. fumigatus (such as TR₃₄/L98H) in various clinical settings, there is few data for patients with FRS. In this study, we aimed to investigate the prevalence of A. fumigatus azole resistance due to TR₃₄/L98H in a multicentre cohort of patients with FRS. One hundred and thirty‐seven patients with FRS admitted between 2002 and 2016 at four French medical centres were retrospectively enrolled. Clinical and mycological findings were collected. Aspergillus fumigatus and the TR₃₄/L98H alteration conferring azole resistance were investigated directly from clinical samples using the commercial CE‐IVD marked MycoGENIE^® A. fumigatus real‐time PCR assay. Fungal ball was the more frequent clinical form (n = 118). Despite the presence of fungal hyphae at direct microscopic examination, mycological cultures remained negative for 83 out of the 137 patients (60.6%). The PCR assay proved to be useful allowing the identification of A. fumigatus and etiological diagnosis in 106 patients (77.4%) compared with 44 patients (32.1%) when using culture as the reference method. Importantly, neither TR₃₄ nor L98H alterations were evidenced.     

Effect of CRP value on <Superscript>18</Superscript>F–FDG PET vascular positivity in Takayasu arteritis: a systematic review and per-patient based meta-analysis

Purpose

The aim of this study was to quantify the association between the CRP value and ¹⁸F–FDG PET vascular positivity in Takayasu arteritis (TAK) through a structured dedicated systematic review and meta-analysis.

Methods

From January 2000 to December 2016, the PubMed/MEDLINE database was searched for articles specifically dealing with the assessment of vascular inflammation using ¹⁸F–FDG PET and CRP biomarkers in TAK. Inclusion criteria for the qualitative analysis were (1) ¹⁸F–FDG PET used to assess the disease activity, (2) The use of the ACR criteria for the diagnosis of TAK, (3) No case mixed vasculitis (i.e., no giant cell arteritis), and (4) CRP concentration and clinical disease activity available. For the meta-analysis, PET-positive and PET-negative subgroups with the corresponding CRP concentrations were generated based on per patient data. The standard mean difference, which represents the effect of the CRP concentrations on the ¹⁸F–FDG PET vascular uptake, was computed for all studies, and then the results were pooled together.

Results

Among the 33 initial citations, nine complete articles including 210 patients fulfilled the inclusion criteria. Five studies found a significant correlation between the ¹⁸F–FDG PET and CRP concentration, one provided a trend towards association and three did not find any association between the two biomarkers. Six studies found a significant association between ¹⁸F–FDG PET and clinical disease activity, one found a trend towards association and the last two studies did not evaluate this correlation. The meta-analysis (121 patients) provided the following results: Standard Mean Deviation = 0.54 [0.15;0.92]; Chi² = 3.35; I² = 0%; Test for overall effect: Z = 2.70 (P = 0.007).

Conclusion

The CRP concentration only moderately reflects the ¹⁸F–FDG PET vascular positivity in TAK, suggesting dissociated information. Standardized longitudinal prospective studies are necessary to assess the value of ¹⁸F–FDG PET as an independent biomarker for subtle vascular wall inflammation detection.

     

Rational use of CT in acute pyelonephritis: Findings and relationships with reflux

Enhanced renal CT scanners were performed in 38 children (82% girls) to rule out acute pyelonephritis. Patients were divided in 2 groups on the basis of clinical presentation and bacteriology data. In patients of group A (n=16, preliminary study), upper urinary tract infection (UTI) was certain. CT confirmed the diagnosis in all but 3 patients (a 2-year-old child and 2 patients with UTI developed on prior obstruction). In subsequently studied patients of group B (n=22), clinical findings or bacteriology data were negative or questionable. CT made the diagnosis of acute pyelonephritis in 11 patients. As well as DMSA scintigraphy, CT scanner can help to diagnose or to rule out upper UTIs in difficult cases. In all boys of both groups, ipsilateral vesico-ureteric reflux (VUR) was found by subsequent voiding cystourethrography (VCUG) on the side of pyelonephritis. In girls, this correlation was shown in only 7 of the 25 kidneys with pyelonephritis. This result supports the hypothesis of a gender-dependent contamination. We believe that absence of radiologic reflux cannot exclude the possibility of bacterial crossings of ureteric meatus capable to lead to genuine upper UTIs.     

Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function

BackgroundPhase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV₁) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV₁.MethodsTo evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV₁<40 or ppFEV₁≥90 in comparison with those with ppFEV₁ [40–90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers.Results827 patients were classified into 3 subgroups according to ppFEV₁ at treatment initiation (ppFEV₁<40, n = 121; ppFEV₁ [40–90[, n = 609; ppFEV₁≥90, n = 97). Treatment discontinuation rate was higher in ppFEV₁<40 patients (28.9%) than in those with ppFEV₁ [40–90[(16.4%) or ppFEV₁≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV₁ occurred in the ppFEV₁ [40–90[subgroup (+2.9%, P<0.001), and in those ppFEV₁<40 (+0.5%, P = 0.03) but not in those with ppFEV₁≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV₁<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups.ConclusionPhe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function_, but the characteristics and magnitude of the response vary depending on ppFEV₁ at baseline.     

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3⁺BIRC3⁺ DCs enriched in immunoregulatory molecules (mregDC) and CD14⁺ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14⁺ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14⁺ DC3s as potential promoters of inflammation in PSO.     

Absolute benefit, number needed to treat and gain in life expectancy: which efficacy indices for measuring the treatment benefit?

The absolute benefit (AB) is extensively used to summarize the results of clinical trials. As the AB depends directly on the patient's baseline risk, therapeutic decisions based on AB tend to favor patients at high risk. To evaluate the consequences of this decision's procedure for life-long therapy, we compare the AB with the gain in event-free life expectancy in a simulated hypertensive population. Our results show that the AB goes through a maximum and then declines as the duration of treatment increases. The amplitude of the variation of AB is independent of the baseline risks but the maximum is reached more quickly in the high-risk patients. Considering the gain in event-free life expectancy, low-risk patients benefit more than high-risk patients do, at the expense of a longer treatment exposure. The interpretation of the AB changes depending on follow-up.     

Future reef decalcification under a business-as-usual CO2 emission scenario

Increasing atmospheric partial pressure of CO₂ (pCO₂) is a major threat to coral reefs, but some argue that the threat is mitigated by factors such as the variability in the response of coral calcification to acidification, differences in bleaching susceptibility, and the potential for rapid adaptation to anthropogenic warming. However the evidence for these mitigating factors tends to involve experimental studies on corals, as opposed to coral reefs, and rarely includes the influence of multiple variables (e.g., temperature and acidification) within regimes that include diurnal and seasonal variability. Here, we demonstrate that the inclusion of all these factors results in the decalcification of patch-reefs under business-as-usual scenarios and reduced, although positive, calcification under reduced-emission scenarios. Primary productivity was found to remain constant across all scenarios, despite significant bleaching and coral mortality under both future scenarios. Daylight calcification decreased and nocturnal decalcification increased sharply from the preindustrial and control conditions to the future scenarios of low (reduced emissions) and high (business-as-usual) increases in pCO₂. These changes coincided with deeply negative carbonate budgets, a shift toward smaller carbonate sediments, and an increase in the abundance of sediment microbes under the business-as-usual emission scenario. Experimental coral reefs demonstrated highest net calcification rates and lowest rates of coral mortality under preindustrial conditions, suggesting that reef processes may not have been able to keep pace with the relatively minor environmental changes that have occurred during the last century. Taken together, our results have serious implications for the future of coral reefs under business-as-usual environmental changes projected for the coming decades and century.Tropical coral reef ecosystems face significant challenges from anthropogenic changes in ocean temperature and chemistry (1). Short periods of anomalously high sea temperatures have triggered mass coral bleaching and mortality events since the early 1980s (2, 3), and projected pH and carbonate ion concentrations reduce the calcification rate of many organisms such as reef-building corals and crustose coralline algae (reviewed in ref. 4). Generally, the projected impacts associated with future increases in sea temperature have been examined independently of those associated with ocean acidification (2, 5–8). When multiple drivers have been considered, extrapolation of the results to the future outlook of coral reefs has been complicated by a lack of replication, the use of artificial light, and/or experimental designs that exclude the potentially important influence of natural variation in ocean temperature and chemistry over diel and seasonal cycles (9–11). Furthermore, most studies have focused on corals or calcareous algae in isolation rather than on broader communities that may better represent the responses of coral reefs (9–11). Excluding the interaction of changing temperature and ocean chemistry, natural variability, and the wider set of organisms and processes places important limitations on our ability to understand the future and ascertain whether, for coral reefs, there is any real difference between action and no action regarding CO₂ emissions. This issue is fundamentally important given the time lag between reducing CO₂ emissions and establishing atmospheric stability, but has not been addressed adequately via studies that seek mechanistic understandings for the individual effects of temperature and acidification on specific organisms, because the sum of the parts may not equal the whole.Some argue that the potential and imminent threat to coral reefs posed by anthropogenic CO₂ emissions is mitigated by potential rapid evolutionary adaptation by key reef organisms such as corals (12). Within this argument, greater inherent environmental variability is seen as a facilitator of adaptation (13), and the transition within some corals to thermally tolerant symbionts is presented as a current coral plasticity that is likely to enhance adaptation toward warmer water (12). The latter suggestion is debatable because the enhancement in host performance is not typically recorded in terms of a property that belongs uniquely to the host (e.g., coral survival, growth, or reproduction) but rather as properties (bleaching tolerance, sustained maximum quantum yields of photosystem II) that may be more attributable to the symbiont than to the host (14). That is, it is not always clear that the statement “having thermally tolerant symbionts leads to thermally tolerant hosts” is anything more than a tautology. Especially given observations in the current literature that corals harboring thermally tolerant symbionts experience reduced growth (15, 16), that heterotrophic feeding can sustain some coral species postbleaching (17), and finally that while food may be relatively unavailable in the oceans that surround reefs, this is not typically the case on a reef (reviewed in ref. 18). Evolution will occur over multiple generations. Presently, however, we lack the experimental evidence to support scientifically the contention that organism evolution over the next decades will protect features such as the maintenance of a positive carbonate balance that are essential to reef viability and the functional utility of reefs to mankind (1). However, the ocean environment has changed significantly over the last 100 y in terms of both ocean temperature and acidification (19, 20), suggesting that reefs in the Southern Great Barrier Reef (GBR), where seasonal environmental variability is great, should provide ample opportunity to evaluate experimentally the degree to which key ecosystem features are retained over decadal time frames.In the present study, we simulated past and future ocean temperature and chemistry on replicated patches of coral reef reconstructed from a broad range of organisms collected from the growth zone of a coral reef (Harry’s Bommie, Heron Island, GBR, 151.9357°E, 23.4675°S) (Fig. S1). The experiment was designed to answer two major questions. The first was whether processes such as the maintenance of maximum net reef calcification rates, measured independently of episodic events such as cyclones, are optimal under the preindustrial (PRE) or present-day (control) scenarios. The second was whether the response of coral reefs differs between action scenarios that result in business-as-usual unabated rates of CO₂ emission (A1FI) as compared to reduced rates of CO₂ emission (B1) through 2050. Here, the Special Report on Emission Scenarios (SRES) A1FI is equivalent to a Representation Concentration Pathway (RCP) 8.5; and, SRES B1 is equivalent to RCP4.5 (21).

Table 1.

November composition of the reassembled patch-reefs