Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C^high monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.     

Effectiveness of permanet in Côte d'Ivoire rural areas and residual activity on a knockdown-resistant strain of Anopheles gambiae

The effectiveness of long-lasting preimpregnated nets of Permanet type (deltamethrin, 50 mg/m2) erected in households in rural areas of C?te d'Ivoire was tested on two laboratory strains of Anopheles gambiae s.s.: the Kisumu susceptible strain and the Vk per pyrethroids resistant strain with >70% kdr allelic frequency. Treated nets were distributed in households in three villages of Danan6 forest area in western part of C?te d'Ivoire. In each village, a net was sampled for bioassays. Three Permanets also were erected in the laboratory, serving as control samples. From May 2001 to July 2002, the effectiveness of these deltamethrin-pretreated nets was monitored using World Health Organization-cone tests on the two strains of An. gambiae. Mortality rates were recorded 24 h postexposure. Knockdown times for 50 and 95% mosquitoes (kdT50 and kdT95, respectively) were estimated by means of WIN DL software. One-way analysis of variance was used to compare the knockdown times. Times to failure of nets were analyzed using Cox model. The kdT50 of the Kisumu susceptible strain with both laboratory samples and nets used in the field varied around 10 min. No significant difference was recorded between the kdT50 of the Kisumu susceptible strain with laboratory kept nets and samples of nets used in the field. The kdT95 values were in the same scale with the two types of nets. The kdT50 of the Vk per resistant strain when exposed to used nets were twofold that of the Kisumu susceptible strain at the beginning of the trial, and they increased to fivefold 15 mo later. These latter kdT50 significantly differed to those of the Kisumu susceptible strain tested with laboratory and field samples of nets. The kdT95 significantly differed from those of the Kisumu strain with laboratory kept nets and with field kept nets. Baseline bioassay mortality rates were always 99-100% with the Kisumu susceptible strain, and they did not show any significant difference between laboratory-kept nets and field-used nets during the 15-mo trial. With the Vk per resistant strain, the expected long-lasting activity was not achieved. A high decrease of mortality rates was observed from 69 to 75% in the first 3 mo to 2% at the month 15. This mortality was associated with significant differences between Vk per resistant strain tested with field-used nets compared with Kisumu susceptible strain tested with both laboratory kept-nets and field-used nets. This study emphasized the actual long-lasting effectiveness of Permanet against the An. gambiae Kisumu susceptible reference strain and a rapid decrease of residual activity against a strain with kdr-based resistance to pyrethroids.     

State insurance mandates and off‐label use of chemotherapy

Access to cancer drugs used off‐label is important to cancer patients but may drive up healthcare costs with little evidence of clinical benefit. We hypothesized that state health insurance mandates for private insurers to provide coverage for off‐label use of cancer drugs cause higher rates of off‐label use. We used Truven MarketScan data from 1999 to 2007 on utilization of 35 infused chemotherapy drugs in private health plans in the United States, covering the period when eight states implemented off‐label coverage laws. We studied trends in off‐label use of drugs, distinguishing between appropriate and inappropriate off‐label use according to drug compendia, and estimated difference‐in‐difference regressions of the effect of state laws on off‐label use. We estimate 41% of utilization was off‐label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in off‐label use over time. We also find no discernable effect of state laws mandating coverage of off‐label use of cancer drugs on utilization patterns under multiple empirical specifications. Our conclusion is that policymakers should consider shifting away from mandating coverage as a way to ensure access to drugs off‐label and towards incentivizing adherence to clinical practice guidelines to improve the quality and value of off‐label use.     

Comparison of Fracture Prediction Tools in Individuals Without and With Early Chronic Kidney Disease: A Population-Based Analysis of CARTaGENE

Whether fracture prediction tools developed for the management of osteoporosis can be used in chronic kidney disease (CKD) is poorly known. We aimed to compare the performance of fracture prediction tools in non-CKD and CKD. We analyzed CARTaGENE, a population-based survey of 40-year-old to 69-year-old individuals recruited between 2009 and 2010. Renal function was assessed using baseline creatinine and categorized according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines (non-CKD, stage 2, stage 3). Individuals without creatinine measurements or with advanced CKD (stage 4 or 5; prevalence <0.25%) were excluded. Predicted 5-year fracture probabilities (using Fracture Risk Assessment Tool [FRAX], QFracture, and Garvan) were computed at baseline. Fracture incidence (major fracture [MOF] or any fracture) was evaluated in administrative databases from recruitment to March 2016. Discrimination (hazard ratios [HRs] per standard deviation [SD] increase in Cox models; c-statistics) and calibration (standardized incidence ratios [SIRs] before and after recalibration) were assessed in each CKD strata. We included 19,393 individuals (9522 non-CKD; 9114 stage 2; 757 stage 3). A total of 830 patients had any fracture during follow-up, including 352 MOF. FRAX (HR = 1.89 [1.63–2.20] non-CKD; 1.64 [1.41–1.91] stage 2; 1.76 [1.10–2.82] stage 3) and QFracture (HR = 1.90 [1.62–2.22] non-CKD; 1.57 [1.35–1.82] stage 2; 1.86 [1.19–2.91] stage 3) discriminated MOF similarly in non-CKD and CKD. In contrast, the discrimination of Garvan for any fracture tended to be lower in CKD stage 3 compared to non-CKD and CKD stage 2 (HR = 1.36 [1.22–1.52] non-CKD; 1.34 [1.20–1.50] stage 2; 1.11 [0.79–1.55] stage 3). Before recalibration, FRAX globally overestimated fracture risk while QFracture and Garvan globally underestimated fracture risk. After recalibration, FRAX and QFracture were adequately calibrated for MOF in all CKD strata whereas Garvan tended to underestimate any fracture risk in CKD stage 3 (SIR = 1.31 [0.95–1.81]). In conclusion, the discrimination and calibration of FRAX and QFracture is similar in non-CKD and CKD. Garvan may have a lower discrimination in CKD stage 3 and underestimate fracture risk in these patients. © 2020 American Society for Bone and Mineral Research.     

Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases

CARD15 is a major susceptibility gene for a frequent multifactorial chronic inflammatory bowel disorder, Crohn disease (CD). By using NF-kappaB activation assays, the cytosolic CARD15 was shown to efficiently detect bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 CD-associated variants and 13 additional variants carried by CD patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable CD manifestations. In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.     

Malignant non-Hodgkin's lymphoma presenting with arrhythmia and conduction defects. Report of 2 cases

Primary cardiac lymphoma is very rare. Secondary localisations are more common, observed in 15 to 30% of autopsy series. Clinical symptoms of cardiac involvement are rare, explaining the usual post-mortem diagnosis. The presentation of cardiac involvement by arrhythmias and conduction defects is very uncommon. The authors report two cases, the first of a 35 year old man in whom primary cardiac lymphoma presented with ventricular tachycardia complicated secondarily by complete atrioventricular block (AVB) with pseudo-inferior wall infarction. The second case was a 37 year old man with a cutaneous T cell lymphoma in whom complete AVB was the first sign of a secondary cardiac localisation of his disease. The finding of cardiac lymphoma should lead to aggressive chemotherapy as soon as possible.