Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial

Background: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. Methods: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. Discussion: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. Trial registration: ClinicalTrials.gov, NCT03057431. Registered on February 20 2017

Importance and evolutionary consequences of crop-to-weed gene flow in Helianthus annuus L

International audienc

Flowering phenology and hybridization rates between cultivated varieties and weedy populations of sunflower in France

absen

How to escape from crop-to-weed gene flow: phenological variation and isolation-by-time within weedy sunflower populations.

AGAP : équipe Génomique évolutive et gestion des populations (GE²pop)The evolution of crop-related weeds may be constrained by recurrent gene flow from the crop. However, flowering time variation within weedy populations may open the way for weed adaptation by allowing some weeds to escape from this constraint. We investigated this link between phenology, gene flow and adaptation in weedy sunflower populations that have recently emerged in Europe from crop-wild hybridization. We studied jointly flowering phenology and genetic diversity for 15 microsatellite loci in six cultivated sunflower (Helianthus annuus) fields infested by weedy sunflower populations. The flowering overlap of cultivated and weedy sunflowers varied between and within populations: some weedy individuals were found to be completely isolated from the crop, the frequency of these plants being higher in populations from highly infested fields. Within weedy populations, we detected a pattern of isolation-by-time: the genetic divergence between individuals was positively correlated with their divergence in flowering period. In addition, earlier weeds, which flowered synchronously with the crop, were genetically more similar than late-flowering weeds to the cultivated varieties. Overall, our results suggest that crop-to-weed gene flow occurred, but was limited by divergent phenologies. We discuss the roles of weed adaptation and population history in the generation of this partial reproductive isolation

Data from: How to escape from crop-to-weed gene flow: phenological variation and isolation-by-time within weedy sunflower populations

The evolution of crop-related weeds may be constrained by recurrent gene flow from the crop. However, flowering time variation within weedy populations may open the way for weed adaptation by allowing some weeds to escape from this constraint. We investigated this link between phenology, gene flow and adaptation in weedy sunflower populations recently emerged in Europe from crop-wild hybridization. We studied jointly flowering phenology and genetic diversity for 15 microsatellite loci in six cultivated sunflower fields infested by weedy sunflower populations. The flowering overlap of cultivated and weedy sunflowers varied between and within populations: some weedy individuals were found completely isolated from the crop, the frequency of these plants being higher in populations from highly infested fields. Within weedy populations, we detected a pattern of isolation-by-time: the genetic divergence between individuals was positively correlated with their divergence in flowering period. Additionally, earlier weeds, which flowered synchronously with the crop, were genetically more similar to the cultivated varieties than late-flowering weeds. Overall our results suggest that crop-to-weed gene flow did occur but was limited by divergent phenologies. We discuss the roles of weed adaptation and population history in generating this partial reproductive isolation

Phenotypic_data

The Excel file has both the data (one worksheet per weedy population, one worksheet for phenological data of cultivated fields), and a worksheet explaining each of the columns/fields

Genetypic_data

Genotypic data for 15 microsatellites for weedy individuals and 24 varieties; missing data coded as N