Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. ...Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.
A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.
Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
The use of more than a single nursery habitat type is examined for oviparous elasmobranchs using data summarized from studies conducted on the Alaska skate Bathyraja parmifera and the Aleutian skate ...Bathyraja aleutica in the eastern Bering Sea. The eastern Bering Sea skate species use two discrete areas as nurseries, one for egg deposition and a second for newly emergent juveniles. Egg deposition sites were located along the outer shelf and upper slope near canyons in the eastern Bering Sea. Newly emergent juveniles were found along the outer and middle shelf for B. parmifera and deep‐slope for B. aleutica, suggesting that habitat used by newly emergent juvenile skates is distinct from habitat used for egg deposition and embryo development. In reviewing many studies on oviparous elasmobranchs, similar patterns emerge of habitat use during their early life history. To distinguish these distinct habitats, appropriate terminology is proposed. Egg case nursery is suggested for areas of egg deposition and juvenile nursery is suggested for areas where juveniles aggregate after emergence. Criteria to describe each habitat type are outlined.
Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear.
We performed a pragmatic, randomized ...trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio either to receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause.
Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval CI, 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04).
In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).
Background
Distal renal tubular acidosis (dRTA) is characterized by hyperchloraemic metabolic acidosis, hypokalaemia, hypercalciuria and nephrocalcinosis. It is due to reduced urinary acidification ...by the α-intercalated cells in the collecting duct and can be caused by mutations in genes that encode subunits of the vacuolar H
+
-ATPase (
ATP6V1B1
,
ATP6V0A4
) or the anion exchanger 1 (
SLC4A1
). Treatment with alkali is the mainstay of therapy.
Methods
This study is an analysis of clinical data from a long-term follow-up of 24 children with dRTA in a single centre, including a genetic analysis.
Results
Of the 24 children included in the study, genetic diagnosis was confirmed in 19 patients, with six children having mutations in
ATP6V1B1
, ten in
ATP6V0A4
and three in
SLC4A1
; molecular diagnosis was not available for five children. Five novel mutations were detected (2 in
ATP6V1B1
and 3 in
ATP6V0A4
). Two-thirds of patients presented with features of proximal tubular dysfunction leading to an erroneous diagnosis of renal Fanconi syndrome. The proximal tubulopathy disappeared after resolution of acidosis, indicating the importance of following proximal tubular function to establish the correct diagnosis. Growth retardation with a height below −2 standard deviation score was found in ten patients at presentation, but persisted in only three of these children once established on alkali treatment. Sensorineural hearing loss was found in five of the six patients with an
ATP6V1B1
mutation. Only one patient with an
ATP6V0A4
mutation had sensorineural hearing loss during childhood. Nine children developed medullary cysts, but without apparent clinical consequences. Cyst development in this cohort was not correlated with age at therapy onset, molecular diagnosis, growth parameters or renal function.
Conclusion
In general, the prognosis of dRTA is good in children treated with alkali.
Postgraduate medical education in the Netherlands has adopted competency-based education since the turn of the century. In 2006, the CanMEDS competency framework was introduced. A 2013 government ...plan to reduce the length and budgets of training programs led the Dutch Association of Medical Specialists (DAMS) to respond with a proposal to create more flexibility and individualization rather than a blunt cut in the length across all training programs. DAMS launched a government-funded, nation-wide, 4-year project (2014-2018) to blueprint the reform of postgraduate medical education in this direction. To achieve competency-based individualization, the fixed duration of postgraduate programs was abandoned, and entrustable professional activities (EPAs) were introduced in all specialty programs. Implementation of this new generation of programs took place in 2017-2019 in all disciplines. The project focused on EPA-based individualization of all programs, while addressing issues of the continuity of patient care in time-variable programs and the legal and regulatory consequences of individualization. About 30 specialty programs were revised at national, regional, local, and individual levels to incorporate EPAs; portfolio systems were adapted, clinical competency committees were installed for all programs, and procedures for summative entrustment decision making were elaborated. This paper reports on the rationale and the process that led to a more time-variable postgraduate education landscape, and, on average, a shortening of training length by 3 months.
Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism ...by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.
Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for ...Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on colonoscopic surveillance following adenoma removal includes 24 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of surveillance and other elements in the screening process, including multi-disciplinary diagnosis and management of the disease.
In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference ...therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1.
This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics.
Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal.
Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels.
Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
To evaluate the effect of implementation of the WHO's Surgical Safety Checklist on mortality and to determine to what extent the potential effect was related to checklist compliance.
Marked ...reductions in postoperative complications after implementation of a surgical checklist have been reported. As compliance to the checklists was reported to be incomplete, it remains unclear whether the benefits obtained were through actual completion of a checklist or from an increase in overall awareness of patient safety issues.
This retrospective cohort study included 25,513 adult patients undergoing non-day case surgery in a tertiary university hospital. Hospital administrative data and electronic patient records were used to obtain data. In-hospital mortality within 30 days after surgery was the main outcome and effect estimates were adjusted for patient characteristics, surgical specialty and comorbidity.
After checklist implementation, crude mortality decreased from 3.13% to 2.85% (P = 0.19). After adjustment for baseline differences, mortality was significantly decreased after checklist implementation (odds ratio OR 0.85; 95% CI, 0.73-0.98). This effect was strongly related to checklist compliance: the OR for the association between full checklist completion and outcome was 0.44 (95% CI, 0.28-0.70), compared to 1.09 (95% CI, 0.78-1.52) and 1.16 (95% CI, 0.86-1.56) for partial or noncompliance, respectively.
Implementation of the WHO Surgical Checklist reduced in-hospital 30-day mortality. Although the impact on outcome was smaller than previously reported, the effect depended crucially upon checklist compliance.
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