Time to Update and Quantitative Changes in the Results of Cochrane Pregnancy and Childbirth Reviews

Background

The recommended interval between updates for systematic reviews included in The Cochrane Library is 2 years. However, it is unclear whether this interval is always appropriate. Whereas excessive updating wastes time and resources, insufficient updating allows out-of-date or incomplete evidence to guide clinical decision-making. We set out to determine, for Cochrane pregnancy and childbirth reviews, the frequency of updates, factors associated with updating, and whether updating frequency was appropriate.

Methodology/Principal Findings

Cochrane pregnancy and childbirth reviews published in Issue 3, 2007 of the Cochrane Database of Systematic Reviews were retrieved, and data were collected from their original and updated versions. Quantitative changes were determined for one of the primary outcomes (mortality, or the outcome of greatest clinical significance). Potential factors associated with time to update were assessed using the Cox proportional hazard model. Among the 101 reviews in our final sample, the median time before the first update was 3.3 years (95% CI 2.7–3.8). Only 32.7% had been updated within the recommended interval of 2 years. In 75.3% (76/101), a median of 3 new trials with a median of 576 additional participants were included in the updated versions. There were quantitative changes in 71% of the reviews that included new trials (54/76): the median change in effect size was 18.2%, and the median change in 95% CI width was 30.8%. Statistical significance changed in 18.5% (10/54) of these reviews, but conclusions were revised in only 3.7% (2/54). A shorter time to update was associated with the same original review team at updating.

Conclusions/Significance

Most reviews were updated less frequently than recommended by Cochrane policy, but few updates had revised conclusions. Prescribed time to update should be reconsidered to support improved decision-making while making efficient use of limited resources.     

A protease-activatable luminescent biosensor and reporter cell line for authentic SARS-CoV-2 infection

Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.     

Highly syntenic regions in the genomes of soybean, <Emphasis Type="Italic">Medicago truncatula</Emphasis>, and <Emphasis Type="Italic">Arabidopsis thaliana</Emphasis>

Background  

Recent genome sequencing enables mega-base scale comparisons between related genomes. Comparisons between animals, plants, fungi, and bacteria demonstrate extensive synteny tempered by rearrangements. Within the legume plant family, glimpses of synteny have also been observed. Characterizing syntenic relationships in legumes is important in transferring knowledge from model legumes to crops that are important sources of protein, fixed nitrogen, and health-promoting compounds.     

Secure Surveillance of Antimicrobial Resistant Organism Colonization or Infection in Ontario Long Term Care Homes

Background

There is stigma attached to the identification of residents carrying antimicrobial resistant organisms (ARO) in long term care homes, yet there is a need to collect data about their prevalence for public health surveillance and intervention purposes.

Objective

We conducted a point prevalence study to assess ARO rates in long term care homes in Ontario using a secure data collection system.

Methods

All long term care homes in the province were asked to provide colonization or infection counts for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum beta-lactamase (ESBL) as recorded in their electronic medical records, and the number of current residents. Data was collected online during the October-November 2011 period using a Paillier cryptosystem that allows computation on encrypted data.

Results

A provably secure data collection system was implemented. Overall, 82% of the homes in the province responded. MRSA was the most frequent ARO identified at 3 cases per 100 residents, followed by ESBL at 0.83 per 100 residents, and VRE at 0.56 per 100 residents. The microbiological findings and their distribution were consistent with available provincial laboratory data reporting test results for AROs in hospitals.

Conclusions

We describe an ARO point prevalence study which demonstrated the feasibility of collecting data from long term care homes securely across the province and providing strong privacy and confidentiality assurances, while obtaining high response rates.     

Nocturne for an unknown pollinator: first description of a night‐flowering orchid (Bulbophyllum nocturnum)

Bulbophyllum nocturnum , a species of section Epicrianthes from New Britain, is described and illustrated. It is the first known example of an orchid species in which the flowers open after dark and close in the morning. The poorly understood pollination biology of section Epicrianthes, a clade with highly unusual flowers, is discussed. Attention is drawn to the close resemblance between the petal appendages of some species and the fruiting bodies of certain Myxogastria. © 2011 The Linnean Society of London, Botanical Journal of the Linnean Society, 2011, 167 , 344–350.     

Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials

Background

Selective serotonin reuptake inhibitors are increasingly used in the long-term treatment of depression. Much of the supporting evidence about the effects of these drugs comes from discontinuation trials, a variant of randomized controlled trials whose design is problematic to interpret. We conducted a systematic review to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of unipolar depression.

Methods

We identified placebo-controlled randomized trials with a treatment duration of at least 6 months by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to update a recently published systematic review. Efficacy was defined in terms of response to treatment (50% improvement in depression score relative to baseline) and remission (score of 7 or below on the Hamilton rating scale for depression). Key secondary outcomes included quality of life, return to work, need for additional treatment and self-harm. Overall acceptability was defined in terms of dropouts for any reason over a course of treatment.

Results

Of the 2693 records identified initially, we included 6 randomized controlled trials that met our eligibility criteria. These studies had a moderate risk of bias, had assigned a total of 1299 participants with depression to either treatment or placebo and had followed both groups for 6–8 months. We observed statistically significant improvements in response to treatment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.12–2.48), but not in remission (OR 1.46, 95% CI 0.92–2.32) or acceptability (OR 0.87, 95% CI 0.67–1.14). The effects appeared greater among patients without comorbidities.

Interpretation

There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6–8 months of antidepressant treatment following initial recovery but provide no guidance for longer treatment.Over the past decade, the use of selective serotonin reuptake inhibitors for the management of depression has increased dramatically, and preliminary evidence suggests that long-term use, for more than 1 or 2 years, accounts for much of this rise.^1–3 Clinical practice guidelines generally recommend a 6- to 9-month course following initial recovery after a first episode of depression and longer, sometimes indefinite, therapy after subsequent episodes, to prevent relapse.^4–10Long-term randomized controlled trials of antidepressants have typically used 1 of 2 possible designs, each answering different questions (Figure 1).¹¹ The most widely used design is called the “discontinuation trial,” a 2-phase study in which all participants are initially treated with an open (unblinded) course of drug therapy. Participants attaining a certain response during the open-treatment phase enter the second phase, during which they are randomly assigned to continue active drug treatment or to receive placebo.^12–14 Discontinuation trials are believed to minimize the number of participants with depression who must be exposed to placebo. This advantage comes at a cost, since the results apply only to patients with a response to the medication, not to those who experience spontaneous recovery; furthermore, withdrawal symptoms may lead to an overestimate of the true effect of the medication. When this design is used to test long-term therapy with selective serotonin reuptake inhibitors for the treatment of depression, the results are difficult to interpret with confidence because rates of spontaneous recovery in depression are potentially high and because withdrawal effects can mimic depression.^13–15Open in a separate windowFigure 1: Two designs of randomized controlled trials used to investigate long-term antidepressant therapy.The second type of randomized trial used to test long-term therapy with selective serotonin reuptake inhibitors is a 2-arm parallel randomized controlled trial, hereafter referred to as a classic randomized controlled trial (Figure 1).¹⁶ In this type of trial, participants with acute depression are assigned to receive either placebo or active drug, and all those achieving a certain response, either to the drug or to the placebo, are followed. The advantage of classic randomized controlled trials is that data from all participants contribute to our understanding of the drug''s real-world effectiveness. Their main drawback is that a greater number of acutely ill people may have to receive placebo than in a discontinuation trial.¹³ Most classic trials of antidepressants are short-term studies. Fergusson and colleagues,¹⁷ in a systematic review examining selective serotonin reuptake inhibitors and suicide, identified 702 classic trials involving a total of 18 413 participants, the majority of which (93%) lasted less than 6 months.A recent systematic review based mainly on studies with discontinuation designs showed that, in a subgroup of patients who experienced recovery while taking medications, long-term therapy with selective serotonin reuptake inhibitors reduced the chances of relapse by up to 70% for up to 36 months, relative to patients whose therapy was discontinued earlier.⁶ However, there has been no systematic review of classic randomized trials of long-term therapy with this drug class to determine the potential benefits in all patients with depression, including those with spontaneous recovery.We sought to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of moderate to severe depression, including subgroups of patients with major chronic health conditions. We also examined a number of key indicators of the quality of evidence and its clinical importance.