Use of Neuraminidase Inhibitors for Rapid Containment of Influenza: A Systematic Review and Meta-Analysis of Individual and Household Transmission Studies

Objectives

To assess the effectiveness of neuraminidase inhibitors for use in rapid containment of influenza.

Method

We conducted a systematic review and meta-analysis in accordance with the PRISMA statement. Healthcare databases and sources of grey literature were searched up to 2012 and records screened against protocol eligibility criteria. Data extraction and risk of bias assessments were performed using a piloted form. Results were synthesised narratively and we undertook meta-analyses to calculate pooled estimates of effect, statistical heterogeneity and assessed publication bias.

Findings

Nine randomised controlled trials (RCTs) and eight observational studies met the inclusion criteria. Neuraminidase inhibitors provided 67 to 89% protection for individuals following prophylaxis. Meta-analysis of individual protection showed a significantly lower pooled odds of laboratory confirmed seasonal or influenza A(H1N1)pdm09 infection following oseltamivir usage compared to placebo or no therapy (n = 8 studies; odds ratio (OR) = 0.11; 95% confidence interval (CI) = 0.06 to 0.20; p<0.001; I² = 58.7%). This result was comparable to the pooled odds ratio for individual protection with zanamivir (OR = 0.23; 95% CI 0.16 to 0.35). Similar point estimates were obtained with widely overlapping 95% CIs for household protection with oseltamivir or zanamivir. We found no studies of neuraminidase inhibitors to prevent population-wide community transmission of influenza.

Conclusion

Oseltamivir and zanamivir are effective for prophylaxis of individuals and households irrespective of treatment of the index case. There are no data which directly support an effect on wider community transmission.

Protocol Registry

PROSPERO registration number: CRD42013003880     

Low Carbohydrate versus Isoenergetic Balanced Diets for Reducing Weight and Cardiovascular Risk: A Systematic Review and Meta-Analysis

Background

Some popular weight loss diets restricting carbohydrates (CHO) claim to be more effective, and have additional health benefits in preventing cardiovascular disease compared to balanced weight loss diets.

Methods and Findings

We compared the effects of low CHO and isoenergetic balanced weight loss diets in overweight and obese adults assessed in randomised controlled trials (minimum follow-up of 12 weeks), and summarised the effects on weight, as well as cardiovascular and diabetes risk. Dietary criteria were derived from existing macronutrient recommendations. We searched Medline, EMBASE and CENTRAL (19 March 2014). Analysis was stratified by outcomes at 3–6 months and 1–2 years, and participants with diabetes were analysed separately. We evaluated dietary adherence and used GRADE to assess the quality of evidence. We calculated mean differences (MD) and performed random-effects meta-analysis. Nineteen trials were included (n = 3209); 3 had adequate allocation concealment. In non-diabetic participants, our analysis showed little or no difference in mean weight loss in the two groups at 3–6 months (MD 0.74 kg, 95%CI −1.49 to 0.01 kg; I² = 53%; n = 1745, 14 trials; moderate quality evidence) and 1–2 years (MD 0.48 kg, 95%CI −1.44 kg to 0.49 kg; I² = 12%; n = 1025; 7 trials, moderate quality evidence). Furthermore, little or no difference was detected at 3–6 months and 1–2 years for blood pressure, LDL, HDL and total cholesterol, triglycerides and fasting blood glucose (>914 participants). In diabetic participants, findings showed a similar pattern.

Conclusions

Trials show weight loss in the short-term irrespective of whether the diet is low CHO or balanced. There is probably little or no difference in weight loss and changes in cardiovascular risk factors up to two years of follow-up when overweight and obese adults, with or without type 2 diabetes, are randomised to low CHO diets and isoenergetic balanced weight loss diets.     

I222 Neuraminidase Mutations Further Reduce Oseltamivir Susceptibility of Indonesian Clade 2.1 Highly Pathogenic Avian Influenza A(H5N1) Viruses

We have tested the susceptibility to neuraminidase inhibitors of 155 clade 2.1 H5N1 viruses from Indonesia, isolated between 2006–2008 as well as 12 clade 1 isolates from Thailand and Cambodia from 2004–2007 using a fluorometric MUNANA-based enzyme inhibition assay. The Thailand and Cambodian clade 1 isolates tested here were all susceptible to oseltamivir and zanamivir, and sequence comparison indicated that reduced oseltamivir susceptibility we observed previously with clade 1 Cambodian isolates correlated with an S246G neuraminidase mutation. Eight Indonesian viruses (5%), all bearing I222 neuraminidase mutations, were identified as mild to extreme outliers for oseltamivir based on statistical analysis by box plots. IC₅₀s were from 50 to 500-fold higher than the reference clade 1 virus from Viet Nam, ranging from 43–75 nM for I222T/V mutants and from 268–349 nM for I222M mutants. All eight viruses were from different geographic locales; all I222M variants were from central Sumatra. None of the H5N1 isolates tested demonstrated reduced susceptibility to zanamivir (IC₅₀s all <5 nM). All I222 mutants showed loss of slow binding specifically for oseltamivir in an IC₅₀ kinetics assay. We identified four other Indonesian isolates with higher IC₅₀s which also demonstrated loss of slow binding, including one virus with an I117V mutation. There was a minimal effect on the binding of zanamivir and peramivir for all isolates tested. As H5N1 remains a potential pandemic threat, the incidence of mutations conferring reduced oseltamivir susceptibility is concerning and emphasizes the need for greater surveillance of drug susceptibility.     

Reporting Quality of Systematic Reviews/Meta-Analyses of Acupuncture

Background

The QUOROM and PRISMA statements were published in 1999 and 2009, respectively, to improve the consistency of reporting systematic reviews (SRs)/meta-analyses (MAs) of clinical trials. However, not all SRs/MAs adhere completely to these important standards. In particular, it is not clear how well SRs/MAs of acupuncture studies adhere to reporting standards and which reporting criteria are generally ignored in these analyses.

Objectives

To evaluate reporting quality in SRs/MAs of acupuncture studies.

Methods

We performed a literature search for studies published prior to 2014 using the following public archives: PubMed, EMBASE, Web of Science, the Cochrane Database of Systematic Reviews (CDSR), the Chinese Biomedical Literature Database (CBM), the Traditional Chinese Medicine (TCM) database, the Chinese Journal Full-text Database (CJFD), the Chinese Scientific Journal Full-text Database (CSJD), and the Wanfang database. Data were extracted into pre-prepared Excel data-extraction forms. Reporting quality was assessed based on the PRISMA checklist (27 items).

Results

Of 476 appropriate SRs/MAs identified in our search, 203, 227, and 46 were published in Chinese journals, international journals, and the Cochrane Database, respectively. In 476 SRs/MAs, only 3 reported the information completely. By contrast, approximately 4.93% (1/203), 8.81% (2/227) and 0.00% (0/46) SRs/Mas reported less than 10 items in Chinese journals, international journals and CDSR, respectively. In general, the least frequently reported items (reported≤50%) in SRs/MAs were “protocol and registration”, “risk of bias across studies”, and “additional analyses” in both methods and results sections.

Conclusions

SRs/MAs of acupuncture studies have not comprehensively reported information recommended in the PRISMA statement. Our study underscores that, in addition to focusing on careful study design and performance, attention should be paid to comprehensive reporting standards in SRs/MAs on acupuncture studies.     

Efficacy of Non-Pharmacological Interventions to Prevent and Treat Delirium in Older Patients: A Systematic Overview. The SENATOR project ONTOP Series

Background

Non-pharmacological intervention (e.g. multidisciplinary interventions, music therapy, bright light therapy, educational interventions etc.) are alternative interventions that can be used in older subjects. There are plenty reviews of non-pharmacological interventions for the prevention and treatment of delirium in older patients and clinicians need a synthesized, methodologically sound document for their decision making.

Methods and Findings

We performed a systematic overview of systematic reviews (SRs) of comparative studies concerning non-pharmacological intervention to treat or prevent delirium in older patients. The PubMed, Cochrane Database of Systematic Reviews, EMBASE, CINHAL, and PsychINFO (April 28th, 2014) were searched for relevant articles. AMSTAR was used to assess the quality of the SRs. The GRADE approach was used to assess the quality of primary studies. The elements of the multicomponent interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis. Risk ratios were estimated using a random-effects model. Twenty-four SRs with 31 primary studies satisfied the inclusion criteria. Based on the AMSTAR criteria twelve reviews resulted of moderate quality and three resulted of high quality. Overall, multicomponent non-pharmacological interventions significantly reduced the incidence of delirium in surgical wards [2 randomized trials (RCTs): relative risk (RR) 0.71, 95% Confidence Interval (CI) 0.59 to 0.86, I²=0%; (GRADE evidence: moderate)] and in medical wards [2 CCTs: RR 0.65, 95%CI 0.49 to 0.86, I²=0%; (GRADE evidence: moderate)]. There is no evidence supporting the efficacy of non-pharmacological interventions to prevent delirium in low risk populations (i.e. low rate of delirium in the control group)[1 RCT: RR 1.75, 95%CI 0.50 to 6.10 (GRADE evidence: very low)]. For patients who have developed delirium, the available evidence does not support the efficacy of multicomponent non-pharmacological interventions to treat delirium. Among single component interventions only staff education, reorientation protocol (GRADE evidence: very low)] and Geriatric Risk Assessment MedGuide software [hazard ratio 0.42, 95%CI 0.35 to 0.52, (GRADE evidence: moderate)] resulted effective in preventing delirium.

Conclusions

In older patients multi-component non-pharmacological interventions as well as some single-components intervention were effective in preventing delirium but not to treat delirium.     

Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. In the last decades pirfenidone an anti-inflammatory and anti-fibrotic agent has shown benefit in inhibit collagen production and has also demonstrated benefit in decline progression in IPF in physiological outcomes as Forced vital capacity (FVC), in clinical outcomes such as progression free survival (PFS) and a benefit in mortality but no in clinically relevant outcomes as exacerbations or worsening of IPF. Methods: We conducted a systematic review to evaluate the effectiveness of physiological and clinical outcomes of pirfenidone compared to placebo in IPF. We performed a search with no language restriction. Two researchers performed literature search, quality assessment, data extraction and analysis. And was performed a summary of findings table following the GRADE approach. Results: We included 5 RCTs (Randomized controlled trials) in analysis. The meta-analysis resulted in a decrease in all cause-mortality (RR 0.52 IC 0.32–0.88) and IPF related mortality (RR 0.32 IC 0.14–0.75); other outcomes evaluated were worsening of IPF (RR 0.64 IC 0.50–0.83) and acute exacerbation (RR: 0.72 IC 0.30–1.66 respectively). Also there was a decrease in progression free survival (PFS) (RR 0.83 IC 0.74–0.92) compared to placebo. Conclusions: We observed significant differences in physiologic and clinically relevant outcomes such as reduction in all-cause mortality, IPF related mortality, worsening and exacerbation of IPF and PFS. So pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also by its clinically relevant outcomes.     

Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study

Background

The influenza A (H1N1) pandemic swept across the globe from April 2009 to August 2010 affecting millions. Many WHO Member States relied on antiviral drugs, specifically neuraminidase inhibitors (NAIs) oseltamivir and zanamivir, to treat influenza patients in critical condition. Such drugs have been found to be effective in reducing severity and duration of influenza illness, and likely reduced morbidity during the pandemic. However, it is less clear whether NAIs used during the pandemic reduced H1N1 mortality.

Methods

Country-level data on supply of oseltamivir and zanamivir were used to predict H1N1 mortality (per 100,000 people) from July 2009 to August 2010 in forty-two WHO Member States. Poisson regression was used to model the association between NAI supply and H1N1 mortality, with adjustment for economic, demographic, and health-related confounders.

Results

After adjustment for potential confounders, each 10% increase in kilograms of oseltamivir, per 100,000 people, was associated with a 1.6% reduction in H1N1 mortality over the pandemic period (relative rate (RR) = 0.84 per log increase in oseltamivir supply). While the supply of zanamivir was considerably less than that of oseltamivir in each Member State, each 10% increase in kilogram of active zanamivir, per 100,000, was associated with a 0.3% reduction in H1N1 mortality (RR = 0.97 per log increase).

Conclusion

While there are limitations to the ecologic nature of these data, this analysis offers evidence of a protective relationship between antiviral drug supply and influenza mortality and supports a role for influenza antiviral use in future pandemics.     

Impact of Inclusion of Industry Trial Results Registries as an Information Source for Systematic Reviews

Background

Clinical trial results registries may contain relevant unpublished information. Our main aim was to investigate the potential impact of the inclusion of reports from industry results registries on systematic reviews (SRs).

Methods

We identified a sample of 150 eligible SRs in PubMed via backward selection. Eligible SRs investigated randomized controlled trials of drugs and included at least 2 bibliographic databases (original search date: 11/2009). We checked whether results registries of manufacturers and/or industry associations had also been searched. If not, we searched these registries for additional trials not considered in the SRs, as well as for additional data on trials already considered. We reanalysed the primary outcome and harm outcomes reported in the SRs and determined whether results had changed. A “change” was defined as either a new relevant result or a change in the statistical significance of an existing result. We performed a search update in 8/2013 and identified a sample of 20 eligible SRs to determine whether mandatory results registration from 9/2008 onwards in the public trial and results registry ClinicalTrials.gov had led to its inclusion as a standard information source in SRs, and whether the inclusion rate of industry results registries had changed.

Results

133 of the 150 SRs (89%) in the original analysis did not search industry results registries. For 23 (17%) of these SRs we found 25 additional trials and additional data on 31 trials already included in the SRs. This additional information was found for more than twice as many SRs of drugs approved from 2000 as approved beforehand. The inclusion of the additional trials and data yielded changes in existing results or the addition of new results for 6 of the 23 SRs. Of the 20 SRs retrieved in the search update, 8 considered ClinicalTrials.gov or a meta-registry linking to ClinicalTrials.gov, and 1 considered an industry results registry.

Conclusion

The inclusion of industry and public results registries as an information source in SRs is still insufficient and may result in publication and outcome reporting bias. In addition to an essential search in ClinicalTrials.gov, authors of SRs should consider searching industry results registries.     

I223R Mutation in Influenza A(H1N1)pdm09 Neuraminidase Confers Reduced Susceptibility to Oseltamivir and Zanamivir and Enhanced Resistance with H275Y

Background

Resistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility.

Methods

The NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0–15) and zanamivir (days 15–25 and 70–80).

Results

Compared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6–69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin.

Conclusions

Reduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines the importance of close monitoring of treated patients especially those immunocompromised.     

Acupuncture Therapy for Sudden Sensorineural Hearing Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

ObjectiveAcupuncture has commonly been used in China, either alone or in combination with Western medicine, to treat sudden sensorineural hearing loss (SSHL). The purpose of this systematic review is to assess the efficacy and safety of acupuncture therapy for patients with SSHL.MethodsWe searched PubMed, the Cochrane Library, Embase, China National Knowledge Internet (CNKI), Database for Chinese Technical Periodicals (VIP), and Chinese Biomedical literature service system (SinoMed) to collect randomized controlled trials of acupuncture for SSHL published before July 2014. A meta-analysis was conducted according to the Cochrane systematic review method using RevMan 5.2 software. The evidence level for each outcome was assessed using the GRADE methodology.ResultsTwelve trials involving 863 patients were included. A meta-analysis showed that the effect of manual acupuncture combined with Western medicine comprehensive treatment (WMCT) was better than WMCT alone (RR 1.33, 95%CI 1.19–1.49) and the same as the effect of electroacupuncture combined with WMCT (RR 1.33, 95%CI 1.19–1.50). One study showed a better effect of electroacupuncture than of WMCT (RR 1.34, 95%CI 1.24–1.45). For mean changes in hearing over all frequencies, the meta-analysis showed a better effect with the combination of acupuncture and WMCT than with WMCT alone (MD 10.85, 95%CI 6.84–14.86). However, the evidence levels for these interventions were low or very low due to a high risk of bias and small sample sizes in the included studies.ConclusionThere was not sufficient evidence showing that acupuncture therapy alone was beneficial for treating SSHL. However, interventions combining acupuncture with WMCT had more efficacious results in the treatment of SSHL than WMCT alone. Electroacupuncture alone might be a viable alternative treatment besides WMCT for SSHL. However, given that there were fewer eligible RCTs and limitations in the included trials, such as methodological drawbacks and small sample sizes, large-scale RCTs are required to confirm the current findings regarding acupuncture therapy for SSHL.     

Reporting Quality of Systematic Reviews and Meta-Analyses of Otorhinolaryngologic Articles Based on the PRISMA Statement

Background

Systematic reviews (SRs) and meta-analyses (MAs) provide the highest possible level of evidence. However, poor conduct or reporting of SRs and MAs may reduce their utility. The PRISMA Statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) was developed to help authors report their SRs and MAs adequately.

Objectives

Our objectives were to (1) evaluate the quality of reporting of SRs and MAs and their abstracts in otorhinolaryngologic literature using the PRISMA and PRISMA for Abstracts checklists, respectively, (2) compare the quality of reporting of SRs and MAs published in Ear Nose Throat (ENT) journals to the quality of SRs and MAs published in the ‘gold standard’ Cochrane Database of Systematic Reviews (CDSR), and (3) formulate recommendations to improve reporting of SRs and MAs in ENT journals.

Methods

On September 3, 2014, we searched the Pubmed database using a combination of filters to retrieve SRs and MAs on otorhinolaryngologic topics published in 2012 and 2013 in the top 5 ENT journals (ISI Web of Knowledge 2013) or CDSR and relevant articles were selected. We assessed how many, and which, PRISMA (for Abstracts) items were reported adequately per journal type.

Results

We identified large differences in the reporting of individual items between the two journal types with room for improvement. In general, SRs and MAs published in ENT journals (n = 31) reported a median of 54.4% of the PRISMA items adequately, whereas the 49 articles published in the CDSR reported a median of 100.0 adequately (difference statistically significant, p < 0.001). For abstracts, medians of 41.7% for ENT journals and 75.0% for the CDSR were found (p < 0.001).

Conclusion

The reporting of SRs and MAs in ENT journals leaves room for improvement and would benefit if the PRISMA Statement were endorsed by these journals.     

Effects of Vaccination and the New Neuraminidase Inhibitor,Laninamivir, on Influenza Infection

Background

Evidence of the effectiveness of influenza vaccination in children and elderly adults is limited, although this population has the highest risk for influenza infection.

Materials and Methods

We enrolled 4443 participants, aged 3–97 years, who had influenza-kit-positive resultsduring seasons 2007–12, including 2135 with influenza A, 534 with A/H1N1, and 1643 with influenza B. Eligible subjects completed a questionnaire to identify past influenza infection and vaccination history. For the diagnosis of current influenza infection, subjects were examined, and pharyngeal swabs were collected and tested using the Capilia flu rapid diagnosis kit to confirm influenza infection. An interim analysis was performed using clinician-based surveillance data for the entire four seasons of influenza infection in Japan.

Results

In 3035 adultsaged 14–64 years, administration of the influenza vaccine significantly reduced the frequency of infection (P<0.01) in the 2008 and 2010 seasons, but not in the 2009 and 2011 seasons. Moreover, the vaccine did not reduce the frequency of infection in children (aged <13 years) and older adults (aged >65 years) significantly. Laninamivir, oseltamivir phosphate, zanamivir hydrate, and amantadine hydrochloride were administered to 1381, 2432, 1044, and 100 patients, respectively. They were effective in >97% of patients, with no significant differences being found. Adverse effects were few. However, the recurrence rate of influenza infection after treatment was significantly reduced in patients who received laninamivir compared with that in those who received oseltamivir and zanamivir (P<0.01). The effectiveness of laninamivirdid not decrease.

Conclusions

The vaccines administered had limited efficacy in reducing the frequency of influenza infection in young adults. Laninamivir significantly reduced the recurrence of influenza infection when compared with other neuraminidase inhibitors.     

The Effectiveness of Mobile-Health Technologies to Improve Health Care Service Delivery Processes: A Systematic Review and Meta-Analysis

Background

Mobile health interventions could have beneficial effects on health care delivery processes. We aimed to conduct a systematic review of controlled trials of mobile technology interventions to improve health care delivery processes.

Methods and Findings

We searched for all controlled trials of mobile technology based health interventions using MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, Cochrane Library, UK NHS HTA (Jan 1990–Sept 2010). Two authors independently extracted data on allocation concealment, allocation sequence, blinding, completeness of follow-up, and measures of effect. We calculated effect estimates and we used random effects meta-analysis to give pooled estimates.We identified 42 trials. None of the trials had low risk of bias. Seven trials of health care provider support reported 25 outcomes regarding appropriate disease management, of which 11 showed statistically significant benefits. One trial reported a statistically significant improvement in nurse/surgeon communication using mobile phones. Two trials reported statistically significant reductions in correct diagnoses using mobile technology photos compared to gold standard. The pooled effect on appointment attendance using text message (short message service or SMS) reminders versus no reminder was increased, with a relative risk (RR) of 1.06 (95% CI 1.05–1.07, I ² = 6%). The pooled effects on the number of cancelled appointments was not significantly increased RR 1.08 (95% CI 0.89–1.30). There was no difference in attendance using SMS reminders versus other reminders (RR 0.98, 95% CI 0.94–1.02, respectively). To address the limitation of the older search, we also reviewed more recent literature.

Conclusions

The results for health care provider support interventions on diagnosis and management outcomes are generally consistent with modest benefits. Trials using mobile technology-based photos reported reductions in correct diagnoses when compared to the gold standard. SMS appointment reminders have modest benefits and may be appropriate for implementation. High quality trials measuring clinical outcomes are needed. Please see later in the article for the Editors'' Summary     

Communication Tools for End-of-Life Decision-Making in Ambulatory Care Settings: A Systematic Review and Meta-Analysis

BackgroundPatients with serious illness, and their families, state that better communication and decision-making with healthcare providers is a high priority to improve the quality of end-of-life care. Numerous communication tools to assist patients, family members, and clinicians in end-of-life decision-making have been published, but their effectiveness remains unclear.ObjectivesTo determine, amongst adults in ambulatory care settings, the effect of structured communication tools for end-of-life decision-making on completion of advance care planning.MethodsWe searched for relevant randomized controlled trials (RCTs) or non-randomized intervention studies in MEDLINE, EMBASE, CINAHL, ERIC, and the Cochrane Database of Randomized Controlled Trials from database inception until July 2014. Two reviewers independently screened articles for eligibility, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence for each of the primary and secondary outcomes.ResultsSixty-seven studies, including 46 RCTs, were found. The majority evaluated communication tools in older patients (age >50) with no specific medical condition, but many specifically evaluated populations with cancer, lung, heart, neurologic, or renal disease. Most studies compared the use of communication tools against usual care, but several compared the tools to less-intensive advance care planning tools. The use of structured communication tools increased: the frequency of advance care planning discussions/discussions about advance directives (RR 2.31, 95% CI 1.25–4.26, p = 0.007, low quality evidence) and the completion of advance directives (ADs) (RR 1.92, 95% CI 1.43–2.59, p<0.001, low quality evidence); concordance between AD preferences and subsequent medical orders for use or non-use of life supporting treatment (RR 1.19, 95% CI 1.01–1.39, p = 0.028, very low quality evidence, 1 observational study); and concordance between the care desired and care received by patients (RR 1.17, 95% CI 1.05–1.30, p = 0.004, low quality evidence, 2 RCTs).ConclusionsThe use of structured communication tools may increase the frequency of discussions about and completion of advance directives, and concordance between the care desired and the care received by patients. The use of structured communication tools rather than an ad-hoc approach to end-of-life decision-making should be considered, and the selection and implementation of such tools should be tailored to address local needs and context.RegistrationPROSPERO CRD42014012913     

Screening Coverage Needed to Reduce Mortality from Prostate Cancer: A Living Systematic Review

IntroductionScreening for prostate cancer remains controversial because of conflicting results from the two major trials: The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC).ObjectiveMeta-analyze and meta-regress the available PSA screening trials.MethodsWe performed a living systematic review and meta-regression of the reduction in prostate cancer mortality as a function of the duration of screening provided in each trial. We searched PubMed, Web of Science, the Cochrane Registry, and references lists from previous meta-analyses to identify randomized trials of PSA screening. We followed PRISMA guidelines and qualified strength of evidence with a GRADE Profile.ResultsWe found 6 trials, but excluded one that also screened with trans-rectal ultrasound. We considered each ERSPC center as a separate trial. When pooling together all 11 trials we found no significant benefit from screening; however, the heterogeneity was 28.2% (95% CI: 0% to 65%). Heterogeneity was explained by variations in the duration of serial screening (I² 0%; 95% CI: 0% to 52%). When we analyzed the subgroup of trials that added more than 3 years of screening (range 3.2 to 3.8) we found a significant benefit for screening with risk ratio 0.78 (95% CI 0.65–0.94; I² = 0%; 95% CI: 0% to 69%) and a number needed to invite for screening of 1000. We downgraded the quality of evidence to moderate due to our retrospective identification of subgroups and limited data on control group screening.ConclusionsAdequate duration of screening reduces mortality from prostate cancer. The benefit, while small, compares favorably with screening for other cancers. Our projections are limited by the moderate quality of evidence.     

Long-Term Effect of Agricultural Reclamation on Soil Chemical Properties of a Coastal Saline Marsh in Bohai Rim,Northern China

Over the past six decades, coastal wetlands in China have experienced rapid and extensive agricultural reclamation. In the context of saline conditions, long-term effect of cultivation after reclamation on soil chemical properties has not been well understood. We studied this issue using a case of approximately 60-years cultivation of a coastal saline marsh in Bohai Rim, northern China. The results showed that long-term reclamation significantly decreased soil organic carbon (SOC) (−42.2%) and total nitrogen (TN) (−25.8%) at surface layer (0–30 cm) as well as their stratification ratios (SRs) (0–5 cm:50–70 cm and 5–10 cm:50–70 cm). However, there was no significant change in total phosphorus (TP) as well as its SRs under cultivation. Cultivation markedly reduced ratios of SOC to TN, SOC to TP and TN to TP at surface layer (0–30 cm) and their SRs (0–5 cm:50–70 cm). After cultivation, electrical conductivity and salinity significantly decreased by 60.1% and 55.3% at 0–100 cm layer, respectively, suggesting a great desalinization. In contrast, soil pH at 20–70 cm horizons notably increased as an effect of reclamation. Cultivation also changed compositions of cations at 0–10 cm layer and anions at 5–100 cm layer, mainly decreasing the proportion of Na⁺, Cl⁻ and SO₄ ²⁻. Furthermore, cultivation significantly reduced the sodium adsorption ratio and exchangeable sodium percentage in plow-layer (0–20 cm) but not residual sodium carbonate, suggesting a reduction in sodium harm.     

Soil C,N, P and Its Stratification Ratio Affected by Artificial Vegetation in Subsoil,Loess Plateau China

Artificial vegetation restoration can induce variations in accumulation and distribution of soil carbon (C), nitrogen (N) and phosphorus (P). However, little is known about variations in soil C, N and P nutrient fraction stratification following artificial vegetation in Loess Plateau China. Based on the hypothesis that re-vegetated can improve soil quality and stratification ratios (SR) can be used as an indicator to evaluate soil quality. This study measured contents and storages of soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP) and their SRs in topsoil (0–20 cm) and subsoil (20–60 cm) in three 30-year re-vegetated lands that had been converted from arable land (Robinia pseudoacacia L., Caragana Korshinskii Kom. and abandoned cropland with low interferences and few management measures) and one slope cropland (SC) as a control for three soil profiles(0–20 cm, 20–40 cm and 40–60 cm) from June 2009 to June 2013. The results showed that the contents and storages of SOC, TN and TP in re-vegetated land were significantly higher than those in the SC in both topsoil and subsoil. The storages of SOC, TN and TP in the topsoil (0–20 cm) of the re-vegetated lands increased by 16.2%-26.4%, 12.7%-28.4% and 16.5%-20.9%, respectively, and increased by smaller but significant amounts in subsoil from 2009 to 2013. The SRs for SOC, TN and TP in the re-vegetated lands were mostly >2 (either for 0–20:20–40 cm or 0–20:40–60 cm) and greater than that in the SC. The SRs showed an increasing trend with increasing restoration age. The results also showed that the land use type and soil depth were the most influential factors for the SRs and storages, and the SRs of SOC and TN had significantly positive correlations with their storages. The SRs were concluded to be a good indicator for evaluating the soil quality, which can be significantly enhanced through vegetation restoration. Moreover, vegetation restoration can significantly enhance SOC, TN and TP accumulation in both topsoil and subsoil.     

Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation

The neuraminidase inhibitors zanamivir and oseltamivir are marketed for the treatment and prophylaxis of influenza and have been stockpiled by many countries for use in a pandemic. Although recent surveillance has identified a striking increase in the frequency of oseltamivir-resistant seasonal influenza A (H1N1) viruses in Europe, the United States, Oceania, and South Africa, to date there have been no reports of significant zanamivir resistance among influenza A (H1N1) viruses or any other human influenza viruses. We investigated the frequency of oseltamivir and zanamivir resistance in circulating seasonal influenza A (H1N1) viruses in Australasia and Southeast Asia. Analysis of 391 influenza A (H1N1) viruses isolated between 2006 and early 2008 from Australasia and Southeast Asia revealed nine viruses (2.3%) that demonstrated markedly reduced zanamivir susceptibility and contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible influenza A (H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wild-type virus in MDCK cells but equivalent infectivity and transmissibility in a ferret model.Two classes of antiviral drugs are currently available for the treatment and prophylaxis of influenza, the adamantanes and the neuraminidase (NA) inhibitors (NAIs). The adamantanes were the first agents to be recognized to have anti-influenza virus activities as early as 1964 (2) although the rapid emergence of drug-resistant influenza virus strains has limited their clinical effectiveness (12). The NAIs, zanamivir (Relenza) and oseltamivir (Tamiflu), were the first drugs to be specifically designed as anti-influenza virus agents and have been available on the market in many countries since 1999. During oseltamivir clinical trials, 1 to 4% of treated adults (6) and 5 to 6% of treated children were found to shed resistant viruses (30) although more recent studies have reported resistance in 16 to 18% of viruses from oseltamivir-treated children (20, 29). In contrast to the frequency of resistance seen following oseltamivir treatment, only one occurrence of significant zanamivir resistance has been observed following zanamivir treatment. The zanamivir-resistant strain, an influenza B virus with an R152K NA mutation, was isolated from an immunocompromised patient undergoing prolonged zanamivir treatment (7).In addition to the analysis of influenza viruses isolated from patients undergoing either oseltamivir or zanamivir treatment, surveillance studies that analyze the NAI susceptibility of circulating viruses, predominantly from patients not undergoing NAI treatment, have also been conducted. Studies that have tested viruses isolated prior to the release of the NAIs (1996 to 1999) (23) and after the initiation of clinical use of these drugs (2000 to 2006) (16, 24) have found either no resistance or a very low frequency of resistance. In contrast, analysis of circulating seasonal influenza viruses from Europe during the 2007 to 2008 season revealed that 14% (59/437) of influenza A (H1N1) viruses had significantly decreased susceptibility to oseltamivir (21). Since this initial report, oseltamivir-resistant influenza A (H1N1) strains have spread throughout Europe (11) and have been detected at high frequencies in other countries including the United States (4), Japan (28), South Africa (1) and Oceania and Southeast Asia (17). These influenza A (H1N1) viruses have a mutation of histidine to tyrosine at residue 274 of the NA (N2 NA numbering; residue 275 by N1 NA numbering), which confers a high level of resistance to oseltamivir (10) but has no effect on susceptibility to zanamivir or to the adamantanes.Prior to May 2008, when the oseltamivir-resistant variants became the dominant influenza A (H1N1) strain in Oceania and Southeast Asia (17), NAI sensitivity monitoring conducted at the WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, identified a number of influenza A (H1N1) viruses with reduced zanamivir susceptibility. These viruses contained a previously undescribed mutation at residue 136 of the NA. Here, we report on the detection of these mutant viruses from geographically distinct locations, the in vitro and in vivo fitness of the strains, and the finding that the mutant viruses appear to have been preferentially propagated during viral culture in Madin-Darby canine kidney (MDCK) cells.