Association of Real-time Continuous Glucose Monitoring With Glycemic Control and Acute Metabolic Events Among Patients With Insulin-Treated Diabetes.

Importance: Continuous glucose monitoring (CGM) is recommended for patients with type 1 diabetes; observational evidence for CGM in patients with insulin-treated type 2 diabetes is lacking. Objective: To estimate clinical outcomes of real-time CGM initiation. Design, Setting, and Participants: Exploratory retrospective cohort study of changes in outcomes associated with real-time CGM initiation, estimated using a difference-in-differences analysis. A total of 41 753 participants with insulin-treated diabetes (5673 type 1; 36 080 type 2) receiving care from a Northern California integrated health care delivery system (2014-2019), being treated with insulin, self-monitoring their blood glucose levels, and having no prior CGM use were included. Exposures: Initiation vs noninitiation of real-time CGM (reference group). Main Outcomes and Measures: Ten end points measured during the 12 months before and 12 months after baseline: hemoglobin A1c (HbA1c); hypoglycemia (emergency department or hospital utilization); hyperglycemia (emergency department or hospital utilization); HbA1c levels lower than 7%, lower than 8%, and higher than 9%; 1 emergency department encounter or more for any reason; 1 hospitalization or more for any reason; and number of outpatient visits and telephone visits. Results: The real-time CGM initiators included 3806 patients (mean age, 42.4 years [SD, 19.9 years]; 51% female; 91% type 1, 9% type 2); the noninitiators included 37 947 patients (mean age, 63.4 years [SD, 13.4 years]; 49% female; 6% type 1, 94% type 2). The prebaseline mean HbA1c was lower among real-time CGM initiators than among noninitiators, but real-time CGM initiators had higher prebaseline rates of hypoglycemia and hyperglycemia. Mean HbA1c declined among real-time CGM initiators from 8.17% to 7.76% and from 8.28% to 8.19% among noninitiators (adjusted difference-in-differences estimate, -0.40%; 95% CI, -0.48% to -0.32%; P < .001). Hypoglycemia rates declined among real-time CGM initiators from 5.1% to 3.0% and increased among noninitiators from 1.9% to 2.3% (difference-in-differences estimate, -2.7%; 95% CI, -4.4% to -1.1%; P = .001). There were also statistically significant differences in the adjusted net changes in the proportion of patients with HbA1c lower than 7% (adjusted difference-in-differences estimate, 9.6%; 95% CI, 7.1% to 12.2%; P < .001), lower than 8% (adjusted difference-in-differences estimate, 13.1%; 95% CI, 10.2% to 16.1%; P < .001), and higher than 9% (adjusted difference-in-differences estimate, -7.1%; 95% CI, -9.5% to -4.6%; P < .001) and in the number of outpatient visits (adjusted difference-in-differences estimate, -0.4; 95% CI, -0.6 to -0.2; P < .001) and telephone visits (adjusted difference-in-differences estimate, 1.1; 95% CI, 0.8 to 1.4; P < .001). Initiation of real-time CGM was not associated with statistically significant changes in rates of hyperglycemia, emergency department visits for any reason, or hospitalizations for any reason. Conclusions and Relevance: In this retrospective cohort study, insulin-treated patients with diabetes selected by physicians for real-time continuous glucose monitoring compared with noninitiators had significant improvements in hemoglobin A1c and reductions in emergency department visits and hospitalizations for hypoglycemia, but no significant change in emergency department visits or hospitalizations for hyperglycemia or for any reason. Because of the observational study design, findings may have been susceptible to selection bias.

On the importance of intraindividual variation in nutritional research.

Nutritional intervention studies, like those with pre- and probiotics, are often hampered by low effect sizes, reducing the power to demonstrate potential efficacy. Here, we perform computer simulations of a hypothetical clinical trial using such an intervention in order to elucidate determining factors that can be influenced in order to optimise the statistical power. Our simulations demonstrate that steering the study population towards a low intraindividual variation dramatically improves statistical power. A more than 10-fold decrease of number-to-treat could be reached. Also, a careful balancing between the number of subjects and measurements per subject, in combination with possible stratification of the subjects into responders and non-responders, based on inherent intraindividual variation, improves the likelihood to reach statistically significant results. Our results also show that traditional dogmas, with respect to clinical trials, i.e. aiming at low interindividual variation and a high number (n) of study participants, should be re-evaluated in favour of reducing intraindividual variation. This reduction in intraindividual variation could be achieved by maintaining a steady lifestyle, including dietary habits among others, within the timeframe of the intervention study.

Second-generation antidepressants for preventing seasonal affective disorder in adults.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This review - one of four reviews on efficacy and safety of interventions to prevent SAD - focuses on second-generation antidepressants (SGAs). OBJECTIVES: To assess the efficacy and safety of SGAs (in comparison with other SGAs, placebo, light therapy, melatonin or agomelatine, psychological therapies or lifestyle interventions) in preventing SAD and improving patient-centred outcomes among adults with a history of SAD. SEARCH METHODS: We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 August 2015). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to 19 June 2018). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. SELECTION CRITERIA: For efficacy, we included randomised controlled trials (RCTs) on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we planned to include non-randomised studies. Eligible studies compared a SGA versus another SGA, placebo, light therapy, psychological therapy, melatonin, agomelatine or lifestyle changes. We also intended to compare SGAs in combination with any of the comparator interventions versus placebo or the same comparator intervention as monotherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications, extracted data and assessed risk of bias of included studies. When data were sufficient, we conducted random-effects (Mantel-Haenszel) meta-analyses. We assessed statistical heterogeneity by calculating the Chi2 statistic and the Cochran Q. We used the I2 statistic to estimate the magnitude of heterogeneity. We assessed publication bias by using funnel plots.We rated the strength of the evidence using the system developed by the GRADE Working Group. MAIN RESULTS: We identified 3745 citations after de-duplication of search results and excluded 3619 records during title and abstract reviews. We assessed 126 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates.Overall, moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in people with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; 3 RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 50% and 60%, NNTBs are 5 (95% CI 4 to 7) and 4 (95% CI 3 to 6), respectively.We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest, such as light therapy, psychological therapies, melatonin or agomelatine. AUTHORS' CONCLUSIONS: Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, three out of four people will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment, and might want to consider offering other potentially efficacious interventions, which might confer a lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences.Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.

Years of Life Lost for Older Patients After Colorectal Cancer Diagnosis.

BACKGROUND: An aging population combined with an increased colorectal cancer (CRC) incidence in the older population will increase its prevalence in the elderly, questioning how many years of life are lost (YLLs) in these patients. PATIENTS AND METHODS: Data from 32,568 Dutch CRC patients ≥ 80 years were used to estimate the number of YLLs after diagnosis, using a reference age-, sex- and year-of-onset-matched cohort derived from national life tables. YLLs were additionally adjusted by comorbidities. Number needed to treat (NNT) was used as measure of surgical effect size. RESULTS: Surgery was applied in 74.9% of patients leading to 1.3 YLLs, being superior in 86.1% of cases with respect to alternative therapies (YLLs 4.8 years) and resulting in a number of two patients needed to operate to achieve one positive outcome. YLLs and NNTs depended on CRC stage, patient' age and comorbidities. For Stage I-II patients in the best clinical conditions (80-85 years without comorbidities), YLLs increased up to 4.1 years after surgery and up to 8.8 years without surgery (NNT 3). For Stage III patients, the NNT of surgery varied between 2 when they were in the best clinical conditions and 4 when they were older with high comorbidities. In Stage IV patients, the NNT ranged between 6 and 31. CONCLUSIONS: YLLs represents a novel approach to evaluate CRC prognosis. Stage I-III surgical patients can have a life expectancy similar to that of general population, being the NNT of surgery reasonably small compared with alternatives. Personalized comorbidity data are needed to confirm present findings.

Cannabis-based medicines for chronic neuropathic pain in adults.

BACKGROUND: This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain. OBJECTIVES: To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults. SEARCH METHODS: In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). AUTHORS' CONCLUSIONS: The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.

Number needed to treat in indirect treatment comparison.

AIM: For dichotomous outcomes, odds ratio (OR) is one of the usual summary measures of indirect treatment comparison. A corresponding number needed to treat (NNT) estimate may facilitate understanding of the treatment effect. METHODS: We show how to estimate NNT based on OR results of a matching adjusted indirect comparison. We also have derived the explicit formula of its 95% CIs by applying the delta method, and as an alternative, a simulation-based method. RESULTS: The method was applied in a case study example in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients, comparing lenvatinib to sorafenib. For every two RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have progressed and for every eight RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have died. CONCLUSION: Using NNT to summarize the results of a matching adjusted indirect comparison can help the clinicians to better understand the results in addition to OR.

Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy.

Importance: Treatment of jaundiced newborns with subthreshold phototherapy (phototherapy given to newborns with bilirubin levels below those recommended in American Academy of Pediatrics [AAP] guidelines) is common. However, the use of subthreshold phototherapy may have risks and increase costs, and, to date, it has not been systematically studied in newborns. Objectives: To estimate the efficacy of subthreshold phototherapy for newborns with total serum bilirubin (TSB) levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold during the birth hospitalization in preventing readmissions for phototherapy, and to identify predictors of readmission for phototherapy. Design, Setting, and Participants: Retrospective cohort study of 25 895 newborns born at 35 or more weeks' gestation, born in 1 of 16 Kaiser Permanente Northern California hospitals from January 1, 2010, through December 31, 2014, with at least 1 TSB level from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold and not exceeding the threshold during the birth hospitalization. Data were analyzed from November 1, 2015, to November 28, 2017. Exposure: Subthreshold phototherapy during the birth hospitalization. Main Outcomes and Measures: Readmission for phototherapy. Results: Among 25 895 newborns with qualifying TSB levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold, 4956 (19.1%) received subthreshold phototherapy and 241 of these (4.9%) were readmitted for phototherapy compared with 2690 of 20 939 untreated newborns (12.8%) (unadjusted odds ratio [OR], 0.35; 95% CI, 0.30-0.40). In a logistic regression model, adjustment for confounding variables, including gestational age, race/ethnicity, formula feedings per day, and the difference between the TSB level and the phototherapy threshold, strengthened the association (OR, 0.28; 95% CI, 0.19-0.40). Estimated numbers needed to treat ranged from 60.8 in the lowest quintile of predicted risk to 6.3 in the highest quintile. Newborns who received formula feedings had lower adjusted odds of readmission for phototherapy compared with exclusively breastfed newborns (OR, 0.58; 95% CI, 0.47-0.72 for >0 to <2 formula feedings per day; OR, 0.24; 95% CI, 0.21-0.27 for ≥6 formula feedings per day). Subthreshold phototherapy was associated with a 22-hour longer length of stay (95% CI, 16-28 hours). Conclusions and Relevance: Subthreshold phototherapy during the birth hospitalization is effective in preventing readmissions for phototherapy; however, for each readmission prevented, many newborns require phototherapy who would otherwise not need it.

Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews.

BACKGROUND: Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic, typically osteoarthritis of hand or knee, or neuropathic pain. OBJECTIVES: To provide an overview of the analgesic efficacy and associated adverse events of topical analgesics (primarily nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate rubefacients, capsaicin, and lidocaine) applied to intact skin for the treatment of acute and chronic pain in adults. METHODS: We identified systematic reviews in acute and chronic pain published to February 2017 in the Cochrane Database of Systematic Reviews (the Cochrane Library). The primary outcome was at least 50% pain relief (participant-reported) at an appropriate duration. We extracted the number needed to treat for one additional beneficial outcome (NNT) for efficacy outcomes for each topical analgesic or formulation, and the number needed to treat for one additional harmful outcome (NNH) for adverse events. We also extracted information on withdrawals due to lack of efficacy or adverse events, systemic and local adverse events, and serious adverse events. We required information from at least 200 participants, in at least two studies. We judged that there was potential for publication bias if the addition of four studies of typical size (400 participants) with zero effect increased NNT compared with placebo to 10 (minimal clinical utility). We extracted GRADE assessment in the original papers, and made our own GRADE assessment. MAIN RESULTS: Thirteen Cochrane Reviews (206 studies with around 30,700 participants) assessed the efficacy and harms from a range of topical analgesics applied to intact skin in a number of acute and chronic painful conditions. Reviews were overseen by several Review Groups, and concentrated on evidence comparing topical analgesic with topical placebo; comparisons of topical and oral analgesics were rare.For at least 50% pain relief, we considered evidence was moderate or high quality for several therapies, based on the underlying quality of studies and susceptibility to publication bias.In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high-concentration capsaicin had moderate-quality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).We judged evidence of efficacy for other therapies as low or very low quality. Limited evidence of efficacy, potentially subject to publication bias, existed for topical preparations of ibuprofen gels and creams, unspecified diclofenac formulations and diclofenac gel other than Emulgel, indomethacin, and ketoprofen plaster in acute pain conditions, and for salicylate rubefacients for chronic pain conditions. Evidence for other interventions (other topical NSAIDs, topical salicylate in acute pain conditions, low concentration capsaicin, lidocaine, clonidine for neuropathic pain, and herbal remedies for any condition) was very low quality and typically limited to single studies or comparisons with sparse data.We assessed the evidence on withdrawals as moderate or very low quality, because of small numbers of events. In chronic pain conditions lack of efficacy withdrawals were lower with topical diclofenac (6%) than placebo (9%) (11 studies, 3455 participants, number needed to treat to prevent (NNTp) 26, moderate-quality evidence), and topical salicylate (2% vs 7% for placebo) (5 studies, 501 participants, NNTp 21, very low-quality evidence). Adverse event withdrawals were higher with topical capsaicin low-concentration (15%) than placebo (3%) (4 studies, 477 participants, NNH 8, very low-quality evidence), topical salicylate (5% vs 1% for placebo) (7 studies, 735 participants, NNH 26, very low-quality evidence), and topical diclofenac (5% vs 4% for placebo) (12 studies, 3552 participants, NNH 51, very low-quality evidence).In acute pain, systemic or local adverse event rates with topical NSAIDs (4.3%) were no greater than with topical placebo (4.6%) (42 studies, 6740 participants, high quality evidence). In chronic pain local adverse events with topical capsaicin low concentration (63%) were higher than topical placebo (5 studies, 557 participants, number needed to treat for harm (NNH) 2.6), high quality evidence. Moderate-quality evidence indicated more local adverse events than placebo in chronic pain conditions with topical diclofenac (NNH 16) and local pain with topical capsaicin high-concentration (NNH 16). There was moderate-quality evidence of no additional local adverse events with topical ketoprofen over topical placebo in chronic pain. Serious adverse events were rare (very low-quality evidence).GRADE assessments of moderate or low quality in some of the reviews were considered by us to be very low because of small numbers of participants and events. AUTHORS' CONCLUSIONS: There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions. In chronic musculoskeletal conditions with assessments over 6 to 12 weeks, topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis, as did topical high-concentration capsaicin in postherpetic neuralgia. Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.Use of GRADE in Cochrane Reviews with small numbers of participants and events requires attention.

Arginine supplementation for prevention of necrotising enterocolitis in preterm infants.

BACKGROUND: Decreased concentration of nitric oxide has been proposed as one of the possible cellular mechanisms of necrotising enterocolitis (NEC). Arginine can act as a substrate for production of nitric oxide in the tissues, and arginine supplementation may help to prevent NEC. OBJECTIVES: To examine the effect of arginine supplementation (administered by any route) on the incidence of NEC in preterm neonates. To conduct subgroup analyses based on the dose of arginine and the gestational age of participants (≤ 32 weeks, > 32 weeks). SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4), MEDLINE via PubMed (from 1966 to 12 May 2016), Embase (from 1980 to 12 May 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982 to 12 May 2016). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of arginine supplementation (administered orally or parenterally for at least seven days, in addition to what an infant may be receiving from an enteral or parenteral source) compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials by using information obtained from study reports and through personal communication with study authors. We extracted data on relevant outcomes and estimated and reported the effect size as risk ratio (RR), risk difference (RD) and mean difference (MD), as appropriate. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: We identified three eligible studies that included a total of 285 neonates (140 received arginine) from three countries. We assessed the overall methodological quality of the included studies as good. We noted a statistically significant reduction in risk of development of NEC (any stage) among preterm neonates in the arginine group compared with the placebo group (RR 0.38, 95% confidence interval (CI) 0.23 to 0.64; I2 = 27%) (RD -0.19, 95% CI -0.28 to -0.10; I2 = 0%) and rated the quality of evidence as moderate. The number needed to treat for an additional beneficial outcome (NNTB) as required to prevent the development of NEC (any stage) was 6 (95% CI 4 to 10). Study results showed a statistically significant reduction in risk of development of NEC stage 1 (RR 0.37, 95% CI 0.15 to 0.90; I2 = 52%) (RD -0.07, 95% CI -0.14 to -0.01; I2 = 0%) and NEC stage 3 (RR 0.13, 95% CI 0.02 to 1.03; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 89%) in the arginine group compared with the control group; the quality of evidence was moderate.Arginine supplementation was associated with a significant reduction in death related to NEC (RR 0.18, 95% CI 0.03 to 1.00; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 87%). Results showed clinical heterogeneity in mortality rates. Mortality due to any cause was not significantly different between arginine and control or no treatment groups (RR 0.77, 95% CI 0.41 to 1.45; I2 = 42%) (RD -0.03, 95% CI -0.10 to 0.04; I2 = 79%). Investigators noted no significant side effects directly attributable to arginine, including hypotension or alterations in glucose homeostasis. Follow-up data from one trial revealed no statistically significant differences in adverse outcomes (cerebral palsy, cognitive delay, bilateral blindness or hearing loss requiring hearing aids) at 36 months. Limitations of the present findings include a relatively small overall sample size. AUTHORS' CONCLUSIONS: Administration of arginine to preterm infants may prevent development of NEC. Because information was provided by three small trials that included 285 participants, the data are insufficient at present to support a practice recommendation. A multi-centre randomised controlled study that is focused on the incidence of NEC, particularly at more severe stages (2 and 3), is needed.

Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma.

BACKGROUND: Asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) as first-line therapy for adults and adolescents with persistent asthma. The addition of anti-leukotriene agents to ICS offers a therapeutic option in cases of suboptimal control with daily ICS. OBJECTIVES: To assess the efficacy and safety of anti-leukotriene agents added to ICS compared with the same dose, an increased dose or a tapering dose of ICS (in both arms) for adults and adolescents 12 years of age and older with persistent asthma. Also, to determine whether any characteristics of participants or treatments might affect the magnitude of response. SEARCH METHODS: We identified relevant studies from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the trial registries clinicaltrials.gov and ICTRP from inception to August 2016. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of adults and adolescents 12 years of age and older on a maintenance dose of ICS for whom investigators added anti-leukotrienes to the ICS and compared treatment with the same dose, an increased dose or a tapering dose of ICS for at least four weeks. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was the number of participants with exacerbations requiring oral corticosteroids (except when both groups tapered the dose of ICS, in which case the primary outcome was the % reduction in ICS dose from baseline with maintained asthma control). Secondary outcomes included markers of exacerbation, lung function, asthma control, quality of life, withdrawals and adverse events. MAIN RESULTS: We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years. Anti-leukotrienes and ICS versus same dose of ICSOf 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in ß2-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICSOf 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue ß2-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICSSeven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures. AUTHORS' CONCLUSIONS: For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.

Use of probiotics as an adjuvant to sequential H. pylori eradication therapy: impact on eradication rates, treatment resistance, treatment-related side effects, and patient compliance.

BACKGROUND/AIMS: To evaluate the effect of probiotics administered as an adjuvant to sequential Helicobacter pylori (H. pylori) eradication therapy on treatment outcome and patient compliance. MATERIALS AND METHODS: In total, 159 patients with H. pylori infection receiving sequential H. pylori eradication therapy were included in this randomized placebo-controlled study. Starting from day 0 of sequential eradication therapy (ERA), patients in the ERA+probiotic group [n=53, mean (SD) age: 47.7 (14.0) years, 54.7% were females] also received a probiotic supplement with Bifidobacterium animalis subsp. lactis B94 (1 capsule/day), patients in the ERA+placebo group [n=52, mean (SD) age: 46.4 (13.4) years, 51.9% were males] received placebo treatment (1 capsule/day), and patients in the ERA-only group [n=54, mean (SD) age: 46.3 (11.9) years, 55.6% were females] received no additional treatments. Eradication rates, patient compliance, and side effects of eradication therapy were recorded in each treatment group. RESULTS: Significantly higher eradication rates were noted in the ERA+probiotic group (86.8% vs. 70.8%, p=0.025) than in the combined ERA (ERA-only and ERA-placebo) group. Non-compliance with anti-H. pylori treatment was noted in 24 (15.1%) of 159 patients. Lower rates of first week treatment non-compliance due to diarrhea (1.88% vs. 12.26%, p=0.036) were noted in the ERA+probiotic group than in the combined ERA (ERA-only and ERA-placebo) group. Treatment resistance (p: 0.389) was similar between the groups, indicating pure antibiotic resistance without any compliance problems. The number needed to treat for an additional beneficial outcome (NNTB) was 6.2 (CI 95%, 3.5 to 28.9) for probiotic use. CONCLUSION: In conclusion, adjuvant administration of probiotic (B. animalis subsp. lactis) in 2-week sequential H. pylori eradication therapy is associated with a higher H. pylori eradication rate, lower first week diarrhea-related treatment discontinuation rates, less common self-reported side effects, and higher treatment compliance.

CHEMOPROPHYLAXIS TO CONTROL LEPROSY AND THE PERSPECTIVE OF ITS IMPLEMENTATION IN BRAZIL: A PRIMER FOR NON-EPIDEMIOLOGISTS / Quimioprofilaxia para prevenção de hanseníase e sua implantação no Brasil: uma explicação introdutória para não epidemiologistas

The occurrence of leprosy has decreased in the world but the perspective of its elimination has been questioned. A proposed control measure is the use of post-exposure chemoprophylaxis (PEP) among contacts, but there are still questions about its operational aspects. In this text we discuss the evidence available in literature, explain some concepts in epidemiology commonly used in the research on this topic, analyze the appropriateness of implementing PEP in the context of Brazil, and answer a set of key questions. We argue some points: (1) the number of contacts that need to receive PEP in order to prevent one additional case of disease is not easy to be generalized from the studies; (2) areas covered by the family health program are the priority settings where PEP could be implemented; (3) there is no need for a second dose; (4) risk for drug resistance seems to be very small; (5) the usefulness of a serological test to identify a higher risk group of individuals among contacts is questionable. Given that, we recommend that, if it is decided to start PEP in Brazil, it should start on a small scale and, as new evidence can be generated in terms of feasibility, sustainability and impact, it could move up a scale, or not, for a wider intervention.

A ocorrência de hanseníase tem diminuído no mundo apesar de que a perspectiva de sua eliminação tem sido questionada. Uma proposta para o controle da endemia é a quimioprofilaxia pós-exposição entre contatos (post-exposure chemoprophylaxis, PEP), embora ainda existam dúvidas quanto aos seus aspectos operacionais e generalização de resultados. Nesse texto nós discutimos as evidências disponíveis na literatura, explicamos alguns conceitos epidemiológicos comumente encontrados em pesquisa sobre PEP e a implantação da PEP no contexto brasileiro. Nós argumentamos que: (1) a estimativa em diferentes estudos do numero de contatos necessário para receber PEP para prevenir um novo caso de hanseníase (number needed to treat, NNT) não é facilmente generalizável; (2) áreas cobertas pelo programa de saúde da família são as áreas prioritárias onde PEP poderia ser implantado; (3) não existe necessidade de segunda dose da quimioprofilaxia; (4) o risco de resistência à droga usada na PEP parece ser muito pequeno; (5) questionamos a necessidade de teste sorológico para identificar indivíduos entre os contatos que tenham maior risco de doença. Nós opinamos que, se houver uma decisão para se iniciar PEP no Brasil, essa intervenção deveria ser iniciada em pequena escala e, à proporção que novas evidências são geradas sobre a factibilidade, sustentabilidade e impacto da intervenção, a intervenção com PEP poderia ou não ser usada em larga escala.

Non-prescription (OTC) oral analgesics for acute pain - an overview of Cochrane reviews.

BACKGROUND: Non-prescription (over-the-counter, or OTC) analgesics (painkillers) are used frequently. They are available in various brands, package sizes, formulations, and dose. They can be used for a range of different types of pain, but this overview reports on how well they work for acute pain (pain of short duration, usually with rapid onset). Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. OBJECTIVES: To examine published Cochrane reviews for information about the efficacy of pain medicines available without prescription using data from acute postoperative pain. METHODS: We identified OTC analgesics available in the UK, Australia, Canada, and the USA by examining online pharmacy websites. We also included some analgesics (diclofenac potassium, dexketoprofen, dipyrone) of importance in parts of the world, but not currently available in these jurisdictions.We identified systematic reviews by searching the Cochrane Database of Systematic Reviews (CDSR) on The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. From individual reviews we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also calculated the success rate to achieve at least 50% of maximum pain relief. We also examined the number of participants experiencing any adverse event, and whether the incidence was different from placebo. MAIN RESULTS: We found information on 21 different OTC analgesic drugs, doses, and formulations, using information from 10 Cochrane reviews, supplemented by information from one non-Cochrane review with additional information on ibuprofen formulations (high quality evidence). The lowest (best) NNT values were for combinations of ibuprofen plus paracetamol, with NNT values below 2. Analgesics with values close to 2 included fast acting formulations of ibuprofen 200 mg and 400 mg, ibuprofen 200 mg plus caffeine 100 mg, and diclofenac potassium 50 mg. Combinations of ibuprofen plus paracetamol had success rates of almost 70%, with dipyrone 500 mg, fast acting ibuprofen formulations 200 mg and 400 mg, ibuprofen 200 mg plus caffeine 100 mg, and diclofenac potassium 50 mg having success rates above 50%. Paracetamol and aspirin at various doses had NNT values of 3 or above, and success rates of 11% to 43%. We found no information on many of the commonly available low dose codeine combinations.The proportion of participants experiencing an adverse event were generally not different from placebo, except for aspirin 1000 mg and (barely) ibuprofen 200 mg plus caffeine 100 mg. For ibuprofen plus paracetamol, adverse event rates were lower than with placebo. AUTHORS' CONCLUSIONS: There is a body of reliable evidence about the efficacy of some of the most commonly available drugs and doses widely available without prescription. The postoperative pain model is predominantly pain after third molar extraction, which is used as the industry model for everyday pain. The proportion of people with acute pain who get good pain relief with any of them ranges from around 70% at best to less than 20% at worst; low doses of some drugs in fast acting formulations were among the best. Adverse events were generally no different from placebo. Consumers can make an informed choice based on this knowledge, together with availability and price. Headache and migraine were not included in this overview.

Rivaroxaban: An Evaluation of its Cardiovascular Benefit-Risk Profile Across Indications Based on Numbers Needed to Treat or Harm, and on Clinically Meaningful Endpoint Comparisons.

The decision to prescribe anticoagulant therapy must consider the balance between reducing the risk of thromboembolic events and increasing the risk of bleeding. Although assessments of net clinical outcomes with oral anticoagulants are not new, this article presents an evaluation of benefit-risk by considering only events of substantial and comparable clinical relevance (i.e., events with serious long-term sequelae likely to have irreversible consequences, including death). This is based on the concept of the number of patients who need to be treated to elicit one beneficial [number needed to treat (NNT)] or harmful [number needed to harm (NNH)] event. The approach is illustrated using data from phase III trials of rivaroxaban, selected because it has the broadest range of approved indications of the novel oral anticoagulants. For example, in the ATLAS ACS 2 TIMI 51 trial of rivaroxaban plus standard antiplatelet therapy following an acute coronary syndrome event, the current analysis demonstrates that 63 patients need to be treated (over 24 months) to prevent one all-cause mortality event compared with placebo (NNT = 63). Conversely, 500 patients need to be treated to cause one additional intracranial hemorrhage (NNH = 500). The most relevant and clinically meaningful assessment of benefit-risk may therefore be achieved by focusing only on events of greatest concern to patients and physicians, namely those with (potentially) long-lasting, severe consequences. Although there are clear limitations to this type of analysis, rivaroxaban appears to demonstrate a broadly favorable benefit-risk profile across multiple clinical indications.

Delayed repeat enemas are safe and cost-effective in the management of pediatric intussusception.

BACKGROUND/PURPOSE: The purpose of the study is to compare outcomes between delayed repeat enema (DRE) and immediate surgery (IS) in children with ileocolic intussusception who fail initial enema reduction. METHODS: Retrospective cohort study of children <6 years-of-age from 2008 to 2012 in the Pediatric Health Information System (PHIS) database. Outcomes measured were bowel resection, length of stay (LOS), and adjusted hospital costs (AHC). RESULTS: 4980 of 6889 (72.3%) children with intussusception were discharged without operation following a single successful enema. 1407 of 1909 (73.7%) remaining patients underwent IS while 502 (26.3%) had a DRE. Bowel resection was required in 372 of 1407 (26.4%) patients in IS group compared to 59 of 502 (11.8%) in the DRE group (p<0.001). The number of patients needed to treat by DRE to prevent a bowel resection was 7. In multivariable analysis, the IS patients had a 2.5 times greater likelihood of undergoing bowel resection than the DRE patients (adjusted odds ratio [OR] 2.50, 95% confidence interval [CI] 1.83-3.41, p<0.001). The DRE group had a mean LOS of 3.2 days (95% CI 2.9-3.6) and mean AHC of $9205 (95% CI $7673-$10,735). The IS group had a longer LOS (4.4days, 95% CI 4.0-4.8, p≤0.001) and higher AHC ($14,422, 95% CI $12,631-$16,214, p<0.001). CONCLUSION: Delayed repeat enemas for ileocolic intussusception increase the success of nonoperative reduction, decrease the rate of bowel resection and reduce mean hospital length of stay and costs.

CHEMOPROPHYLAXIS TO CONTROL LEPROSY AND THE PERSPECTIVE OF ITS IMPLEMENTATION IN BRAZIL: A PRIMER FOR NON-EPIDEMIOLOGISTS.

The occurrence of leprosy has decreased in the world but the perspective of its elimination has been questioned. A proposed control measure is the use of post-exposure chemoprophylaxis (PEP) among contacts, but there are still questions about its operational aspects. In this text we discuss the evidence available in literature, explain some concepts in epidemiology commonly used in the research on this topic, analyze the appropriateness of implementing PEP in the context of Brazil, and answer a set of key questions. We argue some points: (1) the number of contacts that need to receive PEP in order to prevent one additional case of disease is not easy to be generalized from the studies; (2) areas covered by the family health program are the priority settings where PEP could be implemented; (3) there is no need for a second dose; (4) risk for drug resistance seems to be very small; (5) the usefulness of a serological test to identify a higher risk group of individuals among contacts is questionable. Given that, we recommend that, if it is decided to start PEP in Brazil, it should start on a small scale and, as new evidence can be generated in terms of feasibility, sustainability and impact, it could move up a scale, or not, for a wider intervention.

Glutamine supplementation for critically ill adults.

BACKGROUND: Glutamine is a non-essential amino acid which is abundant in the healthy human body. There are studies reporting that plasma glutamine levels are reduced in patients with critical illness or following major surgery, suggesting that glutamine may be a conditionally essential amino acid in situations of extreme stress. In the past decade, several clinical trials examining the effects of glutamine supplementation in patients with critical illness or receiving surgery have been done, and the systematic review of this clinical evidence has suggested that glutamine supplementation may reduce infection and mortality rates in patients with critical illness. However, two recent large-scale randomized clinical trials did not find any beneficial effects of glutamine supplementation in patients with critical illness. OBJECTIVES: The objective of this review was to:1. assess the effects of glutamine supplementation in critically ill adults and in adults after major surgery on infection rate, mortality and other clinically relevant outcomes;2. investigate potential heterogeneity across different patient groups and different routes for providing nutrition. SEARCH METHODS: We searched the Cochrane Anaesthesia Review Group (CARG) Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1950 to May 2013); EMBASE (1980 to May 2013) and Web of Science (1945 to May 2013). SELECTION CRITERIA: We included controlled clinical trials with random or quasi-random allocation that examined glutamine supplementation versus no supplementation or placebo in adults with a critical illness or undergoing elective major surgery. We excluded cross-over trials. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the relevant information from each included study using a standardized data extraction form. For infectious complications and mortality and morbidity outcomes we used risk ratio (RR) as the summary measure with the 95% confidence interval (CI). We calculated, where appropriate, the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH). We presented continuous data as the difference between means (MD) with the 95% CI. MAIN RESULTS: Our search identified 1999 titles, of which 53 trials (57 articles) fulfilled our inclusion criteria. The 53 included studies enrolled a total of 4671 participants with critical illness or undergoing elective major surgery. We analysed seven domains of potential risk of bias. In 10 studies the risk of bias was evaluated as low in all of the domains. Thirty-three trials (2303 patients) provided data on nosocomial infectious complications; pooling of these data suggested that glutamine supplementation reduced the infectious complications rate in adults with critical illness or undergoing elective major surgery (RR 0.79, 95% CI 0.71 to 0.87, P ＜ 0.00001, I² = 8%, moderate quality evidence). Thirty-six studies reported short-term (hospital or less than one month) mortality. The combined rate of mortality from these studies was not statistically different between the groups receiving glutamine supplement and those receiving no supplement (RR 0.89, 95% CI 0.78 to 1.02, P = 0.10, I² = 22%, low quality evidence). Eleven studies reported long-term (more than six months) mortality; meta-analysis of these studies (2277 participants) yielded a RR of 1.00 (95% CI 0.89 to 1.12, P = 0.94, I² = 30%, moderate quality evidence). Subgroup analysis of infectious complications and mortality outcomes did not find any statistically significant differences between the predefined groups. Hospital length of stay was reported in 36 studies. We found that the length of hospital stay was shorter in the intervention group than in the control group (MD -3.46 days, 95% CI -4.61 to -2.32, P < 0.0001, I² = 63%, low quality evidence). Slightly prolonged intensive care unit (ICU) stay was found in the glutamine supplemented group from 22 studies (2285 participants) (MD 0.18 days, 95% CI 0.07 to 0.29, P = 0.002, I² = 11%, moderate quality evidence). Days on mechanical ventilation (14 studies, 1297 participants) was found to be slightly shorter in the intervention group than in the control group (MD - 0.69 days, 95% CI -1.37 to -0.02, P = 0.04, I² = 18%, moderate quality evidence). There was no clear evidence of a difference between the groups for side effects and quality of life, however results were imprecise for serious adverse events and few studies reported on quality of life. Sensitivity analysis including only low risk of bias studies found that glutamine supplementation had beneficial effects in reducing the length of hospital stay (MD -2.9 days, 95% CI -5.3 to -0.5, P = 0.02, I² = 58%, eight studies) while there was no statistically significant difference between the groups for all of the other outcomes. AUTHORS' CONCLUSIONS: This review found moderate evidence that glutamine supplementation reduced the infection rate and days on mechanical ventilation, and low quality evidence that glutamine supplementation reduced length of hospital stay in critically ill or surgical patients. It seems to have little or no effect on the risk of mortality and length of ICU stay, however. The effects on the risk of serious side effects were imprecise. The strength of evidence in this review was impaired by a high risk of overall bias, suspected publication bias, and moderate to substantial heterogeneity within the included studies.

Gait retraining and incidence of medial tibial stress syndrome in army recruits.

PURPOSE: Gait retraining, comprising biofeedback and/or an exercise intervention, might reduce the risk of musculoskeletal conditions. The purpose was to examine the effect of a gait-retraining program on medial tibial stress syndrome incidence during a 26-wk basic military training regimen. METHODS: A total of 450 British Army recruits volunteered. On the basis of a baseline plantar pressure variable (mean foot balance during the first 10% of stance), participants classified as at risk of developing medial tibial stress syndrome (n = 166) were randomly allocated to an intervention (n = 83) or control (n = 83) group. The intervention involved supervised gait retraining, including exercises to increase neuromuscular control and flexibility (three sessions per week) and biofeedback enabling internalization of the foot balance variable (one session per week). Both groups continued with the usual military training regimen. Diagnoses of medial tibial stress syndrome over the 26-wk regimen were made by physicians blinded to the group assignment. Data were modeled in a survival analysis using Cox regression, adjusting for baseline foot balance and time to peak heel rotation. RESULTS: The intervention was associated with a substantially reduced instantaneous relative risk of medial tibial stress syndrome versus control, with an adjusted HR of 0.25 (95% confidence interval, 0.05-0.53). The number needed to treat to observe one additional injury-free recruit in intervention versus control at 20 wk was 14 (11 to 23) participants. Baseline foot balance was a nonspecific predictor of injury, with an HR per 2 SD increment of 5.2 (1.6 to 53.6). CONCLUSIONS: The intervention was effective in reducing incidence of medial tibial stress syndrome in an at-risk military sample.

Clinical and microbiological benefits of metronidazole alone or with amoxicillin as adjuncts in the treatment of chronic periodontitis: a randomized placebo-controlled clinical trial.

AIM: To evaluate the effects of the adjunctive use of metronidazole (MTZ) or MTZ+amoxicillin (AMX) in the treatment of generalized chronic periodontitis (ChP). MATERIALS AND METHODS: Fifty-one subjects (n=17/group) were randomly assigned to receive scaling and root planing (SRP) only or combined with MTZ (400 mg t.i.d.) or MTZ+AMX (500 mg t.i.d.) for 14 days. Clinical and microbiological examinations were performed at baseline and 3 months post-SRP. Nine plaque samples/subject were analysed by checkerboard DNA-DNA hybridization for 40 bacterial species. RESULTS: Subjects receiving MTZ+AMX exhibited a greater mean gain of clinical attachment, reduction in probing depth (PD) in intermediate and deep sites and a lower percentage of sites with PD5 mm at 3 months, in comparison with those treated with SRP only (p<0.05). The major benefit from the adjunctive use of MTZ was a greater reduction in PD in deep sites. SRP+MTZ+AMX was the only treatment that significantly reduced the levels and proportions of all red complex pathogens and elicited a significantly greater beneficial change in the microbial profile in comparison with SRP only. CONCLUSION: The adjunctive use of MTZ+AMX offers short-term clinical and microbiological benefits, over SRP alone, in the treatment of non-smokers subjects with generalized ChP. The added benefits of MTZ were less evident.

[Number needed to treat (NNT), an index for clinical therapeutic efficacy assessment--its significance and application].

Number needed to treat (NNT) is a simple and effective index for clinical therapeutic effect assessment worldwide accepted in recent years. By calculation of absolute risk reduction (ARR) of classified variables, it made the effect estimate reflect objectively the therapeutic effect of an intervention. However, clinical application of this index was introduced rarely in Chinese literature. With the examples from some published clinical reports, the calculation of NNT and its 95% confidence interval were demonstrated in this paper, and its application was illustrated by some relevant terms explanation and Meta-analysis methods introduction.