Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess the effects of increased intake of fish- and plant-based omega-3 fats for all-cause mortality, cardiovascular events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily). Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high-certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate-certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high-certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate-certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low-certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low-certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low-certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre-planned subgrouping or meta-regression. There is little evidence of effects of eating fish. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate-certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate-certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate-certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low-certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low-certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate-certainty evidence). Effects on stroke are unclear. Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose-dependent way (high-certainty evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and low-certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5g/d LCn3 to > 5 g/d (16 RCTs gave at least 3g/d LCn3).Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted.Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs) and ALA may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low-quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence with greater effects in trials at low summary risk of bias), and probably reduces risk of arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear.Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression.There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, except LCn3 reduced triglycerides by ˜15% in a dose-dependant way (high-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event and arrhythmia risk.

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake probably slightly decreases triglycerides (by 15%, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants), high-density lipoprotein (HDL) (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably has little or no effect on adiposity (body weight MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via TG reduction.

Omega-6 fats for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Omega-6 fats are polyunsaturated fats vital for many physiological functions, but their effect on cardiovascular disease (CVD) risk is debated. OBJECTIVES: To assess effects of increasing omega-6 fats (linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA)) on CVD and all-cause mortality. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to May 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher versus lower omega-6 fat intake in adults with or without CVD, assessing effects over at least 12 months. We included full texts, abstracts, trials registry entries and unpublished studies. Outcomes were all-cause mortality, CVD mortality, CVD events, risk factors (blood lipids, adiposity, blood pressure), and potential adverse events. We excluded trials where we could not separate omega-6 fat effects from those of other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias of included trials. We wrote to authors of included studies. Meta-analyses used random-effects analysis, while sensitivity analyses used fixed-effects and limited analyses to trials at low summary risk of bias. We assessed GRADE quality of evidence for 'Summary of findings' tables. MAIN RESULTS: We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias.Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes.Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) -0.33 mmol/L, 95% CI -0.50 to -0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD -0.20 kg/m2, 95% CI -0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD -0.01 mmol/L, 95% CI -0.23 to 0.21, 834 participants, 5 trials), HDL (MD -0.01 mmol/L, 95% CI -0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD -0.04 mmol/L, 95% CI -0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity.

Omega-6 fats for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Omega-6 fats are polyunsaturated fats vital for many physiological functions, but their effect on cardiovascular disease (CVD) risk is debated. OBJECTIVES: To assess effects of increasing omega-6 fats (linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA)) on CVD and all-cause mortality. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to May 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher versus lower omega-6 fat intake in adults with or without CVD, assessing effects over at least 12 months. We included full texts, abstracts, trials registry entries and unpublished studies. Outcomes were all-cause mortality, CVD mortality, CVD events, risk factors (blood lipids, adiposity, blood pressure), and potential adverse events. We excluded trials where we could not separate omega-6 fat effects from those of other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias of included trials. We wrote to authors of included studies. Meta-analyses used random-effects analysis, while sensitivity analyses used fixed-effects and limited analyses to trials at low summary risk of bias. We assessed GRADE quality of evidence for 'Summary of findings' tables. MAIN RESULTS: We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias.Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes.Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) -0.33 mmol/L, 95% CI -0.50 to -0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD -0.20 kg/m2, 95% CI -0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD -0.01 mmol/L, 95% CI -0.23 to 0.21, 834 participants, 5 trials), HDL (MD -0.01 mmol/L, 95% CI -0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD -0.04 mmol/L, 95% CI -0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity.

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet.Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted.Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and it may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low-quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence), and probably reduces risk of CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs), and arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear.Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression.There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, although LCn3 slightly reduced triglycerides and increased HDL. ALA probably reduces HDL (high- or moderate-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event risk, CHD mortality and arrhythmia.

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake slightly reduces total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants) and probably slightly decreases triglycerides (MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on high-density lipoprotein (HDL) (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight.

Intracellular Survival of Leishmania major Depends on Uptake and Degradation of Extracellular Matrix Glycosaminoglycans by Macrophages.

Leishmania parasites replicate within the phagolysosome compartment of mammalian macrophages. Although Leishmania depend on sugars as a major carbon source during infections, the nutrient composition of the phagolysosome remains poorly described. To determine the origin of the sugar carbon source in macrophage phagolysosomes, we have generated a N-acetylglucosamine acetyltransferase (GNAT) deficient Leishmania major mutant (∆gnat) that is auxotrophic for the amino sugar, N-acetylglucosamine (GlcNAc). This mutant was unable to grow or survive in ex vivo infected macrophages even when macrophages were cultivated in presence of exogenous GlcNAc. In contrast, the L. major ∆gnat mutant induced normal skin lesions in mice, suggesting that these parasites have access to GlcNAc in tissue macrophages. Intracellular growth of the mutant in ex vivo infected macrophages was restored by supplementation of the macrophage medium with hyaluronan, a GlcNAc-rich extracellular matrix glycosaminoglycan. Hyaluronan is present and constitutively turned-over in Leishmania-induced skin lesions and is efficiently internalized into Leishmania containing phagolysosomes. These findings suggest that the constitutive internalization and degradation of host glycosaminoglycans by macrophages provides Leishmania with essential carbon sources, creating a uniquely favorable niche for these parasites.

Differences in Longer-Term Smoking Abstinence After Treatment by Specialist or Nonspecialist Advisors: Secondary Analysis of Data From a Relapse Prevention Trial.

INTRODUCTION: Smokers receiving support in specialist centers tend to have a higher short-term quit rate, compared with those receiving support in other settings from professionals for whom smoking cessation is only a part of their work. We investigated the difference in longer-term abstinence after short-term smoking cessation treatment from specialist and nonspecialist smoking cessation services. METHODS: We conducted a secondary analysis of data from a randomized controlled trial of self-help booklets for the prevention of smoking relapse. The trial included 1088 short-term quitters from specialist stop smoking clinics and 316 from nonspecialist cessation services (such as general practice, pharmacies, and health trainer services). The difference in prolonged smoking abstinence from months 4 to 12 between specialist and nonspecialist services was compared. Multivariable logistic regression analyses were conducted to investigate the association between continuous smoking abstinence and the type of smoking cessation services, adjusted for possible confounding factors (including demographic, socioeconomic, and smoking history variables). RESULTS: The proportion of continuous abstinence from 4 to 12 months was higher in short-term quitters from specialist services compared with those from nonspecialist services (39% vs. 32%; P = .023). After adjusting for a range of participant characteristics and smoking variables, the specialist service was significantly associated with a higher rate of longer-term smoking abstinence (odds ratio: 1.48, 95% CI = 1.09% to 2.00%; P = .011). CONCLUSIONS: People who receive support to stop smoking from a specialist appear to be at lower risk of relapse than those receiving support from a nonspecialist advisor.

Contextual Factors That Impact the Implementation of Patient Portals With a Focus on Older People in Acute Care Hospitals: Scoping Review.

BACKGROUND: Older people are the highest users of health services but are less likely to use a patient portal than younger people. OBJECTIVE: This scoping review aimed to identify and synthesize the literature on contextual factors that impact the implementation of patient portals in acute care hospitals and among older people. METHODS: A scoping review was conducted according to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines. The following databases were searched from 2010 to June 2020: MEDLINE and Embase via the Ovid platform, CINAHL and PsycINFO via the EBSCO platform, and the Cochrane Library. Eligible reviews were published in English; focused on the implementation of tethered patient portals; included patients, health care professionals, managers, and budget holders; and aimed at identifying the contextual factors (ie, barriers and facilitators) that impact the implementation of patient portals. Review titles and abstracts and full-text publications were screened in duplicate. The study characteristics were charted by one author and checked for accuracy by a second author. The NASSS (Non-adoption, Abandonment, Scale-up, Spread, and Sustainability) framework was used to synthesize the findings. RESULTS: In total, 10 systematic reviews published between 2015 and 2020 were included in the study. Of these, 3 (30%) reviews addressed patient portals in acute care hospitals, and 2 (20%) reviews addressed the implementation of patient portals among older people in multiple settings (including acute care hospitals). To maximize the inclusion of the literature on patient portal implementation, we also included 5 reviews of systematic reviews that examined patient portals in multiple care settings (including acute care hospitals). Contextual factors influencing patient portal implementation tended to cluster in specific NASSS domains, namely the condition, technology, and value proposition. Certain aspects within these domains received more coverage than others, such as sociocultural factors and comorbidities, the usability and functionality aspects of the technology, and the demand-side value. There are gaps in the literature pertinent to the consideration of the provision of patient portals for older people in acute care hospitals, including the lack of consideration of the diversity of older adults and their needs, the question of interoperability between systems (likely to be important where care involves multiple services), the involvement of lay caregivers, and looking beyond short-term implementation to ways in which portal use can be sustained. CONCLUSIONS: We identified important contextual factors that impact patient portal implementation and key gaps in the literature. Future research should focus on evaluating strategies that address disparities in use and promote engagement with patient portals among older people in acute care settings.

Validation of the Identification of Medication Adherence Barriers Questionnaire (IMAB-Q); a Behavioural Science-Underpinned Tool for Identifying Non-Adherence and Diagnosing an Individual's Barriers to Adherence.

Purpose: To validate the Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) as a tool to guide practitioners to identify patients who require support to take their medicines as prescribed, their key barriers to adherence and select relevant behaviour change techniques. Patients and Methods: Adults prescribed medication for cardiovascular disease prevention were recruited from nine community pharmacies in England. Participants completed the IMAB-Q comprising 30 items representing potential barriers to adherence developed from our previous mixed methods study (scoping review and focus groups) underpinned by the Theoretical Domains Framework. Participants also self-reported their adherence on a visual analogue scale (VAS) ranging from perfect adherence (100) to non-adherence (1). A subgroup of 30 participants completed the IMAB-Q twice to investigate test-retest reliability using weighted Kappa. Mokken scaling was used to investigate IMAB-Q structure. Spearman correlation was used to investigate IMAB-Q criterion validity compared to the VAS score. Results: From 1407 invitations, 608 valid responses were received. Respondents had a mean (SD) age of 70.12 (9.9) years and were prescribed a median (IQ) 4 (3, 6) medicines. Worry about unwanted effects (n = 212, 34.5%) and negative emotions evoked by medicine taking (n = 99, 16.1%) were most frequently reported. Mokken scaling did not organise related IMAB-Q items according to the TDF domains (scalability coefficient H = 0.3 to 0.6). Lower VAS self-reported adherence correlated with greater IMAB-Q reported barriers (rho = -0.14, p = 0.001). Test-retest reliability of IMAB-Q items ranged from kappa co-efficient 0.9 to 0.3 (p < 0.05). Conclusion: The IMAB-Q is valid and reliable for identifying people not adhering and their barriers to adherence. Each IMAB-Q item is linked to a TDF domain which in turn is linked to relevant behaviour change techniques. The IMAB-Q can therefore guide patients and practitioners to select strategies tailored to a patient's identified barriers.

BabyBreathe trial: protocol for a randomised controlled trial of a complex intervention to prevent postpartum return to smoking.

INTRODUCTION: Many people quit smoking during pregnancy, but postpartum smoking relapse is common. Maintaining smoking abstinence achieved during pregnancy is key to improving maternal and child health. There are no evidence-based interventions for preventing postpartum smoking relapse. This trial aims to determine whether an intervention to prevent postpartum relapse is effective and cost-effective. METHODS AND ANALYSIS: A randomised controlled trial of a complex intervention to prevent postpartum smoking relapse (BabyBreathe), with internal pilot, economic and process evaluations. Participants are adults who are pregnant and who report having quit smoking in the 12 months before, or during pregnancy. Participants are eligible if they read and understand English, and provide informed consent. Following consent and biochemical validation of smoking abstinence, participants are randomised to intervention or usual care/control (no specific relapse prevention support). The BabyBreathe intervention consists of manualised advice from a trained member of the health visiting service, health information leaflets for participants and partners, access to the BabyBreathe website and app. At the time of birth, participants are posted the BabyBreathe box and support is provided by text message for up to 12 months postpartum. Target sample size is 880, recruiting across midwifery services at four hubs in England and Scotland and through remote advertising in England, Scotland, Wales and Northern Ireland. Outcomes are collected at 6 and 12 months. The primary outcome is self-reported sustained smoking abstinence at 12 months, carbon monoxide verified. Secondary outcomes include self-reported abstinence, time to relapse, partner smoking status and quality of life. ETHICS AND DISSEMINATION: The trial was approved by the North West Preston Research Ethics committee (21/NW/0017). Dissemination will include publication in peer-reviewed journals, presentation at academic and public conferences including patient and public involvement and to policymakers and practitioners. TRIAL REGISTRATION NUMBER: ISRCTN70307341.

Disruption and adaptation in response to the coronavirus pandemic - Assets as contextual moderators of enactment of health behaviours.

PURPOSE: During the COVID-19 UK first national lockdown (March-July 2020) enactment of healthy behaviours was fundamentally changed due to social restrictions. This study sought to understand perspectives on health behaviour change, as part of a wider study tracking reported health behaviour change over time. METHODS: A purposive sample was selected. N = 40 qualitative interviews were conducted remotely (phone/video) from participants across England and Wales, and transcribed verbatim. Descriptive case studies were shared at regular analysis meetings. Inductive reflexive thematic coding was undertaken and coding was discussed using a team approach to agreeing analytical codes. A multiple lens theoretical perspective was adopted to illuminate the perceived influences and restrictions on participants' reports of health behaviour change. RESULTS: There was a clear progressive narrative for all participants, through initial responses and reactions to the pandemic, framed as 'disruption', then, as lockdown was acclimatized to, evidence of 'adaptation'. Adaptation was seen in terms of modification, substitution, adoption, discontinuation/cessation, stultification, maintenance and recalibration of health behaviours. An illustrative case study exemplifies the narrative encompassing these features and demonstrating the complex non-linear interactions between context and enacted health behaviours. CONCLUSIONS: Individuals responded to pandemic-related social restrictions in complex ways. Those in contexts with existing social assets, community links and established patterns of healthy behaviours were able to respond positively, adapting by modifying behaviour and using technology to engage in healthy behaviours in new and innovative ways. For those in more vulnerable contexts, enacting (negative) health behaviour change was an expression of frustration at the limitations imposed by social restrictions.

Development of a Smoke-Free Home Intervention for Families of Babies Admitted to Neonatal Intensive Care.

Neonatal intensive care units (NICUs) have a disproportionately higher number of parents who smoke tobacco compared to the general population. A baby's NICU admission offers a unique time to prompt behaviour change, and to emphasise the dangerous health risks of environmental tobacco smoke exposure to vulnerable infants. We sought to explore the views of mothers, fathers, wider family members, and healthcare professionals to develop an intervention to promote smoke-free homes, delivered on NICU. This article reports findings of a qualitative interview and focus group study with parents whose infants were in NICU (n = 42) and NICU healthcare professionals (n = 23). Thematic analysis was conducted to deductively explore aspects of intervention development including initiation, timing, components and delivery. Analysis of inductively occurring themes was also undertaken. Findings demonstrated that both parents and healthcare professionals supported the need for intervention. They felt it should be positioned around the promotion of smoke-free homes, but to achieve that end goal might incorporate direct cessation support during the NICU stay, support to stay smoke free (relapse prevention), and support and guidance for discussing smoking with family and household visitors. Qualitative analysis mapped well to an intervention based around the '3As' approach (ask, advise, act). This informed a logic model and intervention pathway.

Novel Implementation Strategy to Electronically Screen and Signpost Patients to Health Behavior Apps: Mixed Methods Implementation Study (OptiMine Study).

BACKGROUND: Behavior change apps have the potential to provide individual support on a population scale at low cost, but they face numerous barriers to implementation. Electronic health records (EHRs) in acute care hospitals provide a valuable resource for identifying patients at risk, who may benefit from behavior change apps. A novel, emerging implementation strategy is to use digital technologies not only for providing support to help-seeking individuals but also for signposting patients at risk to support services (also called proactive referral in the United States). OBJECTIVE: The OptiMine study aimed to increase the reach of behavior change apps by implementing electronic signposting for smoking cessation and alcohol reduction in a large, at-risk population that was identified through an acute care hospital EHR. METHODS: This 3-phase, mixed methods implementation study assessed the acceptability, feasibility, and reach of electronic signposting to behavior change apps by using a hospital's EHR system to identify patients who are at risk. Phase 1 explored the acceptability of the implementation strategy among the patients and staff through focus groups. Phase 2 investigated the feasibility of using the hospital EHR to identify patients with target risk behaviors and contact them via SMS text message, email, or patient portal. Phase 3 assessed the impact of SMS text messages sent to patients who were identified as smokers or risky drinkers, which signposted them to behavior change apps. The primary outcome was the proportion of participants who clicked on the embedded link in the SMS text message to access information about the apps. The acceptability of the SMS text messages among the patients who had received them was also explored in a web-based survey. RESULTS: Our electronic signposting strategy-using SMS text messages to promote health behavior change apps to patients at risk-was found to be acceptable and feasible and had good reach. The hospital sent 1526 SMS text messages, signposting patients to either the National Health Service Smokefree or Drink Free Days apps. A total of 13.56% (207/1526) of the patients clicked on the embedded link to the apps, which exceeded our 5% a priori success criterion. Patients and staff contributed to the SMS text message content and delivery approach, which were perceived as acceptable before and after the delivery of the SMS text messages. The feasibility of the SMS text message format was determined and the target population was identified by mining the EHR. CONCLUSIONS: The OptiMine study demonstrated the proof of concept for this novel implementation strategy, which used SMS text messages to signpost at-risk individuals to behavior change apps at scale. The level of reach exceeded our a priori success criterion in a non-help-seeking population of patients receiving unsolicited SMS text messages, disconnected from hospital visits. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/23669.

Effects of fluid and drinking on pneumonia mortality in older adults: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Advice to drink plenty of fluid is common in respiratory infections. We assessed whether low fluid intake (dehydration) altered outcomes in adults with pneumonia. METHODS: We systematically reviewed trials increasing fluid intake and well-adjusted, well-powered observational studies assessing associations between markers of low-intake dehydration (fluid intake, serum osmolality, urea or blood urea nitrogen, urinary output, signs of dehydration) and mortality in adult pneumonia patients (with any type of pneumonia, including community acquired, health-care acquired, aspiration, COVID-19 and mixed types). Medline, Embase, CENTRAL, references of reviews and included studies were searched to 30/10/2020. Studies were assessed for inclusion, risk of bias and data extracted independently in duplicate. We employed random-effects meta-analysis, sensitivity analyses, subgrouping and GRADE assessment. Prospero registration: CRD42020182599. RESULTS: We identified one trial, 20 well-adjusted cohort studies and one case-control study. None suggested that more fluid (hydration) was associated with harm. Ten of 13 well-powered observational studies found statistically significant positive associations in adjusted analyses between dehydration and medium-term mortality. The other three studies found no significant effect. Meta-analysis suggested doubled odds of medium-term mortality in dehydrated (compared to hydrated) pneumonia patients (GRADE moderate-quality evidence, OR 2.3, 95% CI 1.8 to 2.8, 8619 deaths in 128,319 participants). Heterogeneity was explained by a dose effect (greater dehydration increased risk of mortality further), and the effect was consistent across types of pneumonia (including community-acquired, hospital-acquired, aspiration, nursing and health-care associated, and mixed pneumonia), age and setting (community or hospital). The single trial found that educating pneumonia patients to drink ≥1.5 L fluid/d alongside lifestyle advice increased fluid intake and reduced subsequent healthcare use. No studies in COVID-19 pneumonia met the inclusion criteria, but 70% of those hospitalised with COVID-19 have pneumonia. Smaller COVID-19 studies suggested that hydration is as important in COVID-19 pneumonia mortality as in other pneumonias. CONCLUSIONS: We found consistent moderate-quality evidence mainly from observational studies that improving hydration reduces the risk of medium-term mortality in all types of pneumonia. It is remarkable that while many studies included dehydration as a potential confounder, and major pneumonia risk scores include measures of hydration, optimal fluid volume and the effect of supporting hydration have not been assessed in randomised controlled trials of people with pneumonia. Such trials, are needed as potential benefits may be large, rapid and implemented at low cost. Supporting hydration and reversing dehydration has the potential to have rapid positive impacts on pneumonia outcomes, and perhaps also COVID-19 pneumonia outcomes, in older adults.

ABC transporters do not contribute to extracellular translocation of hyaluronan in human breast cancer in vitro.

Extracellular translocation of the polysaccharide, hyaluronan (HA) has been thought to be mediated via its transmembrane synthetic enzyme, hyaluronan synthase (HAS) but recent studies have indicated that the ATP-Binding-Cassette (ABC) transporter, MRP5 contributes to this process. Liberated and cell-associated HA contributes to breast cancer initiation and progression, and therefore the inhibition of ABC transporters and consequently HA transport could provide therapeutic benefit in the treatment of breast cancer. Quantitation of ABC transporter genes, MRP1-5, BCRP and MDR1 were determined in six breast cancer cell lines selected for their differential HA synthetic rates. Low endogenous expression of transporters was detected but no significant correlation existed between ABC transporter and HAS gene expression or HA production. A dose titration of up to ten times the IC(50) of ten small molecule ABC transporter inhibitors did not significantly inhibit HA export in four breast cancer cell lines. Unlike the changes observed after inhibition of HA synthesis by the characterised inhibitor 4-MU, inhibition of ABC transporters did not alter the cell morphology, HA glycocalyx or the intracellular quantity or localisation of HA. Collectively these data indicate that ABC transporters do not contribute to the extracellular transport of HA in breast cancer, supporting a role for the hyaluronan synthase in translocation.

Systematic Review of Behaviour Change Techniques within Interventions to Reduce Environmental Tobacco Smoke Exposure for Children.

Children are particularly vulnerable to environmental tobacco smoke (ETS). There is no routine support to reduce ETS in the home. We systematically reviewed trials to reduce ETS in children in order to identify intervention characteristics and behaviour change techniques (BCTs) to inform future interventions. We searched Medline, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Central Register of Controlled Trials, and Cochrane Tobacco Addiction Group Specialised Register from January 2017 to June 2020 to update an existing systematic review. We included controlled trials to reduce parent/caregiver smoking or ETS in children <12 years that demonstrated a statistically significant benefit, in comparison to less intensive interventions or usual care. We extracted trial characteristics; and BCTs using Behaviour Change Technique Taxonomy v1. We defined "promising" BCTs as those present in at least 25% of effective interventions. Data synthesis was narrative. We included 16 trials, of which eight were at low risk of bias. All trials used counselling in combination with self-help or other supporting materials. We identified 13 "promising" BCTs centred on education, setting goals and planning, or support to reach goals. Interventions to reduce ETS in children should incorporate effective BCTs and consider counselling and self-help as mechanisms of delivery.

Are long working hours associated with weight-related outcomes? A meta-analysis of observational studies.

The relationship between long working hours and body weight outcomes remains inconclusive; thus, we conducted a meta-analysis to assess the effect of long working hours on weight-related outcomes. PubMed and Embase databases were searched from their inception to June 2019. A random-effects model was used to assess the pooled odds ratio (OR) and corresponding confidence interval (CI). Subgroup analyses and sensitivity analyses were conducted to explore sources of heterogeneity. Publication bias was evaluated by the Begg's and Egger's tests. A total of 29 articles involving 374 863 participants were included. The pooled OR of long working hours on weight-related outcomes was 1.13 (95% CI, 1.07-1.19). In subgroup analysis stratified by definition of outcomes, the pooled ORs of long working hours on "weight gain/BMI increase," "BMI ≥ 25 kg/m2 ," and "BMI ≥ 30 kg/m2 " were 1.19 (95% CI, 1.02-1.40), 1.07 (95% CI, 1.00-1.14), and 1.23 (95% CI, 1.09-1.39), respectively. We found evidence of publication bias, but correction for this bias using the trim-and-fill method did not alter the combined OR substantially. There was evidence to suggest that long working hours are associated with adverse weight-related outcomes. Preventative interventions such as improved flexibility and healthy working schedules should be established for employees.

A pilot human evaluation of a formulation of irinotecan and hyaluronic acid in 5-fluorouracil-refractory metastatic colorectal cancer patients.

BACKGROUND: Preclinical data demonstrate that the polysaccharide hyaluronic acid (HA) acts as a macromolecular carrier for chemotherapeutic drugs. In these studies the formulation of HA and irinotecan reduced treatment-related toxicity and improved efficacy via the preferential delivery of irinotecan to the tumor and lymph nodes. This study was designed as a first-in-man investigation of the safety and pharmacokinetics of irinotecan when administered within the HA-Irinotecan formulation. METHODS: 5-Fluorouracil refractory metastatic colorectal cancer patients were intravenously treated with HA-Irinotecan (300 mg/m(2) irinotecan with 1,000 mg/m(2) HA) on day 1 of a 21-day cycle. After safety was demonstrated, the irinotecan dose was increased to 350 mg/m(2) with maintenance of the HA at 1,000 mg/m(2). RESULTS: Twelve patients were treated with HA-Irinotecan. Overall toxicity was low, with an 8 and 17% incidence of grade lll/lV diarrhea and neutropenia, respectively. No grade III/IV nausea or vomiting was observed. Seventeen percent of patients had a partial response and 50% experienced stable disease, indicating that the efficacy of the irinotecan was maintained. Median survival was 16.6 months, while median progression-free survival was 6.2 months. CONCLUSION: HA-Irinotecan containing standard doses of irinotecan can be safely administered to patients. Comparison to historical irinotecan data suggests HA-Irinotecan may have a greater margin of safety without compromising anticancer activity.