Parental risk factors and anorectal malformations: systematic review and meta-analysis

Background

Anderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the SAR1B gene and to evaluate the expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease.

Methods

The SAR1B, SAR1A and PCSK9 genes were sequenced. The expression of the SAR1B and SAR1A genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies.

Results

Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17). The third patient, who had a previously described SAR1B mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the PCSK9 gene. The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects.

Conclusions

Although the proteins encoded by the SAR1A and SAR1B genes are 90% identical, the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD.     

Global burden of influenza-associated lower respiratory tract infections and hospitalizations among adults: A systematic review and meta-analysis

BackgroundInfluenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings.Methods and findingsWe aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996–31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle–Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20–64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%–16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000–46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000–9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000–5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000–44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265–612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources.ConclusionsIn this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide.

In this meta-analysis, Kathryn E. Lafond and colleagues estimate the global hospitalisation burden from influenza infections in adults.     

Cigarette smoking and risk of second primary cancer: a systematic review and meta-analysis

Approximately 5% of the population are living with a diagnosis of cancer. Recent improvements in survival following a diagnosis of cancer have led to an increase in second primary cancers (SPCs) worldwide. Their aetiology remains largely unknown with a large proportion believed to be related to modifiable lifestyle factors. We conducted a systematic review and meta-analysis of published data that evaluated an association between cigarette smoking and risk of SPC. Studies were identified by searching Medline, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Scopus databases through March 2021 using broad search criteria. A meta-analysis was performed to derive pooled relative risks (RRs) for SPC defined a priori as smoking-related based on current evidence (lung, upper aero-digestive tract, stomach, pancreas, colorectum, liver, kidney, ureter, bladder and acute myeloid leukaemia). Eleven cohort studies and ten case-control studies met the eligibility criteria for review. There was marked heterogeneity in methods used in terms of classification and timing of smoking, confounders adjusted for and duration of follow-up across the studies. Nine cohort and seven case-control studies classified smoking habits prior to diagnosis of first cancer while the remaining studies classified post-first cancer smoking habits. In a meta-analysis using six studies, an increased risk of smoking-related SPC was observed for both former (RR=1.42; 95% confidence interval (CI) 1.20–1.67) and current smoking (RR=2.76; 95% CI 2.29–3.33), compared with never smoking. The pooled RRs changed only slightly when studies which measured post-first cancer smoking were excluded. A two-fold increase in risk was observed for ever smoking compared with never smoking. In conclusion, there was evidence that smoking might increase the risk of SPC in cancer survivors. For better informed cancer survivorship practice guidelines, more studies are needed particularly of post-cancer smoking and for cancers not known to be caused by smoking.     

Sexually transmitted infections and prostate cancer risk: A systematic review and meta-analysis

Prostate cancer (PC) is the second most incident cancer and the sixth cause of death by cancer in men worldwide. Despite extensive research efforts, no modifiable risk factors have been consistently identified for PC risk. A number of studies have focused on possible relationships between sexually transmitted infections (STIs) and PC. We performed a meta-analysis to explore the association between infection caused by Neisseria gonorrheae, Treponema pallidum, Chlamydia trachomatis, Trichomonas vaginalis, Ureaplasma urealyticum, Mycoplasma hominis, Herpes Simplex Virus types 1 and 2, Human Herpes Virus 8 and Cytomegalovirus, and PC. We conducted a comprehensive, systematic bibliographic search of medical literature to identify relevant studies. We calculated summary relative risk (SRR) and 95% confidence intervals (CI) for the association between each STI and PC through random effect models. Subgroup, meta-regression and sensitivity analyses were carried out to detect between-study heterogeneity and bias. We included 47 studies published between 1971 and 2011. Men who reported having ever had any STI in lifetime had an increased PC (SRR 1.49, 95% CI 1.19–1.92). We found a significantly increased PC risk in men having had gonorrhoea (SRR 1.20, 95% CI 1.05–1.37). No other single STI was significantly associated with PC. Due to high incidence of both STIs and PC worldwide, prevention of STIs may help preventing a considerable number of PC cases.     

Gamma-glutamyltransferase predicts increased risk of mortality: A systematic review and meta-analysis of prospective observational studies

Abstract

The aim of this study was to evaluate the association between gamma-glutamyltransferase (GGT) and mortality through a comprehensive analysis of existing evidence. PubMed, Embase, Chinese Biomedical Literature, and Science Citation Index databases were electronically searched. Studies were included if the study design was prospective and included reference and at-risk levels of GGT at baseline and mortality as a separate outcome. The quality of the studies included was assessed on the basis of Newcastle–Ottawa scale. Data from selected qualified studies were systematically reviewed, pooled, and analyzed according to the MOOSE guidelines and PRISMA statement. The results included the following: 1. 35 studies including 571 511 participants and 72 196 cases of mortality; 2. GGT, even at physiologic levels, was associated with increased all-cause mortality and cardiovascular mortality, and might also be associated with cancer-related mortality in the general population; and 3. GGT was very likely to be associated with all-cause mortality and cardiovascular mortality in patients with coronary artery disease and type 2 diabetes mellitus. Many of the studies included did not specifically exclude subjects with hepatic diseases or alcohol abuse, which may have obscured the results. Moderate heterogeneity was observed in the meta-analysis of GGT and all-cause mortality. Different compositions of cause-specific mortality might be the reason. However, subgroup analysis could only be performed on cardiovascular death because of insufficient information. GGT, even at physiologic high levels, predicted mortality, especially cardiovascular mortality and cancer mortality. The underlining mechanism and potential effects of GGT-targeted intervention on health warrant further investigation.     

Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis

BACKGROUND:The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID-19) remain uncertain. To support a guideline on COVID-19 management, we conducted a systematic review and meta-analysis of convalescent plasma in COVID-19 and other severe respiratory viral infections.METHODS:In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta-analysis using random-effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.RESULTS:Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID-19. One nonrandomized study (n = 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS-CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70). Pooled estimates from 4 RCTs on influenza (n = 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81), complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference −1.62, 95% CI −3.82 to 0.58, d). The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low-quality evidence).INTERPRETATION:Studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events.

Coronavirus disease 2019 (COVID-19) has been diagnosed in nearly 3 million individuals around the globe, of whom around 0.2 million have died.¹ Many patients with COVID-19 develop severe acute respiratory illness requiring admission to intensive care units (ICU) and often mechanical ventilation.² The case fatality rate in COVID-19 may be as high as 2.3% overall² and from 10% to 40% among severely affected individuals. ^3,4 There is an urgent need for effective therapies.Emerging epidemiologic and clinical data show both similarities and differences between severe COVID-19 and severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).⁵ Similarly, treatment strategies for severe influenza infections tested during the H1N1 pandemic and H5N1 and H7N9 outbreaks could inform the care of patients with severe COVID-19.⁶Of the treatment options proposed for COVID-19,⁷ convalescent plasma has evidence suggesting a mortality benefit for Ebola virus infection.⁸ This intervention has also been tested in other severe acute viral respiratory infections.^6,9,10 “Convalescent plasma” refers to plasma obtained from individuals recently recovered from a viral illness, which is expected to contain the highest levels of polyclonal antibodies directed against the virus.¹¹ Similarly, “hyperimmune plasma” is collected from donors exhibiting high titres of neutralizing antibodies, independent of time elapsed since viral illness. Authors have used the terms interchangeably, and because viral neutralization is only one of the postulated mechanisms by which antibodies exert their antiviral effect, the importance of the distinction between the 2 products remains unclear (Figure 1).Open in a separate windowFigure 1:Potential mechanisms of action of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in coronavirus disease 2019 (COVID-19). This figure illustrates the normal entry of SARS-CoV-2 in a host cell, in which membrane fusion is mediated by the interaction between the SARS-CoV-2 spike glycoprotein (red) and the angiotensin-converting enzyme 2 (ACE2) receptor (green) on the host cell, either through the cytoplasmic or endosomal route. Antibodies directed against the receptor-binding domain (RBD) of the spike protein can interfere with its interaction with the ACE2 receptor and prevent viral entry in the host cell (panel A). Antibodies directed against epitopes outside the RBD can also exert antiviral functions through other mechanisms (panels B, C and D). The relative importance of these various functions in rescuing patients from an active SARS-CoV-2 infection is unknown. Importantly, neutralization assays generally used to qualify hyperimmune products measure only 1 of the 4 mechanisms depicted here and do not necessarily correlate with the others.Clinicians have typically administered convalescent plasma to patients with viral infections whose condition deteriorated despite supportive care.⁶ Although the primary postulated mechanism of action of convalescent plasma is reduction in viremia (passive immunity),¹² an increase in host immune response (active immunity) has also been proposed.¹³ We describe in Figure 1 the possible mechanisms by which convalescent plasma inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Systematic summaries of the available evidence regarding safety and effectiveness can inform the use of convalescent plasma in patients with COVID-19. We therefore conducted a systematic review to summarize the evidence for convalescent plasma to support a guideline on COVID-19 management.¹⁴ Because we anticipated a paucity of direct evidence addressing the use of convalescent plasma in COVID-19, we summarized the available evidence addressing convalescent plasma in the treatment of SARS, MERS and influenza, including H1N1, H7N9 and H5N1, as well as addressing possible adverse effects in patients with Ebola disease.     

Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema

Background

Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices.

Methods

Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.

Results

Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking.

Conclusions

The results confirm and quantify the causal relationships with smoking.     

Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review

Aerosol generating procedures (AGPs) may expose health care workers (HCWs) to pathogens causing acute respiratory infections (ARIs), but the risk of transmission of ARIs from AGPs is not fully known. We sought to determine the clinical evidence for the risk of transmission of ARIs to HCWs caring for patients undergoing AGPs compared with the risk of transmission to HCWs caring for patients not undergoing AGPs. We searched PubMed, EMBASE, MEDLINE, CINAHL, the Cochrane Library, University of York CRD databases, EuroScan, LILACS, Indian Medlars, Index Medicus for SE Asia, international health technology agencies and the Internet in all languages for articles from 01/01/1990 to 22/10/2010. Independent reviewers screened abstracts using pre-defined criteria, obtained full-text articles, selected relevant studies, and abstracted data. Disagreements were resolved by consensus. The outcome of interest was risk of ARI transmission. The quality of evidence was rated using the GRADE system. We identified 5 case-control and 5 retrospective cohort studies which evaluated transmission of SARS to HCWs. Procedures reported to present an increased risk of transmission included [n; pooled OR(95%CI)] tracheal intubation [n = 4 cohort; 6.6 (2.3, 18.9), and n = 4 case-control; 6.6 (4.1, 10.6)], non-invasive ventilation [n = 2 cohort; OR 3.1(1.4, 6.8)], tracheotomy [n = 1 case-control; 4.2 (1.5, 11.5)] and manual ventilation before intubation [n = 1 cohort; OR 2.8 (1.3, 6.4)]. Other intubation associated procedures, endotracheal aspiration, suction of body fluids, bronchoscopy, nebulizer treatment, administration of O2, high flow O2, manipulation of O2 mask or BiPAP mask, defibrillation, chest compressions, insertion of nasogastric tube, and collection of sputum were not significant. Our findings suggest that some procedures potentially capable of generating aerosols have been associated with increased risk of SARS transmission to HCWs or were a risk factor for transmission, with the most consistent association across multiple studies identified with tracheal intubation.     

Sleep disturbances and risk of sick leave: systematic review and meta-analysis

Sleep and Biological Rhythms - Sleep disturbances have multiple negative effects on psychological, social, and occupational aspects. The effects of sleep disturbances on the risk of taking sick...     

Circulating visfatin levels and cancers risk: A systematic review and meta-analysis

Visfatin levels have been reported to be abnormal in many types of cancers. However, epidemiological studies yielded inconsistent results. Therefore, a meta-analysis was performed to assess the association between circulating visfatin levels and cancer risk. A systematic search was conducted for relevant studies in health-related electronic databases up to March 2018. Data related to standard mean difference (SMD) and overall odds ratio (ORS) were collected and analyzed. Summary SMD and pooled OR with 95% CIs were calculated using a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. A total of 27 studies with 2,693 cases and 3,040 healthy controls were included in meta-analysis for pooling SMD analysis. The results of the meta-analysis showed a significant higher visfatin levels in patients with various cancers than in controls, with a pooled SMD of 0.88, 95% CI = 0.56–1.20, p = 0.000. In subgroup, metaregression, Galbraith plot, and sensitivity analysis showed no substantial difference among all the analyzed factors. Data from 14 studies were also used for pooling ORs analysis. Metaresults revealed that high visfatin levels were associated with cancer risk (OR = 1.24, 95% CI: 1.14–1.34, p = 0.000). No evidence of publication bias was observed for pooling ORs and SMD analysis. This meta-analysis indicated a significant association between high circulating visfatin levels and increased risk of various cancers. Visfatin may represent a potential biomarker for early detection of cancers who may benefit from preventive treatment.Note.     

Cognitive impairment and risk of future stroke: a systematic review and meta-analysis

Background:

Several studies have assessed the link between cognitive impairment and risk of future stroke, but results have been inconsistent. We conducted a systematic review and meta-analysis of cohort studies to determine the association between cognitive impairment and risk of future stroke.

Methods:

We searched MEDLINE and Embase (1966 to November 2013) and conducted a manual search of bibliographies of relevant retrieved articles and reviews. We included cohort studies that reported multivariable adjusted relative risks and 95% confidence intervals or standard errors for stroke with respect to baseline cognitive impairment.

Results:

We identified 18 cohort studies (total 121 879 participants) and 7799 stroke events. Pooled analysis of results from all studies showed that stroke risk increased among patients with cognitive impairment at baseline (relative risk [RR] 1.39, 95% confidence interval [CI] 1.24–1.56). The results were similar when we restricted the analysis to studies that used a widely adopted definition of cognitive impairment (i.e., Mini-Mental State Examination score < 25 or nearest equivalent) (RR 1.64, 95% CI 1.46–1.84). Cognitive impairment at baseline was also associated with an increased risk of fatal stroke (RR 1.68, 95% CI 1.21–2.33) and ischemic stroke (RR 1.65, 95% CI 1.41–1.93).

Interpretation:

Baseline cognitive impairment was associated with a significantly higher risk of future stroke, especially ischemic and fatal stroke.Cognitive impairment is a major contributor to disability and dependence worldwide. Globally, stroke is the leading cause of long-term disability among adults and the second leading cause of death.¹ The high cumulative risk of dementia or stroke or both conditions has been shown by the Framingham study,² and the urgent need to improve knowledge regarding cognition and vascular conditions has been emphasized in a specific meeting providing harmonized standards.³ Beyond their personal tolls, both of these conditions carry substantial social and economic burdens. These conditions also correlate strongly with increasing age. Given the projected substantial rise in the number of older people around the world, prevalence rates of cognitive impairment and stroke are expected to soar over the next several decades, especially in high-income countries.^4,5Shared pathophysiologic mechanisms seem to exist between cognitive impairment and cerebrovascular disease.⁶ Indeed, risk factors for stroke (hypertension, hyperlipidemia, diabetes, obesity and physical inactivity) have been shown to play a role in the onset and progression of cognitive impairment,⁷ and it is well established that stroke itself increases the risk of future cognitive impairment.⁸ However, whether cognitive impairment increases the risk of future stroke remains unclear. Early identification and regular surveillance for cognitive impairment could potentially enable prompt initiation of treatment aimed at not only potentially limiting further deterioration of cognitive function (if mild), but also possibly reducing the risk of future stroke through timely and optimal control of risk factors.Several published studies have assessed the association between cognitive impairment and subsequent risk of stroke, but the results have not been consistent. We performed a systematic review and meta-analysis to determine the qualitative and quantitative association between baseline cognitive impairment and risk of future stroke.     

Genetic polymorphisms in adipokine genes and the risk of obesity: a systematic review and meta-analysis

Polymorphisms in adipokine genes, such as leptin (LEP), leptin receptor (LEPR), resistin (RETN), adiponectin (ADIPOQ), interleukin-1β (IL-1β), IL-6 (IL-6), and tumor necrosis factor-α (TNF-α) may be involved in the development of obesity. We conducted a systematic review of published evidence on the association between different adipokine genes and the risk of obesity. Librarian-designed searches of PubMed and HuGeNet, review of reference lists from published reviews and content expert advice identified potentially eligible studies. The genotyping information and polymorphisms of different adipokine genes, numbers of genotyped cases and controls and frequencies of genotypes were extracted from 48 eligible studies included in this review. Twenty-one polymorphisms each associated with obesity in at least one study were identified. Polymorphisms in the adipokine genes, LEP, LEPR, and RETN were not associated with obesity susceptibility, whereas ADIPOQ G276T (T vs. G: odds ratio (OR), 1.59; 95% confidence interval (CI), 1.39-1.81), IL-1β C3953T (CC vs. CT+TT: OR, 1.61; 95% CI, 1.18-2.20), and TNF-α G308A (GG vs. GA+AA: OR, 1.19; 95% CI, 1.02-1.39) polymorphisms were associated with an increased risk of obesity. The IL-6 G174C polymorphism was also associated obesity when using allelic comparisons, the recessive genetic model and the dominant genetic model with OR (95% CI) of 1.95 (1.37-2.77), 1.44 (1.15-1.80), and 1.36 (1.16-1.59), respectively. No significant evidence of publication bias was present. However, these "null" results were underpowered due to a small pooled sample size, and analysis of additional case-control studies with larger sample sizes should provide further clarifications.     

Previous lung diseases and lung cancer risk: a systematic review and meta-analysis

Background

In order to review the epidemiologic evidence concerning previous lung diseases as risk factors for lung cancer, a meta-analysis and systematic review was conducted.

Methods

Relevant studies were identified through MEDLINE searches. Using random effects models, summary effects of specific previous conditions were evaluated separately and combined. Stratified analyses were conducted based on smoking status, gender, control sources and continent.

Results

A previous history of COPD, chronic bronchitis or emphysema conferred relative risks (RR) of 2.22 (95% confidence interval (CI): 1.66, 2.97) (from 16 studies), 1.52 (95% CI: 1.25, 1.84) (from 23 studies) and 2.04 (95% CI: 1.72, 2.41) (from 20 studies), respectively, and for all these diseases combined 1.80 (95% CI: 1.60, 2.11) (from 39 studies). The RR of lung cancer for subjects with a previous history of pneumonia was 1.43 (95% CI: 1.22–1.68) (from 22 studies) and for subjects with a previous history of tuberculosis was 1.76 (95% CI = 1.49, 2.08), (from 30 studies). Effects were attenuated when restricting analysis to never smokers only for COPD/emphysema/chronic bronchitis (RR = 1.22, 0.97–1.53), however remained significant for pneumonia 1.36 (95% CI: 1.10, 1.69) (from 8 studies) and tuberculosis 1.90 (95% CI: 1.45, 2.50) (from 11 studies).

Conclusions

Previous lung diseases are associated with an increased risk of lung cancer with the evidence among never smokers supporting a direct relationship between previous lung diseases and lung cancer.     

The relationship between proteinuria and coronary risk: a systematic review and meta-analysis

Background

Markers of kidney dysfunction such as proteinuria or albuminuria have been reported to be associated with coronary heart disease, but the consistency and strength of any such relationship has not been clearly defined. This lack of clarity has led to great uncertainty as to how proteinuria should be treated in the assessment and management of cardiovascular risk. We therefore undertook a systematic review of published cohort studies aiming to provide a reliable estimate of the strength of association between proteinuria and coronary heart disease.

Methods and Findings

A meta-analysis of cohort studies was conducted to obtain a summary estimate of the association between measures of proteinuria and coronary risk. MEDLINE and EMBASE were searched for studies reporting an age- or multivariate-adjusted estimate and standard error of the association between proteinuria and coronary heart disease. Studies were excluded if the majority of the study population had known glomerular disease or were the recipients of renal transplants. Two independent researchers extracted the estimates of association between proteinuria (total urinary protein >300 mg/d), microalbuminuria (urinary albumin 30–300 mg/d), macroalbuminuria (urinary albumin >300 mg/d), and risk of coronary disease from individual studies. These estimates were combined using a random-effects model. Sensitivity analyses were conducted to examine possible sources of heterogeneity in effect size. A total of 26 cohort studies were identified involving 169,949 individuals and 7,117 coronary events (27% fatal). The presence of proteinuria was associated with an approximate 50% increase in coronary risk (risk ratio 1.47, 95% confidence interval [CI] 1.23–1.74) after adjustment for known risk factors. For albuminuria, there was evidence of a dose–response relationship: individuals with microalbuminuria were at 50% greater risk of coronary heart disease (risk ratio 1.47, 95% CI 1.30–1.66) than those without; in those with macroalbuminuria the risk was more than doubled (risk ratio 2.17, 1.87–2.52). Sensitivity analysis indicated no important differences in prespecified subgroups.

Conclusion

These data confirm a strong and continuous association between proteinuria and subsequent risk of coronary heart disease, and suggest that proteinuria should be incorporated into the assessment of an individual''s cardiovascular risk.     

Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis

Background

A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Our objective was to enhance the precision of estimates of the effect of metformin on the risk of any-site and site-specific cancers in patients with diabetes.

Methods/Principal Findings

We performed a search of MEDLINE, EMBASE, ISI Web of Science, Cochrane Library, and ClinicalTrials.gov for pertinent articles published as of October 12, 2011, and included them in a systematic review and meta-analysis. We calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence. Of the 21,195 diabetic patients reported in 6 studies (4 cohort studies, 2 RCTs), 991 (4.5%) cases of death from cancer were reported. A total of 11,117 (5.3%) cases of incident cancer at any site were reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 case-control studies). The risks of cancer among metformin users were significantly lower than those among non-metformin users: the pooled RRs (95% confidence interval) were 0.66 (0.49–0.88) for cancer mortality, 0.67 (0.53–0.85) for all-cancer incidence, 0.68 (0.53–0.88) for colorectal cancer (n = 6), 0.20 (0.07–0.59) for hepatocellular cancer (n = 4), 0.67 (0.45–0.99) for lung cancer (n = 3).

Conclusion/Significance

The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence. However, this analysis is mainly based on observational studies and our findings underscore the more need for long-term RCTs to confirm this potential benefit for individuals with diabetes.