Association between TNF-α-308 G/A gene polymorphism and gastric cancer risk: A systematic review and meta-analysis

ObjectiveTumor necrosis factor-alpha (TNF-α) has been found to be associated with gastric carcinogenesis, but individually published results have been inconclusive. The aim of this study was to explore the relationship between the TNF-α-308 G/A polymorphism and gastric cancer risk.MethodsMEDLINE, EMBASE and the COCHRANE library databases were searched for relevant articles to identify all available data. The odds ratios (ORs) with 95% confidence intervals (95% CIs) from each study were used to assess the association between the TNF-α-308 G/A polymorphism and gastric cancer risk.ResultsThis meta-analysis included 30 studies (32 datasets) involving 7009 gastric cancer cases and 12,119 control subjects. Overall, a significant association was found between the TNF-α-308 G/A polymorphism and gastric cancer in AA + GA vs. GG (dominant contrast model) (OR = 1.20, 95% CI = 1.07–1.34, p = 0.001). With stratification based on ethnicity, the TNF-α-308 G/A polymorphism was correlated with gastric cancer risk in Caucasians, using the dominant contrast model (OR = 0.74, 95% CI = 0.57–0.96, p = 0.02), but not in East Asians and other ethnic groups. In the comprehensive subgroup analysis, a significant association was also found in recent articles (published after 2005), population-based high-quality studies, hospital-based high-quality studies, studies using the TaqMan method and non-cardia subgroups. However, the TNF-α-308 G/A polymorphism was not associated with specific histological types of gastric cancer risk.ConclusionsThe TNF-α-308 G/A polymorphism may contribute to susceptibility to gastric cancer in Caucasians, especially for non-cardia gastric cancer, as most strongly demonstrated in high-quality studies and in studies using the TaqMan genotyping method. Furthermore, we recommend the TaqMan method as the preferred genotyping method in DNA polymorphism studies.     

Effect of dendritic cell–based immunotherapy on hepatocellular carcinoma: A systematic review and meta-analysis

Background aims

Dendritic cell (DC)-based immunotherapy has recently been reported frequently in the treatment of hepatocellular carcinoma (HCC); however, its efficacy remains controversial. In this study, we aimed to evaluate the clinical efficacy of DC-based immunotherapy on HCC by conducting a systematic review and meta-analysis.

Helicobacter pylori: an invading microorganism? A review

In this review we evaluate the pros and cons of Helicobacter pylori invasion of epithelial cells as part of the natural history of H. pylori infection. H. pylori is generally considered an extracellular microorganism. However, a growing body of evidence supports the controversial hypothesis that at least a subset of H. pylori microorganisms has an intracellular (intraepithelial) location. Most significant is the fact that H. pylori invades cultured epithelial cells with invasion frequencies similar to Yersinia enterocolitica and better than Shigella flexneri; furthermore, studies of invasion mechanisms suggest that H. pylori invasion of and survival within epithelial cells is not merely a passive event, but requires active participation of the microorganism. Although many studies of human gastric biopsy specimens have failed to demonstrate any intracellular H. pylori, some studies have revealed a minor fraction of H. pylori inside gastric epithelial cells, with possible linkage to peptic ulceration and epithelial cell damage. In conclusion, these data encourage further research to establish whether intracellular H. pylori does play a role in H. pylori colonization of the human stomach and in peptic ulcer pathogenesis.     

Effectiveness and safety of chemotherapy with cytokine-induced killer cells in non–small cell lung cancer: A systematic review and meta-analysis of 32 randomized controlled trials

Background aims

Cytokine-induced killer (CIK) cells are the most commonly used cellular immunotherapy for multiple tumors. To further confirm whether chemotherapy with CIK cells improves clinical effectiveness and to reveal its optimal use in non–small cell lung cancer (NSCLC), we systematically reevaluated all relevant studies.

Alcohol drinking and risk of leukemia—A systematic review and meta-analysis of the dose–risk relation

The association between alcohol and leukemia risk has been addressed in several studies in the past two decades, but results have been inconsistent. Therefore, we conducted a systematic review and meta-analysis to quantify the dose–risk relation. Through the literature search up to August 2013, we identified 18 studies, 10 case-control and 8 cohorts, carried out in a total of 7142 leukemia cases. We derived pooled meta-analytic estimates using random-effects models, taking into account the correlation between estimates, and we performed a dose–risk analysis using a class of nonlinear random-effects meta-regression models. Stratified analyses were carried out on leukemia subtypes and groups, in order to identify possible etiologic differences. Compared with nondrinkers, the relative risks (RRs) for all leukemia were 0.94 [95% confidence interval (CI), 0.85–1.03], 0.90 (95% CI, 0.80–1.01) and 0.91 (95% CI, 0.81–1.02) for any, light (≤1 drink/day) and moderate to heavy (>1 drink/day) alcohol drinking, respectively. The summary RRs for any alcohol drinking were 1.47 (95% CI, 0.47–4.62) for acute lymphoblastic leukemia, 0.94 (95% CI 0.77–1.15) for chronic lymphocytic leukemia, 1.02 (95% CI, 0.86–1.21) for acute myeloid leukemia and 0.93 (95% CI 0.75–1.14) for chronic myeloid leukemia. The subgroup analysis on geographical area for all leukemia combined showed RRs of 0.84 (95% CI, 0.76–0.93), 0.92 (95% CI, 0.83–1.01) and 1.32 (95% CI, 1.02–1.70) for studies conducted in America, Europe and Asia, respectively. We did not find an increased risk of leukemia among alcohol drinkers. If any, a modest favorable effect emerged for light alcohol drinking, with a model-based risk reduction of approximately 10% in regular drinkers.     

Does night work increase the risk of breast cancer? A systematic review and meta-analysis of epidemiological studies

Objective: To conduct a systematic review, with meta-analysis, of studies assessing the association between night work and the risk of breast cancer, using available epidemiological evidence. Method: Relevant studies were identified by searching several databases and the reference lists of retrieved articles. We combined the relative risks (RR) from individual studies using a random-effects model. Subgroup analysis was carried out as the data showed statistically significant heterogeneity. Results: Thirteen studies consisting of eight case–control studies and five cohort studies were included in the analysis. In the combined analysis of all studies, night work was associated with an increased risk for breast cancer (RR = 1.20, 95%CI = 1.08–1.33). The higher-quality studies showed a similar finding with a pooled RR of 1.40 (95%CI = 1.13–1.73). Both case–control studies (RR = 1.32, 95%CI = 1.17–1.50) and cohort studies (RR = 1.08, 95%CI = 0.97–1.21) showed a positive association between night work and the risk of breast cancer. No publication bias was found either from Begg's funnel plot (P = 0.086) or the Egger's test (P = 0.107). Additional well-conducted and large-scale epidemiological studies are needed.     

Effects of daily iron supplementation in primary-school–aged children: systematic review and meta-analysis of randomized controlled trials

Background:

Anemia is an important public health and clinical problem. Observational studies have linked iron deficiency and anemia in children with many poor outcomes, including impaired cognitive development; however, iron supplementation, a widely used preventive and therapeutic strategy, is associated with adverse effects. Primary-school–aged children are at a critical stage in intellectual development, and optimization of their cognitive performance could have long-lasting individual and population benefits. In this study, we summarize the evidence for the benefits and safety of daily iron supplementation in primary-school–aged children.

Methods:

We searched electronic databases (including MEDLINE and Embase) and other sources (July 2013) for randomized and quasi-randomized controlled trials involving daily iron supplementation in children aged 5–12 years. We combined the data using random effects meta-analysis.

Results:

We identified 16 501 studies; of these, we evaluated 76 full-text papers and included 32 studies including 7089 children. Of the included studies, 31 were conducted in low- or middle-income settings. Iron supplementation improved global cognitive scores (standardized mean difference 0.50, 95% confidence interval [CI] 0.11 to 0.90, p = 0.01), intelligence quotient among anemic children (mean difference 4.55, 95% CI 0.16 to 8.94, p = 0.04) and measures of attention and concentration. Iron supplementation also improved age-adjusted height among all children and age-adjusted weight among anemic children. Iron supplementation reduced the risk of anemia by 50% and the risk of iron deficiency by 79%. Adherence in the trial settings was generally high. Safety data were limited.

Interpretation:

Our analysis suggests that iron supplementation safely improves hematologic and nonhematologic outcomes among primary-school–aged children in low- or middle-income settings and is well-tolerated.An estimated 25% of school-aged children worldwide are anemic.¹ Iron deficiency is thought to account for about half of the global cases of anemia² and is associated with inadequate dietary iron and, in developing settings, hookworm and schistosomiasis.³ In developed settings, anemia is prevalent among disadvantaged populations, including newly arrived refugees, indigenous people⁴ and some ethnic groups (e.g., Hispanic people in the United States).^5,6 About 3% of primary-school–aged children in Canada are anemic.⁷ Programs to address anemia are constrained by concerns that iron supplements cause adverse effects, including an increased risk of infections such as malaria in endemic areas.⁸In observational studies, iron deficiency has been associated with impaired cognitive and physical development. It has been estimated that each 10 g/L decrement in hemoglobin reduces future intelligence quotient (IQ) by 1.73 points.⁹ However, observational data are susceptible to confounding,¹⁰ and a causal relation between iron deficiency and cognitive impairment has not been confirmed.¹¹ Randomized controlled trials should overcome confounding, but results of trials examining this question have not agreed.Optimizing cognitive and physical development in primary-school–aged children could have life-long benefits.¹² However, anemia-control recommendations must balance safety and efficacy. We performed a systematic review of the effects of daily iron supplementation, a commonly used strategy to combat anemia,² in primary-school–aged children. We examined cognitive, growth and hematologic outcomes and adverse effects across all settings.     

Clinical effect and safety of dendritic cell–cytokine-induced killer cell immunotherapy for pancreatic cancer: a systematic review and meta-analysis

BackgroundAlthough promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC.MethodsPubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0.ResultsA total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%).ConclusionIn contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy.     

Helicobacter pylori promotes epithelial-to-mesenchymal transition by downregulating CK2β in gastric cancer cells

Strains of Helicobacter pylori that are positive for the oncoprotein CagA (cytotoxin-associated gene A) are associated with gastric cancer and might be related to the epithelial-to-mesenchymal transition (EMT). Casein kinase 2 (CK2) is a serine/threonine protein kinase that plays a major role in tumorigenesis through signaling pathways related to the EMT. However, the role played by the interaction between CagA and CK2 in gastric carcinogenesis is poorly understood. Although CK2α protein expression remained unchanged during H. pylori infection, we found that CK2α kinase activity was increased in gastric epithelial cells. We also found that the CK2β protein level decreased in H. pylori-infected gastric cancer cells in CagA-dependent manner and demonstrated that CagA induced CK2β degradation via HDM2 (human double minute 2; its murine equivalent is MDM2). We observed that CagA induced HDM2 protein phosphorylation and that p53 levels were decreased in H. pylori-infected gastric cancer cells. In addition, downregulation of CK2β induced AKT Ser473 phosphorylation and decreased the AKT Ser129 phosphorylation level in gastric cancer cells. We also found that the downregulation of CK2β triggered the upregulation of Snail levels in gastric cancer cells. Furthermore, our in vivo experiments and functional assays of migration and colony formation suggest that CK2β downregulation is a major factor responsible for the EMT in gastric cancer. Therefore, CK2 could be a key mediator of the EMT in H. pylori-infected gastric cancer and could serve as a molecular target for gastric cancer treatment.     

A Second-generation Protein–Protein Interaction Network of Helicobacter pylori

Helicobacter pylori infections cause gastric ulcers and play a major role in the development of gastric cancer. In 2001, the first protein interactome was published for this species, revealing over 1500 binary protein interactions resulting from 261 yeast two-hybrid screens. Here we roughly double the number of previously published interactions using an ORFeome-based, proteome-wide yeast two-hybrid screening strategy. We identified a total of 1515 protein–protein interactions, of which 1461 are new. The integration of all the interactions reported in H. pylori results in 3004 unique interactions that connect about 70% of its proteome. Excluding interactions of promiscuous proteins we derived from our new data a core network consisting of 908 interactions. We compared our data set to several other bacterial interactomes and experimentally benchmarked the conservation of interactions using 365 protein pairs (interologs) of E. coli of which one third turned out to be conserved in both species.Helicobacter pylori is a Gram-negative, microaerophilic bacterium that colonizes the stomach, an unusual highly acidic niche for microorganisms. In 1983, Warren and Marshall found it to be associated with gastric inflammation and duodenal ulcer disease (1, 2). A chronic infection with H. pylori can lead to development of stomach carcinoma and MALT lymphoma (reviewed in (3)). Hence, the World Health Organization has classified H. pylori as a class I carcinogen (4). It is estimated that half of the world′s population harbors H. pylori but with large variations in the geographical and socioeconomic distribution while causing annually 700,000 deaths worldwide (reviewed in (5)).The pathogenesis of H. pylori has been extensively studied, including the effector CagA, cytotoxin VacA, its adhesins and urease (reviewed in (3, 5–7)). The latter allows the bacterium to neutralize the stomach acid through ammonia production. However, H. pylori is not a classical model organism and thus many gaps in our knowledge still exist.The genome of H. pylori reference strain 26695 was completely sequenced in 1997 (8) and encodes 1587 proteins of which about 950 (61%) have been assigned functions (excluding “putatives”; Uniprot, CMR (9)). These numbers indicate that a large fraction of the proteins of H. pylori has not been functionally characterized.Protein–protein interactions (PPIs)¹ are required for nearly all biological processes. Unbiased interactomes are helpful to understand proteins or pathways and how they are linking poorly or uncharacterized proteins via their interactions. For instance, our study of the Treponema pallidum interactome (10) has led to the characterization of several previously “unknown” proteins such as YbeB, a ribosomal silencing factor (11), or TP0658, a regulator of flagellar translation and assembly (12, 13). However, only a few other comprehensive bacterial interactome studies have been published to date, including Campylobacter jejuni (14), Synechocystis sp. (15), Mycobacterium tuberculosis (16), Mesorhizobium loti (17), and recently Escherichia coli (18). In addition, partial interactomes are available for Bacillus subtilis (19) and H. pylori (20). Most of them used the yeast two-hybrid (Y2H) screening technology (21) which allows the pairwise detection of PPIs. Furthermore, a few other studies (22–25) systematically identified protein complexes and their compositions in bacteria.In 2001, Rain and colleagues have established a partial interactome of H. pylori, the first published protein interaction network of a bacterium (20). In this study, 261 bait constructs were screened against a random prey pool library resulting in the detection of over 1500 PPIs. Although this network likely represents a small fraction of all PPIs that occur in H. pylori, many downstream studies were motivated by these results (see below).Recent studies have disproved the notion that Y2H data sets are of poor quality (26, 27). Similarly, a high false-negative rate can be avoided by multiple Y2H expression vector systems (28–30) or protein fragments as opposed to full-length constructs (31). The aim of this study was to systematically screen the H. pylori proteome for binary protein interactions using a complementary approach to that of Rain et al. to produce an extended protein–protein interaction map of H. pylori. As a result, we have roughly doubled the number of known binary protein–protein interactions for H. pylori in this study.     

Adiponectin,TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis

AimsThere has been growing evidence that adiponectin, tumor necrosis factor-α (TNF-α) and inflammatory cytokines involved in insulin resistance and may be attractive candidates for assessing risk of the incident type 2 diabetes (T2DM). A systematic review and meta-analysis of prospective studies was conducted to assess the associations of levels of serum adiponectin, TNF-α and inflammatory markers (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-18 (IL-18), C-reactive protein (CRP)) with risk of T2DM.Materials/methodsWe searched PubMed, ISI Web of Knowledge, EMBASE, and Cochrane Library databases up until February 1, 2016 for eligible studies which were matched to search subjects. Either fixed-effects or random-effects models were used to estimate the summary risk incorporated between study variations.Results19 studies comprising a total of 39,136 participants and 7924 cases were included in the meta-analysis. Our findings showed that an obvious association of elevated CRP levels with T2DM risk (relative risk [RR] 1.48 [95% CI 1.26–1.71]), with the absence of publication bias. For IL-6, the meta-analysis involved 16 cohorts with a total of 24,929 participants and 4751 cases. Using data from all trials, a strong positive correlation (1.32 [1.14, 1.51]) was observed between basal plasma IL-6 and T2DM, whereas relatively lower relation between TNF-α (1.16 [0.87, 1.45]), IL-18 (1.45 [1.16, 1.73]), IL-1β (0.87, [0.59, 1.15]) and independently increased risk to occurrence of T2DM. Conversely, we also found that the level of adiponectin decreased significantly in patients with T2DM. Sensitivity analyses further supported the associations.ConclusionsThis meta-analysis indicates that T2DM risk as whole was strongly associated with elevated levels of inflammatory cytokines (IL-1β, IL-6, IL-18, CRP), TNF-α and low levels of adiponectin. Despite an overall detectable association in the meta-analysis, considerable heterogeneity existed between studies. Further work is needed, it seems clear that a complex interplay of inflammation and the development of DM. Moreover, these biomarkers are predictors of T2DM subjects and should take more attention to measure levels of these as well as to target therapy/interventions.     

Evidence-based hydro- and balneotherapy in Hungary—a systematic review and meta-analysis

Balneotherapy is appreciated as a traditional treatment modality in medicine. Hungary is rich in thermal mineral waters. Balneotherapy has been in extensive use for centuries and its effects have been studied in detail. Here, we present a systematic review and meta-analysis of clinical trials conducted with Hungarian thermal mineral waters, the findings of which have been published by Hungarian authors in English. The 122 studies identified in different databases include 18 clinical trials. Five of these evaluated the effect of hydro- and balneotherapy on chronic low back pain, four on osteoarthritis of the knee, and two on osteoarthritis of the hand. One of the remaining seven trials evaluated balneotherapy in chronic inflammatory pelvic diseases, while six studies explored its effect on various laboratory parameters. Out of the 18 studies, 9 met the predefined criteria for meta-analysis. The results confirmed the beneficial effect of balneotherapy on pain with weight bearing and at rest in patients with degenerative joint and spinal diseases. A similar effect has been found in chronic pelvic inflammatory disease. The review also revealed that balneotherapy has some beneficial effects on antioxidant status, and on metabolic and inflammatory parameters. Based on the results, we conclude that balneotherapy with Hungarian thermal-mineral waters is an effective remedy for lower back pain, as well as for knee and hand osteoarthritis.     

Efficacy and safety of catheter ablation for atrial fibrillation in congenital heart disease – A systematic review and meta-analysis

BackgroundPrevalence of atrial fibrillation (AF) in patients with congenital heart disease (CHD) is on the rise. Anti-arrhythmic drugs are usually the first line of treatment in CHD, however, it is often ineffective and poorly tolerated. We aimed to perform a systematic review to assess the efficacy and safety of catheter ablation for AF in CHD.MethodsWe performed a comprehensive search on catheter ablation for atrial fibrillation in congenital heart disease up until July 2019 through several electronic databases.ResultsAblation of AF in patients with CHD had a modest 12 months AF freedom ranging from 32.8% to 63%, which can be increased by subsequent/repeat ablation. The complexity of CHD appears to have a significant effect on a study but not in others. Catheter ablation in ASD and persistent left superior vena cava had a high success rate. Overall, catheter ablation is safe whichever the type of CHD is.ConclusionCatheter ablation for AF in CHD had modest efficacy that can be increased by subsequent/repeat ablation and it also has an excellent safety profile. Ablation in complex CHD could also have similar efficacy, however, it is preferably done by experts in a high volume tertiary center.     

Are older patients less likely to be treated for pancreatic cancer? A systematic review and meta-analysis

Pancreatic cancer is the seventh commonest cause of cancer-related death worldwide. Although prognosis is poor, both surgery and adjuvant chemotherapy improve survival. However, it has been suggested that not all pancreatic cancer patients who may benefit from treatment receive it. This systematic review and meta-analysis investigated the existence of age-related inequalities in receipt of first-line pancreatic cancer treatment. Medline, Embase, Cochrane Library and grey literature were searched for population-based studies investigating treatment receipt, reported by age, for patients with primary pancreatic cancer from inception until 4th June 2020, and updated 5th August 2021. Studies from countries with universal healthcare were included, to minimise influence of health system-related economic factors. A modified version of the Newcastle-Ottawa Scale was used to assess risk of bias. Random-effects meta-analysis was undertaken comparing likelihood of treatment receipt in older versus younger patients. Sensitivity and subgroup analyses were conducted. Eighteen papers were included; 12 independent populations were eligible for meta-analysis. In most studies, < 10% of older patients were treated. Older age (generally ≥65) was significantly associated with reduced receipt of any treatment (OR=0.14, 95% CI 0.10–0.21, n = 12 studies), surgery (OR=0.15, 95% CI 0.09–0.24, n = 9 studies) and chemotherapy as a primary treatment (OR=0.13, 95% CI 0.07–0.24, n = 5 studies). The effect of age was independent of methodological quality, patient population or time-period of patient diagnosis and remained in studies with confounder adjustment. The mean quality score of included studies was 6/8. Inequalities in receipt of healthcare interventions across social groups is a recognised concern internationally. This review shows that older age is significantly, and consistently, associated with non-receipt of treatment in pancreatic cancer. However, there are risks and side-effects associated with pancreatic cancer treatment. Further research on what influences patient and professional treatment decision-making is required to better understand these apparent inequalities.     

Updating the “Risk Index”: A systematic review and meta-analysis of occupational injuries and work schedule characteristics

Fatigue is a major risk factor for occupational ‘accidents’ and injuries, and involves dimensions of physical, mental, and muscular fatigue. These dimensions are largely influenced by temporal aspects of work schedules. The “Risk Index” combines four fatigue-related components of work schedules to estimate occupational ‘accident’ and injury risk based on empirical trends: shift type (morning, afternoon/evening, night), length and consecutive number, and on-shift rest breaks. Since its first introduction in 2004, several additional studies have been published that allow the opportunity to improve the internal and external validity of the “Risk Index”. Thus, we updated the model’s estimates by systematically reviewing the literature and synthesizing study results using meta-analysis. Cochrane Collaboration directives and MOOSE guidelines were followed. We conducted systematic literature searches on each model component in Medline. An inverse variance approach to meta-analysis was used to synthesize study effect sizes and estimate between-studies variance (‘heterogeneity’). Meta-regression models were conducted to explain the heterogeneity using several effect modifiers, including the sample age and sex ratio. Among 3,183 initially identified abstracts, after screening by two independent raters (95–98% agreement), 29 high-quality studies were included in the meta-analysis. The following trends were observed: Shift type. Compared to morning shifts, injury risk significantly increased on night shifts (RR = 1.36 [95%CI = 1.15–1.60], n = 14 studies), while risk was slightly elevated on afternoon/evening shifts, although non-significantly (RR = 1.12 [0.76–1.64], n = 9 studies). Meta-regressions revealed worker’s age as a significant effect modifier: adolescent workers (≤ 20 y) showed a decreased risk on the afternoon/evening shift compared to both morning shifts and adult workers (p < 0.05). Number of consecutive shifts. Compared to the first shift in a block of consecutive shifts, risk increased exponentially for morning shifts (e.g., 4th: RR = 1.09 [0.90–1.32]; n = 6 studies) and night shifts (e.g., 4th: RR = 1.36 [1.14–1.62]; n = 8 studies), while risk on afternoon/evening shifts appeared unsystematic. Shift length. Injury risk rose substantially beyond the 9th hour on duty, a trend that was mirrored when looking at shift lengths (e.g., >12 h: RR = 1.34 [1.04–1.51], n = 3 studies). Rest breaks. Risk decreased for any rest break duration (e.g., 31–60 min: RR = 0.35 [0.29–0.43], n = 2 studies). With regards to time between breaks, risk increased with every additional half hour spent on the work task compared to the first 30 min (e.g., 90–119 min: RR = 1.62 [1.00–2.62], n = 3 studies). Rest break duration and interval seem to interact such that with increasing duration, the time between breaks becomes irrelevant. The updated “Risk Index”. All four components were combined to form the updated model and the relative risk values estimated for a variety of work schedules. The resulting “Risk Map” shows regions of highest risk when rest breaks are not taken frequently enough (i.e. <4 h) or are too short (i.e. <30 min), when shift length exceeds 11 h, and when work takes place during the night (particularly for >3 consecutive night shifts). The “Risk Index” is proposed as an empirical model to predict occupational ‘accident’ and injury risk based on the most recent data in the field, and can serve as a tool to evaluate hazards and maximize safety across different work schedules.