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.

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

Background aimsEvidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs.MethodsA systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19.ResultsEight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42–0.94, P = 0.02, I² = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB.ConclusionsMSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.     

Global estimate of gastric cancer in Helicobacter pylori–infected population: A systematic review and meta-analysis

There is information regarding the rates of gastric cancer (GC) in different populations and the important role of Helicobacter pylori in GC development; however, no comprehensive study has yet been performed to investigate the prevalence of GC in H. pylori–infected patients. PubMed, Embase, and Cochrane Library through January 1, 2000 were searched without language restrictions. Quality of included studies was assessed with a critical appraisal checklist recommended by the Joanna Briggs Institute. All of the analyses were conducted using Comprehensive Meta-Analysis Software Version 2.0 and Stata 14.0. Forty-four studies from 17 countries were included. The pooled frequency of GC was 17.4% (95% confidence interval: 16.4–18.5) in H. pylori–infected population. The frequency of GC among H. pylori–infected population varied markedly across countries. The highest rate of GC was observed in H. pylori–infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori–infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high-risk populations such as Asian countries.     

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.

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.     

Effects of the juçara fruit supplementation on metabolic parameters in individuals with obesity: a double-blind randomized controlled trial

Adipose tissue inflammation has been proposed as a central mechanism connecting obesity with its metabolic and vascular complications due to the imbalance in the expression of several hormones and adipokines. Berries rich in polyphenols and unsaturated fatty acids have been able to prevent both obesity and adipose tissue inflammation, improving metabolic functions in human subjects and animal models of obesity. Juçara has been considered a super fruit owing to its nutritional composition and relevant biological activities with an interesting response in animals. Thus, we aimed to verify the potential antiobesogenic effect of juçara supplementation in humans. We conducted a double-blind, placebo-controlled, randomized trial with 35 adults with obesity of both sexes. They were assessed for resting metabolic rate, anthropometry and body composition, blood pressure, metabolic parameters and adipokines. Subsequently, they were randomized into two groups to use or not (placebo) 5 g lyophilized juçara for 6 weeks. Supplementation with juçara was significantly effective in reducing body fat, increasing high-density lipoprotein cholesterol and doubling serum adiponectin. Besides, juçara supplementation, high-density lipoprotein cholesterol and neck circumference were predictors to explain the enhancement in adiponectin. Juçara supplementation was determinant to improve adiponectin levels, and it may be considered a novel strategy for the treatment of obesity-related metabolic diseases.     

Fluoroquinolones compared with β-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials

Background

The presumed superiority of newer fluoroquinolones for the treatment of acute bacterial sinusitis is based on laboratory data but has not yet been established on clinical grounds.

Methods

We performed a meta-analysis of randomized controlled trials comparing the effectiveness and safety of fluoroquinolones and β-lactams in acute bacterial sinusitis.

Results

We identified 8 randomized controlled trials investigating the newer “respiratory” fluoroquinolones moxifloxacin, levofloxacin and gatifloxacin. In the primary effectiveness analysis involving 2133 intention-to-treat patients from 5 randomized controlled trials, the extent of clinical cure and improvement did not differ between fluoroquinolones and β-lactams (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.85–1.39) at the test-of-cure assessment, which varied from 10 to 31 days after the start of treatment. Fluoroquinolones were associated with an increased chance of clinical success among the clinically evaluable patients in all of the randomized controlled trials (OR 1.29, 95% CI 1.03–1.63) and in 4 blinded randomized controlled trials (OR 1.45, 95% CI 1.05–2.00). There was no statistically significant difference between fluoroquinolones and amoxicillin–clavulanate (OR 1.24, 95% CI 0.93–1.65). Eradication or presumed eradication of the pathogens isolated before treatment was more likely with fluoroquinolone treatment than with β-lactam treatment (OR 2.11, 95% CI 1.09–4.08). In the primary safety analysis, adverse events did not differ between treatments (OR 1.17, 95% CI 0.86–1.59). However, more adverse events occurred with fluoroquinolone use than with β-lactam use in 2 blinded randomized controlled trials. The associations described here were generally consistent when we included 3 additional studies involving other fluoroquinolones (ciprofloxacin and sparfloxacin) in the analysis.

Interpretation

In the treatment of acute bacterial sinusitis, newer fluoroquinolones conferred no benefit over β-lactam antibiotics. The use of fluoroquinolones as first-line therapy cannot be endorsed.Acute bacterial sinusitis (more accurately known as rhinosinusitis, given that the nasal mucosa is commonly involved¹) is one of the most frequent health disorders;² it has an adverse impact on patients'' quality of life³ and accounts for nearly 3 million ambulatory care visits in the United States annually⁴ and substantial health care costs.⁵Acute bacterial sinusitis typically follows an episode of viral upper respiratory tract illness.² The diagnosis of bacterial disease in routine clinical practice is usually based on the presence of a constellation of clinical manifestations.¹ The bacterial pathogens most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae and, to a lesser degree, Moraxella catarrhalis.^6,7 Over the years, these pathogens have acquired various degrees of resistance to many traditional antibiotics.⁸The benefit of older antibiotics over placebo in the treatment of acute bacterial sinusitis appears limited, mostly because of the high success rate achieved with placebo.^9,10 However, newer, third-and fourth-generation fluoroquinolones possess excellent in vitro activity against the most common respiratory pathogens,¹¹ and for this reason these drugs are often designated as “respiratory.” Based on analysis of the available laboratory data, current guidelines give the newer fluoroquinolones the highest ranking, in terms of expected clinical effectiveness, among the antimicrobials used to treat acute bacterial sinusitis (although admittedly the difference is marginal).⁷The presumed clinical advantage of the respiratory fluoroquinolones over other classes of antimicrobials has not been clearly demonstrated in comparative clinical trials or meta-analyses.^9,10 We aimed to comprehensively reassess the role of fluoroquinolones in the treatment of acute bacterial sinusitis, in terms of effectiveness and safety, by performing a meta-analysis of relevant randomized controlled trials.     

Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials

Concerns about growth retardation and unknown effects on long-term brain development with stimulants have prompted interest in polyunsaturated fatty acid supplementation (PUFA) as an alternative treatment. However, randomized controlled trials (RCTs) and meta-analyses of PUFA supplementation in ADHD have shown marginal benefit, and uncertainty exists as to which, if any, PUFA might be effective in alleviating symptoms of ADHD. We conducted an updated meta-analysis of RCTs in ADHD together with multivariable meta-regression analyses using data on PUFA content obtained from independent fatty acid methyl ester analyses of each study PUFA regimen. The PubMed, Embase and PsycINFO databases were searched with no start date and up to 28th July 2013. Study inclusion criteria were: randomized design, placebo controlled, PUFA preparation as active intervention, reporting change scores on ADHD rating-scale measures. Rating-scale measures of inattention and hyperactive-impulsive symptoms were extracted, study authors were contacted to obtain missing data, studies not reporting negative findings had these data imputed, and study quality was assessed using the Jadad system plus other indicators. Random-effects models were used for pooled effects and for meta-regression analyses. Standardized mean differences (SMD) in inattention, hyperactive-impulsive and combined symptoms were assessed as rated by parents, teachers or all raters. The influence of study characteristics and PUFA regimen content was explored in multivariable meta-regression analyses. The overall pooled estimate from 18 studies showed that combined ADHD symptoms rated by all raters decreased with PUFA supplementation; SMD −0.192 (95% CI: −0.297, −0.086; P<0.001). However, when analyzed by rater, only parent-rated symptoms decreased significantly. Multivariable meta-regression showed that longer study duration, γ-linolenic acid (GLA), and the interaction between GLA and eicosapentaenoic acid (EPA) were associated with significant decreases in inattention; however, PUFA regimen content was unrelated to changes in hyperactive-impulsive symptoms. Certain fatty acids present in placebo preparations may potentially have been psychoactive. This meta-analysis provides modest evidence of PUFA effectiveness in ADHD, especially GLA and EPA for inattention symptoms; however, evidence of reporting bias, publication bias, variable methodological quality, and use of potentially psychoactive placebos limit the generalizability of these findings.     

Potential problems of ascorbate and iron supplementation: pro-oxidant effect in vivo?

The comparison was undertaken between the effects of ascorbate versus ascorbate plus iron supplementation on DNA damage. Twenty healthy subjects with initial levels of plasma ascorbate of 67.2 +/- 23.3 micromol/l were randomly assigned to and cycled through one of three supplementation regimes: placebo, 260 mg/d ascorbate, 260 mg/d ascorbate plus 14 mg/d iron for 6 weeks separated by 8-week washout periods. Supplementation did not cause a rise in total oxidative DNA damage measured by GC-MS. However, a significant decrease occurred in levels of 8-oxo-7,8-dihydroguanine by ascorbate supplementation and 5-hydroxymethyl uracil by both ascorbate and ascorbate plus iron supplementation, relative to the pre-supplemental levels but not to the placebo group. In addition, levels of 5-hydroxymethyl hydantoin and 5-hydroxy cytosine increased significantly, only relative to pre-supplementation, by ascorbate plus iron treatment. No compelling evidence for a pro-oxidant effect of ascorbate supplementation, in the presence or absence of iron, on DNA base damage was observed.     

Can testing clinical significance reduce false positive rates in randomized controlled trials? A snap review

Objective

The use of minimum clinically important difference in the hypothesis formulation for superiority trials is similar in principle to the concept of non-inferiority or equivalence trial. However, most clinical trials are analysed testing zero clinical difference. Since the minimum clinically important difference is pre-defined for power calculation, it is important to incorporate it in both the hypothesis testing and the interpretation of findings from clinical trials.

Results

We reviewed a set of 50 publications (25 with binary outcome, and 25 with survival time outcome). 20% of the 50 published trials that were statistically significant, were also clinically significant based on the minimum clinically important risk differences (or hazard ratio) used for their power calculations. This snap review seems to suggest that most published trials with statistically significant results were less likely to be clinically significant, which may partly explain the high false positive findings associated with findings from superiority trials. Furthermore, none of the reviewed publications explicitly used minimum clinically important difference in the interpretation of their findings. However, a systematic review is needed to critically appraise the impact of the current practice on false positive rate in published trials with significant findings.

     

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.     

Does dietary fat affect inflammatory markers in overweight and obese individuals?—a review of randomized controlled trials from 2010 to 2016

Background

Obesity, a major cause of death and disability, is increasing worldwide. Obesity is characterized by a chronic, low-grade inflammatory state which is suggested to play a critical role in the development of obesity-related diseases like cardiovascular diseases and type 2 diabetes. In fact, in the hours following consumption of a meal, a transient increase in inflammatory markers occurs, a response that is exaggerated in obese subjects. Dietary composition, including content of dietary fatty acids, may affect this inflammatory response both acutely and chronically, and thereby be predictive of progression of disease. The aim of the review was to summarize the literature from 2010 to 2016 regarding the effects of dietary fat intake on levels of inflammatory markers in overweight and obesity in human randomized controlled trials.

Methods and results

We performed a literature search in MEDLINE, EMBASE, and PubMed databases. The literature search included human randomized controlled trials, both postprandial and long-term interventions, from January 2010 to September 2016. In total, 37 articles were included. Interventions with dairy products, vegetable oils, or nuts showed minor effects on inflammatory markers. The most consistent inflammatory-mediating effects were found in intervention with whole diets, which suggests that many components of the diet reduce inflammation synergistically. Furthermore, interventions with weight reduction and different fatty acids did not clearly show beneficial effects on inflammatory markers.

Conclusion

Most interventions showed either no or minor effects of dietary fat intake on inflammatory markers in overweight and obese subjects. To progress our understanding on how diet and dietary components affect our health, mechanistic studies are required. Hence, future studies should include whole diets and characterization of obese phenotypes at a molecular level, including omics data and gut microbiota.

     

Interferon-γ release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis

Background

Despite the widespread use of interferon-γ release assays (IGRAs), their role in diagnosing tuberculosis and targeting preventive therapy in HIV-infected patients remains unclear. We conducted a comprehensive systematic review to contribute to the evidence-based practice in HIV-infected people.

Methodology/Principal Findings

We searched MEDLINE, Cochrane, and Biomedicine databases to identify articles published between January 2005 and July 2011 that assessed QuantiFERON®-TB Gold In-Tube (QFT-GIT) and T-SPOT®.TB (T-SPOT.TB) in HIV-infected adults. We assessed their accuracy for the diagnosis of tuberculosis and incident active tuberculosis, and the proportion of indeterminate results. The search identified 38 evaluable studies covering a total of 6514 HIV-infected participants. The pooled sensitivity and specificity for tuberculosis were 61% and 72% for QFT-GIT, and 65% and 70% for T-SPOT.TB. The cumulative incidence of subsequent active tuberculosis was 8.3% for QFT-GIT and 10% for T-SPOT.TB in patients tested positive (one study each), and 0% for QFT-GIT (two studies) and T-SPOT.TB (one study) respectively in those tested negative. Pooled indeterminate rates were 8.2% for QFT-GIT and 5.9% for T-SPOT.TB. Rates were higher in high burden settings (12.0% for QFT-GIT and 7.7% for T-SPOT.TB) than in low-intermediate burden settings (3.9% for QFT-GIT and 4.3% for T-SPOT.TB). They were also higher in patients with CD4⁺ T-cell count <200 (11.6% for QFT-GIT and 11.4% for T-SPOT.TB) than in those with CD4⁺ T-cell count ≥200 (3.1% for QFT-GIT and 7.9% for T-SPOT.TB).

Conclusions/Significance

IGRAs have suboptimal accuracy for confirming or ruling out active tuberculosis disease in HIV-infected adults. While their predictive value for incident active tuberculosis is modest, a negative QFT-GIT implies a very low short- to medium-term risk. Identifying the factors associated with indeterminate results will help to optimize the use of IGRAs in clinical practice, particularly in resource-limited countries with a high prevalence of HIV-coinfection.     

Is C-reactive protein elevated in obstructive sleep apnea? a systematic review and meta-analysis

Purpose: This study examined whether circulating C-reactive protein (CRP) is elevated in obstructive sleep apnoea (OSA) independent of the confounding effects of comorbidities, smoking, body mass index (BMI), age and gender.

Methods: A systematic review of the literature was performed using PubMed, Embase and Cochrane databases from 1 January 1997 to 1 November 2017 using the key words obstructive sleep apnoea and C-Reactive protein to identify full text English language studies that compared CRP in adult non-smoking OSA participants without comorbidities and adult healthy non-smoking control participants matched for BMI, age and gender. Data from eligible studies were subjected to meta-analysis using RevMan version 5.3.

Results: Five studies (219 OSA participants, 116 controls) met the selection criteria. The total standard mean difference for circulating high sensitivity CRP was 0.61?mg/dL higher in OSA participants than in control participants (confidence interval: 0.38 to 0.84, p?<?0.00001), with low between-studies heterogeneity (df = 7, p?=?0.16, I²?=?33%) and minimal evidence of publication bias.

Conclusions: CRP levels in non-smoking OSA participants without comorbidities were increased relative to levels in healthy matched non-smoking control participants, suggesting that pharyngeal or systemic inflammatory effects attributable to OSA may elevate CRP.     

Effects of in combination antioxidant supplementation on microscopic and oxidative parameters of freeze–thaw bull sperm

The present study was conducted to determine the effect of reduced glutathione (GSH) and superoxide dismutase (SOD) supplementation in the bull semen freezing extender on post-thaw parameters of Holstein and Simmental bull sperm. Semen were collected from seven bulls (four Holstein and three Simmental) and cryopreserved in the Tris-egg-yolk based extender as control group and supplemented with various concentrations of GSH × SOD (5 × 100, 7.5 × 100, 5 × 150, and 7.5 × 150 mM × IU mL^?1) in treatment groups. Microscopic parameters were evaluated in terms of total motility parameters using computer assisted semen analysis and viability and membrane integrity were assessed using Eosin–Nigrosin stains and hypo-osmotic swelling test (HOST), respectively after thawing the semen. Malonaldialdehyde (MDA) level, SOD and glutathione peroxides (GPx) activities were assessed immediately after thawing. Results showed that supplementation of the cryopreservation medium with various concentrations of GSH × SOD improved total motility (TM) and progressive motility parameters for Holstein (P < 0.05) semen, and values of TM and HOST for Simmental semen compared to the control group (P < 0.01) after semen thawing. Addition of antioxidant to Holstein semen samples decreased the level of MDA and increased GPx activities compared to control groups (P < 0.05). SOD activities increased in Simmental bull samples compare to the control group (P < 0.01), but not differ in Holstein, while these activities. In conclusion, supplementation of antioxidant to the semen extender as combination (GSH × SOD) improved the semen post-thaw qualities which may be associated with a reduction in lipid peroxidation as well as an increase in the antioxidant enzyme activities.     

Prevalence of Kaposi’s sarcoma-associated herpesvirus among intravenous drug users: a systematic review and meta-analysis

Intravenous drug users(IDUs) have been demonstrated to be highly vulnerable to HIV/AIDS.Nevertheless, the prevalence of Kaposi's sarcoma associated herpesvirus(KSHV), an important co-infected agent with HIV, among this population remained obscure. We conducted a systematic review on the epidemiological features of KSHV among IDUs worldwide. Eligible studies were retrieved from 6 electronic databases(Pub Med, EMBASE, Web of Science, CBM, CNKI and Wanfang).We calculated the pooled prevalence and 95% confidence interval(CI) overall and among subgroups using either random-effects model or fixed-effects model depending on between-study heterogeneity. The potential publication bias was assessed by the Egger's test. A meta-regression analysis was performed to explore the sources of heterogeneity. Finally, twenty-two studies with a total sample of 7881 IDUs were included in the analysis. The pooled prevalence of KSHV was14.71%(95% CI 11.12%–19.46%) among IDUs. Specifically, KSHV prevalence was 10.86%(95% CI6.95%–16.96%) in HIV-negative IDUs, and 13.56%(95% CI 10.57%–17.38%) in HIV-positive IDUs.Moreover, prevalence among IDUs from the three continents involved in the current study was similar:16.10%(95%CI 7.73%–33.54%) in Asia; 14.22%(95%CI 8.96%–22.57%) in Europe and 14.06%(95%CI11.38%–17.37%) in America. Globally, IDUs are at higher risk of the KSHV infection when compared with the general population, regardless of geographical region or HIV-infection status.     

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.