Franco Momoli

Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts

Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by 356. Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimers disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances.

Association Between Early Participation in Physical Activity Following Acute Concussion and Persistent Postconcussive Symptoms in Children and Adolescents

Importance Although concussion treatment guidelines advocate rest in the immediate postinjury period until symptoms resolve, no clear evidence has determined that avoiding physical activity expedites recovery. Objective To investigate the association between participation in physical activity within 7 days postinjury and incidence of persistent postconcussive symptoms (PPCS). Design, Setting, and Participants Prospective, multicenter cohort study (August 2013-June 2015) of 3063 children and adolescents aged 5.00-17.99 years with acute concussion from 9 Pediatric Emergency Research Canada network emergency departments (EDs). Exposures Early physical activity participation within 7 days postinjury. Main Outcomes and Measures Physical activity participation and postconcussive symptom severity were rated using standardized questionnaires in the ED and at days 7 and 28 postinjury. PPCS (≥3 new or worsening symptoms on the Post-Concussion Symptom Inventory) was assessed at 28 days postenrollment. Early physical activity and PPCS relationships were examined by unadjusted analysis, 1:1 propensity score matching, and inverse probability of treatment weighting (IPTW). Sensitivity analyses examined patients (≥3 symptoms) at day 7. Results Among 2413 participants who completed the primary outcome and exposure, (mean [SD] age, 11.77 [3.35] years; 1205 [39.3%] females), PPCS at 28 days occurred in 733 (30.4%); 1677 (69.5%) participated in early physical activity including light aerobic exercise (n = 795 [32.9%]), sport-specific exercise (n = 214 [8.9%]), noncontact drills (n = 143 [5.9%]), full-contact practice (n = 106 [4.4%]), or full competition (n = 419 [17.4%]), whereas 736 (30.5%) had no physical activity. On unadjusted analysis, early physical activity participants had lower risk of PPCS than those with no physical activity (24.6% vs 43.5%; Absolute risk difference [ARD], 18.9% [95% CI,14.7%-23.0%]). Early physical activity was associated with lower PPCS risk on propensity score matching (n = 1108 [28.7% for early physical activity vs 40.1% for no physical activity]; ARD, 11.4% [95% CI, 5.8%-16.9%]) and on inverse probability of treatment weighting analysis (n = 2099; relative risk [RR], 0.74 [95% CI, 0.65-0.84]; ARD, 9.7% [95% CI, 5.7%-13.7%]). Among only patients symptomatic at day 7 (n = 803) compared with those who reported no physical activity (n = 584; PPCS, 52.9%), PPCS rates were lower for participants of light aerobic activity (n = 494 [46.4%]; ARD, 6.5% [95% CI, 5.7%-12.5%]), moderate activity (n = 176 [38.6%]; ARD, 14.3% [95% CI, 5.9%-22.2%]), and full-contact activity (n = 133 [36.1%]; ARD, 16.8% [95% CI, 7.5%-25.5%]). No significant group difference was observed on propensity-matched analysis of this subgroup (n = 776 [47.2% vs 51.5%]; ARD, 4.4% [95% CI, -2.6% to 11.3%]). Conclusions and Relevance Among participants aged 5 to 18 years with acute concussion, physical activity within 7 days of acute injury compared with no physical activity was associated with reduced risk of PPCS at 28 days. A well-designed randomized clinical trial is needed to determine the benefits of early physical activity following concussion.

The MOBI-Kids study protocol: challenges in assessing childhood and adolescent exposure to electromagnetic fields from wireless telecommunication technologies and possible association with brain tumor risk

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

Evolution of Computed Tomography Angiography Spot Sign Is Consistent With a Site of Active Hemorrhage in Acute Intracerebral Hemorrhage

Background and Purpose— CT angiography spot sign predicts hematoma expansion in patients with acute intracerebral hemorrhage (ICH). The spot sign may represent a site of active extravasation, a locus of arrested hemorrhage forming fibrin globes, or represent associated epiphenomena such as hypertensive microaneurysms. We sought to describe the evolution of spot signs over 60 seconds in acute ICH using dynamic CT angiography and determine whether they grow and diffuse into the hematoma as would be expected with active extravasation. Methods— We prospectively identified consecutive patients presenting with spontaneous ICH <6 hours from symptom onset that completed dynamic CT angiography imaging over a 60-second acquisition protocol. We determined spot positivity, quantified spot volumes, and then used repeated-measures ANOVA to assess changes in spot volume over time. Results— We collected data on 35 patients; 13 of 35 (37%) patients were spot-positive. Spot-positive patients had larger median ICH volume compared with spot-negative patients (median 10.7 versus 49.2 mL; P=0.007). Maximal spot sign volumes ranged from 0.02 to 2.8 mL (median 0.17 mL). Spot sign volumes increased significantly with time (P<0.001) and seemed to disperse into the hematoma in all cases. Three of 13 (23%) spot-positive patients presented with 2 distinct spot signs, but the remaining patients either had only 1 spot sign or different contiguous components of an irregularly shaped spot sign. Conclusions— In this dynamic CT angiography study of ICH, spot signs evolve consistent with sites of active extravasation.

Occupations and Lung Cancer: A Population-Based Case-Control Study in British Columbia

An investigation based on a large population-based case-control study in British Columbia, Canada, was conducted to identify high-risk occupations for lung cancer by histological subtypes. Subjects were 14,755 male incident cancer cases for whom lifetime occupational histories and information on smoking and relevant covariates were collected. Occupational associations for 2998 lung cancer cases, including histological subtypes, were assessed by logistic regression using other cancer cases, excluding smoking-related cancers, as controls. An excess risk of lung cancer was found among workers in metal processing, bakers, and ship deck crew for all histological subtypes, and construction workers, chefs and cooks, and medical workers for specific histological subtypes. Occupational associations that are unique to histological subtypes of lung cancer were identified. Owing to a scarcity of literature in this area, future research needs to focus on confirming these histological associations, and identifying the risk from key exposures found within these occupations (e.g., medical radiation, electromagnetic fields, and cooking fumes).

Neck circumference percentile: A screening tool for pediatric obstructive sleep apnea

Large neck circumference (NC) is associated with obstructive sleep apnea (OSA) in adults, especially males. Since NC changes with age and sex, a lack of reference ranges makes neck size difficult to assess as a screening tool in children.

TAIMA (Stop) TB: The Impact of a Multifaceted TB Awareness and Door-to-Door Campaign in Residential Areas of High Risk for TB in Iqaluit, Nunavut

Background The incidence rate of active tuberculosis (TB) disease in the Canadian Territory of Nunavut has shown a rising trend over the past 10 years. In 2010 it was 60 times greater than the national incidence rate. The objective of the Taima (translates to “stop” in Inuktitut) TB study was to implement and evaluate a public health campaign to enhance existing TB prevention efforts in Nunavut. Methods A TB awareness campaign followed by a door-to-door screening campaign was carried out in Iqaluit, Nunavut. The aim of the campaign was to raise awareness about TB, and to provide in-home screening and treatment for people living in residential areas at high risk for TB. Screening was based on geographic location rather than on individual risk factors. Results During the general awareness campaign an increase in the number of people who requested TB testing at the local public health clinic was observed. However, this increase was not sustained following cessation of the awareness campaign. Targeted TB screening in high risk residential areas in Iqaluit resulted in 224 individuals having TSTs read, and detection of 42 previously unidentified cases of latent TB, (overall yield of 18.8% or number needed to screen = 5.3). These cases of latent TB infection (LTBI) were extra cases that had not been picked up by traditional screening practices (34% relative increase within the community). This resulted in a 33% relative increase in the completion of LTBI treatment within the community. The program directly and indirectly identified 5/17 new cases of active TB disease in Iqaluit during the study period (29.5% of all incident cases). Conclusions While contact tracing investigations remain a cornerstone of TB prevention, additional awareness, screening, and treatment programs like Taima TB may contribute to the successful control of TB in Aboriginal communities.

Analysis of multiple exposures: an empirical comparison of results from conventional and semi-bayes modeling strategies.

Background: Analysts of epidemiologic data often contend with the problem of estimating the independent effects of many correlated exposures. General approaches include assessing each exposure separately, adjusting for some subset of other exposures, or assessing all exposures simultaneously in a single model such as semi-Bayes modeling. The optimal strategy remains uncertain, and it is unclear to what extent different reasonable approaches influence findings. We provide an empirical comparison of results from several modeling strategies. Methods: In an occupational case-control study of lung cancer with 184 exposure substances, we implemented 6 modeling strategies to estimate odds ratios for each exposure-cancer association. These included one-exposure-at-a-time models with various confounder selection criteria (such as a priori selection or a change-in-the-estimate criterion) and semi-Bayes models, one version of which integrated information on previous evidence and chemical properties. Results: While distributions of odds ratios were broadly similar across the 6 analytic strategies, there were some differences in point estimates and in substances manifesting statistically significant odds ratios, particularly between strategies with few or no occupational covariates and those with many. Semi-Bayes models produced fewer statistically significant odds ratios than other methods. A simple semi-Bayes model that shrank all the 184 estimates to a common mean yielded nearly identical results to one that integrated considerable prior information. Conclusion: Different modeling strategies can lead to different results. Considering the conceptual and pragmatic difficulties of identifying confounders, these results suggest that it would be unwise to place uncritical reliance on any single strategy.

Reducing the Harm of Prostate Cancer Screening: Repeated Prostate-Specific Antigen Testing

OBJECTIVE To determine if repeating a prostate-specific antigen (PSA) test in men with an elevated PSA level is associated with a decreased risk of prostate biopsy and cancer diagnosis. PATIENTS AND METHODS A cohort of patients referred to the Ottawa Regional Prostate Cancer Assessment Clinic from April 1, 2008, through May 31, 2013, who had referral PSA levels between 4 and 10 ng/mL were included in the study. Univariate and multivariate associations between a normal result on repeated PSA testing and the risk of prostate biopsy, cancer diagnosis, and Gleason score of 7 or higher were examined. RESULTS The study cohort included 1268 patients. Repeated PSA test results were normal in 315 patients (24.8%). Men with normal results on repeated PSA testing were younger (mean ± SD age, 61.5±8.2 years vs 65.2±8.2 years; P<.001) and had lower referral PSA levels (mean ± SD, 5.5±1.4 ng/mL vs 6.6±1.5 ng/mL; P<.001) than men with an abnormal repeated PSA result. In multivariate analysis, men with normal results on repeated PSA testing were less likely to undergo prostate biopsy (relative risk [RR], 0.42; 95% CI, 0.34-0.50) and were at lower risk for cancer diagnosis (RR, 0.22; 95% CI, 0.14-0.34) and Gleason score of 7 or higher (RR, 0.16; 95% CI, 0.08-0.34) compared with men who had an abnormal repeated PSA test result. CONCLUSION Routinely repeating a PSA test in patients with an elevated PSA level is independently associated with decreased risk of prostate biopsy and prostate cancer diagnosis. Men with an elevated PSA level should be given a repeated PSA test before proceeding to biopsy.

Radiotherapy after Radical Prostatectomy: Treatment Recommendations Differ between Urologists and Radiation Oncologists

Purpose There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy. Methods Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed. Results One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score (Gleason 7 vs. 6, RR 1.37 95% CI 1.19-1.56, p<0.0001 and Gleason 8-10 vs. 6, RR 1.56 95% CI 1.37-1.78, p<0.0001), positive surgical margin (RR 1.43 95% CI 1.26-1.62, p<0.0001), and extraprostatic tumour extension (RR 1.16 95% CI 1.05-1.28, p<0.002) conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios (RR 1.48, 95% CI 1.39, 1.60, p <0.001). Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists). Conclusions Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged.