Physicochemical predictors of Multi‐Walled Carbon Nanotube–induced pulmonary histopathology and toxicity one year after pulmonary deposition of 11 different Multi‐Walled Carbon Nanotubes in mice

Multi‐walled carbon nanotubes (MWCNT) are widely used nanomaterials that cause pulmonary toxicity upon inhalation. The physicochemical properties of MWCNT vary greatly, which makes general safety evaluation challenging to conduct. Identification of the toxicity‐inducing physicochemical properties of MWCNT is therefore of great importance. We have evaluated histological changes in lung tissue 1 year after a single intratracheal instillation of 11 well‐characterized MWCNT in female C57BL/6N BomTac mice. Genotoxicity in liver and spleen was evaluated by the comet assay. The dose of 54 μg MWCNT corresponds to three times the estimated dose accumulated during a work life at a NIOSH recommended exposure limit (0.001 mg/m³). Short and thin MWCNT were observed as agglomerates in lung tissue 1 year after exposure, whereas thicker and longer MWCNT were detected as single fibres, suggesting biopersistence of both types of MWCNT. The thin and entangled MWCNT induced varying degree of pulmonary inflammation, in terms of lymphocytic aggregates, granulomas and macrophage infiltration, whereas two thick and straight MWCNT did not. By multiple regression analysis, larger diameter and higher content of iron predicted less histopathological changes, whereas higher cobalt content significantly predicted more histopathological changes. No MWCNT‐related fibrosis or tumours in the lungs or pleura was found. One thin and entangled MWCNT induced increased levels of DNA strand breaks in liver; however, no physicochemical properties could be related to genotoxicity. This study reveals physicochemical‐dependent difference in MWCNT‐induced long‐term, pulmonary histopathological changes. Identification of diameter size and cobalt content as important for MWCNT toxicity provides clues for designing MWCNT, which cause reduced human health effects following pulmonary exposure.     

Constant high adrenal FDG uptake in PET/CT associated with mitochondrial disease

We describe a patient with the m.3243A>G mitochondrial DNA mutation who developed sepsis caused by Streptococcus constellatus. In the acute phase of illness, abnormally high uptake of ¹⁸F-FDG was observed in both adrenal glands that appeared anatomically normal. In repeated imaging six months later the adrenal uptake had diminished but remained clearly elevated. We did not observe high adrenal FDG uptake as in the patient described here among 30 patients with Staphylococcus aureus sepsis that were investigated with identical imaging protocol. In sepsis, oxygen consumption and metabolic rate are increased compared to normal metabolism. The observed high adrenal FDG uptake during sepsis in this patient probably reflects the acute metabolic stress induced by the infection. Interestingly, in repeated imaging six months later, the adrenal SUVs had diminished but were still abnormally high: this suggests constant high levels of metabolic stress associated with the mitochondrial disorder.     

A prospective 8-year follow-up of posterior resin composite restorations in permanent teeth of children and adolescents in Public Dental Health Service: reasons for replacement

Objectives

The aim of the study was to investigate reasons for replacement and repair of posterior resin composite (RC) restorations placed in permanent teeth of children and adolescents attending Public Dental Health Service in Denmark.

Material and method

All posterior RC placed consecutively by 115 dentists over a period of 4 years were evaluated at baseline and up to 8 years later. The endpoint of each restoration was defined when repair or replacement was performed. The influence of patient, dentist and material factors on reasons for repair or replacement was investigated.

Results

A total of 4,355 restorations were placed. Replacements comprised 406 and repairs 125 restorations. The cumulative survival rate at 8 years was 84 %. Failed restorations were most frequently seen due to secondary caries (57 %), post-operative sensitivity (POS) (10 %) and RC fracture (6 %). POS was observed in 1.5 % of the evaluations and reported more often in girls and from teeth restored with a base material. Older dentists showed lower proportion of replaced restorations due to secondary caries than younger dentists.

Conclusion

Posterior RC restorations in children and adolescents performed in general practice showed a good durability with annual failure rates of 2 %. The main reason for failure was secondary caries followed by post-operative sensitivity and resin composite fracture. A high proportion of replaced/repaired RC restorations were caused by primary caries in a non-filled surface.

Clinical relevance

Secondary caries was the main reason for failure of RC in children and young adults. More teeth with post-operative sensitivity and a shorter longevity of restorations were observed when a base material was used.     

From the Cover: Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries

To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40–80% efficacy, and to be targeted at “infants” or “adolescents/adults.” Vaccine prices were tiered by income group (US $1.50–$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024–2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11–24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42–1.58) million TB cases could be prevented at $1,692 ($634–$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle–, and upper-middle–income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.The bacterium Mycobacterium tuberculosis was responsible for ∼8.6 million cases of tuberculosis (TB) disease and ∼1.3 million deaths in 2012 (1), of which over 80% were in low-income countries (LICs) and middle-income countries. This burden remains despite the widespread use of the infant TB vaccine, bacille Calmette–Guérin (bacillus Calmette–Guérin) (2). Dramatic levels of control are required to reach the World Health Organization (WHO) targets of TB elimination as a public health problem by 2050 (3). Previous mathematical modeling has suggested elimination can only be achieved through the use of new vaccines (4–7).In 2013, there were more than a dozen new TB vaccines in clinical trials, using a large range of antigens and adjuvants (8). A variety of modes of action and target populations are being researched (9, 10). The most recent TB vaccine tested in a large-scale phase II trial reported a nonsignificant impact on TB disease of 17.3% [95% confidence interval (CI): −31.9 to 48.2] (11). However, such an undertaking highlights the progress that has been made in TB vaccine clinical trials, as well as the need for a reevaluation of the potential impact and need for increased investment in new TB vaccines (12).Estimates of the likely impact and cost-effectiveness of new products before and during development are useful for informing target product profiles and guiding product prioritization. Such analyses of future vaccines have been undertaken for several other diseases (13–17) but have been limited to exploring the cost-effectiveness of infant vaccination in Asia and Sub-Saharan Africa for TB (18–20). To inform the products and targeting that will be most useful for achieving the 2050 elimination target (3), there is a need to systematically estimate the impact in a wide range of settings of a variety of potential TB vaccine profiles defined by efficacy, duration of protection, and potential target groups (e.g., by age). The aim of this study was to estimate this potential impact and cost-effectiveness for prospective TB vaccine profiles in LICs and middle-income countries over the time horizon 2024–2050.We used an age-structured M. tuberculosis transmission model. To be conservative in vaccine impact, we model an aggressive scale-up of existing technologies before the introduction of the new vaccine, in line with the recently approved post-2015 WHO global TB strategy (21). New TB vaccines were assumed to be available in 2024, to prevent active TB in infected and uninfected individuals, to have a 5-y to lifetime duration of protection and 40–80% efficacy, and to be targeted at “infants” or “adolescents/adults.” The former involved vaccination at birth, and the latter involved vaccination at the age of 10 y in schools supplemented with mass campaigns directed to those individuals aged 11 y and older at a frequency corresponding to the duration of protection or every 10 y (whichever was longer). These age groups were chosen to reflect the feasibility of vaccine delivery. Infant vaccination would be alongside the routine schedule, and 10-y-olds could be reached in schools, where immunization is becoming increasingly common. Mass campaigns were included as a scenario in which all people at risk from TB could be targeted. Vaccine prices were tiered by country income group, as measured in US dollars ($1.50–$10 per dose), and cost-effectiveness was defined as a cost per disability adjusted life year (DALY) averted of less than the gross national income (GNI) per capita.We carried out two main analyses. The first estimated the impact and cost-effectiveness of a broad range of prespecified potential vaccine characteristics when targeted at infants or adolescents/adults. The second analysis estimated the maximum price per vaccine dose at which the vaccine could still be deemed cost-effective. Full details are provided in Materials and Methods and SI Appendix.     

The cost of outpatient pneumonia in children <5 years of age in Fiji

Objectives Pneumonia is the most common reason for visiting an outpatient facility among children <5 years old in Fiji. The objective of this study is to describe for the first time the costs associated with an episode of outpatient pneumonia in Fiji, in terms of cost both to the government health sector and to the household. Methods Costs were estimated for 400 clinically diagnosed pneumonia cases from two outpatient facilities, one in the capital, Suva, and one in a peri‐urban and rural area, Nausori. Household expenses relating to transport costs, treatment costs and indirect costs were determined primarily through structured interview with the caregiver. Unit costs were collected from a variety of sources. Patient‐specific costs were summarised as average costs per facility. Results The overall average societal cost associated with an episode of outpatient pneumonia was $18.98, ranging from $14.33 in Nausori to $23.67 in Suva. Household expenses represent a significant proportion of the societal cost (29% in Nausori and 45% in Suva), with transport costs the most important household cost item. Health sector expenses were dominated by personnel costs at both sites. Both the average total household expenses and the average total health sector expenses were significantly greater in Suva than Nausori. Conclusions A single episode of outpatient pneumonia represents a significant cost both to the government health sector and to affected households. Given the high incidence of this disease in Fiji, this places a considerable burden on society.     

Provision of small‐quantity lipid‐based nutrient supplements does not improve intestinal health among rural Malawian children

Lipid‐based nutrient supplements (LNS) have been found to improve child growth and reduce child mortality. However, the mechanistic pathways for these improvements warrant exploration. One potential pathway is linked to improvement in intestinal health. Our study aimed to test a hypothesis that small‐quantity LNS (SQ‐LNS) could reduce the levels of intestinal inflammation, repair and permeability of children. As intestinal health markers we measured fecal calprotectin, regenerating 1B protein (REG1B) and alpha‐1‐antitrypsin concentrations at 18 months of age (after 12 months of supplementation) and 1 year later (12 months after cessation of supplementation). In this analysis, we included data of 735 children who participated in a randomised dietary supplementation trial in rural Malawi; 243 children who received 20 g/day SQ‐LNS from 6 to 18 months of age were in the SQ‐LNS group, while the others who received no dietary supplementation during this period were in the control group. At 18 months of age, the mean concentrations of calprotectin, REG1B and alpha‐1‐antitrypsin were 241, 105 µg/g and 7.1 mg/dl, respectively, in the SQ‐LNS group, and 224, 105 µg/g and 7.4 mg/dl, respectively, in the control group, and did not differ between the SQ‐LNS and control groups. We conclude that SQ‐LNS provision did not have an impact on children''s intestinal health in rural Malawi.