Perfluorinated compounds (PFCs) have emerged as important food contaminants. They cause immune suppression in a rodent model at serum concentrations similar to those occurring in the US population, ...but adverse health effects of PFC exposure are poorly understood.
To determine whether PFC exposure is associated with antibody response to childhood vaccinations.
Prospective study of a birth cohort from the National Hospital in the Faroe Islands. A total of 656 consecutive singleton births were recruited during 1997-2000, corrected and 587 participated in follow-up through 2008.
Serum antibody concentrations against tetanus and diphtheria toxoids at ages 5 and 7 years.
Similar to results of prior studies in the United States, the PFCs with the highest serum concentrations were perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Among PFCs in maternal pregnancy serum, PFOS showed the strongest negative correlations with antibody concentrations at age 5 years, for which a 2-fold greater concentration of exposure was associated with a difference of -39% (95% CI, -55% to -17%) in the diphtheria antibody concentration. PFCs in the child's serum at age 5 years showed uniformly negative associations with antibody levels, especially at age 7 years, except that the tetanus antibody level following PFOS exposure was not statistically significant. In a structural equation model, a 2-fold greater concentration of major PFCs in child serum was associated with a difference of -49% (95% CI, -67% to -23%) in the overall antibody concentration. A 2-fold increase in PFOS and PFOA concentrations at age 5 years was associated with odds ratios between 2.38 (95% CI, 0.89 to 6.35) and 4.20 (95% CI, 1.54 to 11.44) for falling below a clinically protective level of 0.1 IU/mL for tetanus and diphtheria antibodies at age 7 years.
Elevated exposures to PFCs were associated with reduced humoral immune response to routine childhood immunizations in children aged 5 and 7 years.
Background: The incidence of acute hamstring injuries is high in several sports, including the different forms of football.
Purpose: The authors investigated the preventive effect of eccentric ...strengthening of the hamstring muscles using the Nordic hamstring exercise compared with no additional hamstring exercise on the rate of acute hamstring injuries in male soccer players.
Study Design: Randomized controlled trial; Level of evidence, 1.
Methods: Fifty Danish male professional and amateur soccer teams (942 players) were allocated to an intervention group (461 players) or a control group (481 players). Players in the intervention group conducted a 10-week progressive eccentric training program followed by a weekly seasonal program, whereas players in the control group followed their usual training program. The main outcome measures were numbers of overall, new, and recurrent acute hamstring injuries during 1 full soccer season.
Results: Fifty-two acute hamstring injuries in the control group compared with 15 injuries in the intervention group were registered. Comparing intervention versus the control group, overall acute hamstring injury rates per 100 player seasons were 3.8 versus 13.1 (adjusted rate ratio RR, 0.293; 95% confidence interval CI, 0.150-0.572; P < .001). New injury rates per 100 player seasons were 3.1 versus 8.1 (RR, 0.410; 95% CI, 0.180-0.933; P = .034), whereas recurrent injury rates per 100 player seasons were 7.1 versus 45.8 (RR, 0.137; 95% CI, 0.037-0.509; P = .003). Number needed to treat NNT to prevent 1 acute hamstring injury (new or recurrent) is 13 (95% CI, 9-23) players. The NNT to prevent 1 new injury is 25 (95% CI, 15-72) players, and NNT to prevent 1 recurrent injury is 3 (95% CI, 2-6) players.
Conclusion: In male professional and amateur soccer players, additional eccentric hamstring exercise decreased the rate of overall, new, and recurrent acute hamstring injuries.
Background
Long‐term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking.
Aims
To present systematic population‐based nation‐wide register data on ...comparative 2‐year non‐response within six antidepressant drug classes and 17 different antidepressants in patients with MDD.
Method
The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non‐response to first antidepressant within a 2‐year study period was defined as switch to or add‐on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders.
Results
Compared with sertraline, there was no difference for citalopram (RR: 1.00 95% CI: 0.98–1.02) but fluoxetine (1.13 95% CI: 1.10–1.17), paroxetine (1.06 95% CI: 1.01–1.10) and escitalopram (1.22 95% CI: 1.18–1.25) were associated with higher risk ratio of non‐responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin‐norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non‐response, whereas there was no difference for imipramine.
Conclusions
These analyses emulating a randomized trial of “real world” observational register‐based data show that 2‐year long‐term non‐responses to some antidepressants within six different drug classes are increased over others.
Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the ...European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits.
We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity.
Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis.
Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results.
Childhood is a sensitive period with rapid brain development and physiological growth, and adverse events in childhood might interfere with these processes and have long-lasting effects on health. In ...this study, we aimed to describe trajectories of adverse childhood experiences and relate these to overall and cause-specific mortality in early adult life.
For this population-based cohort study, we used unselected annually updated data from Danish nationwide registers covering more than 1 million children born between 1980 and 1998. We distinguished between three different dimensions of childhood adversities: poverty and material deprivation, loss or threat of loss within the family, and aspects of family dynamics such as maternal separation. We used a group-based multi-trajectory clustering model to define the different trajectories of children aged between 0 and 16 years. We assessed the associations between these trajectories and mortality rates between 16 and 34 years of age using a Cox proportional hazards model and an Aalen hazards difference model.
Between Jan 1, 1980 and Dec 31, 2015, 2 223 927 children were included in the Danish Life Course cohort. We excluded 1 064 864 children born after 1998, 50 274 children who emigrated before their 16th birthday, and 11 161 children who died before their 16th birthday, resulting in a final sample of 1 097 628 children. We identified five distinct trajectories of childhood adversities. Compared with children with a low adversity trajectory, those who had early-life material deprivation (hazard ratio 1·38, 95% CI 1·27–1·51), persistent deprivation (1·77, 1·62–1·93), or loss or threat of loss (1·80, 1·61–2·00) had a moderately higher risk of premature mortality. A small proportion of children (36 081 3%) had multiple adversities within all dimensions and throughout the entire childhood. This group had a 4·54 times higher all-cause mortality risk (95% CI 4·07–5·06) than that of children with a low adversity trajectory, corresponding to 10·30 (95% CI 9·03–11·60) additional deaths per 10 000 person-years. Accidents, suicides, and cancer were the most common causes of death in this high adversity population.
Almost half of Danish children in our study experienced some degree of adversity, and this was associated with a moderately higher risk of mortality in adulthood. Among these, a small group of children had multiple adversities across social, health, and family-related dimensions. This group had a markedly higher mortality risk in early adulthood than that of other children, which requires public health attention.
None.
Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS ...concentrations in children. To determine the time-dependent impact of this exposure pathway, we examined the serum concentrations of five major PFASs in a Faroese birth cohort at birth, and at ages 11, 18, and 60 months. Information about the children's breastfeeding history was obtained from the mothers. The trajectory of serum-PFAS concentrations during months with and without breastfeeding was examined by linear mixed models that accounted for the correlations of the PFAS measurements for each child. The models were adjusted for confounders such as body size. The duration of exclusive breastfeeding was associated with increases of most PFAS concentrations by up to 30% per month, with lower increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs in infants.
Developmental exposure to perfluorinated alkylate substances (PFASs) is associated with deficient IgG antibody responses to childhood vaccines. As this immunotoxicity outcome may represent a critical ...effect, calculation of benchmark dose (BMD) results would be useful for defining protective limits of exposure. However, exposures to the major PFASs that are associated with this adverse effect are interrelated, and mutually adjusted BMD results would be desirable.
We carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of five major PFASs at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for five major PFASs. BMD and BMDL were expressed in terms of the serum concentration of the PFASs.
The BMDLs for the immunotoxicants were of similar magnitude before and after adjustment. As compared to linear dose-response models, the PFASs showed lower results for a piecewise linear model, which also provided a slightly better fit. Weaker associations with the antibody outcomes were observed after adjustments due to the correlation between the PFASs. However, while the adjustments resulted in elevated BMD results and p values, the BMDL values were not materially changed.
Adjustment for co-exposure to a related immunotoxicant increased both the BMD values and their standard errors, though affected the BMDL values only to a negligible extent. Thus, when correlated toxicants appear to affect the same outcome and none of them is known a priori to be solely responsible, all exposures may be considered responsible in BMD calculations. Our BMDL results, both before and after adjustment are generally below current exposure levels and therefore suggest that all five perfluorinated substances should attract regulatory attention, at least until additional evidence shows otherwise.
The benefit–risk balance is a critical information when evaluating a new treatment. The Net Benefit has been proposed as a metric for the benefit–risk assessment, and applied in oncology to ...simultaneously consider gains in survival and possible side effects of chemotherapies. With complete data, one can construct a U-statistic estimator for the Net Benefit and obtain its asymptotic distribution using standard results of the U-statistic theory. However, real data is often subject to right-censoring, e.g. patient drop-out in clinical trials. It is then possible to estimate the Net Benefit using a modified U-statistic, which involves the survival time. The latter can be seen as a nuisance parameter affecting the asymptotic distribution of the Net Benefit estimator. We present here how existing asymptotic results on U-statistics can be applied to estimate the distribution of the net benefit estimator, and assess their validity in finite samples. The methodology generalizes to other statistics obtained using generalized pairwise comparisons, such as the win ratio. It is implemented in the R package BuyseTest (version 2.3.0 and later) available on Comprehensive R Archive Network.
Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS ...exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.
Objectives
To evaluate a novel deep learning image reconstruction (DLIR) technique for dual-energy CT (DECT) derived virtual monoenergetic (VM) images compared to adaptive statistical iterative ...reconstruction (ASIR-V) in low kiloelectron volt (keV) images.
Methods
We analyzed 30 venous phase acute abdominal DECT (80/140 kVp) scans. Data were reconstructed to ASIR-V and DLIR-High at four different keV levels (40, 50, 74, and 100) with 1- and 3-mm slice thickness. Quantitative Hounsfield unit (HU) and noise assessment were measured within the liver, aorta, fat, and muscle. Subjective assessment of image noise, sharpness, texture, and overall quality was performed by two board-certified radiologists.
Results
DLIR reduced image noise by 19.9–35.5% (
p
< 0.001) compared to ASIR-V in all reconstructions at identical keV levels. Contrast-to-noise ratio (CNR) increased by 49.2–53.2% (
p
< 0.001) in DLIR 40-keV images compared to ASIR-V 50 keV, while no significant difference in noise was identified except for 1 and 3 mm in aorta and for 1-mm liver measurements, where ASIR-V 50 keV showed 5.5–6.8% (
p <
0.002) lower noise levels. Qualitative assessment demonstrated significant improvement particularly in 1-mm reconstructions (
p
< 0.001). Lastly, DLIR 40 keV demonstrated comparable or improved image quality ratings when compared to ASIR-V 50 keV (
p
< 0.001 to 0.22).
Conclusion
DLIR significantly reduced image noise compared to ASIR-V. Qualitative assessment showed that DLIR significantly improved image quality particularly in thin sliced images. DLIR may facilitate 40 keV as a new standard for routine low-keV VM reconstruction in contrast-enhanced abdominal DECT.
Key Points
• DLIR enables 40 keV as the routine low-keV VM reconstruction.
• DLIR significantly reduced image noise compared to ASIR-V, across a wide range of keV levels in VM DECT images.
• In low-keV VM reconstructions, improvements in image quality using DLIR were most evident and consistent in 1-mm sliced images.
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