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BackgroundPer- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied.MethodsUsing a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted.ResultsWe observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women.ConclusionMaternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history. https://doi.org/10.1289/EHP6202.

Background: Pain is a common complaint among patients presenting to the emergency department (ED), yet pain treatment is frequently suboptimal. The aim of this study was to determine the effectiveness of low‐dose ketamine (LDK) as an adjunct to morphine versus morphine alone for treatment of acute pain among ED patients with and without current opioid use. Methods: Adult patients presenting with acute pain of ≥5 on a numeric rating scale (0–10) who were deemed by their treating ED physician to require intravenous opioids were randomized to receive either 0.1 mg/kg ketamine (treatment group) or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain was measured at baseline (T0) and 10, 20, 30, 45, 60, and 120 min after randomization. The primary outcome was pain reduction from T0 to T10. Secondary outcomes included pain intensity over 120 min, need of rescue opioids, side effects, and patient and provider satisfaction. Results: A total of 116 patients were included from May 2022 to August 2023. Median (IQR) age was 51 (36.5–67) years; 58% were male and 36% had current opioid use. Pain reduction from T0 to T10 was greater in the LDK group (4 [IQR 3–6]) compared to the placebo group (1 [IQR 0–2]; p = 0.001). Pain intensity was lower in the LDK group at T10, T20, and T30, compared to the placebo group. There was a higher risk of nausea, vomiting, and dissociation in the LDK group during the first 10 min. Conclusions: LDK may be effective as an adjunct analgesic to morphine for short‐term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, general practices in Denmark rapidly introduced video consultations (VCs) to prevent viral transmission. Aim: To study the use of VCs in daytime general practice by describing the rate of VCs, and the patient characteristics associated with having VCs. Design & setting: Register-based study of consultations in daytime general practice in Denmark. Method: We included all consultations in daytime general practice from 1 January 2019–30 November 2021. We calculated the rate of video use and categorised the general practices into no, low, and high use. Logistic regression was used to calculate adjusted odds ratios (aOR) for having a VC for different patient characteristics when contacting a video-using practice, stratified for low- and high-using practices. Results: A total of 30 148 478 eligible consultations were conducted during the pandemic period. VCs were used mostly during the early stage pandemic period, declining to about 2% of all clinic consultations in the late-stage period. Patients having more VCs were young, had a long education, were employed, and lived in big cities. In low-using practices, native Danes and 'western' immigrants had higher odds of receiving a VC than 'non-western' immigrants, and patients with ≥2 comorbidities had lower odds than those without comorbidities. Conclusion: Patients of a younger age, with long education, or employment had higher odds of receiving a VC, while patients of an older age and patients who had retired had lower odds. This difference in the access to VCs warrants further attention. [ABSTRACT FROM AUTHOR]

BackgroundPerfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited.ObjectivesWe investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.MethodsAmong 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child's sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.ResultsPerfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.ConclusionsIn this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.

Background: Patients with a daily use of opioids have a higher risk of insufficient pain treatment during hospitalization than other patients. This study aimed to examine whether as‐needed opioid doses (PRN) were adequately adjusted when patients were admitted to the emergency department (ED) with pain. Methods: Patients, with a daily use of opioids, who received PRN opioid within the first 3 h after admission at the ED at Aarhus University Hospital, Denmark, were prospectively included from February 2021 to June 2021. The primary outcome was the proportion of patients receiving an inadequate initial dose of PRN opioid, here defined as <15% of daily dose of opioids (DDO) based on sparse evidence, but aligning with the prevailing clinical practice. Secondary outcomes included risk of an inadequate PRN dose in relation to DDO (patients were dichotomized into two groups (DDO <60 or ≥60 mg/day). Results: Among 252 patients admitted to the ED with a daily use of opioids, 149 were admitted with pain and 82 received a PRN opioid dose within 3 h. Twenty‐seven out of 82 (33%) patients received a PRN dose of <15% of DDO (95% CI: 23.7–43). When dichotomised; 10 out of 50 (20%) patients with a DDO <60 mg/day (95% CI: 10.0–33.7) versus 17 out of 32 (53.1%) patients with a DDO ≥60 mg/day (95% CI: 34.7–70.9) received an inadequate PRN dose (relative risk, RR: 2.65 [95% CI: 1.4–5.1]). Conclusions: Patients with daily use of opioids presenting in the ED with acute pain had a high risk of inadequate PRN opioid dose, especially if the DDO was high. Awareness about and education focusing on sufficient PRN doses for patients with a daily use of opioids is (still) called for. [ABSTRACT FROM AUTHOR]

Background Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. Methods and findings The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. Conclusions Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies., Author(s): Lene Wulff Krogsgaard 1,*, Irene Petersen 2,3, Oleguer Plana-Ripoll 4, Bodil Hammer Bech 1, Tina Hovgaard Lützen 1, Reimar Wernich Thomsen 2, Dorte Rytter 1 Introduction Human papilloma virus [...]

Successful prevention of physical child abuse is dependent on improvements in risk assessment. The risk of abuse is assumed to increase when family stressors overcome resources. Severe physical disease can increase stress, and parental physical disease has been studied as a risk factor for physical child abuse, but with heterogeneous definitions. This study evaluated the relation between parental physical disease severity and severe documented physical child abuse. Models were based on data on children aged 0–17 years in Denmark between 1997 and 2018, and their parents. Severe documented physical child abuse was modeled as violence against a child registered by either health authorities in treatment or mortality registries, or police authorities in cases confirmed by the courts. Parental physical disease severity was modeled as the sum of Charlson Comorbidity Index scores for the child's parents. The causal connection was examined in two model types: a survival model comparing exposed with non-exposed children, adjusted for covariates at baseline, and a G-model, taking time-varying covariates, including income and parental psychiatric disease into account. Neither model showed an association between parental physical disease severity and severe documented physical child abuse, with RR 0.99 and 95% CI (0.93–1.05) for the survival model and RR 1.08 for the G-model (CI not calculated). Conclusion: In the model studied, parental physical disease severity was not a risk factor for severe documented physical child abuse. Individual categories of physical disease remain to be examined. Trial registration: The study was pre-registered on Open Science Framework, https://osf.io/fh2sr. What is Known: • Parental physical disease severity has been studied previously as a risk indicator of physical child abuse, but based on heterogeneous definitions. • Previous studies have not studied parental physical disease severity preceding physical child abuse. What is New: • Parental severe physical disease was not prospectively associated with severe documented physical child abuse in a survival model, a G-model and a number of sensitivity analyses, respectively. • Results should be replicated in samples from populations without universal health care, and using different categories of disease. [ABSTRACT FROM AUTHOR]

Background: Maternal thyroid hormones are essential for fetal brain development in early gestation. Perfluoroalkyl substances (PFASs)--widespread and persistent pollutants--have been suggested to interfere with maternal thyroid hormones in the second or third trimesters, but evidence for an association in the early pregnancy period is sparse. Objectives: Our goal was to evaluate the gestational-week specific associations of maternal thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels with plasma concentrations of six PFAS chemicals in the first and second pregnancy trimester. Methods: A cross-sectional analysis was conducted using 1,366 maternal blood samples collected between gestational weeks (GWs) 5 and 19 (median, 8 gestational weeks) in the Danish National Birth Cohort (DNBC) during 1996-2002. We estimated the percentage changes of serum TSH and fT4 levels according to concentrations (in nanograms per milliliter) of six PFAS chemicals modeled as per interquartile range (IQR) increase or by exposure quartiles. Moreover, we contrasted the estimated week-specific TSH or fT4 levels by PFAS quartile and estimated ORs for binary high or low TSH and fT4 status based on the week-specific distribution according to IQR increase of PFAS. Results: TSH levels followed a U-curve trend in early pregnancy with a nadir at GW10, whereas fT4 levels were less fluctuated in the samples. There were no apparent associations between any of the PFASs and changes of average TSH or fT4 levels in total samples. In gestational-week-specific analyses, we found that the estimated TSH values were higher among the highest perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluoroheptane sulfonate (PFHpS) quartiles compared with the lower quartiles from GW5 to GW10, but the difference became null or even reversed after GW10. For binary outcomes, perfluorodecanoic acid (PFDA) was associated with high fT4 status before GW10 [OR = 1.46 (95% CI: 1.04, 2.05)]. Conclusions: We observed some gestational-week-specific associations between high exposure to several PFAS and TSH level in early gestations. Further research of the biology and the potential clinical impact regarding thyroid hormones disruptions in early pregnancy is needed. https://doi.org/10.1289/EHP5482, Introduction Perfluoroalkyl substances (PFASs) are synthetic chemicals manufactured since the 1950s that have been used to water- and stain proof various industrial and consumer products including clothing, carpets, food packing [...]