Targeting patients for early COVID-19 therapy; Pre-infection metabolic dysfunction, polycystic ovary syndrome and risk of severe disease in patients under 65: A Massachusetts community-based observational study.

INTRODUCTION: The demographics of those developing severe coronavirus disease (COVID-19) outcomes are shifting to younger patients. In an observational study utilizing electronic health records from a Massachusetts group medical practice, we identified 5025 patients with confirmed COVID-19 from March 1 to December 18, 2020. Of these, 3870 were under 65 years of age. We investigated the hypothesis that pre-infection metabolic or immunologic dysregulation including polycystic ovary syndrome (PCOS) increased risk of serious COVID-19 outcomes in patients under 65 years of age. MATERIALS AND METHODS: We compared those with COVID-19 related hospitalization or mortality to all other COVID-19 patients, using a case control approach. Using logistic regression and propensity score modeling, we evaluated risk of developing severe COVID-19 outcomes (hospitalization or death) in those with pre-infection comorbidities, metabolic risk factors, or PCOS. RESULTS: Overall, propensity score matched analyses demonstrated pre-infection elevated liver enzymes alanine aminotransferase (ALT) >40, aspartate aminotransferase (AST) >40 and blood glucose ≥215 mg/dL were associated with more severe COVID-19 outcomes, OR = 1.74 (95% CI 1.31, 2.31); OR = 1.98 (95% CI 1.52, 2.57), and OR = 1.55 (95% CI 1.08, 2.23) respectively. Elevated hemoglobin A1C or blood glucose levels were even stronger risk factors for severe COVID-19 outcomes among those aged < 65, OR = 2.31 (95% CI 1.14, 4.66) and OR = 2.42 (95% CI 1.29, 4.56), respectively. In logistic regression models, women aged < 65 with PCOS demonstrated more than a four-fold increased risk of severe COVID-19, OR 4.64 (95% CI 1.98, 10.88). CONCLUSION: Increased risk of severe COVID-19 outcomes in those < age 65 with pre-infection indicators of metabolic dysfunction heightens the importance of monitoring pre-infection indicators in younger patients for prevention and early treatment. The PCOS finding deserves further investigation. Meanwhile women who suffer from PCOS should be carefully evaluated and prioritized for earlier COVID-19 treatment and vaccination.

Paracetamol use during pregnancy - a call for precautionary action.

Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.

Hypertension, medications, and risk of severe COVID-19: A Massachusetts community-based observational study.

It remains uncertain whether the hypertension (HT) medications angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) mitigate or exacerbate SARS-CoV-2 infection. We evaluated the association of ACEi and ARB with severe coronavirus disease 19 (COVID-19) as defined by hospitalization or mortality among individuals diagnosed with COVID-19. We investigated whether these associations were modified by age, the simultaneous use of the diuretic thiazide, and the health conditions associated with medication use. In an observational study utilizing data from a Massachusetts group medical practice, we identified 1449 patients with a COVID-19 diagnosis. In our study, pre-infection comorbidities including HT, cardiovascular disease, and diabetes were associated with increased risk of severe COVID-19. Risk was further elevated in patients under age 65 with these comorbidities or cancer. Twenty percent of those with severe COVID-19 compared to 9% with less severe COVID-19 used ACEi, 8% and 4%, respectively, used ARB. In propensity score-matched analyses, use of neither ACEi (OR = 1.30, 95% CI 0.93 to 1.81) nor ARB (OR = 0.94, 95% CI 0.57 to 1.55) was associated with increased risk of severe COVID-19. Thiazide use did not modify this relationship. Beta blockers, calcium channel blockers, and anticoagulant medications were not associated with COVID-19 severity. In conclusion, cardiovascular-related comorbidities were associated with severe COVID-19 outcomes, especially among patients under age 65. We found no substantial increased risk of severe COVID-19 among patients taking antihypertensive medications. Our findings support recommendations against discontinuing use of renin-angiotensin system (RAS) inhibitors to prevent severe COVID-19.

Prenatal paracetamol exposure and child neurodevelopment: A review.

BACKGROUND: The non-prescription medication paracetamol (acetaminophen, APAP) is currently recommended as a safe pain and fever treatment during pregnancy. However, recent studies suggest a possible association between APAP use in pregnancy and offspring neurodevelopment. OBJECTIVES: To conduct a review of publications reporting associations between prenatal APAP use and offspring neurodevelopmental outcomes. METHODS: Relevant sources were identified through a key word search of multiple databases (Medline, CINAHL, OVID and TOXNET) in September 2016. All English language observational studies of pregnancy APAP and three classes of neurodevelopmental outcomes (autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intelligence quotient (IQ)) were included. One reviewer (AZB) independently screened all titles and abstracts, extracted and analyzed the data. RESULTS: 64 studies were retrieved and 55 were ineligible. Nine prospective cohort studies fulfilled all inclusion criteria. Data pooling was not appropriate due to heterogeneity in outcomes. All included studies suggested an association between prenatal APAP exposure and the neurodevelopmental outcomes; ADHD, ASD, or lower IQ. Longer duration of APAP use was associated with increased risk. Associations were strongest for hyperactivity and attention-related outcomes. Little modification of associations by indication for use was reported. CONCLUSIONS: Together, these nine studies suggest an increased risk of adverse neurodevelopmental outcomes following prenatal APAP exposure. Further studies are urgently needed with; precise indication of use and exposure assessment of use both in utero and in early life. Given the current findings, pregnant women should be cautioned against indiscriminate use of APAP. These results have substantial public health implications.

The cascade of medical services and associated longitudinal costs due to nonadherent magnetic resonance imaging for low back pain.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare type, timing, and longitudinal medical costs incurred after adherent versus nonadherent magnetic resonance imaging (MRI) for work-related low back pain. SUMMARY OF BACKGROUND DATA: Guidelines advise against MRI for acute uncomplicated low back pain, but is an option for persistent radicular pain after a trial of conservative care. Yet, MRI has become frequent and often nonadherent. Few studies have documented the nature and impact of medical services (including type and timing) initiated by nonadherent MRI. METHODS: A longitudinal, workers' compensation administrative data source was accessed to select low back pain claims filed between January 1, 2006 and December 31, 2006. Cases were grouped by MRI timing (early, timely, no MRI) and subgrouped by severity ("less severe," "more severe") (final cohort = 3022). Health care utilization for each subgroup was evaluated at 3, 6, 9, and 12 months post-MRI. Multivariate logistic regression models examined risk of receiving subsequent diagnostic studies and/or treatments, adjusting for pain indicators and demographic covariates. RESULTS: The adjusted relative risks for MRI group cases to receive electromyography, nerve conduction testing, advanced imaging, injections, and surgery within 6 months post-MRI risks in the range from 6.5 (95% CI: 2.20-19.09) to 54.9 (95% CI: 22.12-136.21) times the rate for the referent group (no MRI less severe). The timely and early MRI less severe subgroups had similar adjusted relative risks to receive most services. The early MRI more severe subgroup cases had generally higher adjusted relative risks than timely MRI more severe subgroup cases. Medical costs for both early MRI subgroups were highest and increased the most over time. CONCLUSION: The impact of nonadherent MRI includes a wide variety of expensive and potentially unnecessary services, and occurs relatively soon post-MRI. Study results provide evidence to promote provider and patient conversations to help patients choose care that is based on evidence, free from harm, less costly, and truly necessary. LEVEL OF EVIDENCE: N/A.

Iatrogenic consequences of early magnetic resonance imaging in acute, work-related, disabling low back pain.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the effect of early (receipt ≤30 d postonset) magnetic resonance imaging (MRI) on disability and medical cost outcomes in patients with acute, disabling, work-related low back pain (LBP) with and without radiculopathy. SUMMARY OF BACKGROUND DATA: Evidence-based guidelines suggest that, except for "red flags," MRI is indicated to evaluate patients with persistent radicular pain, after 1 month of conservative management, who are candidates for surgery or epidural steroid injections. Prior research has suggested an independent iatrogenic effect of nonindicated early MRI, but it had limited clinical information and/or patient populations. METHODS: A nationally representative sample of workers with acute, disabling, occupational LBP was randomly selected, oversampling those with radiculopathy diagnoses (N = 1000). Clinical information from medical reports was used to exclude cases for which early MRI might have been indicated, or MRI occurred more than 30 days postonset (final cohort = 555). Clinical information was also used to categorize cases into "nonspecific LBP" and "radiculopathy" groups and further divided into "early-MRI" and "no-MRI" subgroups. The Cox proportional hazards model examined the association of early MRI with duration of the first episode of disability. Multivariate linear regression models examined the association with medical costs. All models adjusted for demographic and medical severity measures. RESULTS: In our sample, 37% of the nonspecific LBP and 79.9% of the radiculopathy cases received early MRI. The early-MRI groups had similar outcomes regardless of radiculopathy status: much lower rates of going off disability and, on average, $12,948 to $13,816 higher medical costs than the no-MRI groups. Even in a subgroup with relatively minimal disability impact (≤30 d of total lost time post-MRI), medical costs were, on average, $7643 to $8584 higher in the early-MRI groups. CONCLUSION: Early MRI without indication has a strong iatrogenic effect in acute LBP, regardless of radiculopathy status. Providers and patients should be made aware that when early MRI is not indicated, it provides no benefits, and worse outcomes are likely. LEVEL OF EVIDENCE: 3.

Prenatal and perinatal analgesic exposure and autism: an ecological link.

BACKGROUND: Autism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk. METHODS: To explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates - a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med. RESULTS: Using all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country's circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision. CONCLUSIONS: This ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism.