Impact of the Covid-19 pandemic and ensuing online teaching on pre-clinical medical education.

BACKGROUND: Major disruptions and changes in education have occurred worldwide as a result of the coronavirus disease (COVID-19) pandemic and the ensuing shift from in-person to online education. However, the effect of such changes on medical education, its magnitude, and the learning domains impacted by such rapid changes have not been adequately addressed, particularly with regard to objective assessment approaches. METHODS: Second-year medical students enrolled in our Medical English Course between 2019 and 2021 were recruited from Hokkaido University, Japan (N = 321) to participate in this study. We evaluated the potential impact of teaching styles on the academic performance of students before (2019; face-to-face) and during (2020; online; 2021; in-person and online) the pandemic. We examined the potential effect of three teaching styles--in-person (2019), online (2020), and a combination of these (2021) on the academic performance of medical students using: (i) subjective assessment of self-reported general English skills, including reading, writing, listening, and speaking; and (ii) objective assessment of medical terminology scores, evidence-based medicine (EBM) skills, and final written exam scores. RESULTS: In-person education significantly improved listening and speaking skills in 2019 (p < 0.001). This trend was observed for writing skills in an online course in 2020 (p = 0.001). With the combined teaching method, students reported significant improvements in all four English skills. In our objective assessments, medical terminology improved significantly post-test versus pre-test for all three teaching styles, and we found that the online course did not adversely affect the gain in medical terminology knowledge during the course. Additionally, we did not find any significant differences across the three applied teaching styles regarding EBM skill levels. It is noteworthy that the students taking online courses had a significantly higher final exam score (mean ± SD; 82.8 ± 8.2) than in in-person (78.6 ± 8.8) and combined (79.7 ± 12.1) teaching styles. CONCLUSIONS: In our study, the online/combined courses showed better academic outcomes compared to the face-to-face course in the preclinical clerkship. Although the current results need to be replicated on a larger scale, online/combined courses can continue and evolve in the post-pandemic education of medical students. Medical schools and institutions should consider incorporating such courses, especially combined courses, into their curricula in the future to improve the effectiveness, accessibility, and flexibility of medical education.

Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation.

BACKGROUND: Real-time asthma exacerbation prediction and acute asthma attack detection are essential for patients with severe asthma. Peak expiratory flow (PEF) exhibits a potential for use in long-term asthma self-monitoring. However, the method for processing PEF calculations remains to be clarified. OBJECTIVE: To develop clinically applicable novel exacerbation predictors calculated using PEF records. METHODS: Previously proposed exacerbation predictors, including the slope of PEF, percentage predicted PEF, percentage best PEF, the highest PEF over the lowest PEF within specific periods, and PEF coefficient of variation, in addition to a novel indicator delta PEF moving average (ΔMA), defined as the difference between 14-day and 3-day average PEF values, along with moving average (MA) adjusted for PEF reference (%ΔMA), were verified using the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma data of 127 patients with severe asthma from whom 73,503 PEF observations were obtained. Receiver operating characteristic curves for all predictors were drawn, and the corresponding areas under the curve (AUCs) were computed. Regression analysis for MA and percentage MA were conducted. RESULTS: The most outstanding performance was shown by ΔMA and %ΔMA, with AUC values of 0.659 and 0.665 in the univariate model, respectively. When multivariate models were incorporated with random intercepts for individual participants, the AUC for ΔMA and %ΔMA increased to 0.907 and 0.919, respectively. CONCLUSION: The MA and percentage MA are valuable indicators that should be considered when deriving predictors from the PEF trajectory for monitoring exacerbations in patients with severe asthma. TRIAL REGISTRATION: The Hokkaido-based Investigative Cohort Analysis for Refractory Asthma was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN ID: 000003254). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003917.

Exposure to organophosphate flame retardants and plasticizers is positively associated with wheeze and FeNO and eosinophil levels among school-aged children: The Hokkaido study.

Exposure to organophosphate flame retardants and plasticizers (PFRs) increases the risk of asthma and allergies. However, little is known about its association with type 2 inflammation (T2) biomarkers used in the management of allergies. The study investigated associations among urinary PFR metabolite concentrations, allergic symptoms, and T2 biomarkers. The data and samples were collected between 2017 and 2020, including school children (n = 427) aged 9-12 years living in Sapporo City, Japan, among the participants of "The Hokkaido Study on Environment and Children's Health." Thirteen urinary PFR metabolites were measured by LC-MS/MS. Allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. For T2 biomarkers, the peripheral blood eosinophil counts, fraction of exhaled nitric oxide level (FeNO), and serum total immunoglobulin E level were measured. Multiple logistic regression analysis, quantile-based g-computation (qg-computation), and Bayesian kernel machine regression (BKMR) were used to examine the associations between the health outcomes of the individual PFRs and the PFR mixtures. The highest concentration of PFR was Σtris(1-chloro-isopropyl) phosphates (ΣTCIPP) (Median:1.20 nmol/L). Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was significantly associated with a high odds ratio (OR, 95%CI:1.36, 1.07-1.72) for wheeze. TDCIPP (OR, 95%CI:1.19, 1.02-1.38), Σtriphenyl phosphate (ΣTPHP) (OR, 95%CI:1.81, 1.40-2.37), and Σtris(2-butoxyethyl) phosphate (ΣTBOEP) (OR, 95%:1.40, 1.13-1.74) were significantly associated with increased odds of FeNO (≥35 ppb). ΣTPHP (OR, 95%CI:1.44, 1.15-1.83) was significantly associated with high eosinophil counts (≥300/µL). For the PFR mixtures, a one-quartile increase in all PFRs (OR, 95%CI:1.48, 1.18-1.86) was significantly associated with high FeNO (≥35 ppb) in the qg-computation model. The PFR mixture was positively associated with high FeNO (≥35 ppb) and eosinophil counts (≥300/µL) in the BKMR models. These results may suggest that exposure to PFRs increases the probability of asthma, allergies, and T2 inflammation.

Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma.

BACKGROUND: There are knowledge gaps in the potential role of Club cell 16-kDa secretory protein (CC16) in severe asthma phenotypes and type 2 inflammation, as well as the longitudinal effect of CC16 on pulmonary function tests and exacerbation risk in epidemiological studies. OBJECTIVE AND METHODS: To assess whether serum CC16 is associated with eosinophilic inflammation in patients with severe asthma. We also examined the effect of this protein on the annual decline in forced expiratory volume in the first second (FEV1) and the risk of exacerbation using a longitudinal approach. We recruited 127 patients with severe asthma from 30 hospitals/pulmonary clinics in Hokkaido, Japan. The least square means and standard error were calculated for T-helper 2 (Th2) biomarkers and pulmonary function test across CC16 tertiles at baseline. We did the same for asthma exacerbation and annual decline in FEV1 with 3 and 5 years' follow-up, respectively. RESULTS: We found that serum CC16 was inversely associated with sputum eosinophils and blood periostin in a dose-response manner. Baseline CC16 and FEV1/forced vital capacity ratio were positively associated in adjusted models (p for trend = 0.008). Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over 5 years of follow-up (p for trend = 0.031, fully adjusted model). We did not find any association of CC16 with exacerbation risk. CONCLUSION: Patients with severe asthma with lower circulatory CC16 had enhanced eosinophilic inflammation with rapid FEV1 decline over time.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.

BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma.

BACKGROUND: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. METHODS: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150-299, ≥300 cells/µL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. RESULTS: Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/µL in COPD and ≥300 cells/µL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. CONCLUSIONS: We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

Potential determinants of T helper 2 markers and their distribution in school-aged children.

BACKGROUND: There is growing data on T helper 2 (Th2) biomarker determinants in adult populations. However, the determinants and typical range of these biomarkers have not been well studied in general populations of children. Therefore, we assessed the determinants and typical range of three Th2 biomarkers, including blood eosinophils, FeNO, and serum total IgE in 9-11-year-old children in a prospective birth cohort. METHODS: We examined the pre- and postnatal factors associated with Th2 biomarkers using multivariable logistic regression analysis (n = 428) and extended the results to the original cohort (n = 17,009) using inverse probability weighting. We also measured typical Th2 biomarker distribution in all examined children and healthy participants without allergic diseases (n = 180). RESULTS: At age 9-11, wheeze (odds ratio (OR) 7.63), rhinitis (OR 3.14), and eczema (OR 2.46) were significantly associated with increased blood eosinophils. All three allergic conditions were associated with FeNO and total serum IgE, but the ORs were smaller than those for blood eosinophils. Secondhand smoking was inversely associated with the blood eosinophils (OR, 0.38). Similar results were found in the original cohort. Male sex and prenatal factors (maternal smoking and parental history of allergies) were not independent predictors of high Th2 levels. CONCLUSIONS: In addition to wheezing and rhinitis, eczema and secondhand smoke exposure are independent factors for Th2 biomarker interpretation in children. Furthermore, the typical values and cutoff values of blood eosinophils in adults may not be applicable to children.

Impact of COVID-19 on international medical education and the future plans of medical students in Japan.

Background: The aim of this study was to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on the current study methods and future plans of medical students compared to those in the pre-pandemic period. Methods: Second-grade medical students reported their academic experiences, study methods, and future career plans before (between 2016 and 2019) and during the pandemic (2020) using a questionnaire-based survey at Hokkaido University, Japan (n = 534). Results: From 2016 to 2019, we found an increasing trend for participation in short-term international exchange programs, taking the United States Medical Licensing Examination (USMLE), clinical training, and undertaking research abroad among the students. However, these percentages significantly declined (to 35.5%) during the COVID-19 pandemic in 2020 for all the assessed future plans, including short-term exchange programs (-27.9%), taking USMLE (-19.8%), clinical training (-24.5%), and undertaking research abroad (-13.2%) compared to 2019, wherein 67.9% of the students wished to have at least one of these four above-mentioned academic activities. Conclusions: The COVID-19 pandemic adversely and significantly influenced our medical students' plans to go abroad for clinical and research training. Future studies are warranted to assess the long-term influence of this pandemic on the career planning of medical students.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Further evidence for association of YKL-40 with severe asthma airway remodeling.

BACKGROUND: The chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. OBJECTIVE: To evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. METHODS: The patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography-derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). RESULTS: Circulating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = -0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was -33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (ß = -0.24, P = .02), even after controlling for exponent D (ß = -0.26, P = .01). CONCLUSION: These results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

The association between prenatal perfluoroalkyl substance exposure and symptoms of attention-deficit/hyperactivity disorder in 8-year-old children and the mediating role of thyroid hormones in the Hokkaido study.

BACKGROUND: Disruption of thyroid hormone (TH) levels during pregnancy contributes to attention deficit hyperactivity disorder (ADHD). Exposure to perfluoroalkyl substances (PFAS) during gestation may affect levels of maternal and neonatal TH; however, little is known about the effect of PFAS on ADHD mediated by TH. OBJECTIVES: We investigated the impact of maternal PFAS exposure on children's ADHD symptoms with the mediating effect of TH. METHODS: In a prospective birth cohort (the Hokkaido study), we included 770 mother-child pairs recruited between 2002 and 2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFAS were measured in maternal serum obtained at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. TH and thyroid antibody, including thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks) and in cord blood at birth. ADHD symptoms in the children at 8 years of age were rated by their parents using the ADHD-Rating Scale (ADHD-RS). The cut-off value was set at the 80th percentile for each sex. RESULTS: Significant inverse associations were found between some PFAS in maternal serum and ADHD symptoms among first-born children. Assuming causality, we found only one significant association: maternal FT4 mediated 17.6% of the estimated effect of perfluoroundecanoic acid exposure on hyperactivity-impulsivity among first-born children. DISCUSSION: Higher PFAS levels in maternal serum during pregnancy were associated with lower risks of ADHD symptoms at 8 years of age. The association was stronger among first-born children in relation to hyperactivity-impulsivity than with regard to inattention. There was little mediating role of TH during pregnancy in the association between maternal exposure to PFAS and reduced ADHD symptoms at 8 years of age.

Associations between maternal mono-(2-ethylhexyl) phthalate levels, nuclear receptor gene polymorphisms, and fatty acid levels in pregnant Japanese women in the Hokkaido study.

We assessed how the interaction between mono-(2-ethylhexyl) phthalate (MEHP) in maternal sera and the maternal genotypes associated with nuclear receptors affect fatty acid levels in a prospective birth cohort study of pregnant Japanese individuals (n = 437) recruited in Sapporo between 2002 and 2005. We analyzed MEHP and fatty acids using gas chromatography-mass spectrometry. Thirteen single nucleotide polymorphisms of peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma (PPARG), PPARG coactivator 1A (PPARGC1A), PPAR delta, constitutive androstane receptor, liver X receptor (LXR) alpha, and LXR beta (LXRB) were analyzed using real-time PCR. Multiple linear regression models were used to confirm the influence of log10-transformed MEHP levels and maternal genotypes on log10-transformed fatty acid levels. When the effects of the interaction between MEHP levels and the maternal PPARGC1A (rs8192678) genotype on oleic acid levels were evaluated, the estimated changes (95 % confidence intervals) in oleic acid levels against MEHP levels, maternal PPARGC1A (rs8192678)-GA/AA genotype, and the interaction between them showed a mean reduction of 0.200 (0.079, 0.322), mean reduction of 0.141 (0.000, 0.283), and mean increase of 0.145 (0.010, 0.281), respectively, after adjusting for the perfluorooctanesulfonate level. The effects of the interaction between MEHP levels and maternal LXRB (rs2303044) genotype on linoleic acid levels was also significant (pint = 0.010). In conclusion, the interaction between MEHP and the maternal genotypes PPARGC1A (rs8192678) and LXRB (rs2303044) decreased fatty acid levels. Further, the interaction between MEHP and PPARGC1A (rs8192678) may have a greater effect on fatty acid levels than the interaction between PFOS and PPARGC1A.

Relationships between maternal perfluoroalkyl substance levels, polymorphisms of receptor genes, and adverse birth outcomes in the Hokkaido birth cohort study, Japan.

We assessed the associations between perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) levels in third trimester maternal serum, the maternal genotypes of genes encoding nuclear receptors, and birth outcomes. We studied a prospective birth cohort of healthy pregnant Japanese women (n = 372) recruited in Sapporo between July 2002 and October 2005. We analyzed PFOS and PFOA levels using liquid chromatography-tandem mass spectrometry and analyzed 13 single nucleotide polymorphisms (SNPs) of proliferator-activated receptor alpha, gamma, gamma coactivator 1A, delta, constitutive androstane receptor, liver X receptor alpha, and beta (LXRB) using real-time polymerase reaction (PCR). We employed multiple linear regression models to establish the influences of log10-transformed PFOS and PFOA levels and maternal genotypes on birth size. In female infants, we identified interactions between PFOS levels, the maternal genotype of LXRB (rs1405655), and birth weight. The estimated mean changes in birth weight in response to PFOS levels, the maternal genotype LXRB (rs1405655)-TC/CC (compared to TT), and their interactions were -502.9 g (95 % confidence interval [CI] = -247.3, -758.5 g), -526.3 g (95 % CI = -200.7, -852.0 g), and 662.1 g (95 % CI = 221.0, 1,103.2 g; pint = 0.003), respectively. Interactions between PFOS levels and the maternal genotype of LXRB (rs1405655) also significantly affected birth chest circumference and the Ponderal index (pint = 0.037 and 0.005, respectively). Thus, interactions between PFOS levels and the maternal genotype of LXRB (rs1405655) affects birth sizes in female infants. We found that certain SNPs modify the effects of PFOS levels on birth size.

Future career plans of medical students and the COVID-19 pandemic: Time to recover?

In 2019 and before the COVID-19 pandemic, about 68% of our medical students in Japan wished to engage in academic activities abroad. However, in 2020 and during the pandemic, this percentage fell to 35%. We found a significant increase in the number of students wishing to go abroad for studies/training in 2021 than in 2020, taking the percentage to the prepandemic level in 2019.

Associations among maternal perfluoroalkyl substance levels, fetal sex-hormone enzymatic gene polymorphisms, and fetal sex hormone levels in the Hokkaido study.

Prenatal sex hormones affect fetal growth; for example, prenatal exposure to low levels of androgen accelerates female puberty onset. We assessed the association of perfluoroalkyl substances (PFASs) in maternal sera and infant genotypes of genes encoding enzymes involved in sex steroid hormone biosynthesis on cord sera sex hormone levels in a prospective birth cohort study of healthy pregnant Japanese women (n = 224) recruited in Sapporo between July 2002 and October 2005. We analyzed PFAS and five sex hormone levels using liquid chromatography-tandem mass spectrometry. Cytochrome P450 (CYP) 17A1 (CYP17A1 rs743572), 19A1 (CYP19A1 rs10046, rs700519, and rs727479), 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1 rs6203), type 2 (HSD3B2 rs1819698, rs2854964, and rs4659175), 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1 rs605059, rs676387, and rs2676531), and type 3 (HSD17B3 rs4743709) were analyzed using real-time PCR. Multiple linear regression models were used to establish the influence of log10-transformed PFAS levels and infant genotypes on log10-transformed sex steroid hormone levels. When the interaction between perfluorooctanesulfonate (PFOS) levels and female infant genotype CYP17A1 (rs743572) on the androstenedione (A-dione) levels was considered, the estimated changes (95 % confidence intervals) in A-dione levels against PFOS levels, female infant genotype CYP17A1 (rs743572)-AG/GG, and interaction between them showed a mean increase of 0.445 (0.102, 0.787), mean increase of 0.392 (0.084, 0.707), and mean reduction of 0.579 (0.161, 0.997) (Pint = 0.007), respectively. Moreover, a female-specific interaction with testosterone levels was observed. A-dione and T levels showed positive main effects and negative interaction with PFOS levels and the female infant CYP17A1 genotype.

Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study.

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log10 scale) decreased palmitic, palmitoleic, and oleic acid levels (log10 scale), with the observed ß in the range of - 0.452 to - 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed ß in the range of - 0.266 to - 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (Pint = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.

Hokkaido birth cohort study on environment and children's health: cohort profile 2021.

BACKGROUND: The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. METHODS: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. RESULTS: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. CONCLUSIONS: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Multidrug treatment for COVID-19.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which began in Wuhan, China in December 2019, has rapidly spread all over the world. The World Health Organization characterized the disease caused by SARS-CoV-2 (COVID-19) as a pandemic in March 2020. In the absence of specific treatments for the virus, treatment options are being examined. Drug repurposing is a process of identifying new therapeutic uses for approved drugs. It is an effective strategy to discover drug molecules with new therapeutic indications. This strategy is time-saving, low-cost, and has a minimal risk of failure. Several existing approved drugs such as chloroquine, hydroxychloroquine, doxycycline, azithromycin, and ivermectin are currently in use because of their efficacy in inhibiting COVID-19. Multidrug therapy, such as a combination of hydroxychloroquine and azithromycin, a combination of doxycycline and ivermectin, or a combination of ivermectin, doxycycline, and azithromycin, has been successfully administered. Multidrug therapy is efficacious because the mechanisms of action of these drugs differ. Moreover, multidrug therapy may prevent the emergence of drug-resistant SARS-CoV-2.

Tetracycline plus macrolide: A potential therapeutic regimen for COVID-19?

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that struck in late 2019 and early 2020 is a serious threat to human health. Since there are no approved drugs that satisfactorily treat this condition, all efforts at drug design and/or clinical trials are warranted and reasonable. Drug repurposing is a well-known strategy that seeks to deploy existing licensed drugs for newer indications and that provides the quickest possible transition from the bench to the bedside to meet therapeutic needs. At present, several existing licensed drugs such as chloroquine, hydroxychloroquine, methylprednisolone, dexamethasone, and remdesivir have been used because of their potential efficacy in inhibiting COVID-19. Recently, antibiotics such as tetracyclines and macrolides have been reported to be effective against COVID-19. A combination of tetracyclines and macrolides may be a potential treatment for COVID-19 because there are some differences in the mechanism of action of tetracyclines and macrolides.