Higher Daily Dose Research Articles

Vitamin D deficiency and malignancies

The analysis of domestic and foreign literature shows that oncological diseases are most often accompanied by a low level of 25(OH)D in the blood serum of patients and a high prevalence of deficiency and severe deficiency of vitamin D. It can be confidently stated that the level of 25(OH)D in serum blood of oncological patients, on average, is lower than in healthy people of the corresponding sex and age. In this regard, statistical studies were carried out, which demonstrated the prevalence of vitamin D deficiency in the countries of Europe and North America, which is directly proportional to the level of annual mortality from cancer and the probability of death from cancer, any type of cardiovascular disease, diabetes and chronic respiratory diseases, and this relationship is statistically significant (p < 0.001). Oncological morbidity and mortality from cancer in the Russian Federation naturally increases especially in higher latitudes, which, along with other reasons, is associated with a limitation in the duration of the effective production of vitamin D3 in human skin under the influence of ultraviolet radiation. Some clinical studies of vitamin D supplementation as a therapeutic agent are showing measurable positive results in cancer, with far more positive than in placebo groups. However, negative results that are harmful to patients participating in clinical experiments have not been established in the study of many hundreds of studied articles on this issue. The most commonly seen beneficial effects of vitamin D supplementation have been in the treatment of breast and colorectal cancer, which are particularly noticeable in patients with low baseline serum levels of 25(OH)D and high daily doses of 25(OH)D3 supplementation well above standard recommendations of 400–800 IU daily. Due to the high prevalence of vitamin D deficiency among cancer patients, taking into account international positive experience, it seems very useful and necessary to create domestic scientific foundations and expand the clinical practice of using vitamin D supplements as a therapeutic agent for cancer.

47 Clinical Approach to Febrile Urinary Tract Infections in Young Children Presenting to the Paediatric Emergency Department: A Retrospective Study of National Guideline Compliance

Abstract Background Antimicrobial resistance is one of the greatest threats to global health. Antibiotic overuse drives antimicrobial resistance. Suspected urinary tract infection (UTI) is a key area of over-prescribing in many clinical settings but has not been investigated in the paediatric emergency department (ED). Objectives Here, we explore compliance with national UTI management guidelines in a paediatric emergency department setting and characterize patient and provider factors associated with guideline non-compliance. Design/Methods We performed retrospective chart review of patients ages 60 days to 36 months, discharged with a diagnosis of UTI from a single, urban, tertiary care paediatric emergency department (PED) with a diagnosis of UTI. Random visits were chosen using a computer algorithm. Primary outcomes were: 1) proportion of patients receiving guideline-compliant investigation and treatment, and 2) the proportion of children whose antibiotic prescriptions were appropriately adjusted upon return of urine culture and antibiotic susceptibilities (C&S). The guideline was the Canadian Paediatric Society statement on management of UTI, as well as the BC Children’s Hospital institutional UTI management guideline. Descriptive statistics and odds ratios between associations were calculated. Results We reviewed 402 charts. The proportion of infants receiving guideline-compliant testing and treatment was 25.9% (95% CI: 21.8-30.4%). Of those who were prescribed antibiotics, 79.6% (95% CI: 74.7-83.8%) received a first-line recommended agent and 58.9% (95% CI: 53.8-63.8%) received fully compliant therapy with respect to agent, dose, duration, and frequency. 19.4% (15.4-24.2%) of patients who were prescribed empiric cephalexin received an inappropriately high total daily dose. The proportion of patients receiving age-appropriate testing method was 52.2% (95% CI: 47.4-57.1). Febrile children were more likely to receive age-appropriate urine sample collection by catheterized sample (OR: 2.77 95% CI: 1.81-4.25) compared with afebrile children. Ultimately, 50.7% (95% CI: 40.4-49.6%) of patients discharged with a diagnosis of UTI and prescription for antibiotic met diagnostic criteria for UTI based on urinalysis and culture results. Of patients whose C&S mandated a change in therapy, 60.8% (95% CI: 55.8-65.7%) had their agent changed or discontinued. Conclusion Paediatric emergency medicine physicians frequently order inappropriate investigation and empiric treatment of UTI in young children. Discontinuation of empiric antibiotics in culture-negative children may be an impactful stewardship intervention in the PED.

Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis

Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis

Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680. Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias. Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Temporal patterns of cytokine and injury biomarkers in hospitalized COVID-19 patients treated with methylprednisolone.

The novel coronavirus disease 2019 (COVID-19) presents with complex pathophysiological effects in various organ systems. Following the COVID-19, there are shifts in biomarker and cytokine equilibrium associated with altered physiological processes arising from viral damage or aggressive immunological response. We hypothesized that high daily dose methylprednisolone improved the injury biomarkers and serum cytokine profiles in COVID-19 patients. Injury biomarker and cytokine analysis was performed on 50 SARS-Cov-2 negative controls and 101 hospitalized severe COVID-19 patients: 49 methylprednisolone-treated (MP group) and 52 placebo-treated serum samples. Samples from the treated groups collected on days D1 (pre-treatment) all the groups, D7 (2 days after ending therapy) and D14 were analyzed. Luminex assay quantified the biomarkers HMGB1, FABP3, myoglobin, troponin I and NTproBNP. Immune mediators (CXCL8, CCL2, CXCL9, CXCL10, TNF, IFN-γ, IL-17A, IL-12p70, IL-10, IL-6, IL-4, IL-2, and IL-1β) were quantified using cytometric bead array. At pretreatment, the two treatment groups were comparable demographically. At pre-treatment (D1), injury biomarkers (HMGB1, TnI, myoglobin and FABP3) were distinctly elevated. At D7, HMGB1 was significantly higher in the MP group (p=0.0448) compared to the placebo group, while HMGB1 in the placebo group diminished significantly by D14 (p=0.0115). Compared to healthy control samples, several immune mediators (IL-17A, IL-6, IL-10, MIG, MCP-1, and IP-10) were considerably elevated at baseline (all p≤0.05). At D7, MIG and IP-10 of the MP-group were significantly lower than in the placebo-group (p=0.0431, p=0.0069, respectively). Longitudinally, IL-2 (MP-group) and IL-17A (placebo-group) had increased significantly by D14. In placebo group, IL-2 and IL-17A continuously increased, as IL-12p70, IL-10 and IP-10 steadily decreased during follow-up. The MP treated group had IL-2, IFN-γ, IL-17A and IL-12p70 progressively increase while IL-1β and IL-10 gradually decreased towards D14. Moderate to strong positive correlations between chemokines and cytokines were observed on D7 and D14. These findings suggest MP treatment could ameliorate levels of myoglobin and FABP3, but appeared to have no impact on HMGB1, TnI and NTproBNP. In addition, methylprednisolone relieves the COVID-19 induced inflammatory response by diminishing MIG and IP-10 levels. Overall, corticosteroid (methylprednisolone) use in COVID-19 management influences the immunological molecule and injury biomarker profile in COVID-19 patients.

Use of optical coherence tomography retinal thickness deviation map for hydroxychloroquine retinopathy screening

Background: Hydroxychloroquine (HCQS) is widely used to treat several rheumatic and skin diseases and can cause damage to the outer retina, known as HCQS retinopathy, and is common among long-term users of the drug with higher daily dose by weight. The goal of screening for retinopathy is to recognize signs of toxicity at an early enough stage to prevent the loss of visual acuity. Aims and Objectives: This study aimed to evaluate the diagnostic performance of a commercially available retinal thickness deviation map obtained by spectral-domain (SD) optical coherence tomography (OCT) for screening of HCQS retinopathy. Materials and Methods: This study was a prospective comparative study between unaffected (patients who did not develop retina toxicity) and affected (who developed toxicity) of 50 patients of the age group of 14–60 years taking HCQS medication for several dermatological and rheumatologic disorders. The patients who fulfilled the inclusion criteria were screened for HCQS retinal toxicity using SD-OCT, standard automated perimetry, fundus autofluorescence, and comprehensive ophthalmic examinations. Results: In this study, in group 2 patients, 60% were having parafoveal, 30% having perifoveal, and 10% having a mixed pattern (P&lt;0.001) of HCQS retinopathy, and the mean deviation and pattern standard deviation increase as the severity of disease increases (P&lt;0.005). Conclusion: This study concluded that HCQS is a safer drug and can be used safely in these patients with proper HCQS retinal toxicity monitoring with an SD-OCT-generated retinal thickness deviation map and with regular follow-up to monitor reduced thickness in the parafoveal region.

Inhaled Corticosteroids and the Risk of Nontuberculous Mycobacterial Pulmonary Disease in Chronic Obstructive Pulmonary Disease: Findings from a Nationwide Population-Based Study.

Studies have shown increased nontuberculous mycobacterial pulmonary disease (NTM) incidence with inhaled corticosteroid (ICS) use in patients with chronic respiratory diseases; however, this association in chronic obstructive pulmonary disease (COPD) remains insufficiently studied. Using a nationwide population-based database of the Korean National Health Insurance Service, newly diagnosed COPD patients (2005-2018) treated with inhaled bronchodilators were selected. An NTM case was defined by the presence of the first diagnostic code following inhaled bronchodilator use. Results indicated that ICS users did not have an increased risk of NTM disease compared to non-ICS users (hazard ratio (HR), 1.121; 95% confidence interval (CI), 0.950-1.323; p = 0.176). However, in a subgroup analysis, the highest quartile of the cumulative ICS dose was associated with the development of NTM (1.200, 0.950-1.323, p = 0.050). Medium (1.229, 1.008-1.499, p = 0.041) and high daily doses of ICS (1.637, 1.241-2.160, p < 0.001) were associated with an increased risk of NTM disease. There was no difference in the risk of NTM according to ICS type. ICS use may increase the risk of developing NTM disease in patients with COPD. Physicians should weigh the potential benefits and risks of ICS, especially when using high doses and prolonged durations.

Radioterapija raka dojke - promjene u shemama frakcioniranja kroz desetljeća

Traditionally, as a standard dose fractionation schedule, adjuvant radiotherapy for breast cancer has been performed using prescribed doses of 46–50 Gy divided into daily fractions of 1.8–2 Gy. Overall, radiotherapy treatment took 5 weeks. In the 1990s, schedules using higher daily doses (2.5–3 Gy), a smaller number of fractions (hypofractionation), and a reduced overall prescribed dose started in the context of clinical trials. First results revealed an equivalent cosmetic effect of hypofractionated protocols compared to standard fractionation, and after longer follow-up, hypofractionation was connected with better control of the disease. Hypofractionation started to be considered the new treatment standard. Results of newer clinical trials confirm the efficacy and safety of adjuvant breast cancer radiotherapy lasting 5 working days using daily fractions of 5.2 Gy in certain subgroups of breast cancer patients.

Prevalence and correlates of high-dose opioid use among survivors of head and neck cancer.

We characterized prescription opioid medication use up to 2 years following the head and neck cancer (HNC) diagnosis and examined associations with moderate or high daily opioid prescription dose. Using administrative data from Veterans Health Administration, we conducted a retrospective cohort analysis of 5522 Veterans treated for cancers of the upper aerodigestive tract between 2012 and 2019. Data included cancer diagnosis and treatments, pain severity, prescription opioid characteristics, demographics, and other clinical factors. Two years post-HNC, 7.8% (n = 428) were receiving moderate or high-dose opioid therapy. Patients with at least moderate pain (18%, n = 996) had 2.48 times higher odds (95% CI = 1.94-3.09, p < 0.001) to be prescribed a moderate opioid dose or higher at 2 years post diagnosis. Survivors of HNC with at least moderate pain were at elevated risk of continued use of moderate and high dose opioids.

High-risk Prescribing Following Surgery Among Payer Types for Patients on Chronic Opioids.

Among those on chronic opioids, to determine whether patients with Medicaid coverage have higher rates of high-risk opioid prescribing following surgery compared with patients on private insurance. Following surgery, patients on chronic opioids experience gaps in transitions of care back to their usual opioid prescriber, but differences by payer type are not well understood. This study aimed to analyze how new high-risk opioid prescribing following surgery compares between Medicaid and private insurance. In this retrospective cohort study through the Michigan Surgical Quality Collaborative, perioperative data from 70 hospitals across Michigan were linked to prescription drug monitoring program data. Patients with either Medicaid or private insurance were compared. The outcome of interest was new high-risk prescribing, defined as a new occurrence of: overlapping opioids or benzodiazepines, multiple prescribers, high daily doses, or long-acting opioids. Data were analyzed using multivariable regressions and a Cox regression model for return to usual prescriber. Among 1435 patients, 23.6% (95% CI: 20.3%-26.8%) with Medicaid and 22.7% (95% CI: 19.8%-25.6%) with private insurance experienced new, postoperative high-risk prescribing. New multiple prescribers was the greatest contributing factor for both payer types. Medicaid insurance was not associated with higher odds of high-risk prescribing (odds ratio: 1.067, 95% CI: 0.813-1.402). Among patients on chronic opioids, new high-risk prescribing following surgery was high across payer types. This highlights the need for future policies to curb high-risk prescribing patterns, particularly in vulnerable populations that are at risk of greater morbidity and mortality.

Insulin Refill Adherence among Type 2 Diabetes Mellitus Patients Attending Public Health Clinics in Perlis, Malaysia

Poor adherence to diabetes medications, particularly insulin, is still a concern. This study aimed to assess insulin refill adherence among diabetes patients attending public health clinics in Perlis before and during the COVID-19 pandemic. The underlying factors associated with insulin refill adherence were also investigated. This cross-sectional study was conducted among type 2 diabetes mellitus patients with insulin therapy from five primary health clinics in Perlis. Simple random sampling method was used to select participants from the Pharmacy Information System (PhIS) database. Adherence to insulin refill was measured by medication possession ratio before and during the COVID-19 pandemic. A general linear model was used to identify factors associated with adherence to insulin refills. A total of 426 patients were included in this study. Patients in this study were mostly Malay (94.3%) and female (63.1%). The insulin refill adherence was significantly poorer during the COVID-19 pandemic (mean=59.24, SD=28.97) than before the pandemic (mean=68.31, SD=31.27) (p&lt;0.001). Only total daily insulin dose (adjusted β = -0.129; p=0.012) and not having hypertension (adjusted β = -7.359; p=0.043) were significantly associated with insulin refill adherence. This study highlighted that overall insulin refill adherence among patients in public health clinics in Perlis was still low, especially during the COVID-19 pandemic. Special attention should be given to patients using high total daily insulin doses and having no hypertension to improve adherence.

Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants.

Hyperbilirubinemia is a common pathological condition in neonates. Free bilirubin can penetrate the blood-brain barrier (BBB), which can lead to bilirubin neurotoxicity. In the context of predicting the risk of bilirubin neurotoxicity, although the specificity and sensitivity of free bilirubin levels are higher than those of total serum bilirubin (TSB), free bilirubin is not widely monitored in clinical practice. The threshold TSB levels at which phototherapy must be administered have been established previously. However, TSB levels are not well correlated with neurodevelopmental outcomes. Currently, TSB levels are commonly used to guide phototherapy for neonatal hyperbilirubinemia. Some clinical drugs can displace bilirubin from its albumin-binding sites, and consequently upregulate plasma bilirubin. Daily dosages play a vital role in regulating bilirubin levels. A drug with both a high protein binding capacity and high daily dosage significantly increases bilirubin levels in infants. Premature or very low birth weight (VLBW) infants are vulnerable to the upregulation of bilirubin levels as they exhibit the lowest reserve albumin levels and consequently the highest bilirubin toxicity index. Because bilirubin is involved in maintaining the balance between pro-oxidant and antioxidant agents, the downregulation of bilirubin levels is not always desirable. This review provides insights into the impact of protein binding capacity and daily dosage of drugs on the bilirubin levels in susceptible infants.

Amorphous Solid Dispersion of Niclosamide with Water‐Soluble β‐Cyclodextrins for Dissolution and Bioavailability Enhancement

AbstractCyclodextrins (CDs) are cyclic oligosaccharides widely employed for the solubility enhancement of poorly water‐soluble drugs. Niclosamide is a BCS class II drug for tapeworm infections and is currently under repurposing for various other indications, including COVID‐19. Due to its low aqueous solubility, a high daily dose (2 g) is required for clinical efficacy. Herein, we investigate the potential of beta‐cyclodextrin (β‐CD) and its sulfobutylether and hydroxypropyl derivatives for the dissolution enhancement of niclosamide. The solid dispersions were prepared by kneading the drug and cyclodextrins together by adding solvent, water: methanol (1 : 1 v/v). Among various CDs studied, 2‐Hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) in the 1: 2 molar ratio (SB‐IC‐N4 batch) shows the most significant improvement in water solubility of niclosamide (6.3 vs. 182 μg/ml), resulting in 2‐fold improved in‐vitro dissolution. The comparative oral pharmacokinetics in Wistar rats at 50 mg/kg produced 1.69‐fold higher plasma exposure of niclosamide. The spectral characterization provided molecular insights into interactions of niclosamide with HP‐β‐CD. These results suggest that the dispersion of niclosamide with HP‐β‐CD aid in faster dissolution and better drug bioavailability.

Atmospheric phthalate esters in a multi-function area of Hangzhou: Temporal variation, gas/particle phase distribution, and population exposure risk

Phthalate esters (PAEs) are prevalent in both indoor and outdoor environments. However, there are relatively few studies on phthalate contamination in the air of multi-function areas. Experiments were conducted to analyze the concentrations of 14 distinct PAEs in outdoor air in the college town of Hangzhou throughout both the warm and cold seasons. Correlation and principal component analyses were performed to investigate the influence and source factors of PAEs. This study also focused on the relationship between the gas/particle partition coefficient Kp and temperature, as well as the application of the gas/particle partition model. The risk of exposure to PAEs via inhalation was predicted for four groups of the general population: toddlers, adolescents, adults, and older adults. The results indicated that the concentration levels of Σ14PAEs in outdoor air were 1573 ng/m3 in the gaseous phase and 126 ng/m3 in the particulate phase. Additionally, this study indicated three primary sources of PAEs: indoor diffuse sources, industrial emission sources, and building construction sources. The gas/particle partitioning of PAEs also revealed that low-molecular-weight PAEs are more prevalent in gas, whereas high-molecular-weight PAEs are more predominant in the particle phase. A health risk analysis revealed high estimations of daily intakes (EDI) for toddlers and adolescents and high lifetime average daily doses (LADD) for older adults. This study establishes a solid foundation for formulating scientific and effective air pollution control measures by analyzing the characteristics and assessing the health risks of PAEs.

Antioxidant and Lipid-Lowering Effects of Buriti Oil (Mauritia flexuosa L.) Administered to Iron-Overloaded Rats.

The indiscriminate use of oral ferrous sulfate (FeSO4) doses induces significant oxidative damage to health. However, carotene-rich foods such as buriti oil can help the endogenous antioxidant defense and still maintain other body functions. This study aimed to assess the effects of buriti oil intake in iron-overloaded rats by FeSO4 administration. Buriti oil has β-carotene (787.05 mg/kg), α-tocopherol (689.02 mg/kg), and a predominance of monounsaturated fatty acids (91.30 g/100 g). Wistar rats (n = 32) were subdivided into two control groups that were fed a diet containing either soybean or buriti oil; and two groups which received a high daily oral dose of FeSO4 (60 mg/kg body weight) and fed a diet containing either soybean (SFe) or buriti oil (Bfe). The somatic and hematological parameters, serum lipids, superoxide dismutase (SOD), and glutathione peroxidase (GPx) were determined after 17 days of iron overload. Somatic parameters were similar among groups. BFe showed a decrease in low-density lipoprotein (38.43%) and hemoglobin (7.51%); an increase in monocytes (50.98%), SOD activity in serum (87.16%), and liver (645.50%) hepatic GPx (1017.82%); and maintained serum GPx compared to SFe. Buriti oil showed systemic and hepatic antioxidant protection in iron-overloaded rats, which may be related to its high carotenoid, tocopherol, and fatty acid profile.

Prevalence and Risk Factors of Hydroxychloroquine Retinopathy in Rheumatic Patients with Dry Eye Symptoms

Purpose: Hydroxychloroquine is widely used for long-term treatment of rheumatic diseases, but the drug can trigger irreversible toxic retinopathy. We studied the prevalence of, and the risk factors for, hydroxychloroquine retinopathy in rheumatic patients with dry eye symptoms and we introduce a representative case.Methods: We retrospectively studied a cohort of 133 rheumatological patients who had taken hydroxychloroquine for at least 12 months and who visited our ophthalmology clinic with dry eye symptoms from April 2016 to December 2021. Hydroxychloroquine retinopathy was diagnosed via fundus photography, spectral-domain optical coherence tomography, the Humphrey visual field test, autofluorescence fundus photography, and multifocal electroretinography. The principal outcomes were the prevalence of retinopathy at the first screening and the risk factors.Results: Of the 133 patients, hydroxychloroquine retinopathy was diagnosed in seven (5.2%) at the first screenings. The Mann-Whitney U-test revealed that older age; higher daily doses; longer dosing duration; greater cumulative doses; and higher daily and cumulative doses/kg were statistically significant in terms of retinopathy development. On multivariate logistic regression analysis, the average daily dose (odds ratio [OR] 6.02; 95% confidence interval [CI] 1.64-22.12, 100 mg increments) and duration of dosing (OR 3.39; 95% CI 1.19-9.62, 5 years increments) remained statistically significant (P = 0.021, P = 0.007 respectively)Conclusions: Ophthalmologists should enquire about any history of hydroxychloroquine therapy, and perform a retinal examination, when encountering dry eye in patients with rheumatic disease. Early detection of hydroxychloroquine retinopathy followed by discontinuation of hydroxychloroquine is the only way to prevent visual loss. High daily drug doses and long dosing durations are risk factors for retinopathy.

Prolactin-Raising and Prolactin-Sparing Antipsychotic Drugs and the Risk of Fracture and Fragility Fracture in Patients With Schizophrenia, Dementia, and Other Disorders

Patients who require antipsychotic drug treatment are at increased risk of fractures, including osteoporosis-related fragility fractures, for reasons related to demographics, illness-related factors, and treatment-related factors. As examples, patients with dementia may be vulnerable to falls due to cognitive and psychomotor impairment, patients with schizophrenia may be vulnerable to injury related to physical restlessness or physical aggression, and patients receiving antipsychotics may suffer falls related to sedation, psychomotor impairment, bradykinesia, or postural hypotension. Antipsychotics may also increase the risk of fracture through long-term hyperprolactinemia and resultant osteoporosis. A meta-analysis of 36 observational studies conducted in mostly elderly samples found that antipsychotic exposure was associated with an increased risk of hip fracture as well as increased risk of any fracture; the findings were consistent in almost all subgroup analyses. An observational study that controlled for confounding by indication and illness severity found that fragility fractures in patients with schizophrenia were associated with higher daily doses, higher cumulative doses, longer duration of treatment, and prolactin-raising rather than prolactin-sparing antipsychotics; in patients receiving prolactin-raising antipsychotics, the concurrent use of aripiprazole appeared protective. The absolute risks of fracture are unknown and could vary depending on patient age, patient sex, indication for antipsychotic use, nature of the antipsychotic (and associated risk of sedation, psychomotor impairment, bradykinesia, and postural hypotension), daily dose prescribed, duration of antipsychotic exposure, baseline risk of fracture, and other risk factors. Patients should therefore be individually evaluated for risk factors for falls and fractures related to sociodemographic, clinical, and treatment-related risk factors. Patients identified to be at risk should be advised about risk-mitigating strategies. If prolactin-raising antipsychotics are required in the long term, prolactin levels should be monitored and prolactin-lowering strategies should be considered. Osteoporosis should be investigated and managed, if identified, to prevent fragility fractures.

The effect of high-dose vitamin D supplementation on hepcidin-25 and erythropoiesis in patients with chronic kidney disease

BackgroundHepcidin is considered to play a central role in the pathophysiology of renal anemia. Recent studies in healthy individuals have demonstrated a suppressive effect of vitamin D (VD) on the expression of hepcidin. In this post-hoc analysis based on a randomized controlled study, we evaluated the effect of supplementing chronic kidney disease (CKD) patients (stage G3-G4) with a high daily dose of native VD on serum levels of hepcidin-25, the hepcidin/ferritin ratio, as well as on markers of erythropoiesis.MethodsPatients with CKD stage G3-G4 included in a double blind, randomized, placebo (PBO) controlled study with available hepcidin measurements were analyzed. Study subjects received either 8000 international units (IU) of cholecalciferol daily or PBO for 12 weeks. We evaluated the change in markers of hepcidin expression, erythropoiesis, and iron status from baseline to week 12 and compared the change between the groups.ResultsEighty five patients completed the study. Calcitriol, but not 25-hydroxyvitamin D (25(OH) D), was inversely correlated with serum levels of hepcidin-25 (rho = -0,38; p = < 0, 01 and rho = -0,02; p = 0, 89, respectively) at baseline. Supplementation with VD significantly raised the serum concentration of serum 25(OH)D in the treatment group (from 54 (39–71) to 156 (120–190) nmol/L; p = < 0, 01)) but had no effect on any of the markers of hepcidin, erythropoiesis, or iron status in the entire cohort. However, we did observe an increase in hemoglobin (HB) levels and transferrin saturation (TSAT) as compared to the PBO group in a subgroup of patients with low baseline 25(OH)D levels (< 56 nmol/L). In contrast, in patients with high baseline 25(OH)D values (≥ 56 nmol/L), VD supplementation associated with a decrease in HB levels and TSAT (p = 0,056) within the VD group in addition to a decrease in hepcidin levels as compared to the PBO group.ConclusionHigh-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort. However, in patients with low baseline 25(OH)D levels, high-dose VD supplementation associated with beneficial effects on erythropoiesis and iron availability. In contrast, in patients with elevated baseline 25(OH)D levels, high-dose VD supplementation resulted in a decrease in hepcidin levels, most likely due to a deterioration in iron status.

Pirfenidone–flavonoid cocrystals with reduced solubility and dissolution rate

Two pirfenidone–flavonoid cocrystals with sustained release property were obtained.

Scientific opinion on the tolerable upper intake level for selenium.

Following a request from the European Commission, the EFSA Panelon Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for selenium. Systematic reviews of the literature were conducted to identify evidence regarding excess selenium intake and clinical effects and potential biomarkers of effect, risk of chronic diseases and impaired neuropsychological development in humans. Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, is selected as the critical endpoint on which to base a UL for selenium. A lowest-observed-adverse-effect-level (LOAEL) of 330μg/day is identified from a large randomised controlled trial in humans (the Selenium and Vitamin E Cancer Prevention Trial (SELECT)), to which an uncertainty factor of 1.3 is applied. A UL of 255μg/day is established for adult men and women (including pregnant and lactating women). ULs for children are derived from the UL for adults using allometric scaling (body weight0.75). Based on available intake data, adult consumers are unlikely to exceed the UL, except for regular users of food supplements containing high daily doses of selenium or regular consumers of Brazil nuts. No risk has been reported with the current levels of selenium intake in European countries from food (excluding food supplements) in toddlers and children, and selenium intake arising from the natural content of foods does not raise reasons for concern. Selenium-containing supplements in toddlers and children should be used with caution, based on individual needs.