Nevin Manimala

Rheumatology (Oxford). 2021 Jul 17:keab572. doi: 10.1093/rheumatology/keab572. Online ahead of print.

ABSTRACT

OBJECTIVES: Limited data about use of biosimilars are available in children with Juvenile Idiopathic Arthritis (JIA). This study therefore aimed to evaluate long-term efficacy and safety of switching from etanercept (ETA) and adalimumab (ADA) originators to their biosimilars, in children with JIA, in a real-world setting.

METHODS: This is a retro-prospective non-interventional multicentre Italian comparative cohort study. Medical charts of JIA children treated with biosimilars of ETA or ADA were included. Efficacy and safety of TNF-inhibitors therapy was evaluated at last follow-up during originator and at 3, 6 and 12 months following the switch to biosimilar.

RESULTS: 59 children (42 female, median age at onset 88 months) were treated with biosimilar of ETA (21) and ADA (38). Forty-five switched from the originator to the BIO (17 ETA, 28 ADA). At time of switch, 12/17 patients on ETA and 18/28 on ADA were in remission. No significant difference has been found at 3, 6 and 12 months after the switch. Ten patients discontinued biosimilars due to disease remission (4 ETA, 3 ADA), family willing (1 ETA), occurrence of burning at injection site (1 ETA), and persistent activity (1 ADA). No statistically significant difference was observed between originator and BIOs, nor between originator and BIOs, and between ADA and ETA in time to disease remission achievement, time to relapse and number of patients who experienced AE.

CONCLUSION: Our real-life results seem to confirm the efficacy and safety profile of switching from originator of ADA and ETA to their respective BIOs also in paediatric patients with JIA.

PMID:34273158 | DOI:10.1093/rheumatology/keab572

Brain. 2021 Jul 17:awab267. doi: 10.1093/brain/awab267. Online ahead of print.

ABSTRACT

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression, and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases=59,674; n controls=316,078), bipolar disorder (n cases=20,352; n controls=31,358), depression (n cases=170,756; n controls=328,443) and schizophrenia (n cases=40,675, n controls=64,643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterised to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8K disorder-influencing variants) compared to mental disorders (8.1K-12.3K disorder-influencing variants). Bivariate analysis estimated that 0.8K (0.3K), 2.1K (SD = 0.1K) and 2.3K (SD = 0.3K) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1.8K, SD = 0.3K) and educational attainment (2.1K, SD = 0.3K) but not height (1K, SD = 0.1K). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2, SLC9B1. Gene-set analysis identified several putative gene-sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants which influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

PMID:34273149 | DOI:10.1093/brain/awab267

Thorac Cancer. 2021 Jul 17. doi: 10.1111/1759-7714.14076. Online ahead of print.

ABSTRACT

BACKGROUND: There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression-free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score.

METHODS: This was a post hoc analysis of a multicenter, double-blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively.

RESULTS: The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5-11.0) versus 3.2 (95% CI: 1.2-5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2-0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0-11.0) vs. 4.8 (95% CI: 1.2-8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses.

CONCLUSIONS: The occurrence of hypertension might be a clinical indicator predicting the efficacy of third-line anlotinib treatment in patients with SCC.

PMID:34273139 | DOI:10.1111/1759-7714.14076

J Med Virol. 2021 Jul 17. doi: 10.1002/jmv.27215. Online ahead of print.

ABSTRACT

AIMS: We have previously demonstrated that vitamin D deficiency might be associated with worse outcomes in hospitalised Covid-19 patients. The aim of our study was to explore this relationship with dexamethasone therapy.

METHODS: We prospectively studied two cohorts of hospitalised Covid-19 patients between March and April and between September and December 2020 (n=192). Patients were tested for serum 25-hydroxyvitamin D (25-OH-D) levels during admission. The first cohort not treated with dexamethasone (n=107) were divided into vitamin D deficient (25-OH-D ≤30nmol/L) (n=47) and replete subgroups (25-OH-D >30nmol/L) (n=60). The second cohort treated with dexamethasone (n=85) was similarly divided into deficient (25-OH-D ≤30nmol/L) (n=27) and replete subgroups (25-OH-D >30nmol/L) (n=58). Primary outcome was in-hospital mortality and secondary outcomes were elevation in markers of cytokine storm and ventilatory requirement.

RESULTS: No mortality difference was identified between cohorts and subgroups. The “no dexamethasone” cohort 25-OH-D deplete subgroup recorded significantly higher peak D-Dimer levels (1874ugFEU/L vs 1233ugFEU/L) (p value = 0.0309), CRP (177 vs 107.5) (p=0.0055) and ventilatory support requirement (25.5% vs 6.67%) (p value = 0.007) compared to the replete subgroup. Among the 25-OH-D deplete subgroup higher peak neutrophil counts, peak CRP, peak LDH, peak ferritin and lower trough lymphocyte counts were observed, without statistical significance. In the “dexamethasone” cohort, there was no apparent association between 25-OH-D deficiency and markers of cytokine storm or ventilatory requirement.

CONCLUSION: Vitamin D deficiency is associated with elevated markers of cytokine storm and higher ventilatory requirements in hospitalised Covid-19 patients. Dexamethasone treatment appears to mitigate adverse effects of vitamin D deficiency. This article is protected by copyright. All rights reserved.

PMID:34273116 | DOI:10.1002/jmv.27215

Drug Saf. 2021 Jul 17. doi: 10.1007/s40264-021-01087-7. Online ahead of print.

ABSTRACT

INTRODUCTION: The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited.

OBJECTIVE: The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design.

METHODS: The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS)^® Disease Analyzer Germany database during the study period (2009-2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions. Each patient was followed for specific liver events for 90 days after the prescription. In case of a new prescription within 90 days, a new 90-day observation period started, up to a maximum of 270 days. Cox regression was used to compare the risk of liver injury in the two groups.

RESULTS: Metamizole was associated with a higher risk of liver injury compared with paracetamol (adjusted hazard ratio 1.69, 95% confidence interval 1.46-1.97). Sensitivity analyses were performed to evaluate the robustness of these findings. In all the sensitivity analyses, metamizole was still associated with a higher risk of liver injury, including an analysis where naproxen was used as a comparator instead of paracetamol.

CONCLUSIONS: Results from this study support previous studies suggesting that metamizole is associated with a significant risk of liver injury. Nevertheless, a possible impact of residual confounding cannot be excluded.

PMID:34273099 | DOI:10.1007/s40264-021-01087-7

Environ Sci Pollut Res Int. 2021 Jul 17. doi: 10.1007/s11356-021-14978-0. Online ahead of print.

ABSTRACT

The TransMilenio (TM) is a transport system. Twenty-year-old TM is a fast, highly efficient, and self-sufficient mode of passenger transport. This work aims to evaluate the effects of changing current TM diesel buses by electricity-powered buses (battery, wire-based), on the PM_2.5 concentrations at surface level. Emissions calculations considering combustions and resuspension of TM and Non-TM were performed. A CFD model was implemented to estimate current PM_2.5 concentrations at the roadside level, and the CFD results were validated using the statistic parameters: MB, RMSE, r, and IOA. Results from the emission calculations indicate that TM buses (30-50%) are one of the main sources of primary PM_2.5 in all the considered urban sites in this study. Non-exhaust emissions from most vehicle categories were also identified as an important source of primary PM_2.5 (40% of total emissions). The CFD model reproduced closely the trends and levels of PM_2.5 concentrations measured at the roadside level in all the locations. Replacing TM diesel vehicles with electric vehicles reduces PM_2.5 concentrations between 10 and 30% according to the CFD results obtained. Higher reductions can be achieved if policies are adopted to control other types of vehicles and non-exhaust emissions since they have a contribution of about 60%. Finally, this study shows that the combined use of emission calculations and advanced near-road dispersion models are useful tools to study and manage air quality in large cities.

PMID:34273076 | DOI:10.1007/s11356-021-14978-0

J Clin Immunol. 2021 Jul 17. doi: 10.1007/s10875-021-01083-7. Online ahead of print.

ABSTRACT

BACKGROUND: The relationship of host immune response and viral replication with health outcomes in patients with COVID-19 remains to be defined. We aimed to characterize the medium and long-term clinical, virological, and serological outcomes after hospitalization for COVID-19, and to identify predictors of long-COVID.

METHODS: Prospective, longitudinal study conducted in COVID-19 patients confirmed by RT-PCR. Serial blood and nasopharyngeal samples (NPS) were obtained for measuring SARS-CoV-2 RNA and S-IgG/N-IgG antibodies during hospital stay, and at 1, 2, and 6 months post-discharge. Genome sequencing was performed where appropriate. Patients filled out a COVID-19 symptom questionnaire (CSQ) at 2-month and 6-month visits, and those with highest scores were characterized.

RESULTS: Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2 months and 6 months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct = 38) and 3% (median Ct = 36) patients at 2 months and 6 months, respectively, but no reinfections were demonstrated. Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66-0.94]) and higher WHO severity score (2.57 [1.20-5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79-0.99]) and female sex (2.41 [1.20-4.82]); no association was found with prolonged viral RNA shedding.

CONCLUSIONS: Long-COVID is associated with weak anti-SARS-CoV-2 antibody response, severity of illness, and female gender. Late clinical events and persistent symptoms in the medium and long term occur in a significant proportion of patients hospitalized for COVID-19.

PMID:34273064 | DOI:10.1007/s10875-021-01083-7

Support Care Cancer. 2021 Jul 17. doi: 10.1007/s00520-021-06422-3. Online ahead of print.

ABSTRACT

PURPOSE: The aim of this study is to identify sources of distress among cancer patients attending rehabilitation in the community.

METHODS: Participants were 430 patients recruited from a cancer rehabilitation center in Singapore between 2017 and 2018, who had rated their distress using the distress thermometer (DT) and indicated associated problems on the problem list. Chi-square tests were used to detect differences in the reported symptoms among three age groups. Exploratory factor analysis was used to identify symptom clusters. Partial correlational analysis was then performed to examine the relationship between distress, symptom clusters, and age controlling for gender and cancer type.

RESULTS: About 30% of the participants reported distress ≥ 5 on the DT (mean 3.3 ± 2.5), and the mean number of problems endorsed was 8 ± 6. A higher total number of reported problems (r = .63) and younger age (r = – .21) were associated with increased distress. The younger age group also reported more problems surrounding emotions, finance, work/school, children-related issues, and physical symptoms such as sleep and nausea. Of the 12 factors identified, 9 psychosocial and physical symptom clusters correlated with distress (r ranging from .12 to .41). All results were statistically significant after adjustment (p ≤ 0.05).

CONCLUSION: Younger survivors are more at risk of distress and report greater role functioning concerns related to childcare, partner relationship, and work participation. Age-tailored and multimodal interventions may be necessary to adequately address age-related differences and help coordinate management of multiple symptom clusters across physical and psychosocial concerns.

PMID:34273033 | DOI:10.1007/s00520-021-06422-3

J Neural Transm (Vienna). 2021 Jul 17. doi: 10.1007/s00702-021-02373-5. Online ahead of print.

ABSTRACT

Atomoxetine (ATO) is a second line medication for attention-deficit hyperactivity disorder (ADHD). We proposed that part of the therapeutic profile of ATO may be through circadian rhythm modulation. Thus, the aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after ATO exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with a diagnosis of ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different ATO concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. No statistical significant effect of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, sleep WASO and total number of wake bouts was observed. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. ATO induced the rhythmicity of Clock in the ADHD group. This effect, however, was not observed in HDF cultures of healthy controls. Bmal1 and Per2 expression showed a significant ZT × group interaction via mixed ANOVA. Strong positive correlations for chronotype and circadian genes were observed for Bmal1, Cry1 and Per3 among the study participants. Statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as healthy participants with morning preferences. The results of the present study illustrate that ATO impacts on circadian function, particularly on Clock, Bmal1 and Per2 gene expression.

PMID:34273025 | DOI:10.1007/s00702-021-02373-5

Clin Oral Investig. 2021 Jul 17. doi: 10.1007/s00784-021-04066-5. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aims to assess craniofacial dimensions in obstructive sleep apnea (OSA) patients treated with a mandibular advancement device (MAD) and to identify anatomic influences on OSA severity and MAD therapy outcomes.

MATERIALS AND METHODS: Twenty patients with OSA were prospectively treated with MAD. Clinical, cone-beam computed tomography, and polysomnography exams were performed before treatment and 4-6 months after achieving the MAD therapeutic position. Polysomnographic exams and three-dimensional maxillary, mandibular, and upper airway (UA) measurements were evaluated. Pearson’s correlation and t-tests were applied.

RESULTS: Before MAD treatment, the transverse width measured at the frontomaxillary suture and the angle between the mandibular ramus and Frankfurt horizontal were statistically correlated with apnea and the hypopnea index (AHI), while the gonial angle was correlated with therapeutic protrusion. After MAD treatment, all patients showed a significant AHI reduction and an improvement in minimum oxyhemoglobin saturation. The UA total volume, superior and inferior oropharynx volume, and area were statistically correlated with MAD therapeutic protrusion. The UA total area showed a statistical correlation with the improvement in AHI, and the superior oropharynx volume and area increased significantly.

CONCLUSIONS: The transversal frontomaxillary suture width and the mandibular ramus facial angle may influence OSA severity. The gonial angle, volume, and area of all UA regions may indicate the amount of protrusion needed for successful MAD treatment.

CLINICAL RELEVANCE: The craniofacial characteristics reported as important factors for OSA severity and MAD treatment outcomes impact therapy planning for OSA patients, considering individual anatomic characteristics, prognosis, and cost benefits.

PMID:34273012 | DOI:10.1007/s00784-021-04066-5