Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs).2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs , we repeated the analyses excluding those individuals who developed CVDs.Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants . Overall, 50%  of the total effect of PM2.5 on dementia was due to mediation of tHcy  and/or interaction  with tHcy and 48.4% (p = 0.03) to the direct effect of PM2.5 on dementia. High levels of methionine reduced the dementia hazard linked to PM2.5 by 31%  with 24.8% attributable to the interaction with methionine and 25.9% (p = 0.001) to the direct effect of PM2.5. No mediation effect was found through methionine. Attenuated results were obtained for NOx. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine.The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years , 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PMHigh levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia. In addition, stroke is deemed as a relevant intermediate condition between air pollution and dementia, suggesting that vascular pathologies may also play a role in this relationship.8 Oxidative stress, endothelial dysfunction, and systemic inflammation have all been implicated in the pathogenesis of dementia and have been involved in both Aβ deposition and vascular damage.9 Homocysteine (tHcy), an amino acid generated through demethylation of methionine, may be an important contributor to these pathologic processes,10 and it has been linked to the development of cardiovascular diseases11 and dementia.13 Conversely, high levels of methionine, an essential amino acid and a precursor of tHcy, are associated with a decreased risk of cardiovascular and neurologic conditions including dementia.14-16 Few studies have explored the impact of air pollution on these amino acids, and a recent study found a positive association between high levels of particulate matter (PM) and tHcy and contrasting findings for methionine.17Although most of the studies indicate an increased dementia risk linked to ambient air pollution, the mechanisms through which air pollution affects the brain are poorly understood. Findings from animalIn this study, we aimed to explore the impact of tHcy and methionine on the pathway linking air pollution to dementia. Furthermore, we examined whether cardiovascular diseases (CVDs) could have a role in explaining such association. We based our analyses on a clinically characterized population-based cohort with spatially highly resolved information on air pollution and longitudinal clinical evaluations of dementia.Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study18 including individuals older than 60 years and residents of the Kungsholmen district in central Stockholm. At baseline (2001–2004), 3,363 (response rate 73.3%) participants were evaluated. Participants have then been followed up every 6  or 3 years .For this study, we used data from the ongoing links.lww.com/WNL/C980).All participants or a proxy provided a written informed consent. The Regional Ethical Review Board in Stockholm, Sweden, approved the protocols of the SNAC-K study. This study was reported in keeping with the STROBE Recommendations  alleles genotyped. Participants have been categorized as ε4 and ε4 noncarriers.Information on age, sex, education, and retirement age were collected during the nurse interview. The highest level of formal education was categorized as elementary school, high school, and college/university or above. Socioeconomic position was operationalized considering the longest occupation held and was categorized into 3 groups20For a subsample of SNAC-K participants (N = 1976), a self-administered semiquantitative questionnaire assessed food frequency and was used to retrieve dietary habits over the year before the assessment. The national food composition database was used to compute nutrient intake by multiplying each dish portion by the expected nutrient standard content.21 A first and preliminary diagnosis was made by the examining physician who met the participant; second, a second preliminary diagnosis was made by a reviewing physician from the data collection team. In case of disagreement between the first and the second diagnoses, the final diagnosis was made by senior neurologists not involved in the data collection. To further ascertain possible diagnoses of dementia among individuals who died between the SNAC-K follow-up examinations, clinical charts of those who died were collected with their death certificates and examined by the same physicians.The clinical diagnosis of dementia was performed in keeping with the criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, based on the clinical examination conducted by physicians. In brief, it includes medical—with questions regarding comorbidities—and drug history and general and neurologic physical examination. Physicians assess cognitive functioning also by administering tests related to subjective cognitive complaints, problem-solving, abstract thinking, self-orientation and time-space orientation, and general knowledge. In addition, the Mini Mental State Examination (MMSE), Clock Drawing test, counting forward and backward, and a short story assessing frontal lobe are administered. Finally, independence of daily living both basic and instrumental are assessed. The diagnosis follows a procedure consisting in 3 steps.We considered the following conditions as CVDs: ischemic heart disease, heart failure, atrial fibrillation, and stroke.22 In brief, diagnoses were based on medical history collected by physicians during the interviews, clinical examinations, diagnostic tests , inpatient and outpatient records, medical journals, and registers from the Swedish National Patient Register.22 Diagnoses were coded in accordance with the International Classification of Diseases, 10th revision on a clinical review performed by trained physicians.A comprehensive clinical procedure was followed to detect all diseases, as detailed elsewhere.2.5 and NOx at the home addresses of the participants with dispersion modeling according to local emission inventories.23 The inventories consist of local emissions of traffic and nontraffic sources for the following years: 1990, 1995, 2000, 2005, and 2011. The local emission of NOx mainly consisted of exhaust emissions from road traffic, while residential wood burning, road traffic exhaust, and particles from road wear were the dominant sources of PM2.5. A Gaussian dispersion model was applied to the local emission databases. Annual mean levels of PM2.5 and NOx were obtained from linear interpolation over the 4 years between each model simulation. To obtain total levels of PM2.5 and NOx, annual long-range contributions, homogeneous over the model domain, were added to the simulated locally generated levels. The long-range contributions were based on measurements at the rural monitoring site Norr Malma, located outside the calculation domain, 60 km northeast of Stockholm. We compared the model that calculated yearly levels with the one that measured the values at 3 curbside (traffic) monitoring sites and 1 urban background site in Stockholm City, and we obtained r2 values of 0.97 for NOx and 0.86 for PM2.5.We calculated annual mean levels of PM2.5 and NOx were 8.4 ± 0.7 and 8.3 ± 0.7 and 33.9 ± 11.7 and 32.7 ± 11.7 for Kungsholmen residents and those who moved, respectively). Those who moved outside of Stockholm County (n = 9) were instead excluded from the study.Of the 2,512 participants included at baseline, 248 moved outside the district of Kungsholmen during the entire follow-up time. The exposure level of the pollutants for these individuals was calculated at the new home address. No major differences were detected between those who were residents of the Kungsholmen district for the entire period and those who moved outside the study area  were considered as high, respectively. We also considered the ratio between methionine and tHcy (Met:tHcy) as a possible indicator of methylation activity with high ratios considered proxy for greater methylation activity.15 The 2 upper tertiles of Met:tHcy levels were defined as a high level (cutoff: 1.47 µmol/L).At baseline, nonfasting venous blood samples were collected. Routine analyses were conducted within 2 hours, through a chemiluminescence microparticle folate-binding protein assay at the Sabbatsberg Hospital, Stockholm, Sweden. Plates in dry ice were then shipped to the University of Oxford, United Kingdom. The levels of tHcy and methionine were measured using tandem mass spectrometry after treatment of the serum with a reducing agent, as previously detailed.2.5 and NOx before baseline assessment. Individuals were considered at risk until dementia diagnosis, death, or end of follow-up, whichever came first. We assumed a linear relationship between PM2.5, NOx, and the log(HR). The proportional hazard assumption was assessed by regressing the scaled Schoenfeld residuals against survival time. No deviation from proportionality was detected (p: 0.3313 for PM2.5 and p: 0.1649 for NOx).Cox models were used to derive hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia in relation to 5-year average PM27 by decomposing the total effect of PM2.5 (and NOx) on dementia into 4 potential causal pathways: (1) a direct effect (pathways associating air pollution and dementia independently of serum markers of methylation status); (2) the effect due to mediation alone (pathways associating air pollution and dementia only through serum markers induced by air pollution); (3) the effect of interaction between air pollution and serum markers (pathways that only operate when both increased serum biomarkers and air pollution are present without mediation effect); and (4) the effect due to both mediation and interaction (pathways that only operate when both increased serum biomarkers and air pollution are present with mediation effect). The decomposition allows estimating and testing the proportion of the total effect due to each of these 4 components. The 4-way decomposition of the total effect requires jointly testing the associations between the exposures and the mediators/modifiers, which were assessed using linear or logistic regression, and the associations between the exposures and outcome, which were assessed using survival model. eFigure 1 (links.lww.com/WNL/C980) shows the 4 different pathway models.The potential mediating and interactive effects of serum markers of methylation status were analyzed through the counterfactual approachTo test whether CVDs played a role in the associations, we repeated the analyses after excluding those who developed CVDs during the follow-up (cases with incident CVD: 364).2 and available data from the study population: age, sex, educational level, year of assessment, smoking, early retirement, socioeconomic position, physical activity, creatinine, and use of supplements.Potential confounding factors were a priori identified–based literature reviewAPOE genotype and reported the analyses by sex and APOEε4 carriers/noncarriers. As sensitivity analysis, we additionally adjusted the models for food intake of folate and vitamin B12. All statistical analyses were performed with Stata, version 17 .To evaluate the potential modifier effects of sex and APOE, we tested for interaction between air pollutants and both sex and Access to the data for this study (snac-k.se) will be possible on request and approval by the SNAC-K data management and maintenance committee at the Aging Research Center, Karolinska Institutet, Stockholm, Sweden.p < 0.001), while no differences concerning sex and education arose .The analytical sample resulted in 2,512 dementia-free individuals because we excluded 240 persons affected by dementia at baseline, 1 person with intellectual disability, and 4 participants with tHcy levels >69.97 μmol/L or creatinine levels >400 μmol/L. In addition, 410 individuals had missing information on biomarkers or air pollution, and 196 had missing dementia information at follow-up. Those with missing information on exposure or covariates were more likely to be older , 376 cases with incident dementia  were identified. Baseline characteristics of the analytic sample overall and by incident dementia are reported in 3) of PM2.5 and NOx during the 5 years preceding baseline assessment. During the 5 years before baseline, there was a slight decrease in the concentration of both air pollutants, specifically −2.04 µg/m3 (SD: 0.02) for PM2.5 and −4.68 µg/m3 (SD: 2.03) for NOx.2.5 concentration was associated with higher tHcy and methionine levels at baseline, by 0.36 µmol/L for tHcy (95% CI 0.07–0.66) and 0.36 µmol/L (95% CI 0.02–0.70) for methionine, per 1 µg/m3 PM2.5, after adjusting for potential confounders . Similarly, higher levels of NOx were associated with a higher tHcy concentration, by 0.31 (95% CI 0.07–0.5) per 10 µg/m3 increase in 5-year mean NOx. NOx levels were not associated with a difference in methionine . Neither PM2.5 nor NOx concentrations showed a significant association with Met:tHcy.A higher 5-year mean residential outdoor PMIn adjusted models, a tHcy concentration above 15 µmol/L was associated with 55% higher hazard of dementia , and methionine above 20.7 µmol/L was associated with approximately 30% lower hazard to develop dementia . Met:tHcy ratio above 1.47 µmol/L was associated with 37% lower hazard of developing dementia .3 increase of PM2.5 , whereas a 30% increased risk of dementia was found per 10 µg/m3 increase of NOx .After considering potential confounders, 70% higher incidence of dementia was found per 1 µg/m2.5 and incident dementia decomposed by tHcy and methionine. We found that 51.6% of the total effect of PM2.5 on dementia was due to mediation and/or interaction with tHcy. Overall, 47.8% of the association was explained only by interaction, while 6.6% only by mediation. Furthermore, 48.4% of the association between PM2.5 and dementia could be attributed to a direct effect.2.5 exposure by 26%. No statistically significant mediation effect was found through methionine in the association between PM2.5 and dementia. A direct effect of PM2.5 on dementia was also found here.High concentrations of methionine reduced dementia risk linked to PMx .Similar, but attenuated, results were obtained for NOlinks.lww.com/WNL/C980) summarizes the association between PM2.5 and NOx and incident dementia decomposed by Met:tHcy. A high Met:tHcy ratio was associated with a reduced dementia risk  per 1 µg/m3 increase of PM2.5. This was mainly due to a large proportion attributable to interaction between PM2.5 and Met:tHcy, while no mediation effect was detected. Similar results were obtained for NOx.eTable3 . High concentrations of methionine reduced the dementia risk linked to PM2.5 exposure by 30%, but mediation remained nonsignificant. Similar results were obtained for NOx .The results for tHcy were attenuated and no longer statistically significant, whereas the results remained similar for methionine when we repeated the analyses after excluding individuals with incident CVDs . For PM2APOE genotype and reported the results in eTable 5 (links.lww.com/WNL/C980). Overall, 1 µg/m3 increase of PM2.5 was associated with an 87% (1.61–2.16) higher hazard for dementia in women and a 66% (1.32–2.09) increased hazard in men, while a 10 µg/m3 increase of NOx was linked with a 3% increased dementia risk both in women (1.02–1.04) and men (1.01–1.05). Concerning APOE genotype, 1 µg/m3 increase of PM2.5 was associated with a 78% (1.53–2.0) higher hazard for dementia in APOEε4 noncarriers and an 83% (1.48–2.26) increased hazard in ε4 carriers, while a 10 µg/m3 increase of NOx was linked with a 3% increased dementia risk both in noncarriers (1.02–1.04) and carriers (1.01–1.05). When we further adjusted the analyses for food intake of folate and vitamin B12, the results were consistent for homocysteine while slightly attenuated for methionine .We tested the modifying effect of sex and This study led to the following main findings: First, similar to previous studies, air pollution emerged as a risk factor of dementia development; Second, homocysteine and methionine, and the Met:tHcy ratio (an indirect sign of methylation activity), played a relevant role in this association; Third, their role was mainly as effect modifiers, with homocysteine exacerbating, while methionine mitigating the effect; Finally, the role played by homocysteine was observed only in participants who had developed CVDs, whereas the protective role of methionine was likely independent of CVD development.1 Despite methodological heterogeneity in study designs, differences in exposure assessments, and different settings, most recent studies provide evidence in support of an association, especially when considering PM2.5 exposure.2 In our study, we observed a 70% and 30% increased dementia risk per 1 µg/m3 and 10 µg/m3 increase in PM2.5 and NOx, respectively. These results come from an urban area in central Stockholm where substantial improvements in air quality have occurred in the past decade and where mean concentrations of air pollutants are quite low in comparison with the average in the rest of Europe, United States, or China. As a comparison with our mean concentration of 8.3 μg/m3, a recent study28 in Europe reported an average annual concentration of PM2.5 in 2019 of 13.8 μg/m3, but it is noteworthy that mean concentrations in our study were higher compared with those of 5.7 μg/m3 reported in the Nordic countries. Our results are in line with other Swedish studies investigating air pollution and dementia onset30 and suggest once again that even low concentrations of air pollution are associated with poor health outcomes.32 However, unlike previous studies that have reported stronger associations between PM2.5 and dementia in women when compared with men,33 we were unable to detect such a difference. Identifying vulnerable subgroups who might particularly benefit of air quality improvements continues to be important to safeguard public health and in setting efficient and appropriate air quality standards.34Air pollution has recently been included in the list of modifiable risk factors of dementia.12, and vitamin B6),13 and a number of factors can, directly or indirectly, raise blood concentration of tHcy, including age, renal impairment, and B vitamin insufficiency.10 Notably, it has been suggested that PM exposure may raise Hcy levels by inducing systemic inflammation and oxidative stress, reducing the activity of enzymes implicated in Hcy metabolism and/or competing with methyl groups with the Hcy remethylation process.17In this study, we found that higher concentrations of tHcy increased the detrimental effect of air pollution by 50%, whereas raised methionine reduced the air pollutant–related dementia risk by 30%. We also found that a higher Met:tHcy ratio was associated with a reduced dementia risk related to air pollution exposure. Met:tHcy ratio can be considered a possible indicator of methylation activity, and reduced values of this ratio reflect impaired methylation activity. Hcy reflects the functional status of 3 B vitamins . We, however, would like to point out that in the SNAC-K study, most of the cases with dementia are late onset, and previous studies have shown that dementia occurring after the age of 75 years is rarely purely AD but more commonly demonstrating a mixed pathology.Collectively, our findings support the evidence of air pollution as a risk factor of dementia in older adults. This was evident in an area with comparatively high standard of air quality and argues for additional actions in further reducing air pollution in our cities. We here found, once again, that an indirect link between air pollution and dementia may exist and that the homocysteine/methionine cycle and cardiovascular burden may be implicated. In addition to these pathways, our results indicated a substantial direct effect of air pollution on dementia, suggesting that air pollution affects the development of dementia through multiple pathways. This highlights the need to further elucidate the exact biological mechanisms behind the brain damage of air pollution.


Chronic kidney disease is a condition, which worsens the quality of life in many ways including thyroid disorder in many cases. The aim of the study was to find out the prevalence of subclinical hypothyroidism among chronic kidney disease patients admitted to the Nephrology Department of a tertiary care centre.A descriptive cross-sectional study was carried out on the patients diagnosed with chronic kidney disease at a tertiary care hospital from 15 May 2022 to 10 October 2022 after getting ethical approval from the Institutional Review Committee (Reference number: 621/2022). Pre-designed proforma was used to collect demographic data like age, sex, height and weight. Blood samples of the patients were analysed for thyroid function tests  by chemiluminescence immunoassay. Convenience sampling was used. Point estimate and 95% Confidence Interval were calculated.Out of 156 study participants with chronic kidney disease, subclinical hypothyroidism was present in 34 (21.79%)  patients.The prevalence of subclinical hypothyroidism amongst chronic kidney disease patients was found to be lower than in other similar studies conducted in similar settings. Reports suggest that CKD is largely associated with thyroid dysfunction; especially most common is primary and subclinical hypothyroidism.8Maintaining healthy renal function regulates thyroid hormone metabolism and elimination.The main objective of the study is to find out the prevalence of subclinical hypothyroidism among chronic kidney disease admitted to the Nephrology Department of a tertiary care centre.A descriptive cross-sectional study was conducted at Nobel Medical College Teaching Hospital (NMCTH), Biratnagar, Morang, Nepal on the patients diagnosed with CKD from 15 May 2022 to 10 October 2022. The study was conducted after receiving ethical approval from the Institutional Review Committee (IRC) of the NMCTH (Reference number: 621/2022). All CKD patients who were admitted to the nephrology ward during the study period were included in this study. Patients with other comorbidities and who do not give consent were excluded. A convenience sampling method was used. The sample size was calculated by using the formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence interval (CI)9p = prevalence of subclinical hypothyroidism taken from the previous study as, 27.2%q = 1-pe = margin of error, 7%2 The level of triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) was estimated in the blood samples of these patients by chemiluminescence immunoassay (CLIA) in a fully automatic analyzer (Maglumi 800) at the clinical laboratory services, NMCTH.The calculated final sample size was 156. Predesigned proforma was used to gather personal information like age, sex, height, and weight. The formula used to determine body mass index (BMI) is BMI= Weight in Kg/ (Height in m).The level of T3/T4 in the blood sample was estimated by a competitive chemiluminescence immunoassay. The sample, ABEI labelled anti-T3/T4 monoclonal antibody, buffer and solution of the magnetic microbeads coated withT3/T4 antigens were incubated at 37° C. T3/T4 present in the sample competed with T3/T4 antigen immobilised on the magnetic microbeads for a limited number of binding sites on the ABEI labelled anti-T3/T4 antibody forming immune-complexes. After washing, the starter was added to initiate a chemiluminescent reaction. The light was measured by a photomultiplier within 3 seconds as relative light units, which was inversely proportional to the concentration of T3/T4 present in the sample.The TSH level in the blood sample was measured by a sandwich chemiluminescence immunoassay. The sample, ABEI labelled anti-TSH monoclonal antibody, magnetic microbeads coated with another anti-TSH monoclonal antibody were mixed and incubated at 37°C, forming sandwich immune complexes. After washing, the starter was added to initiate a chemiluminescent reaction. The light was measured by a photomultiplier within 3 seconds as relative light units, which was proportional to the concentration of TSH present in the sample.The collected data were entered into and analysed using Microsoft Excel version 2010. Point estimate and 95% CI were calculated.2 (Range: 19.50-40.90)   patients. Among them, 14 (41.17%) were male and 20 (58.82%) were female. The mean age was 53.47±16.33 years. The mean value of body mass index (BMI) of the CKD patients with subclinical hypothyroidism was 25.31±5.28 kg/m0-40.90) .The mean value of T3 among patient with subclinical hypothyroidism was 3.01±0.35 .The maximum number 8 (23.52%) of male patients were reported from age group 41-60 years; whereas the maximum number 8 (23.52%) of female patients was reported from age group 61-80 years .9 In another research conducted on hemodialysis patients in western Nepal revealed that 26.6% of them had both subclinical and clinical hypothyroidism.10 Another study from North India reported that subclinical hypothyroidism was observed in 39.9% of total chronic kidney disease patients.11 A research from Oman revealed a result, reporting a prevalence of subclinical hypothyroidism of 62.9% among CKD patients.12 In literature, it is reported that when compared to people with euthyroidism, those with hypothyroidism had a CKD or (95% CI) of 1.25 (1.21-1.29) and therefore concluded that people with CKD were more likely to have hypothyroidism.13 Almost similar finding was observed in large cohort research, 22% of CKD patients with eGFRs ≤60 had hypothyroidism.7Out of 156 CKD patients, subclinical hypothyroidism was observed in 21.79% of patients. Amongst them, the number of males and females in the study was 14 (41.17%) and 20 (58.82%) respectively with a mean age of 53.5 years. Females were more sufferers than males. A higher prevalence of subclinical hypothyroidism among CKD patients was observed in a study carried out in BPKIHS, Dharan, Nepal, which showed that subclinical hypothyroidism was seen in 27.2% of CKD patients. The mean age of all patients was 44.1±16.4 years with 53.8% male and 46.1% female.14 A study from Italy concluded that in people with CKD who do not need chronic dialysis, subclinical primary hypothyroidism is a rather frequent disease (18%) and is independently linked to steadily declining estimated GFR in a sizable population of unselected outpatient adults.15 A study was conducted in the Japanese population with CKD, which showed the prevalence of subclinical hypothyroidism as 14.9% among the patients.16A lower rate of prevalence of subclinical hypothyroidism among CKD patients was observed in a study carried out in Saudi Arabia, which reported that amongst CKD patients, 16.9% suffered from subclinical hypothyroidism.11 In the same way, in another report, it was seen that the mean value of TSH in CKD patients with subclinical hyperthyroidism was 5.40 uIU/ml.14 A study from Bangalore, India reported the mean±SD value of TSH as 7.23± 4.21 among CKD patients.17 The mean±SD value of TSH was reported as 7.15± 5.94 among CKD stage-IV patients in Gujarat, India in research.18In the present study, we also observed the mean value of T3, T4 and TSH amongst the patients of CKD with subclinical hypothyroidism. The mean±SD value of T3, T4 and TSH in the blood of the CKD patients with subclinical hypothyroidism was 3.01±0.35 pg/ml, 1.06±0.24 ng/dl and 12.76±22.54 uIU/ml respectively. In a study, it has been reported that the mean±SD value of TSH among CKD patients with subclinical hyperthyroidism was 9.01±4.40 uIU/ml respectively. Similarly, the mean±SD value of T4 was 1.22±0.13 ng/ dl.18Thyroid dysfunction was observed in CKD patients ages more than 40 in the current study. In the age group 4160 and 61-80, the patients diagnosed with subclinical hyperthyroidism were 41.17% and 29.41%. In a study, it was observed that CKD patients from 36-45 years and 45-55 years were 48% and 32% respectively.The data were only gathered from one centre and at one specific moment, which is one of the study's limitations. If data on CKD patients had also been collected from other centres in Nepal and the patients had been followed up for a longer period, the findings would have been more generalisable.The prevalence of subclinical hyperthyroidism among CKD patients was lower than the other similar studies done in similar settings. Subclinical hypothyroidism was observed more in females and also in advanced-age patients with chronic kidney disease.


To study the synergistic effects of water management and silicon (Si) foliar spraying on the uptake and transport of cadmium (Cd) in rice, we designed four treatments: conventional intermittent flooding + no Si foliar spraying (CK), continuous flooding throughout the growth stage + no Si foliar spraying (W), conventional intermittent flooding + Si foliar spraying (Si) and continuous flooding throughout the growth stage + Si foliar spraying (WSi). The results show that WSi treatment reduced the uptake and translocation of Cd by rice and significantly reduced the brown rice Cd content, with no effect on rice yield. Compared with CK, the Si treatment increased the net photosynthetic rate (Pn), stomatal conductance (Gs) and transpiration rate (Tr) of rice by 6.5–9.4%, 10.0–16.6% and 2.1–16.8%, respectively. The W treatment decreased these parameters by 20.5–27.9%, 8.6–26.8% and 13.3–23.3%, respectively, and the WSi treatment decreased them by 13.1–21.2%, 3.7–22.3% and 2.2–13.7%, respectively. The superoxide dismutase (SOD) and peroxidase (POD) activity decreased by 6.7–20.6% and 6.5–9.5%, respectively, following the W treatment. Following the Si treatment, SOD and POD activity increased by 10.2–41.1% and 9.3–25.1%, respectively, and following the WSi treatment, they increased by 6.5–18.1% and 2.6–22.4%, respectively. Si foliar spraying ameliorated the detrimental effects of continuous flooding throughout the growth stage on photosynthesis and antioxidant enzyme activity. We conclude that synergistic continuous flooding throughout the growth stage, combined with Si foliar spraying, can significantly block Cd uptake and translocation and is therefore an effective means of reducing the accumulation of Cd in brown rice. Cadmium (Cd) is a biotoxic environmental heavy metal with high water solubility, mobility and persistence . ApproxiAt present, passivation materials such as lime, sea foam and biochar can effectively reduce Cd accumulation in rice . HoweverSilicon (Si) foliar spraying has been shown to be an effective means of reducing Cd accumulation in rice . In addiIn summary, a single measure cannot simultaneously take into account the effects on Cd reduction and rice yield. Therefore, it is necessary to investigate the effects of different synergistic measures of water management and Si foliar spraying on Cd accumulation in rice. For this reason, we designed a pot experiment with two types of water management  and two types of Si foliar spraying treatment (no Si foliar spraying and Si foliar spraying). We explored the synergistic effects of these treatments on rice growth and yield and their combined effects on Cd uptake and accumulation in rice, with the aim of providing theoretical support to effectively reduce Cd accumulation in brown rice.p < 0.05), increased the Cd content in the leaves by 50.8%, 32.0% and 87.8% (p < 0.05) and reduced the Cd content in brown rice by 67.1%, 42.1% and 68.5% (p < 0.05), respectively. The W and WSi treatments significantly reduced the Cd content in the stems by 47.9% and 44.7% (p < 0.05), respectively. Si treatment significantly increased the Cd content in the cob by 49.1% (p < 0.05) and reduced the Cd content in the husks by 29.5% (p < 0.05). The W treatment significantly reduced rice yield by 8.7% compared to the CK treatment (p < 0.05).The synergistic effects of water management and silicon foliar spraying on the Cd content in rice organs and on rice yield are shown in p < 0.05) and significantly reduced the Cd content in the brown rice by 26.9% (p < 0.05) compared to the CK treatment. The Si and WSi treatments significantly increased the Cd content in the stems by 146.5% and 120.2% (p < 0.05) and significantly increased the Cd content in the cob by 61.8% and 60.9% (p < 0.05), respectively. The W, Si and WSi treatments significantly reduced the Cd content in the husk by 36.0%, 41.0% and 39.6%, respectively (p < 0.05). Both the W and WSi treatments resulted in significant reductions in rice yield of 18.7% and 12.8%, respectively (p < 0.05).At concentration B, the WSi treatment significantly increased the Cd content in the roots by 62.2% (p < 0.05). Both the W and WSi treatments significantly reduced the Cd content in the stems by 70.4% and 61.5%, respectively (p < 0.05). The W treatment resulted in a significant reduction in Cd content of 20.1% and 19.9% in the leaves and cob, respectively (p < 0.05). Si treatment significantly increased the Cd content in the leaves and cob by 26.4% and 62.8%, respectively (p < 0.05). The W, Si and WSi treatments resulted in a significant reduction in Cd content in the husks and brown rice and reduced the Cd content in the husks by 54.4%, 33.8% and 56.0% (p < 0.05) and in the brown rice by 29.7%, 12.6% and 33.8% (p < 0.05), respectively. The W treatment resulted in a significant 13.8% (p < 0.05) reduction in rice yield compared to the CK treatment.At concentration C, the W treatment significantly reduced the Cd content in the roots by 29.0% compared to the CK treatment ; TFstem−brown rice by 35.9%, 51.4% and 40.3% (p < 0.05); and TFleaf−brown rice by 78.7%, 57.3% and 83.5% (p < 0.05), respectively. The W and WSi treatments resulted in a significant increase in TFstem−leaf of 192.5% and 257.2%, respectively (p < 0.05).The synergistic effects of the water management and silicon foliar spraying treatments on the Cd translocation factor of rice organs are shown in root−stem by 121.0% relative to the CK treatment. The W, Si and WSi treatments all significantly reduced TFstem−leaf by 23.2%, 56.1% and 57.0%, respectively (p < 0.05). The Si and WSi treatments significantly reduced TFstem−brown rice by 61.2% and 66.2%, respectively (p < 0.05). However, the W, Si and WSi treatments had no significant effect on TFleaf−brown rice.At concentration B, the Si treatment significantly increased TFroot−stem and increased TFstem−leaf and TFstem−brown rice relative to the CK treatment. They reduced TFroot−stem by 57.7% and 57.0% (p < 0.05), increased TFstem−leaf by 170.7% and 153.9% (p < 0.05) and increased TFstem−brown rice by 138.1% and 50.3%, respectively (p < 0.05). The W, Si and WSi treatments significantly reduced TFleaf−brown rice by 12.0%, 30.9% and 40.6%, respectively (p < 0.05).At concentration C, both the W and WSi treatments significantly reduced TFWith the increase in Cd concentration, Cd transport from root to stem increased, and its transport from stem to leaf decreased. There were differences in the Cd transport coefficient of rice organs under the three different Cd concentrations, which explains the significant decrease in Cd in brown rice.p < 0.05). The Si treatment significantly increased the SPAD values at all three Cd concentrations relative to the W treatment. The WSi treatment also significantly increased the SPAD values in rice compared to the W treatment at concentration A. The W treatment decreased the SPAD values, the Si treatment increased the SPAD values and the WSi treatment decreased the SPAD values but increased them relative to the W treatment.The effects of different water management and Si foliar spraying treatments on the soil and plant analyzer development (SPAD) values of rice leaves are shown in The synergistic effects of water management and silicon foliar spraying on the photosynthesis parameters of rice are shown in The synergistic effects of water management and silicon foliar spraying on malondialdehyde (MDA), superoxide dismutase (SOD) and peroxidase (POD) content in rice leaves are shown in As the Cd concentration increased, the Cd content in every rice organ gradually increased, as did rice yield. The accumulation of Cd in rice affects its ultrastructure and inhibits its normal growth, thereby reducing its yield. At concentrations A and B, the continuous flooding treatment used in this study increased the Cd content in the roots, stems and leaves and decreased the Cd content in the husks and brown rice. This is inconsistent with the results of previous studies on the reduction in Cd content in rice roots via continuous flooding treatment . The pH At concentration A, Si treatment significantly increased the Cd content in the roots, leaves and cob and significantly reduced the Cd content in the husks and brown rice. At concentration B, the Si treatment significantly increased the Cd content in the stems and cob and significantly decreased the Cd content in the husks. At concentration C, the Si treatment significantly increased the Cd content in the leaves and cob and significantly reduced the Cd content in the husks and brown rice. For all three Cd concentrations, the Si treatment had no significant effect on rice yield. Some studies have shown that Si foliar spraying not only increases rice yield  but alsoAt all three Cd concentrations, the WSi treatment resulted in the lowest Cd content in brown rice compared with the W and Si treatments and did not affect rice yield. The WSi treatment had the best reduction effect on Cd. This is consistent with previous research results, indicating that water management and foliar spraying can achieve a good effect in terms of reducing Cd ,37. In c2+ to form insoluble Cd, which may reduce the mobility and bioavailability of Cd in soil [root−stem, TFstem−brown rice and TFleaf−brown rice and significantly increased TFstem−leaf. This is consistent with previous research results. Si foliar spraying inhibits the transport of Cd from root to stem and from the stem to brown rice and increases the transport of Cd from stem to leaf [2+ in rice leaves, promotes the coprecipitation of Cd on the cell wall, reduces the proportion of Cd in the plastid and inhibits the transport of Cd [This study showed that continuous flooding treatment had a significant effect on Cd translocation in rice. At concentrations A and C, the W treatment reduced brown rice Cd content by increasing stem-to-leaf transport and by decreasing root-to-stem and leaf-to-brown rice transport. It enriched Cd in the roots, stems and leaves and reduced Cd translocation to brown rice, thereby reducing the Cd content in brown rice. This is consistent with previous research results . Floodin in soil . Continu in soil . Therefo to leaf . Researc to leaf . Si foli to leaf . In addirt of Cd . The benrt of Cd .stem−leaf and significantly decreased TFroot−stem and TFleaf−brown rice. The continuous flooding and Si foliar spraying treatments had significant synergistic effects on the translocation of Cd to rice brown rice and were responsible for a significant decrease in Cd content in brown rice.The WSi treatment significantly increased TFChlorophyll is the primary pigment for photosynthesis in plants, and changes in its content are a direct reflection of the strength of photosynthesis . The SPA2 diffusion and carbon fixation; ribulose 1, 5–bisphosphate carboxylase oxygenase (RuBisCO), the rate-limiting enzyme for carbon assimilation, plays a decisive role in Pn and can mitigate the toxic effects of Cd stress on plants by increasing the carboxylation efficiency of RuBisCO [Photosynthesis is highly sensitive to Cd stress, and Pn is a determinant of rice yield . Cd stre RuBisCO . Si foli RuBisCO . The WSiCd stress increases reactive oxygen species (ROS), and the excessive accumulation of ROS results in cellular redox imbalance and disrupted signaling, leading to growth inhibition and cell damage . SOD andMDA is a major product of lipid peroxidation, and changes in its content occur in response to the degree of lipid peroxidation and the relative permeability of cellular membranes in response to the degree of membrane damage, both of which have been shown to negatively correlate with plant stress resistance . The ric2 . In the Si foliar spraying of “Jianggeling” rice foliar silicon fertilizer , the active ingredient was primarily high-purity SiO2 sols  at a concentration of 2.5 g·L−1. One spray was administered at the jointing stage and one at the heading stage, at 18:00–19:00 p.m. The basic physical and chemical indicators of soils are shown in A rice pot experiment was conducted at the Guiyang Comprehensive Test Station of the Guizhou Academy of Agricultural Sciences, Guizhou, China . The rice cultivar used in the experiment was “Jingliangyou 534”. The exogenous Cd added was CdCl−1) and C (0.40 mg·kg−1); these were mixed with air-dried soil prior to rice planting, filled with water until they reached saturation and allowed to equilibrate for 30 s. The soil background value was 0.20 mg·kg−1, and the actual measured values of soil Cd content at maturity after Cd addition were 0.20 mg·kg−1 (A), 0.60 mg·kg−1 (B) and 1.60 mg·kg−1 (C). The four treatments were: conventional intermittent flooding + no Si foliar spraying (CK), continuous flooding throughout the growth stage + no Si foliar spraying (W), conventional intermittent flooding + Si foliar spraying (Si) and continuous flooding throughout the growth stage + Si foliar spraying (WSi) , B (0.20 mg·kgng (WSi) . There w3). The sample was digested using a 120 °C graphite digestion instrument for 2 h until there was no sediment in the digestion tank. Then, the temperature was adjusted to 150 °C to evaporate the acid. The sample was removed and allowed to cool, diluted to a volume of 50 mL in a volumetric flask, filtered and analyzed via ICP–OES.The Cd content of rice was determined using the ICP–OES software package  . We weigThe relative chlorophyll content of the leaves was determined using SPAD-502 Plus  . Three u2 concentration was set at 400 μmol·mol−1, the light intensity at 1200 μmol·m−2·s−1 and the air flow rate at 0.5 L·min−1 on a sunny day from 10:00 a.m. to 12:00 p.m. The net photosynthetic rate (Pn), transpiration rate (Tr), stomatal conductance (Gs) and intercellular CO2 concentration (Ci) of rice were determined on uniformly grown rice leaves at 25 °C and 70% relative humidity.The parameters of photosynthesis during the tasseling of rice were determined using a GFS-3000  . The CO2−1 phosphate buffer (pH 7.8); then, we adjusted to volume to 4 mL. We mixed the solution well using a vortexer, placed in a frozen high-speed centrifuge at 4 °C and 10,000 r·min−1 for 10 min and transferred the supernatant into a refrigerator at 4 °C. To determine the contents of SOD, POD and MDA in rice leaves, a photochemical reduction method using nitrogen blue tetrazolium (NBT) [We weighed 100 mg fresh rice leaves, ground them to a homogenate in a mortar using liquid nitrogen and placed the homogenate in a 4 mL centrifuge tube, followed by the addition of 1 mL of 0.05 mol·Lum (NBT) , the guaThe translocation factor (TF) of Cd in rice was calculated as follows .TFroot−The results obtained in this study were expressed as the mean value ± standard deviation of 3 repetitions. Statistical analysis was performed using SPSS 24.0 software . One-way analysis of variance (ANOVA) with Fisher’s least significant difference (LSD) test was used to evaluate the significance of the effects of different levels on measured parameters.In this study, we investigated the synergistic effects of water management and silicon foliar spraying on rice yield and Cd accumulation. Compared with the CK treatment, the W treatment reduced the chlorophyll content and photosynthesis in rice, and the Si treatment protected against the damage caused to photosynthetic structures. Si foliar spraying mitigated the adverse effects of continuous flooding treatment and Cd stress on rice by reducing the membrane permeability and MDA content and enhancing SOD and POD activities. The results show that, although the W treatment significantly reduced the Cd content of brown rice, it reduced the yield. Si treatment not only improved the rice yield but also reduced the Cd content in brown rice; however, the reduction was not significant. WSi treatment significantly reduced the Cd content in brown rice while ensuring a good rice yield. In conclusion, synergistic continuous flooding throughout the growth stage, combined with Si foliar spraying, is an effective means of reducing Cd accumulation in brown rice.


Spleen stiffness did not correlate with spleen fat content and liver stiffness but a statistically significant correlation with spleen volume was found. Conclusions: The findings of this study provide normative values for 2D MRE-based measurement of spleen stiffness in young adults, a basis for assessing the value of this biomarker in young patients with portal system pathologies.Purpose: Magnetic resonance elastography (MRE) has been established as the most accurate noninvasive technique for diagnosing liver fibrosis. Recent publications have suggested that the measurement of splenic stiffness is useful in setting where portal hypertension may be present. The goal of the current study was to compile normative data for MRE-assessed stiffness measurements of the spleen in young adults. Materials and Methods: A total of 100 healthy young Caucasian volunteers  in the age range of 20 to 32 years were enrolled in this study. The participants reported no history of chronic spleen and liver disease, normal alcohol consumption, and a normal diet. The MRE data were acquired by using a 1.5 T whole-body scanner and a 2D GRE pulse sequence with 60 Hz excitation. Spleen stiffness was calculated as a weighted mean of stiffness values in the regions of interest manually drawn by the radiologist on three to five spleen slices. Results: Mean spleen stiffness was 5.09 ± 0.65 kPa for the whole group. Male volunteers had slightly higher splenic stiffness compared to females: 5.28 ± 0.78 vs. 4.98 ± 0.51 kPa, however, this difference was not statistically significant ( Magnetic resonance elastography (MRE) is an innovative diagnostic technique used to assess the stiffness of soft tissues in a non-invasive manner. MRE was developed by researchers at the Mayo Clinic in Rochester, USA, during the 1990s . InitialFrom a physical perspective, MRE involves three steps. The first step is to induce shear waves in the targeted area. This is achieved by applying vibrations generated by an active acoustic driver located outside the diagnostic room. Typically, the vibration frequency ranges from 20 to 100 Hz  spleen stiffness value in the cohort was 5.09 [0.65] kPa , ranging from 3.89 to 7.24 kPa.2 with a mean [SD] of 21.33 [2.16] kg/m2. The spleen volume ranged from 123.94 to 422.43 cm3 while the mean [SD] value was 231.13 [58.44] cm3.The BMI was in the range of 16.85–25.76 kg/mp = 0.12)  and male volunteers  was not significant statistically ( = 0.12) . p = 0.20) (p = 0.74), BMI  (p = 0.95) (p < 0.001)  . Spleen  = 0.36) , and liv = 0.95) . However< 0.001) . The resThe spleen stiffness obtained in the group of healthy volunteers ranged from 3.89 to 7.24 kPa with a mean value of 5.09 kPa. These results show that the normal spleen is stiffer than the normal liver, pancreas, prostate, and uterus ,43,44,45The spleen stiffness value from our study was higher than in a group of 12 volunteers recruited by Talwalkar et al.: 3.6 ± 0.3 kPa . Other rThe splenic stiffness was higher in men than in women but this difference did not show statistical significance. Prior reports have been mixed in this regard ,47.In contrast to the results of Talwalkar et al. , the splThe estimated fat content in the spleen and spleen R2* also did not impact its stiffness in healthy volunteers. On the other hand, we observed a statistically significant correlation between spleen stiffness and spleen volume in healthy volunteers. Alternative shear wave-based methods for elasticity assessment of the spleen are ultrasound-based transient elastography (TE), point shear wave elastography (pSWE), and 2D and 3D shear wave elastography (SWE) ,49. The It is worth emphasizing that ultrasound-based elastography techniques differ from each other and MRE in terms of technological and physical details as well as methods of data acquisition . Hence, The presented study has several limitations. In this project, we focused on assessing the spleen stiffness of healthy young adults, therefore, the age range of the subjects was relatively narrow. Future studies including individuals within a wider age range should be conducted to verify the results. The study included exclusively Caucasian volunteers, which might be also perceived as a limitation. Finally, the study was conducted with a 2D MRE technique, which has known limitations compared with 3D MRE for splenic stiffness measurement but the latter technique is not yet widely available.The current research is the largest prospective study compared with all other reports on this topic. Another strength of the presented study is the meticulous selection of participants, which increases the credibility of the obtained findings.The findings of this study provide normative values for 2D MRE-based measurement of spleen stiffness, a basis for assessing the value of this biomarker in young patients with portal system pathologies.


Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS. During the course of the study discussed here, deferasirox became available as a film-coated tablet (FCT) formulation that just needs to be swallowed [®) is available as an FCT or a solution for oral administration, as a monotherapy, or in combination with another iron chelator. Deferiprone is used in exceptional cases  in other relevant indications, such as MDS, too. All of these drugs may lead to a decrease in serum ferritin levels via elevated elimination of iron through feces while showing a favorable profile of side effects. The exact percentage distribution of the choice of treatment in Germany is unknown. Quantification of IOL in clinical daily practice is measured via patients’ serum ferritin, and treatment is mostly initiated when serum ferritin levels are higher than 1000 µg/L and repetitive RBC transfusions are necessary. A dose-dependent impact of IOL on overall survival of patients has been demonstrated for this serum ferritin threshold, observing a 30% higher risk of death for each 500 µg/L increase in serum ferritin above 1000 µg/L [Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) both represent hematologic diseases associated with bone marrow failure eventually resulting in cytopenia. Clinically, anemia is one of the leading problems in MDS and, in part, MPN patients, and transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL). Physiologically, the human body requires a certain amount of iron for important cellular processes such as energy acquisition or oxygen transport . Unfortuwallowed , which i000 µg/L . Further000 µg/L . To asseEXCALIBUR was a prospective, multicenter, noninterventional study assessing iron chelation therapy in patients with chronic iron overload. Male and female adult patients suffering from chronic iron overload who never received an iron chelator, who received an iron chelation therapy for less than 6 months, or who interrupted an iron chelation therapy for longer than 6 months were included. In total, 502 patients from 106 German hospitals and medical practices for hematology and oncology, who met the inclusion criteria and signed the written informed consent, were enrolled. The entire duration of the study was approximately 6 years. Treatment with iron chelators did not follow a predefined protocol, but was administered according to routine medical practice. The observation period was 24 months for patients without a change of iron chelator and was extended by 24 months if the iron chelator was changed. Follow-up visits were documented after 1, 3, 6, 9, 12, and 18 months, with a final visit after 24 months or at the end of the observation phase, whichever occurred first. In- and exclusion criteria were based on the summary of product characteristics of the respective iron chelator, i.e., deferasirox DT, deferasirox FCT, and deferoxamine. Patients’ general satisfaction with all approved iron chelators in everyday life was assessed using the treatment satisfaction questionnaire for medication (TSQM-14) after approx. 1 and 3 months. Data were collected via an eCRF by the treating physician or authorized personnel. Statistical analyses were performed using the software package SAS release 9.4. Continuous data were described by the number of patients in the respective population, non-missing and missing values, mean, standard deviation, median, and interquartile range. Categorical data including categories of continuous data were presented in frequency tables containing absolute and relative frequencies. For the hematological response analyses, patients’ cumulative incidences of the respective response were estimated considering death without response as a competing risk. Analysis of hematological response regarding erythroid, platelet, and neutrophil response followed the criteria of the international working group (IWG) [Overall, 502 patients were enrolled in the study database, with 418 patients in the safety analysis set (SAF), 403 patients in the full analysis set (FAS), and 266 patients in the hematological response analysis set (HRAS). Reasons for exclusion from the different analysis sets are shown in In total, 267 patients started with deferasirox FCT (66.3%), while 111 patients received deferasirox DT (27.5%), and 25 patients received deferoxamine (6.2%). During the entire observation period, 310 patients were treated with deferasirox FCT (76.9%), 116 patients with deferasirox DT (28.8%), and 30 patients with deferoxamine (7.4%). The mean time to premature discontinuation of treatment was approximately 9 months, and 77.9% of patients discontinued prematurely. This was similar for patients who were last treated with deferasirox FCT and deferoxamine. Notably, 93.2% of the 74 patients who were last treated with deferasirox DT discontinued their treatment prematurely. The main reasons for premature discontinuation were AEs (29.9%) and death (28.3%) with a median time to premature discontinuation of 200 days. The reason for treatment initiation was a high serum ferritin value of more than 1000 ng/mL in 90.8% of cases, followed by transfusion of more than 20 red blood cell units in 30.3% of patients. The frequencies of treatment changes are shown in The general satisfaction with iron chelation treatment was measured with the standardized patient questionnaire TSQM-14, which consisted of 14 questions assigned to 4 subscales. The questionnaire was answered at month 1 and month 3 of the initial treatment and again at month 1 and month 3 after treatment change, if applicable. The median (IQR) overall satisfaction score was 68.1 (50.0–77.8) points (n = 224) at month 1 and 63.9 (50.0–77.8) points (n = 181) at month 3 of the initial treatment. After treatment change, the score reached 73.6 (52.8–87.5) points (n = 16) at month 1 and 80.6 (47.2–91.7) points (n = 18) at month 3. The differences show a tendency toward higher satisfaction after treatment change and even higher satisfaction after two months following the change, but this was statistically not relevant.The vast majority of patients experienced AEs (92.6%) and around two-thirds of patients experienced serious AEs (SAEs). For around 50% of patients, non-serious events were assessed to have a suspected causal relationship with the respective treatment; thus, they were classified as adverse drug reactions (ADRs), and 20.6% of patients had serious ADRs (SADRs) . OverallThe median serum ferritin value decreased notably throughout treatment, with 1802.50 µg/L at baseline and 1240.50 µg/L at month 24. The median change from baseline at month 24 was −458.0 µg/L; the change from baseline throughout treatment is shown in 3/µL for MDS patients and from 112.7 (95% CI: 84–151) to 80.2 (95% CI: 58–111) × 103/µL for MPN patients. Nonetheless, 24-month cumulative incidences of platelet response were 18.9% (95% CI: 9.1–31.5%) for MDS patients and 31.2% (95% CI: 7.6–59.1%) for MPN patients. Cumulative incidence at 24 months for neutrophil response was 30.0% (95% CI: 11.4–51.3%) for MDS patients, while none was observed in the MPN patients, with mean neutrophil values that increased from 3.0 (95% CI: 2.8–3.3) to 3.4 (95% CI: 2.9–3.9) × 103/µL for MDS patients, and from 5.3 (95% CI: 4.3–6.5) to 5.9 (95% CI: 4.7–7.5) × 103/µL for MPN patients (Changes in blood parameters were estimated based on mixed linear models using the time as independent variable and the patient as random. Cumulative incidence at 24 months for hemoglobin response was 15.2% (95% CI: 9.6–22.0%) for MDS patients and 9.3% (95% CI: 2.3–22.4%) for MPN patients with increasing mean hemoglobin values from 8.3 (95% CI: 8.2–8.5) to 8.9 (95% CI: 8.5–9.2) g/dL for MDS patients and from 8.3 (95% CI: 8.0–8.7) to 8.9 (95% CI: 8.4–9.3) g/dL for MPN patients. Cumulative incidence at 24 months for transfusion response was 16.3% (95% CI: 9.4–24.8%) for MDS patients and 23.1% (95% CI: 6.4–45.9%) for MPN patients. Mean platelet values decreased from 145.4 (95% CI: 127–166) to 103.4 (95% CI: 85–125) × 10patients . CumulatEXCALIBUR was a prospective, noninterventional study that was performed under conditions of clinical daily practice in Germany, thereby allowing the enrollment of a heterogeneous patient population with regard to demographic and disease characteristics. The inclusion of patients with various diagnoses treated with three different iron chelators represented a realistic population, and the observational design of the study allowed the collection of real-life data without influencing the physicians’ treatment decisions. To minimize possible study site effects, a large number of different hospitals and medical practices were enrolled, depicting a geographically representative selection of German sites. As the study was only conducted in Germany, the generalizability of the results for other countries may be limited. Due to the observational aspect of the study, there are associated limitations like the lack of blinding and randomization, as well as a relevant amount of missing or inconsistent data. However, the overall data quality reflects a typical MDS population, as well as a real-life treatment situation, and provides information regarding clinical practice and patient behavior that randomized clinical trials do not obtain.EXCALIBUR evaluated the use and application of all approved iron chelators with respect to safety, tolerability and patient satisfaction, including treatment switches, as well as the effectiveness of iron chelation therapy and the hematological response in MDS/MPN patients. As the treating physician decided on the prescription of medication and inclusion of the patient in this NIS, there was a potential aspect of influencing the patients’ decisions and course of treatment, herewith introducing bias. To account for the effect of premature withdrawals and treatment changes, the data for all patients at the last completed visit were summarized in the form of a “last visit” in the analyses. The patient characteristics within the study were in line with previous studies conducted in Germany—for example, the 2-year prospective observational study that aimed at describing the routine use of DFX in patients with hematological malignancies by Nolte et al. .One main objective of our study was to assess the use of approved iron chelators in Germany under real-life conditions. Deferasirox DT was released in Germany in 2006 as a more convenient alternative to deferoxamine, which had to be administered parenterally. However, some subjective burden remained as deferasirox DT had to be dispersed in a relatively time-consuming procedure, taken on an empty stomach, and was associated with relevant gastrointestinal side effects ,12. TherWith the TSQM-14 questionnaire, convenience was assessed with a slightly lower score by patients with deferasirox DT as starting treatment compared to the overall population. These results indicated that patients indeed preferred deferasirox FCT over deferasirox DT and deferoxamine because of the changed formulation, which is in line with the ECLIPSE study that could show consistently greater adherence and higher satisfaction for deferasirox FCT compared to deferasirox DT . A patieThe ADRs observed in this study were in line with the known safety profiles of deferasirox and deferoxamine ,14. OverThe main reason for initiation of iron chelation was a serum ferritin value of >1000 ng/mL. To assess the effectiveness of iron chelation therapy, serum ferritin values were repeatedly measured throughout the study. The median serum ferritin value decreased from 1802.50 µg/L at baseline to 1240.50 µg/L at month 24; the median change from baseline at month 24 was −458.0 µg/L. Persistence of elevated serum ferritin levels is most likely due to the continuing transfusion dependence of the patient cohort. In the phase IIIb EPIC study, patients with MDS showed comparatively larger decreases between −115 µg/L and −976 µg/L after 1 year of treatment with deferasirox . Due to For patients with MDS and MPN, the hematological response was determined according to IWG criteria. In this competing-risks setting, death without prior response usually had a higher probability than the achievement of a response. At 24 months, the probability of hemoglobin response was 15.2% for MDS patients and 9.3% for MPN patients. After the same time, the probability of transfusion response was 16.3% for MDS and 23.1% for MPN patients. At 24 months, we estimated that 18.9% of MDS patients and 31.2% of MPN patients reached platelet response, and for 30.0% of MDS patients but for none of the MPN patients, a neutrophil response could be documented, which might be due to the small number of MPN patients being evaluable for neutrophil response. When performing literature research, there are more than 10 studies assessing the rates of hematologic improvement in patients with MDS receiving iron chelation therapy between 2012 and 2019 , resultsEXCALIBUR provided valuable insights into the utilization, effectiveness, safety, and patient satisfaction of iron chelation therapy in clinical daily practice, while additionally documenting change of iron chelator medication over time. The observational design of the study allowed the enrollment of a heterogeneous patient population with regard to demographic and disease characteristics, thereby collecting real-life data without influencing the physicians’ treatment decisions. The prospective documentation in a broad patient population with various diagnoses treated with three different iron chelators led to a high representativeness of a realistic patient population. A large proportion of patients switched from deferasirox DT to deferasirox FCT, mainly because of more convenient application, and this was also reflected in the TSQM-14 scores. Iron chelation was effective in lowering serum ferritin levels, with the observed ADRs being in line with the known safety profile. Hematologic response occurred in a small number of patients, comparable to other studies that examined hematologic improvement in patients with MDS.


The source of PM2.5 concentration is not explicitly mentioned; however, the article published by Upadhyay et al. [2.5 concentrations were obtained from the ground-based air quality monitoring stations installed at the US embassies in major cities in South Asian countries. These concentrations are limited to specific cities and do not represent country-level air pollution scenarios. The purpose of this comment is not to discuss the PM2.5 concentrations provided by the US embassies, but instead to comment on the use of the PM2.5 exposure data, which are used in Abdul Jabbar et al.’s paper. These exposure data are obtained from the World Bank database (https://databank.worldbank.org/source/world-development-indicators (accessed on 17 October 2022)). PM2.5 exposure (EXP) is related to PM2.5 concentrations through Exp = SUM{(Pi/P) × Ci}, where Ci = annual mean PM10 or PM2.5 concentration in sub-population Pi, P = SUM (Pi), which is the total population in cities with data [This comment discusses the use of PMr et al. . The autith data .2.5 concentrations [2.5 exposure [2.5 exposure data reported by Abdul Jabbar et al. [2.5 in Pakistan over the period was “steady”. We illustrate the discrepancy in 2.5 exposure data (2010–2017) obtained from the World Bank database  reanalysis data (2010–2017) and the World Health Organization (WHO) website  (2010–2016).It is well established that both PMtrations  and PM2.r et al.  do not se data 200–2017 ob2.5 exposure and concentration data from different sources before they can be used in any scientific research or policy application.Pakistan is the second-most polluted country among South Asian countries, as reported by the authors . Therefo


This study aimed to evaluate and compare the time required to return to sports (RTS) after surgery, the rate of revision surgery and the time required for RTS after revision surgery in elite athletes undergoing meniscal repair or partial meniscectomy, particularly analysing the difference between medial and lateral menisci. It was hypothesised that both procedures would entail similar, high rates of RTS, with the lateral meniscus exhibiting higher potential healing postprocedure compared to the medial meniscus.A systematic review was conducted based on the PRISMA guidelines. Quality assessment of the systematic review was performed using the AMSTAR-2 checklist. The following search terms were browsed in the title, abstract and keyword fields: ‘meniscus’ or ‘meniscal’ AND ‘tear,’ ‘injury’ or ‘lesion’ AND ‘professional,’ ‘elite’ or ‘high-level’ AND ‘athletes,’ ‘sports,’ ‘sportsman,’ ‘soccer,’ ‘basketball,’ ‘football’ or ‘handball’. The resulting measures extracted from the studies were the rate of RTS, level of RTS, complications, revision surgery and subsequent RTS, Tegner, International Knee Documentation Committee (IKDC) and Visual Analogue Scale (VAS).In this study, the cohort consisted of 421 patients [415 (98.6%) men and 6 (1.4%) women] with a mean age of 23.0 ± 3.0 years. All patients were elite athletes in wrestling, baseball, soccer, rugby or handball. While 327 (77.7%) patients received partial meniscectomy at a mean age of 23.3 ± 2.6 years, 94 (22.3%) patients received meniscal repair at a mean age of 22.1 ± 4.0 years. After partial meniscectomy, 277 patients (84.7%) returned to their competitive sports activity and 256 (78.3%) returned to their pre-injury activity levels. A total of 12 (3.7%) patients required revision surgery because of persistent pain [5 (1.5%) patients], chondrolysis [2 (0.7%) patients] or both chondrolysis and lateral instability [5 (1.5%) patients]. Ten (83.3%) of the twelve patients had involvement of the lateral meniscus, whereas the location of injury was not specified in the remaining two patients. After revision surgery, all patients (100%) resumed sports activity. However, after meniscal repair, 80 (85.1%) athletes returned to their competitive sports activity and 71 (75.5%) returned to their pre-injury activity levels. A total of 16 (17.0%) patients required partial meniscectomy in cases of persistent pain or suture failure. Of these, 4 (25%) patients involved lateral and medial menisci each and 8 (50%) patients were not specified. After revision surgery, more than 80.0% of the patients (13) resumed sports activity.In elite athletes with isolated meniscal injury, partial meniscectomy and meniscal suture exhibited similar rates of RTS and return to pre-injury levels. Nonetheless, athletes required more time for RTS after meniscal repair and exhibited an increased rate of revision surgery associated with a reduced rate of RTS after the subsequent surgery. For lateral meniscus tears, meniscectomy was associated with a high rate of revision surgery and risk of chondrolysis, whereas partial medial meniscectomy allowed for rapid RTS but with the potential risk of developing knee osteoarthritis over the years. The findings of this systematic review suggested a suture on the lateral meniscus in elite athletes because of the high healing potential after the procedure, the reduced risk of developing chondrolysis and the high risk of revision surgery after partial meniscectomy. Furthermore, it is important to evaluate several factors while dealing with the medial meniscus. If rapid RTS activity is needed, a hyperselective meniscectomy is recommended; otherwise, a meniscal suture is recommended to avoid accelerated osteoarthritis.Level IV.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351979).PROSPERO-CRD42022351979 ( Meniscal injuries constitute the majority of injuries to the knee, with more than 60% of knee injuries reported to be injuries to the menisci . The ovehttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351979)  with a mean age of 23.0 ± 3.0 years. All patients were elite athletes involved in wrestling, baseball, soccer, rugby or handball.The mean age of the 327 (77.7%) patients who received a partial meniscectomy was 23.3 ± 2.6 years; 326 (99.7%) of them were men and 1 (0.3%) was a woman.Of the 94 (22.3%) patients who received meniscal repair, 89 (94.7%) were men and 5 (5.3%) were women, with a mean age of 22.1 ± 4.0 years.In partial meniscectomy, 329 menisci were treated in 327 patients, of which 166 (50.5%) were medial menisci, 147 (44.6%) lateral menisci and both in 16 (4.9%) patients. The lesions were classified in only 3 studies, for a total of 151 tears, as follows: 9 (6.0%) simple, 18 (11.9%) bucket-handle, 71 (47.0%) complex, 18 (11.9%) radial, 5 (3.3%) horizontal, 1 (0.7%) flap and 29 (19.2%) vertical. Surgical details are reported in Table Table p < 0.05) [The meniscectomy time to return to sports ranged from a small cohort of patients who returned after less than 30 days  to a mea < 0.05) .A total of 12 (3.7%) patients required revision surgery due to persistent pain in 5 (1.5%) patients, chondrolysis in 2 (0.7%) patients, and chondrolysis and lateral instability in 5 (1.5%) patients.Of these, ten out of twelve (83.3%) involved the lateral meniscus, while in the remaining patients, they were not specified. After revision surgery, all patients (100%) resumed sports activity.Of the 88 procedures analysed in meniscal repair, 31 (35.3%) were treated medially, 42 (47.7%) were treated laterally and 1 (1.1%) was treated for both tears, while in 14 (15.9%) patients, these parameters were not specified. The lesions were classified into 63 patients as follows: 15 (23.8%) simple, 12 (19.1%) bucket-handle, 4 (6.3%) complex, 14 (22.2%) longitudinal and 18 (28.6%) longitudinal/vertical. For the repair, 3 (3.4%) were performed with bioabsorbable arrows, 59 (67.1%) all-inside, 13 (14.8%) inside-out, 4 (4.5%) root repair, 6 (6.8%) combined and 3 (3.4%) outside-in. Surgical details are reported in Table After the first surgery of meniscal repair, 80 (85.1%) of the athletes returned to their competitive sports activity and 71 (75.5%) returned to the same pre-injury activity level.After meniscal suture, the mean time to return to sports ranged from 129 to 209 days (mean 184.1 days) .After meniscal repair, 16 (17.0%) patients required a partial meniscectomy in all patients for persistent pain or suture failure.Of these, 4/16 (25%) involved the lateral meniscus, 4/16 (25%) involved the medial menisci and 8 (50%) patients were not specified. After revision surgery, more than 80.0% of the patients (13) resumed sports activity.The most important finding of the current systematic review was that the rate of return to competitive sports was similar for both meniscal repair and partial meniscectomy, and similar rates were found for return to the pre-injury level of sports activity. However, there was a shorter time for return to sport with meniscectomy compared to meniscal suture repair and a higher level of revision surgeries after meniscal repair, with a lower rate of return to sport after revision for failed meniscal repair. In particular, a very high percentage of revision surgery was required for lateral meniscus (> 80%) after partial meniscectomy, while for meniscal repair, data are poorly evaluated because in 50% of the failures, it was not specified whether it was medial or lateral meniscus but certainly compared with meniscectomy, there is a higher failure rate in the medial meniscus and a lower failure rate in the lateral.The systematic review by Eberbach et al. assessed the return to sport (RTS) after isolated medial meniscus repair. Their review found a return to sports activity rate of 89%, which is similar to the current study .Lee et al. analysed return to sports in high-level athletes after either partial meniscectomy, meniscal repair or a meniscal allograft transplant. They found that the shortest time to return to sports was with partial meniscectomy, and the highest rate of return to sports was again with partial meniscectomy (up to 100%). However, the rate of RTS after meniscal repair was 81–88.9% in the studies the authors analysed, which is in keeping with what the current review found . An earlA more recent systematic review by Blanchard et al. also found similar rates of return to sport activity following isolated medial meniscus repairs, of 83.1%. However, in comparison to the current study, those authors found a higher rate of revision following medial meniscal repair, at 12.4% [The mean time to return to sport was lower with meniscectomy in the current review. Eberbach et al. reported in their systematic review on the mean time to RTS after isolated medial meniscal repair . They foHowever, the type of surgery on the injured meniscus may only be one of multiple factors with bearing on time to RTS. The meniscus that is injured may also influence RTS, as it was found to have a greater time of resumption of sports with lateral meniscal injuries compared with medial meniscal injuries . There hRecent studies indicate that the lateral meniscus has better healing potential with a lower revision rate following repairs . This waWith respect to revision surgeries after partial meniscectomy, although a greater number were found with lateral meniscus, concomitant chondrolysis and chondrolysis with lateral instability were also found. These confounding factors need to be taken into account when interpreting the results of the current study regarding postmeniscectomy revision surgery, as a knee with lateral instability will understandably have greater stresses on the lateral compartment and will result in greater damage to the lateral meniscus. Similar results were also reported by Nawabi et al., who found a longer time for return to play after lateral meniscectomy than after medial meniscectomy in elite professional soccer athletes .This is one of the first systematic reviews that has analysed return to sports in high-level elite athletes in multiple sporting disciplines after either meniscal repair or partial meniscectomy and, to the best of the authors’ knowledge, the first systematic review to analyse return to sport after revision surgery for a meniscal injury. The strengths of the current study are a large study population, inclusion of only elite level athletes, inclusion of multiple disciplines of sport and the analysis of return to sport after revision surgery. Previous systematic reviews on the current topic had either a small study population, included only a single sport, or included no information on return to sport after revision surgery.This study exhibits several limitations. First, all studies were categorised as level 3 or 4, which prevented a meta-analysis  of the rThe findings of this systematic review and the current literature suggested a suture on the lateral meniscus (the technique is indifferent) in elite athletes because of the high healing potential after the procedure, the reduced risk of developing chondrolysis and the high risk of revision surgery after partial meniscectomy. Furthermore, it is important to evaluate several factors while dealing with the medial meniscus. If rapid RTS activity is needed, a hyperselective meniscectomy is recommended; otherwise, a meniscal suture is recommended to avoid accelerated osteoarthritis, considering that meniscal suture exhibits a high probability of failure owing to the low reparative ability of the medial meniscus. Therefore, it was suggested that all of the abovementioned factors must be evaluated before deciding on surgically addressing a meniscal injury of an elite athlete Table .Table 4IIn elite athletes with isolated meniscal injury, partial meniscectomy and meniscal suture exhibited similar rates of RTS and return to pre-injury levels. Nonetheless, athletes required more time for RTS after meniscal repair and exhibited an increased rate of revision surgery associated with a reduced rate of RTS after the subsequent surgery. For lateral meniscus tears, meniscectomy was associated with a high rate of revision surgery and risk of chondrolysis, whereas partial medial meniscectomy allowed for rapid RTS but with the potential risk of developing knee osteoarthritis over the years.


The current SARS Covid-19 pandemic has negatively affected primary care and health system services provided to chronically ill patients, such as patients with Diabetes MellitusThe comparison of glycemic regulation as demonstrated by the levels of glycated hemoglobin HbA1c % in Psychiatric patients monitored at the Psychiatric Hospital of Attica before the pandemic (9/2018 -2/2020) and during its progression (3/2020-2/2022)The study was done retrospectively and included 543 diabetic patients who were examined in Outpatient Clinics during the aforementioned time intervals. HbA1c % levels were measured in peripheral blood and at least two measurements were averaged for each patient. The statistical method used to compare the mean value of HbA1c % was the paired t-test and the level of significance was p<0.05.The mean of the mean values of HbA1c % before the pandemic was 7.22% while (sd 6.6-7.9) while during the pandemic period it was 8.56% (sd 7.1-9.9). The t score was calculated as 3.3 with a significance level of p=0.0165 (p<0.05).n the present study, a statistically significant increase in the HbA1c % of the Diabetic patients of the Psychiatric Hospital over the last two years is found, which indicates a worsening of the glycemic control of this particular group of patients. It is worth noting that 24 out of 543 (4.4%) missed a scheduled follow-up visit, while the greater variation in HbA1c % values during the second period indicates the varied way the pandemic affected the behavior of psychiatric patientsNone Declared