Grapes are widely cultivated around the world and their quality has distinct regional characteristics. In this study, the qualitative characteristics of the ‘Cabernet Sauvignon’ grape variety in seven regions, from half-véraison to maturity, were analyzed comprehensively at physiological and transcriptional levels. The results indicated that the quality traits of ‘Cabernet Sauvignon’ grapes in different regions were significantly different with obvious regionality. Total phenols, anthocyanins, and titratable acids were the main factors of the regionality of berry quality, which were very sensitive to changes in the environment. It should be noted that the changes in titrating acids and total anthocyanin of berries vary greatly from half-véraison to maturity between regions. Moreover, the transcriptional analysis showed that the co-expressed genes between regions characterized the core transcriptome of berry development, while the unique genes of each region reflected the regionality of berries. The differentially expressed genes (DEGs) between half-véraison and maturity can be used to demonstrate that the environment of the regions could promote or inhibit gene expression. The functional enrichment suggested that these DEGs help to understand the interpretation of the plasticity of the quality composition of grapes according to the environment. Taken together, the information generated by this study could contribute to the development of viticultural practices aimed at making better use of native varieties for the development of wines with regional characteristics.  Vitis vinifera is the most economically valuable fruit tree in the world, which is widely used in the food and beverage industries [dustries . Grapes dustries ,3. ‘Cabedustries . Meanwhidustries . Experimental evidence demonstrated that berry development is a complex process and environmental factors such as temperature, humidity, water, and altitude had a profound influence on berry quality formation, giving it a metabolic model with regional characteristics ,7,8,9. FDifferent regions with different climates possess a variety of environmental factors which may influence gene expression in grape berries. There were major differences in the amount and quality of expressed genes of ‘Cabernet Sauvignon’ in the regions in response to environmental stimuli . It was During berry development, the process of the color change of grapes is called véraison, which is accompanied by changes in physical and chemical factors, both intracellular and intercellular, and continues to maturity . This stIn this study, the changes in grape berry quality from half-véraison to maturity in different regions of Shandong were analyzed extensively, and the influence of the regional environment on the formation of berry metabolites was discussed. In addition, RNA-seq is used to monitor the changes in grape quality in the regional environment, thereby deepening the understanding of grape quality regionality. This study can provide a new theoretical basis for the regional analysis of the berry quality of ‘Cabernet Sauvignon’ grapes and provide a reference for the practice of directional viticulture. The wine-grape-growing regions of China display unique ecological conditions either from south to north or from east to west. In this work, the seven regions including Dezhou (DZ), Laixi (LX), Penglai (PL), Rizhao (RZ), Rushan (RS), Tai’an (TA), and Zaozhuang (ZZ) were in Shandong province, China . The envThe sugar-acid ratios of berries in 7 regions were above 22, which was an important indicator of grape maturity . Berry wIn detail, an analysis of the main components of sugars, acids, anthocyanins, and phenolics in the berries from various regions showed that the content of each component was variable. For example, the berries in LX regions were rich in TSS, and the accumulation of glucose and fructose indicated a significant difference from other regions E. The beHalf-véraison is the important intermediate process of the maturation phase of grapes, which leads to drastic physical and chemical changes in berries. In this study, five quality indices were studied including berry weight, TSS, titratable acids, anthocyanins, and total phenols between half-véraison and maturity of grape berries. Of these, titratable acids and anthocyanins were more variable, with a variance ratio of approximately 72.91% and 70.36%. The variation in total phenols, TSS, and berry weight was relatively less, with a variance ratio from 35.42 to 37.11% A. FurtheTranscriptomes of ‘Cabernet Sauvignon’ in seven regions of half-véraison and maturity were sequenced. In total, 177.82 Gb of raw data were obtained, and the number of reads varied from 39.80 to 46.15 million for 91.46–97.54% of accounting data. It provided adequately for the next expression profiling analysis, which could be used for the subsequent quantitative analysis of gene expression . PCA alsThe number of genes detected during berry development  varied substantially in this study. At half-véraison, the highest and lowest number of genes were in the collected samples of RS  and TA , respectively. At maturity, the lowest was 22,085 belonging to the DZ region, and the highest was 23,479 belonging to the RS region. The petal map indicated that about 85% of the genes were co-expressed and about 15% of the unique genes across regions A,B. AsseThe Kruskal-Wallis test indicated that the berry transcriptions from different regions were very different at maturity A. K_meanUp-set plots indicated that the DEGs varied widely across regions, ranging from 976 in PL to 4891 in RZ. Furthermore, DEGs had different expression patterns among regions. For example, the RZ, LX, and ZZ regions possess a higher number of up-regulated DEGs than down-regulated genes, while it was vice versa in DZ, PL, RS, and TA. Interestingly, the regions with high multiple-quality traits tended to have a higher number of up-regulated genes A. In addThe biological functions of DEGs were assessed based on gene ontology (GO) . The DEGs were enriched into 843 categories of biological functions, containing 434 biological processes, 114 cellular components, and 295 molecular functions . Among tThe DEGs between half-véraison and maturity from different regions were mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) to obtain 115 metabolic pathways . Some ofIt is common knowledge that the interaction between the environment and plants is the main factor in the quality of the grape. Environmental change plays a crucial role in quality formation ,23,24. SThe quality of berries is mainly on sugars, organic acids, and secondary metabolites such as polyphenols and anthocyanins . MultivaAlso, malvidin was the main anthocyanin component detected in this study C, moreovIn this study, sugar, acid, anthocyanins, phenols, and other traits had a significant change from the half-véraison to maturity. Since the growth and development of grapes follow a double sigmoidal curve, the characteristic of rapid change corresponded to an S-shaped growth curve. The first phase of the curve is mainly manifested by an increase in berry size and weight, and the second phase of the curve is mainly manifested by an increase in fruit sugar, anthocyanin, and other quality traits that are defined as maturity. While veraison is the beginning of the second phase curve, characterized by the beginning of coloring and softening of the berries, rapid accumulation of sugars, and degradation of acids ,23. In tAs the berries mature, the titratable acid decreases dramatically. The rate of change from half-véraison to maturity in RS regions was as high as 88.98% A,D. AnthRapid advances in the sequencing of grapevine reference genomes and the development of new tools for transcriptomic data have contributed to recent advances in the analysis of dynamic gene expression during berry development ,45,46. RThe abundance of multiple genes in all regions could be used as a useful lever to adjust berry quality . Based oCurrent data suggested that the amount and expression of DEGs varied greatly among regions A,B. ThisVitis vinifera) ‘Cabernet Sauvignon’ was used in this study. All plant material was cultivated in an east-west orientation and managed in the same viticultural practices , in 2020 harvested. Collected grape berries when 50% of the berry skin color was completed as the sample at the half-véraison [Grapevine  based on latitude and longitude of sampling regions [The environmental conditions  were obt regions .Berry weight was measured through an analytical balance. TSS of berries were measured using a portable hand-held dialyzer , and the titratable acidity was titrated with 0.1 mol/L NaOH. Total phenols of the berry were measured using the Folin-Ciocalteu method  with somSugar components mainly glucose and fructose were determined by HPLC  according to a method previously reported with some modifications . Three r2HPO4 solution (pH adjusted to 2.4 with phosphoric acid); column temperature 30 °C; flow rate 0.5 mL/min; injection volume 20 μL, detection wavelength was 210 nm. Organic acid standards  were purchased from Shanghai Macklin Biochemical Technology Co., Ltd. .Organic acid components were determined by HPLC  according to a method previously reported with some modifications . Three rPhenolic components were determined by HPLC with three replicates . 1.00 g Anthocyanin components were determined by LC-MS with three replicates . 1.00 g Total RNA of all samples was extracted using the modified Hexadecyltrimethylammonium Bromide (CTAB) method . DNase  and the accession number of RNA-seq data is PRJNA890029.After checking with the library, all samples were sequenced on Illumina Hiseq, and paired-end 150 bp reads were generated. Transcriptome data of ‘Cabernet Sauvignon’ from multiple regions were registered in NCBI (Vitis vinifera cultivar: Muscat Hamburg (wine grape))  to obtain uni-genes using Hisat2 v2.0.5 [http://www.geneontology.org/) and KEGG database (http://www.genome.jp/kegg/) were used for all genes enrichment analysis, and the function defining padj ≤ 0.05 was significantly enriched. The Up-set Plot in TBtools [https://github.com/CJ-Chen/TBtools/releases, accessed on 5 March 2021) was used to perform statistical analysis on the common or specific DEGs. The Graphics of Circos software in TBtools was used for the analysis of the gene expression and the distribution of DEGs on the chromosomes.Raw sequences were filtered to remove the adaptor sequence, low-quality reads, and short reads. The resulting sets of high-quality clean reads were used for transcriptome analysis. High-quality clean reads were mapped to the grape reference genome   analysis using the designed specific primers by NCBI Primer Blast (er 2020) . First-sT method . The expp < 0.05. The correlation between environmental conditions and quality characteristics was analyzed using Pearson correlation coefficient. The Origin Pro 9  was used to produce the figures.The data were presented as mean ± standard deviation (SD) (n = 3). Statistical analysis of variance (ANOVA) was performed using SPSS 17.0  with Duncan’s multiple range test at A comprehensive analysis herein of the quality of ‘Cabernet Sauvignon’ in different regions revealed that regional diversity provided a significant effect in forming the unique quality of ‘Cabernet Sauvignon’. This research contributed to the understanding of the interaction of grape quality with environmental conditions and the effect of the latter on the formation of berry metabolites. Among them, phenols, anthocyanins, and titratable acids were the most sensitive indicators of environmental factors and the main factors making up the regionality of berry quality. It should be noted that the change in titrating acids and anthocyanins from half-véraison to maturity varies greatly between regions. Additionally, RNA-seq has proved to be a valuable tool for monitoring changes in grape quality dependent on the regional environment, improving the interpretation of plasticity in the quality physiological composition of grapes depending on the environment. The information generated from this study could contribute to the elaboration of viticultural practices aimed at making better use of native varieties to develop wines with regional characteristics.


Background: Assessment of physical and respiratory function in the intensive care unit (ICU) is useful for developing an individualized treatment plan and evaluating patient progress. There is a need for measurement tools that are culturally adapted, reliable and easy to use. The Chelsea Critical Care Physical Assessment Tool (CPAx) is a valid measurement tool with strong psychometric properties for the intensive care population. This study aims to translate, adapt and test face validity and inter-rater reliability of the Norwegian version of CPAx (CPAx-NOR) for use in critically ill adult patients receiving prolonged mechanical ventilation. Method: CPAx-NOR was forward backward translated, culturally adapted and tested by experts and patients for face validity. Thereafter tested by 10 physiotherapists in five hospitals for inter-rater reliability. Results: The experts and pilot testers reached consensus on the translation and face validity. Patients were tested at time point A (n = 57) and at time point B (n = 53). The reliability of CPAx-NOR at “A” was 0.990 (0.983–0.994) and at “B” 0.994 (0.990–0.997). Based on A+B combined and adjusted, the ICC was 0.990 (95% CI 0.996–0.998). Standard error of measurement (SEM) was 0.68 and the minimal detectable change (MDC) was 1.89. The Bland–Altman plot showed low bias and no sign of heteroscedasticity. CPAx-NOR changed with a mean score of 14.9, and showed a moderate floor effect at the start of physiotherapy and low ceiling effects at discharge. Conclusion: CPAx-NOR demonstrated good face validity and excellent inter-rater reliability. It can be used as an assessment tool for physical function in critically ill adults receiving prolonged mechanical ventilation in Norway. Intensive care unit–acquired weakness (ICU-AW) is common, and if patients survive, it negatively affects quality of life  and leadThe Chelsea Critical Care Physical Assessment Tool (CPAx) is an observation-based measurement tool developed by Dr. Evelyn Corner. The tool is unique as it incorporates assessment of respiratory function and cough, and both functional and specific muscle testing ,11,12. CTo make the measurement tool available and ready for implementation in Norway, it is necessary to agree on a translated and adapted Norwegian version and to test its reliability and ability to detect changes in physical function. It is important to investigate systematic and random errors and establish the minimal detectable change to make the Norwegian version a reliable outcome measure in a Norwegian ICU population.The aims of this study were to translate, cross-culturally adapt and test face validity of the Chelsea Critical Care Physical Assessment Tool into Norwegian (CPAx-NOR) and to test its inter-rater reliability in critically ill adult patients receiving prolonged mechanical ventilation.The study had two stages:Stage I (August 2021–January 2022): Translation, discussions on face validity and cross-cultural adaption of CPAx to Norwegian, andStage II (February 2022–September 2022): Evaluation of CPAx-NOR’s inter-rater reliabilityThe reporting of this study has been structured according to the STROBE recommendations for observational studies .CPAx consists of ten different items graded from 0 (unable/dependent) to 5 (independent) on a Guttman scale. The ten items are summarized in an aggregated total score, which indicates the total need for help with a minimum score of 0 (completely dependent) and a maximum score of 50 (independent). The patient is observed and assessed bedside, and the only equipment needed is a handheld dynamometer for measuring grip strength. The use of CPAx is considered feasible in clinical practice, and its visual display makes it easy to understand for both healthcare professionals and patients .Based on international recommendations ,19,20, aAs rehabilitation is a multidisciplinary process in the ICU, it was important to ensure that CPAx-NOR was easy to understand both for multidisciplinary teams and for patients. The expert committee members, eight persons, were therefore carefully chosen from hospitals in the South-East health region to involve a broad professional environment. The committee consisted of one senior ICU nurse PhD, one anesthesiologist, one former intensive care patient and five physiotherapists. Three of the physiotherapists had long experience in ICU (>10 years), MSc and specialization in ICU physiotherapy . The other physiotherapists had little ICU experience, whereas one was newly educated. The physiotherapists in the expert committee did not participate in the data collection to test reliability.The preliminary CPAx-NOR (T12) was then tested in a pilot conducted by another three physiotherapists employed at three of the included hospitals. The physiotherapists: one male and two female with experience ranging from 2–15 years, were not involved in the translation process. They tested one patient each. During a roundtable discussion with the three physiotherapists and CMS and AKB, the final version of CPAx-NOR was agreed upon with one minor change , Step 4.Assessment of face validity as described by COSMIN  was condA multicentre study with a prospective cross-sectional design was conducted in five hospitals in Norway’s South-East health region including both large university hospitals and smaller local hospitals. All the units were general ICUs and included 33 ICU beds at the time of the inclusion period. The study was presented to the Regional Ethics Committee, which concluded that it did not require approval. The Data Inspectorate at all the local hospitals and SIKT , approved the study, project number 777606. The study was conducted according to the Helsinki Declaration, and all participants (physiotherapists and patients) gave informed, written consent before inclusion in the study.The aim of this part of the study was to investigate inter-rater reliability and therefore the participants of interest were the physiotherapists using CPAx-NOR, and how they used CPAx-NOR to rate patients in clinical practice in the ICU. Ten physiotherapists (one man and nine women), age 28 to 64 years, participated as testers for CPAx-NOR. Six of them were specialists in ICU physiotherapy. They all had more than four years clinical experience from a hospital, and their clinical experience at the ICU ranged from one to more than 30 years. None of the physiotherapists had used CPAx routinely prior to the study.The median length of stay in Norwegian ICUs is 2.1 days and median time on mechanical ventilation is 1.5 days . TherefoThe only demographic data collected were age, sex, diagnosis and CPAx-NOR score.All the participating physiotherapists completed the same education to use CPAx-NOR in clinical practice. The original English eLearning platform used in previous studies was not available, therefore a six-hour digital course in Norwegian was developed and discussed in agreement with the original CPAx developer, Evelyn Corner. It consisted of three parts, (1) a theory part on the use of standardized measurement tools in general, (2) a comprehensive review of the CPAx, (3) an instructional video of a physiotherapy treatment session with a simulated patient to be scored and discussed in a plenary setting. At each hospital, two physiotherapists completed all the assessments at the same time in pairs with separate roles; one conducted the assessment while the other observed. They both scored separately and blinded. The testers decided the roles without further instructions from the project leader. To facilitate patient inclusion and to help with practical problem-solving during testing of CPAx-NOR, monthly digital meetings were arranged for all the participating physiotherapists in combination with an open invitation to correspond via e-mail, and one in-person meeting at each participating hospital.Inter-rater reliability was assessed at start of physiotherapy and at discharge from ICU, according to COSMIN criteria , and a sChange in scores, understood as CPAx-NOR’s ability to detect change in a patient trajectory in the ICU unit over time, was described by effect size (ES) and standard response mean (SRM) ,27.Descriptive and non-parametric statistics were used to describe the demographic characteristics and distribution of scores, expressed as the mean, standard deviation (SD), median, interquartile range (IQR), frequency and percentage of the data. To analyze the inter-rater reliability, we used the intraclass correlation coefficient (ICC) with 95% confidence intervals for aggregated scores. Because this was a multicenter study, and not every patient was rated by each rater, we used a one-way random effects model (single measurement) as described in Koo and Li  and Shroasticity  on each asticity . The meaasticity . Floor aasticity . Data weThe CPAx-NOR was translated in a step-by-step protocol shown in After the CPAx-NOR was established and the education completed, the five hospitals started including patients from their ICUs, see The ICC was 0.990 (0.983–0.994) at time point A and 0.994 (0.990–0.997) at time point B. The ICC for both time points combined (A+B) was 0.998, SEM 0.68 and the MDC was 1.89. See The Bland–Altman plot for the total scores combined shows the mean difference between raters was −0.13 (SD 1.50) and 95% limits of agreement were from −2.82 to 3.07. The limits of agreement are shown in At time point A, the mean difference between raters was −0.12 (SD 1.58) and 95% limits of agreement was −3.22 to 2.98. At time point B, the mean difference between raters was 0.40 (SD 1.38) and 95% limits of agreement was −2.31 to 3.09. The limits of agreement are shown in The ten individual items showed weighted kappa values between 0.957 and 0.996 at time point A and between 0.925 and 0.980 at time point B. The percentage agreement for individual items, as a parameter for measurement error, ranged from 77.2% to 98.2% at time point A and 73.6% to 98.1% at time point B. Results are presented in The mean difference in CPAx-NOR score between time points A and B (n = 42) was 14.9 . ES was 1.3 and SRM was calculated as 1.2.Nine patients scored 0 (16%) and one patient scored 50 (1.8%) at the start of physiotherapy . At ICU discharge, none of the patients scored 0. One patient scored 50 points (2%) . These results indicate that problems related to floor effects may be moderate while problems related to ceiling effects are minimal.The objective of this study was to translate, adapt, test face validity and the inter-rater reliability of CPAx-NOR in critically ill adult patients undergoing prolonged mechanical ventilation in the ICU. CPAx-NOR was successfully translated in a forward-backward translation, cross-culturally adapted and pilot tested in clinical practice. Face validity was assessed through expert group and patient discussions, and demonstrated good results. CPAx-NOR demonstrated excellent inter-rater reliability for both aggregated score and all ten individual items across the ICU stay. The measurement error was small with a minimal detectable change of two points. CPAx-NOR exhibited a moderate floor effect at start of physiotherapy and low floor and ceiling effects at ICU discharge, as expected. These results indicate that CPAx-NOR is a valid and reliable measurement tool for physical function during the continuum of an ICU stay for adult patients on mechanical ventilation for more than 48 h. Whether the results are generalizable to other ICU patients with shorter time on mechanical ventilation has not been investigated.The MDC is of great importance when evaluating change in physical function. Previous studies investigating CPAx ,14,30, hDifferent MDC’s corresponds to the finding that the agreement was somewhat lower for the items ‘cough’ (77.2% and 79.2%), ‘moving within the bed’ (86.0% and 73.6%) and ‘dynamic sitting’ (87.7% and 79.2%). Despite the clarification of the item ‘cough’ during the translation, disagreements among the raters were still present at both time points. Suctioning is a part of the item ‘cough’, and in Norway, this task is assigned to nurses, which might have complicated the evaluation. The minimal, moderate and maximal assistance ratings were the subject of several discussions between clinicians during the testing period and may be the reason for the lower agreement on these items, similar to findings from previous publications using CPAx ,13,14. TOur SEM and MDC at time point A are similar to the original version , and theCPAx-NOR is a clinically useful tool for assessing low-functioning patients receiving prolonged mechanical ventilation in the study population representative of the Norwegian ICU population expressed as the SEM, MDC and LOA throughout the ICU trajectory. The results of previous studies assessing inter-rater reliability, together with the current study, support the claim that CPAx is in general a reliable tool to assess function in the ICU population.Our results showed a mean change of 15 points in scores between the start of physiotherapy and discharge from the ICU. This indicates that the patients’ physical function improved during the trajectory, a finding supported by the large ES and SRM. These findings are similar to those in studies of responsiveness of the original and the Danish version ,30. GeneAs with the original version of CPAx , the floAt time point B, no patients scored 0 points, and only 2% scored 50 points, meaning no floor effect and a highly acceptable ceiling effect. This corresponds with the results reported in the original  and threCPAx-NOR is an important tool in clinical practice to help establish rehabilitation goals for ICU patients, as they fight their way back toward regaining independent respiratory and physical function . StandarBoth the similarities and differences between the original and translated CPAx versions, highlights the importance of a solid translation- and cross-cultural adaptation process that is needed for further standardization when implementing the CPAx versions into clinical practice. These findings are of importance in future research when designing international multicenter studies, with aims to investigate the effect of early rehabilitation at the ICU. Of clinical importance, is how to apply the MDC results of this study. The authors recommend applying the combined result of the two time points A+B (MDC = 2 points) in clinical practice, similar to the Danish and German versions ,15.The strengths of the present study include the comprehensive translation process with two professional translators and two clinicians involved in both the forward and backwards translations, along with a multidisciplinary expert committee including a former intensive care patient, before further evaluation of inter-rater reliability. Due to the multicentre design of this study, with five hospitals considered representative of Norwegian ICUs in terms of size, organization and patient population, the results can be considered generalizable to other ICUs in Norway. Further, the use of raters with a range of experience as physiotherapists in acute hospital settings supports our confidence that the use of CPAx-NOR is feasible for a wide variety of physiotherapists working in ICUs.As in the other European translation studies, all the raters completed a digital course to the testing period, but unlike in those studies, the original English eLearning platform was not available. All raters received training before assessing patients, and generalizability for physiotherapists without any training is limited. Another possible limitation of the design was that the assessments were completed in pairs with raters alternating between the roles of leader and observer without structure. This made it difficult to identify systematic between-raters error.Moreover, we did not have data on median time on time point A or on length of stay (ICU LOS) in the patients that were tested. Therefore we were not able to link CPAx-NOR to a specific time point in the patient trajectory and to make any conclusions regarding responsiveness.CPAx has been successfully translated and cross-culturally adapted into Norwegian, resulting in CPAx-NOR. The adapted tool has been found to show good face validity in clinical practice and has demonstrated excellent inter-rater reliability. CPAx-NOR can be considered an important measurement instrument for physiotherapists working in the ICU for assessing respiratory and physical function and planning and setting goals for early rehabilitation in the multidisciplinary team in intensive care units in Norway. Future studies should focus on an extended validation, establishing MCID and studying responsiveness in order to insure CPAx-NOR as a clinically important and knowledge based robust tool for physiotherapists working in the intensive care unit with critically ill patients.


SLE patients had higher rates of moderate-to-severe OSA (p = 0.04), PSQI (p = 0.001), and FACIT scores (p = 0.0008). Multivariate analysis revealed that the SDI was associated with OSA (p = 0.03). There was a positive association between SLEDAI-2K and moderate-to-severe OSA (p = 0.03). Patients with SLE had an increased prevalence of OSA and poorer quality of sleep compared to healthy controls. Our findings suggest that active disease and accumulated damage may be associated with OSA. These findings highlight the importance of identifying the presence of OSA in patients with SLE.Marked fatigue is common in patients with systemic lupus erythematosus (SLE). This study aimed to assess the association of sleep disorders, including obstructive sleep apnea (OSA), with SLE. Forty-two consecutive patients with SLE and 20 healthy controls were recruited and underwent a one-night ambulatory sleep examination. They completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI) and Functional Assessment of Chronic Illness Therapy (FACIT). SLE disease activity and damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI). A significantly increased apnea/hypopnea index was noted in the SLE group compared to healthy controls ( Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that can affect various organ systems in the body and is thought to have both genetic and environmental factors. SLE primarily affects women of childbearing age. Its symptoms are not specific and can vary widely, possibly including arthralgias and arthritis, skin rashes, pleuritis and pericarditis, and renal and neurologic involvement .Fatigue is a common and debilitating symptom experienced by patients with SLE. It is reported to be present in up to 90% of patients and able to have a significant impact on the quality of life . FatigueSome studies suggested that sleep disturbances correlate with SLE disease activity and the presence of additional symptoms such as pain and steroid use . ImportaIndividuals with SLE, as well as other rheumatological diseases, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, are known to experience sleep disturbances, which can have a significant impact on their overall health and quality of life ,10,11,12Obstructive sleep apnea (OSA) is an important sleep disorder that has been reported in individuals with rheumatological diseases, including SLE ,17,18. OPrevious studies that evaluated sleep disturbances in patients with SLE have mainly been based on subjective measures, such as sleep questionnaires, which can be prone to bias and inaccuracies. Few studies have used objective measures, such as polysomnography (PSG), which is considered the gold standard sleep examination. Multiple parameters are assessed during PSG, including an encephalogram, eye movements, an electrocardiogram, oxygen saturation, breathing rate and patterns, and limb movement ,20,21,22Several studies employing PSG have found that patients with SLE have a higher occurrence of sleep disorders compared to healthy controls. Flores et al. assessed 14 patients with SLE and 11 healthy controls and found an increased presence of sleep disorders . Iaboni The association between OSA and a higher incidence of autoimmunity is complex. A possible explanation linking OSA and autoimmunity might be the presence of a chronic inflammatory state caused by repeated episodes of interrupted breathing and desaturation during sleep. Apneas causing chronic intermittent hypoxia may activate an inflammatory cascade leading to elevated cytokine levels, such as tumor necrosis factor alpha, interleukin 1β, interleukin 6, and interleukin 8, possibly contributing to autoimmunity. Alternatively, the chronic inflammatory state in an autoimmune disease might have a role in the excess risk of OSA ,27.In this study, we sought to investigate the relationship between OSA and SLE. We aimed to assess whether individuals with SLE have a higher prevalence of sleep disorders, specifically OSA, compared to a healthy control population. We also aimed to explore any potential predictors for OSA, such as disease activity, damage accumulation, and medications. Possible interactions with additional clinical features frequently observed in patients with SLE, such as fatigue, secondary fibromyalgia, and depression, were assessed as well.This is a single-center, cross-sectional, controlled study. The study group included consecutive patients with SLE at the Rheumatology Clinic of the Tel Aviv Sourasky Medical Center (TASMC), a tertiary-level hospital in Israel, between August 2020 and December 2020.Consecutive patients who met the American College of Rheumatology (ACR) revised criteria for SLE and were 18 years of age or older were invited to participate in the study. Healthy controls were recruited from the Department of Rheumatology department employees and relatives. Healthy controls were matched to the study group based on sex, age, and body mass index (BMI). Women who were pregnant or had given birth in the year prior to enrollment were excluded, as were individuals with a known sleep disorder and those unable to provide informed consent. All of the patients and controls provided informed consent to participate, and the study was approved by the institutional review board .All study participants were asked to complete a series of validated questionnaires in order to assess various aspects of sleep and health-related quality of life. These questionnaires were selected based on their established reliability and validity in measuring the specific aspects of sleep and health that the study aimed to investigate.The Epworth Sleepiness Scale (ESS) is a widely used questionnaire that assesses the general level of daytime sleepiness. The ESS questionnaire score ranges from 0 to 24, with higher scores indicating increased daytime sleepiness and a score above 10 considered to reflect excessive sleepiness .The Pittsburgh Sleep Quality Index (PSQI) is a widely used self-rated questionnaire for assessing sleep quality and sleep disturbances. The PSQI questionnaire score ranges from 0 to 21, and a score above 5 indicates poor sleep quality .The Functional Assessment of Chronic Illness Therapy (FACIT) measures fatigue on a scale of 0–52, with higher scores indicating increased levels of fatigue .The Symptoms Severity Scale (SSS) and the Widespread Pain Index (WPI) questionnaire, which measures the number of painful body regions, are used to assess the presence of fibromyalgia. A combined SSS of ≥5 and a WPI of ≥7 is suggestive of fibromyalgia, and higher scores might be indicative of increased symptomatology of fibromyalgia .The Beck Depression Inventory (BDI) is a widely used 21-item self-reporting questionnaire that evaluates the severity of depression in both normal and psychiatric populations, with higher scores indicating worse depression .The assessment of SLE disease activity and damage accumulation in the current study group was performed with validated scoring systems, including the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) ,34.Additional clinical data, including BMI, medication usage, and laboratory test results, were collected from the medical records of the study participants.Each study participant was given the “WatchPAT 200”, a home sleep testing device, for a single night of testing. This device is a validated tool for the diagnosis of sleep disorders, including OSA, whose accuracy and reliability were demonstrated in previous studies . The devOxygen saturation levels: measured by pulse oximetry;Respiratory events, including:Some of the key parameters included in the report are:AHI—Apnea Hypopnea Index—a measure of the number of apnea events defined as a complete cessation of breathing for more than ten seconds, and hypopneas, which is a partial cessation of breathing leading to desaturation per hour of sleep ;RDI—Respiratory Disturbance Index—a wider definition than AHI that includes apneas, hypopneas, and respiratory effort-related arousal (RERA), which is a limitation in breathing that results in increased respiratory effort and culminates in arousal from sleep;ODI—Oxygen Desaturation Index—defined as the number of episodes of oxygen desaturation in one hour of sleep, with oxygen desaturation considered a decrease in blood oxygen saturation to lower than 3% below baseline ,40.Sleep/wake status: indication of whether the patient was awake or asleep during various periods of the night;The number of arousals: measurement of the number of times the patient had woken up or became partially awake during the night;Sleep efficiency: measurement of the percentage of time the patient spent asleep during the night;Actigraphy information: estimation of wakefulness and sleep according to the patient’s motion as measured by an accelerometer located on the patient’s wrist ;Sleep stages: detection and determination of light sleep, deep sleep, and rapid eye movement (REM) sleep stages.The severity of OSA is commonly measured by the AHI. An AHI of up to 4.9 per hour is considered normal. Mild OSA is defined as an AHI of 5 to 14.9, moderate OSA as an AHI of 15 to 29.9, and severe OSA as an AHI above 30 . Sleep eAll participants in the study were informed of their results and were referred to a sleep clinic for further evaluation if needed.p-value of less than 0.05 was considered statistically significant.The statistical analysis for this study was conducted using R software version 4.0.2. The sample size was determined by considering a significance level of 0.05, a power of 0.8, and an expected effect of 0.4. The ratio between the study group and the comparison group was set to 2:1. Continuous data were reported using means and standard deviations, and they were compared between groups by the Mann–Whitney test. Categorical data were reported as frequency and percentage, and they were compared between the groups by the Fisher exact test. Both continuous and categorical data were also analyzed with the use of linear and logistic regression. All statistical tests were two-sided, and a p = 0.12; mean age 39.8 ± 10.8 vs. 38.1 ± 7.9 years, p = 0.49; and BMI 23.7 ± 4.4 vs. 22.8 ± 2.1, p = 0.51, respectively).The study cohort consisted of 42 patients with SLE and 20 healthy controls. The characteristics of the patients with SLE are described in The study group reported worse sleep quality compared to the control group, as shown by higher scores on the PSQI questionnaire, increased fatigue as reflected by higher scores on the FACIT questionnaire, and more severe symptoms of fibromyalgia, as indicated by significantly higher scores on the WPI and SSS questionnaires. However, there were no group differences in the level of daytime sleepiness as measured by the ESS questionnaire .p = 0.01 and 83.4 ± 6.1 vs. 87.2 ± 4.2, p = 0.03, respectively). The SLE group had higher AHI, ODI, and RDI than the control group . It alsop = 0.045). Although the difference did not reach a level of significance, the patients with SLE had a greater number of periods of light sleep, less deep sleep, and less REM sleep compared to the control group. There were no group differences in the measured saturation indexes, including average saturation and minimal saturation levels.The percentage of moderate-to-severe OSA (AHI ≥ 15) was significantly higher among patients with SLE compared with controls . The results of the multivariate analysis are shown in A multivariate analysis with AHI as a dependent variable and significant or marginally significant univariate predictors as covariates  revealedp = 0.03).In a univariate logistic regression analysis, with moderate-severe OSA (AHI ≥ 15) as a dependent variable and all other variables as predictors, SLEDAI-2K was found to be positively associated with an AHI of ≥15 (No significant correlation was found between the AHI and the following parameters: sex, age, SLE disease duration, the presence of nephritis, the presence of anti-phospholipid antibodies, or specific medications, including corticosteroids. Interestingly, three patients had a history of neuropsychiatric SLE, and two of them had significant OSA with AHIs of 26.8 and 18.2. The subjective scores of the PSQI, ESS, FACIT, WPI, SSS, and Beck questionnaires were not found to correlate with an elevated AHI.This study aimed to objectively evaluate the presence of sleep-disordered breathing in patients with SLE by means of a sleep examination device. We also subjectively assessed the quality of sleep, daytime sleepiness, symptomatology of pain, fibromyalgia, fatigue, and depression. The results revealed an increased prevalence of OSA in patients with SLE compared to healthy controls. OSA severity, as assessed by measuring AHI, RDI, and ODI, was greater in patients with SLE, who had lower sleep efficiency scores and an increased number of arousals. Our evaluation of an association between OSA and other factors demonstrated that an elevated BMI, as well as SLE-related damage accumulation, as reflected by the SDI, were associated with a higher AHI. Increased SLEDAI-2K scores emerged as being associated with moderate-to-severe OSA.Iaboni et al. conducted a study on a cohort of 35 patients with SLE, aiming to investigate the presence of sleep-related disorders. Those authors used PSG to evaluate the patients’ AHIs and found that 57% of the patients had an AHI > 5, which is indicative of sleep-related breathing disorders, such as OSA. We found a slightly higher OSA rate among patients with SLE, with 68% of patients having an AHI greater than 5. A more severe form of OSA, with an AHI equal to or greater than 10, was reported by Iaboni et al. in 26% of their cohort, similar to our finding of an AHI ≥ 15 in 23.6% of the patients with SLE . In our The findings of this current study demonstrate comparable rates of OSA in SLE patients to previously reported data on rheumatoid arthritis patients; in their PSG-based study, Wali et al. found an estimated OSA prevalence of 58.1%, with a prevalence of moderate-to-severe OSA of 22.9% . In contWe used the PSQI and the FACIT questionnaires to assess sleep quality and fatigue. The PSQI and FACIT questionnaire scores were worse in patients with SLE compared to the control group, reflecting the poorer quality of sleep and increased fatigue. There was no association with OSA contrary to our expectations. One possible reason for this could be the relatively small sample size of the study, which may preclude the detection of any significant associations. Moreover, PSQI and FACIT questionnaire scores reflect several factors, and they can be increased due to reasons other than OSA.OSA has been well established as a risk factor for a wide range of cardiovascular diseases, including hypertension, coronary artery disease, arrhythmias, heart failure, and stroke. The association is thought to be due to the repetitive apnea events that expose the cardiovascular system to cycles of hypoxia, increase sympathetic activity, raise blood pressure, heart rate, and myocardial wall stress, provoke oxidative stress and systemic inflammation, cause endothelial dysfunction, and lead to other changes in the cardiovascular system . Given tInterestingly, our results have shown a significant association between SLE disease activity and damage accumulation with an increased risk of OSA. This finding is in line with previous reports in the literature ,22. HoweWe believe that our findings of an association between OSA and SLE add important information to the current knowledge in several aspects. Increased awareness of the presence of OSA in patients with SLE is warranted in view of similar clinical manifestations shared by active SLE and OSA, such as fatigue, pain, and increased inflammatory markers. Thus, the detection of OSA may possibly prevent unnecessary treatment aimed at the management of a suspected flare of SLE. Moreover, the diagnosis and management of OSA may improve the quality of life of SLE patients. Increased awareness and early OSA detection are in accordance with previous studies assessing sleep disturbances in rheumatoid arthritis patients, as several studies have recommended considering OSA screening in patients with rheumatic diseases and referral to a sleep disorders clinic when needed ,44.Future studies addressing the optimal OSA management in these patients and its impact on SLE disease activity and fatigue are needed. Additionally, the increased cardiovascular risk present in both SLE and OSA emphasizes the importance of recognizing OSA in patients with SLE and possibly including OSA as an SLE comorbidity. Importantly, none of the sleep questionnaires predicted the presence of OSA; therefore, we suggest that physicians who treat SLE patients should consider performing an objective sleep assessment screening with a simple home device to allow early detection and enhanced management.A limitation of our study was the use of the WatchPAT 200 device and not polysomnography, which is considered the gold standard for the assessment of sleep-disordered breathing and sleep architecture. However, since several studies have shown the validity of a diagnosis of OSA with the WatchPAT 200 device, we believe that its accuracy is appropriate for the purposes of this study . In addiOur study has several notable strengths that contribute to the current understanding of objective sleep disorder evaluation in patients with SLE. One major strength is the relatively large cohort size compared to those of previous studies, thereby allowing meaningful and comprehensive data analyses. This is particularly important given the limited body of research in this field. Another strength of our study is the use of a home sleep testing device, which may provide a simple and easily accessible screening test for OSA in patients with SLE.The patients with SLE had an increased occurrence of OSA and poorer quality of sleep compared to healthy controls. Our findings suggest an association between OSA, SLE damage accumulation, and disease activity. The increased prevalence and severity of OSA in patients with SLE suggest that evaluation for this condition is important for patient management. In view of the poor correlation between subjective tools and objective findings of OSA in patients with SLE, we believe that objective screening of sleep assessment with a simple home device may allow early detection and management. Further larger studies are warranted to support our findings.


Hand movements were fastest and smoothest for the reach-to-eat task, and least straight for the bilateral reaching task. Hand movements were also straighter in the object transport phases than the prehension and withdrawal phases. These results indicate that children with typical development change their timing and coordination of reach based on the task they are performing. These results can inform the design of rehabilitation interventions targeting arm and hand function.Understanding whether and how children with typical development adapt their reaches for different functional tasks could inform a more targeted design of rehabilitation interventions to improve upper extremity function in children with motor disabilities. This prospective study compares timing and coordination of a reach-to-drink, reach-to-eat, and a bilateral reaching task in typically developing school-aged children. Average speed, straightness, and smoothness of hand movements were measured in a convenience sample of 71 children, mean age 8.77 ± 0.48 years. Linear mixed models for repeated measures compared the variables by task, phases of the reach, task x phase interactions, and dominant versus non-dominant hands. There were significant main effects for task and phase, significant task x phase interactions ( Functional reach is essential for children to complete tasks like feeding, self-care, school participation, and leisure activities. Intentional reach is essential for driving other areas of development, such as cognitive and fine motor, in young children. Intentional reach-to-grasp skills emerge between 4–6 months of age in typical development as infants begin reaching for toys ,2 and reWhen quantifying upper extremity movement, a reach is typically defined as a movement towards an object, ending when the hand contacts the object. Straightness and smoothness are variables that quantify the coordination of a reach . StraighIn the past decade, a few studies have applied 3D kinematics to objectively measure reach in a functional task, such as reaching for food to eat or a cup to drink ,19,20,21We adapted the set-up, procedure, and movement sequence from the Reach and Grasp Cycle  to threeParticipants were 71 typically developing children , 7–10 years old (mean 8.77 ± 0.48), with 10 left-hand dominant and 61 right-hand dominant, as determined by the child’s preferred writing hand. Participants were a convenience sample of children recruited from low-resource neighborhoods in Central Ohio, USA. Children were excluded if they were unable to follow instructions given in English, or if they had a motor impairment that prevented them from being able to perform the reach and grasp tasks. Given the exploratory nature of this investigation, the sample size was determined based on recommendations for normative datasets in pediatric populations .This study was approved by the Institutional Review Board at The Ohio State University (2017B0110). Parents or legal guardians provided informed consent, and all child participants provided verbal assent.Participants were assessed at the Pediatric and Rehabilitation (PEARL) Laboratory at The Ohio State University. Retroreflective markers (8 mm) were placed on the children on their sternum, bilateral acromia, lateral epicondyles, radial and ulnar styloid processes, and heads of the third metacarpals. Markers were also placed on the 4 corners of the table, the back of the chair, and the objects that the children were reaching for . ChildrePrehension: The movement begins with the hand(s) in the marked start position and ends when the hand(s) contact the object.Transport 1: The movement begins with the hand(s) lifting the object from the table and ends with the object contacting the mouth or chin.Transport 2: The movement begins with the object leaving the mouth or chin and ends with the object contacting the table at its marked position.Withdrawal: The movement begins with the hand(s) releasing the object and ends with the hands contacting the marked start position on the table.Phases of the movement  were visStraightness (ratio): ratio of the hand path length  to the movement length (difference between start- and end-points of the movement), with a value closer to one indicating a straighter movement.Smoothness (count): measured as the number of velocity peaks in a movement, with fewer velocity peaks indicating a smoother movement.Average speed (mm/s): calculated at each position of the marker using a 4-point central difference numerical differentiation.A custom MATLAB script was used to calculate spatial and temporal variables of reach for each phase of the Reach and Grasp Cycle. The variables were calculated based on the hand position, which was defined as the center point between the markers on the 3rd metacarpal, ulnar styloid process, and radial styloid process. The spatial and temporal variables were defined as:A generalized linear mixed model for repeated measures for Gaussian distributions was applied using the SAS GLIMMIX procedure to compare each kinematic variable by task, phase, task x phase interactions, and dominant versus non-dominant hand for unilateral tasks (reach-to-drink and reach-to-eat). The model was created using a restricted maximum likelihood estimation technique, and the Kenward–Roger degrees of freedom method and fixed effects standard error adjustment. The alpha level was set to α = 0.05. This model was chosen because it accounts for correlations between dependent variables, as well as a response that is not normally distributed. This is the case for straightness ratio and smoothness, for which values can only be >1. Least squared means were calculated for post hoc testing of task x phase interactions. The Bonferroni correction was applied for post hoc comparisons, setting α = 0.0005.Means and standard deviation for kinematic variables of interest by task, type, and phase were calculated .p < 0.0001), phase of task (F(3) = 801.98, p < 0.0001), type x phase interaction (F(6) = 12.59, p < 0.0001), and hand dominance (F(1) = 13.05, p = 0.0003), with straighter movement on the dominant side (p < 0.0005) for all comparisons, except: the prehension, transport 1, and transport 2 phases between the reach-to-drink versus the reach-to-eat tasks; the transport 1 and withdrawal phases between the bilateral versus reach-to-eat tasks; and within the reach-to-drink and reach-to-eat tasks, the transport 1 versus transport 2 phases; these comparisons showed no significant differences (There were significant main effects of straightness ratio for type of task (F(2) = 107.26, ant side a. Post hferences .p < 0.0001). Main effects for phase, type x phase interaction, and dominant versus non-dominant hand were not significant (p < 0.0005). The reaching movement for transport 2 was also significantly less smooth than withdrawal for the bilateral task (p = 0.0005). All other comparisons were not significantly different (There was a significant main effect of smoothness for type of task (F(2) = 21.06, nificant b. Post hifferent .p < 0.0001), phase of task (F(3) = 64.87, p < 0.0001), and type x phase interaction (F(6) = 25.38, p < 0.0001), but not for dominant versus non-dominant hand (There were significant main effects of speed for type of task (F(2) = 176.31, ant hand c. Post hant hand . The folThe objective of this study was to evaluate the coordination and timing of reaching movements in typically developing school-aged children when performing functional reaching tasks, applying the Reach and Grasp Cycle . We wereResearch in adults has demonstrated changes in reaching behaviors with different task constraints. For example, when adults reach for an empty cup of water, their movements are significantly faster than reaches toward a full cup of water ,27. It iChanges in object size also affects reach speed in adults performing a reach and grasp task, with slower reaches toward smaller objects ,28. In cThe differences between phases of the Reach and Grasp Cycle in this study were partially consistent with our hypotheses and might indicate that familiarity with specific movements has a strong influence on timing and coordination of the reach. For example, reaches were fastest and straightest in the object transport phases, which is consistent with previous research and our predictions ,32. It iLast, we found that the dominant hand movements were significantly straighter than the non-dominant hand movements, as we expected. Contrary to our hypothesis, and contrary to studies in adults, we found no differences in speed or smoothness of movement between the dominant and non-dominant hands ,35. GiveKinematic measurement of coordination and timing of reaching movement in functional reaching tasks is a promising objective, quantitative measure of upper extremity function in a pediatric population, as it can provide detailed information about movement timing and coordination. Results from this study provide insight into how task familiarity, constraints, and motivation might impact the coordination and timing of reach in typically developing children, and the role that motor control systems might play in those differences. This information could be used to further refine clinical rehabilitation approaches for pediatric populations with upper extremity motor impairment. Application to clinical practice could include: (1) routinely using kinematics as an outcome measure to track progress; (2) using information about timing and coordination and task constraints to target improvements in skills that are inherent to participation in daily life activities. Some examples of precise treatment planning based on the results of this study would be to choose larger target objects or more motivating tasks to train increased reach speed, and to use tasks that require feedback control, such as transporting a cup of water, to train straightness and smoothness. Future research could further investigate the impact of specific task characteristics on kinematics in a reach and grasp task in children. An important next step would be to determine a minimal clinically important difference for average speed, smoothness, and straightness of hand movement in the Reach and Grasp Cycle. In the future, data could be used as a normative comparison for age-matched children with motor disability to measure improvements in everyday reaching function with targeted upper extremity therapy interventions.


Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes. SLE is a heterogenous disease, and the pattern of organ involvement and response to treatment differs significantly among patients. Novel biological markers are necessary to assess the extent of organ involvement and predict treatment response in SLE. Lysophosphatidic acid is a lysophospholipid involved in various biological processes, and autotaxin (ATX), which catalyzes the production of lysophosphatidic acid in the extracellular space, has gained attention in various diseases as a potential biomarker. The concentration of ATX is increased in the serum and urine of patients with SLE and lupus nephritis. Recent evidence suggests that ATX produced by plasmacytoid dendritic cells may play an important role in the immune system and pathogenesis of SLE. Furthermore, the production of ATX is associated with type I interferons, a key cytokine in SLE pathogenesis, and ATX may be a potential biomarker and key molecule in SLE. SLE is characterized by the production of various autoantibodies, such as anti-nuclear and anti-dsDNA antibodies, and deposition of immune complexes. SLE can affect various organs including the skin, heart, kidneys, and central nervous system. Current treatment for SLE includes antimalarials, corticosteroids, immunosuppressants, and biologics; however, it is far from perfect, and many patients do not achieve an adequate response or experience side effects.SLE is a heterogenous disease and the pattern of organ involvement and response to treatment differs significantly among patients. Various biological markers, such as complement levels, anti-dsDNA antibody titers, and urine tests, are used in clinical settings to assess disease activity of SLE . DiffereRecently, lysophosphatidic acid (LPA) and autotaxin (ATX), an enzyme that catalyzes the production of LPA, have recently gained attention in many fields. Many ATX inhibitors are being developed as potential therapeutic agents for cancer and idiopathic pulmonary fibrosis, and there are currently several clinical trials underway –11. Rece2.Via signaling through G protein-coupled receptors, lysophospholipids play an important role in regulating cell function. LPA and sphingosine-1-phosphate are among the most well-studied lysophospholipids involved in cell signaling.Lysophospholipids are lipids with one carbon chain and a polar head group. They are classified into two groups, lysoglycerophospholipids and lysosphingolipids. LPA transduces signals through LPA receptors (LPAR1–6) and is involved in various biological processes, including cell migration, proliferation, and aggregation of platelets . Under p3.in vitro. Therefore, to accurately measure the concentration of LPA in clinical specimens, samples must be handled carefully to avoid the production and degradation of LPA  and is involved in the induction of inflammation after AMI . LPA is 4.4.ATX is also implicated in fibrosis, and ATX levels are increased in lungs of patients with idiopathic pulmonary fibrosis (IPF). The ATX-LPA axis may be a potential therapeutic target in IPF, and clinical trials of ziritaxestat, an ATX inhibitor, are being conducted , 36. The4.5.The ATX-LPA axis is also involved in pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA) . TNF-α, 5.ATX is also expressed by cells of the immune system. In the immune system, ATX and LPA exert various effects––regulating the development, function, and migration of various immune cells––and there is growing evidence that ATX may also play a role in the pathogenesis of SLE. In the following section we will discuss the role of ATX in the immune system and in SLE.5.1.ENPP2, which encodes ATX, is highest in pDCs (Production of type I interferons by plasmacytoid dendritic cells (pDCs) plays a central role in the pathogenesis of SLE –44. Type in pDCs , 50, andFirst, type I interferons are involved in the production of ATX. The induction of ATX by interferons has been reported in various cell types, including THP-1 cells, human monocyte-derived DCs, and human monocytes. The production of type I interferons upon TLR stimulation plays a critical role in the induction of ATX, and blocking interferons inhibits this process .ENPP2 is increased in pDCs of patients with SLE, especially those with high disease activity  enriched in genes involved with interferon signaling (RASGRP3, whose expression is increased in pDCs of patients with the SLE risk allele at rs13425999. Although it is not clear whether there is a direct causal relationship between the expression of those genes with ATX, it suggests that ATX may be involved in the connection between genetic risk factors of SLE and disease pathogenesis (Other studies have suggested an interaction between the ATX-LPA axis and pDCs in SLE. In our recent weighted gene co-expression network analysis  of transignaling . Furtherogenesis .LPAR1 gene, is associated with anti-Ro and anti-Sm antibody positivity, which are known to be associated with high serum levels of interferon α. Among patients with anti-Ro and anti-Sm antibody positivity, the T allele at rs10980684 was associated with high serum levels of interferon α (Furthermore, among patients with SLE, rs10980684, an intron SNP located in the rferon α .Together, these studies suggest that there is an association of the ATX-LPA axis in pDCs with type I interferons and that genetic factors of SLE play a possible role in this process.5.2.Other DC subsets and macrophages are also involved in the pathogenesis of SLE , 54, and5.3.In lymph nodes, high endothelial venules express ATX at high levels . Activatin vivo studies suggest that B cells may also be involved in production of ATX during inflammation (via signaling through LPAR5, LPA has been reported to inhibit B cell receptor signaling (The ATX-LPA axis is also important for B cells. Some ammation . Furtherignaling .LPAR3 has been reported to be upregulated in CD4+ and CD8+ T cells of patients with SLE (via GPCRs” (Various abnormalities involving the ATX-LPA axis have been reported in lymphocytes of patients with SLE . LPAR3 hwith SLE . In addia GPCRs” .5.4.Cardiovascular diseases are a major cause of mortality among patients with SLE in many cohorts , 69. SteThe ATX-LPA axis is also involved in neuropathic pain , 73. Amo6.Reflecting the potential role of the ATX-LPA axis in SLE pathogenesis, various studies have addressed the potential role of ATX as a biological marker in SLE .6.1.ENPP2 mRNA expression levels observed in patients with SLE, the concentration of ATX in the serum is increased in patients with active, untreated SLE compared with that in healthy controls (Consistent with the increase in controls . It has controls . The levcontrols , and ATXcontrols . Therefo6.2.d-glucosaminidase, and α1-microglobulin in the urine (The concentration of ATX in urine shows correlation with various parameters associated with kidney injury, such as the concentration of proteins, N-acetyl-β-he urine . Urinaryhe urine . The conhe urine  and actihe urine . Therefo7.SLE is a heterogenous disease, and to provide better care for patients with SLE, there is an eminent for biological markers to assess the pattern and extent of organ involvement and to predict treatment response. The ATX-LPA axis is involved in various biological processes, including immune responses. Recent evidence suggests that the ATX-LPA axis is associated with the abnormal production of type I interferons in pDCs that characterizes SLE , 51; thuENPP2 is high in pDCs of patients with SLE, especially those with high disease activity (In the immune system, expression of ATX is high in pDCs and induced by type I interferons . ATX mayactivity , and ATXactivity  and lupuactivity . The conactivity . Althougactivity , and novactivity . ATX mayactivity , which mactivity . More stIn conclusion, the ATX-LPA axis plays a critical role in the pathogenesis of SLE and is associated with the production of interferons by pDCs. ATX may serve as a potential marker for assessing disease activity, the pattern of organ involvement, and predicting treatment responses. Thus, further investigation of the role of ATX in these aspects are warranted.YT, HS, TS, and KF contributed to the literature review and drafting of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hemodialysis is life-saving and life-altering, affecting patients' quality of life. The management of dialysis patients often focuses on renal replacement therapy to improve clinical outcomes and remove excess fluid; however, the patient's quality of life is often not factored in.  This study aimed to explore the factors affecting the quality of life of patients on dialysis in Palestine using the Kidney Disease Quality of Life (KDQOL-SFTM) questionnaire.  A multicenter cross-sectional observational study was conducted at multiple dialysis centers in Palestine, including 271 participants receiving renal replacement therapy. Demographics, socioeconomic, and disease status data were collected. The Arabic version of KDQOL-SFTM was used to assess dialysis patient quality of life. Statistical analysis was performed using SPSS to find correlations among patient factors and the questionnaire's three main domains, the kidney disease component summaries (KDCS), mental component summaries (MCS), and physical component summaries (PCS). r = 0.634, P-value <0.001), PCS and KDCS , as well as MCS and PCS .  Mean KDCS, MCS, and PCS scores were 59.86, 47.10, and 41.15, respectively. KDC scores were lower among participants aged 40 years or older, with lower incomes, and with diabetes. PCS and MCS scores were lower among patients aged >40, less educated, and lower-income participants. There was a positive correlation between MCS and KDCS ( In this study, the KDQOL-SFTM questionnaire revealed lower PCS scores among hemodialysis patients in Palestine. Furthermore, the three domains of the questionnaire were adversely affected by patient income and education status. In addition, physical role, work status, and emotional role showed the lowest scores among the three main domains. Therefore, continuous assessment of patients' quality of life during their journey of hemodialysis using the KDQOL-SFTM along with the clinical assessment will allow the healthcare professionals to provide interventions to optimize their care. Chronic kidney disease affects more than 10% of the world's population, associated with poor quality of life (QOL) and increased healthcare costs , 3. HemoAccording to the World Health Organization Quality of Life (WHOQOL) assessment, QOL is defined as “individual's perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns.” Therefore, the QOL depends on the individual's disease state and physical, mental, and social wellness .HD patients experience poor quality of life (QOL) during different stages of their medical condition . This maSeveral studies have been conducted to assess QOL in patients undergoing dialysis. A regional study performed in Tabriz, Iran, showed that parameters such as economic, educational, and occupational status significantly affect the QOL of HD patients. The KDQOL-SF™ was used to assess the QOL in HD patients. Poor QOL was also linked greatly to sleep disturbances. The results showed that poor sleep quality and insomnia are prevalent in HD patients . AnotherIn this study, the KDQOL-SF™ was utilized for the first time in Palestine to assess the QOL of patients with chronic kidney disease on hemodialysis; furthermore, parameters that changed over the years and have not been studied previously in Palestine, such as government support and the availability of dialysis centers, are included in this study.This multicenter cross-sectional observational study was conducted at different HD centers in Palestine. These included the Palestine Medical Complex , Al Hussein Hospital , Thabit Hospital (Tulkarm), Yasser Arafat Hospital , and Alia Hospital (Hebron).According to the Palestinian Ministry of Health's annual report for 2021, 1570 HD patients are being treated across the West Bank . The RaoThe study included HM patients who were 18 years and older who receive hemodialysis on regular bases and have received HD for at least one month with a minimum of one session per week. Patients with a physical disability (wheel chaired), patients with an altered level of consciousness, patients on peritoneal dialysis, very sick patients, and those unable to understand either English or Arabic or have incomplete questionnaires were excluded from the study.The Kidney Disease Quality of Life (KDQOL-SF™) instrument was used in this research . The KDQAs described in the supplementary materials, the questionnaire consisted of 44 questions organized into six sections in the following order: patients' demographic information, overall health, information regarding the patient's kidney disease, the effects of kidney disease on the patient's daily life, and the patient's satisfaction with care. .The demographic information section included questions regarding age, sex, marital status, accessibility to a dialysis center, type of insurance, income, employment status, patients' medical history, and other questions regarding HD. Next, the overall health section included the effects of HD on the physical and mental health of the patient. Next, the information regarding the kidney disease section involved questions about the burden of the patient's kidney disease, type of access, cognitive function, and complications associated with HD. The following section included questions about the effects of kidney disease on the patient's daily life, sexual function, sleep, and quality of social interaction. Finally, the patient's satisfaction with care section involved questions regarding the dialysis staff's encouragement and concern about the patient's satisfaction.The questionnaire covered 19 aspects. These aspects are grouped into three main domains . These dt-tests and one-way ANOVA were conducted to compare the means for normally distributed variables. A P-value of 0.05 or less was considered to be statistically significant. In addition, a posthoc test was conducted for the sig. means to determine the association level. Finally, the Pearson Correlation test was performed to assess the association between the three main domains. Analysis was performed using the SPSS software program, version 22.The data from the different domains were recoded into numeric values of 0 and 100. A value of 0 represents the lowest score which indicates the worst QOL, and a value of 100 represents the highest score which indicates the best QOL. After the scoring process, each scale item was averaged to obtain a scale score. Finally, the mean score for each of the three main domains was calculated . InternaThe Palestinian Ministry of Health provided permission to conduct this study in dialysis units at various centers. The IRB committee of Birzeit University Faculty of Pharmacy, Nursing, and Health Professions granted ethical approval (reference number BZU-PNH-2120). The participants were informed about the study and completed a consent form before participating; consequently, informed consent was obtained from each participant. All methods were performed following the Declaration of Helsinki.A total of 348 questionnaires were distributed to HD patients, of which 271 completed the questionnaire (response rate of 78%) since some patients declined to participate due to fatigue and discomfort. Of the total, 184 (67.9%) were aged 40 years or older, and 149 (55%) of the patients were males. Married patients represented 207 (76.4%) of the total. About 122 (45%) of patients had an income of 530–1429 USD, and patients with Bachelor's degrees or higher represented 99 (36.5%) of the total. The main common cause of renal failure was diabetic nephropathy 94 (34.7%) and hypertension 65 (24%). In addition, 106 (39.1%) had been dialyzed for 2-3 years. 180 (66.4%) patients were reported to have dialysis sessions 3 times or more weekly .In terms of the participant's overall health this year (2022) as compared to the previous year (2021), 41% of patients rated their health to be “poor,” while only 13.3% of them rated their general health to be “excellent” . ReferriP-value <0.001) than younger participants. The scores were 66.47 ± 11.59, 53.72 ± 19.80, and 48.63 ± 20.38, respectively. Participants with bachelor's degree or higher had significantly higher mean scores regarding MCS  and PCS . However, the P-value of the KDCS mean score was 0.161, which indicates that educational level had no significant effect on the KDCS score. A total income of 529 USD or lower showed significantly lower mean scores regarding the KDCS (55.60 ± 11.44), MCS (41.33 ± 17.83), and PCS (33.73 ± 18.22) scales upon participants. The P-values for the MCS and the PCS mean scores were <0.001, while the KDCS's P-values were 0.015. The PCS and KDCS scores were significantly higher for nondiabetic patients. The values were  and , respectively. On the other hand, the P-value of the MCS score was 0.153, which shows no significant association with the diabetic state among participants. There was no significant effect on scores regarding gender, marital status, duration of dialysis, frequency of dialysis sessions, and access site.The impact of age, gender, marital status, educational level, income, cause of kidney disease, duration of dialysis, frequency of dialysis sessions, and site access on the three main domains  is shown . ParticiThis multicenter observational study assessed the quality of life of hemodialysis patients using the KDQOL-SF questionnaire. The effect of patient demographics, socioeconomic status, finances, education, and comorbidities was evaluated on the questionnaire's three domains. When the scores in the three domains were compared in this study, the lowest score (41.15) was found in the PCS domain, followed by the MCS domain (47.10), while the KDCS domain had the highest score (59.86). Furthermore, the lowest scores were found in physical role (27.58), work status (34.87), and emotional role (37.39). This could be attributed to unemployment, comorbidities, and weekly dialysis sessions. The same results are also seen in a study conducted in Saudi Arabia in 2011 . On the Participants with a higher level of education showed a significant positive association in the PCS and MCS domains because they have better knowledge of their chronic disease, can cope with it, and thus receive the best possible therapy they can manage. The higher educational level did not significantly affect the KDCS score, which can be attributed to Palestine's lack of jobs and unemployment among all segments of society. The lower income affects the accessibility to the dialysis center and the ability to buy the required medications. Khatib et al. showed in a study conducted in Palestine that a higher educational level is associated with better quality of life. Patients with a higher level of education can better understand their diseases, their complications, and the need to adhere to dialysis sessions . AnotherIt is important to note that a significant proportion of the participants did not have sufficient financial stability and suffered a loss of income during the hemodialysis period. The MCS, PCS, and KDCS scores were significantly lower than those in patients with financial stability, most likely due to life stress associated with decreased financial stability. As a result, patients' quality of life (QOL) deteriorated. Previous studies have also shown that lower-income patients had lower scores for PCS, MCS, and KDCS. The results of this study are consistent with other studies in Romania, which found an association between low economic status and poor QOL .Age significantly affected participants' quality of life. Patients aged 40 years or older had significantly lower PCS, MCS, and KDCS scores because they had more comorbidities and poorer overall health. These findings were also observed in several other studies. For example, a study conducted in Palestine in 2016, which looked at factors affecting patients' quality of life at HD, found that age was one of the most important sociodemographic factors associated with HD-related quality of life .The PCS and KDCS scores of diabetes mellitus patients were significantly lower than those of nondiabetics, resulting in poorer quality of life in diabetic participants. As mentioned earlier, diabetic nephropathy was the participants' most common cause of renal failure. Therefore, they experience more symptoms of renal disease. In addition, diabetic peripheral neuropathy is a common complication in DM patients. As a result, it affects the physical functioning of these participants by causing significant morbidity  . HoweverThis study showed no statistically significant difference between women and men in the PCS, MCS, and KDCS. Some studies had controversial results. A study published in Saudi Arabia had different results in which male patients had higher scores than females. The author explained that more males than females in their sample were married and earned good income . AnotherIn this study, no significant statistical difference was observed in access sites with respect to the three domains. A 2018 Pennsylvania article examined the associations between hemodialysis access type and satisfaction with access and health-related quality of life. It suggested that patients with the AV fistula had the greatest satisfaction, leading to a better HRQOL .There was no statistical difference between the duration and frequency of dialysis for the PCS, MCS, and KDCS. Furthermore, a study from Iran published in 2017 showed no significant difference between the duration of dialysis and quality of life in dialysis patients , 25 thatIn this study, the KDQOL-SF™ questionnaire revealed lower PCS scores among hemodialysis patients in Palestine. Furthermore, the three domains of the questionnaire were adversely affected by patient income and education status. Furthermore, physical role, work status, and emotional role showed the lowest scores among the three main domains. Therefore, continuous assessment of patients' quality of life during their journey of hemodialysis using the KDQOL-SF™ along with the clinical assessment will allow the healthcare professionals to provide interventions to optimize their care.The strength of this study is the use of a standard instrument (KDQOL-SF™) that allowed the measurement of specific physical and psychological symptoms. A limitation of this study was the face-to-face interview during data collection, which may have influenced patients' responses, as some may not have provided detailed answers for various reasons, and the sample size was less than calculated.


In Japan, people have rich access to 24-h convenience stores where they can buy sweets, juice and fluoride hygiene products, among others. However, the association between the number of convenience stores in a neighbourhood and caries in elementary school children status has not been studied. This study aimed to investigate this particular association.Data were derived from a population-based longitudinal cohort study (A-CHILD study) of elementary school children from first-grade to fourth-grade in Adachi City, Tokyo. Caregivers were asked to complete a questionnaire in 2015, 2016, and 2018. A total of 3,136 caregivers provided a valid response. We analysed the association using multilevel Poisson regression.p for trend: 0.042).The mean number of caries among children in school districts with low, middle, and high number of convenience stores was 0.31 (SD: 0.81), 0.21 (SD: 0.69), and 0.16 (SD: 0.58). After covariate adjustment, children in the school districts with high and middle number of convenience stores had 44%  and 31%  fewer caries in their permanent teeth, respectively, than children in the school districts with low number of convenience stores. We also found dose–response relationship (Higher number of convenience stores in a school district was associated with fewer caries in permanent teeth among elementary school children. Further study elucidating the mechanism on this protective association is warranted. Dental caries is the most common disease in the world, with a prevalence of about 50% in permanent teeth of children worldwide . In JapaMany prior studies have focused on the risk factors for dental caries at the individual level , 9; relaIn Japan, people have rich access to convenience stores. There are approximately 56,000 convenience stores in Japan, one store for every 2,246 people or a ratio of 0.45 stores for every 1,000 people . Unlike n = 5,355). We obtained 4,291 valid responses from caregivers for the first questionnaire survey (response rate: 80.1%). Caregivers were then asked to complete a questionnaire in 2016 and 2018, and 3,168 of them provided a valid response in all 3 years (follow-up rate: 73.8%). This survey data was also linked to information on children’s health status, such as dental caries, obtained through annual school checkups. For those who responded to the survey and agreed to participate in the study, the exclusion criterion for this study was the presence of missing values in the outcome variable. We excluded 32 responses due to missing on caries data in 2015 and 2018, resulting in an analytic sample size of 3,136. This study was approved by the Ethics Committee at the National Center for Child Health and Development (Study ID: 1147) and Tokyo Medical and Dental University (Study ID: M2016-284).Data were derived from the Adachi Child Health Impact of Living Difficulty (A-CHILD) study, a population-based longitudinal cohort study of elementary school children in Adachi City, Tokyo . DetailsInformation on the address of convenience stores in 2018 was derived from the Japanese Yellow Pages database of phone numbers, addresses, and job titles  . Each adIn Japan, dental checkups by school dentists are included in the mandatory annual school health checkups. Dental checkups must follow national guidelines , and cheCovariates included maternal age, education, paternal education, household income, marital status, parental psychological distress, child sex, birth order, baseline number of caries in permanent teeth (in 2015) , 26 and Geographical data on dental clinic addresses, school district boundaries, and land prices were derived from National Land Numerical Information by Ministry of Land Infrastructure Transport and Tourism of Japan . Number Parental psychological distress was assessed with the Kessler 6 (K6), a six-item scale for screening psychological distress; total K6 scores ranges from 0 to 24, with higher scores indicating greater psychological distress , 28. In First, to compare values across different groups, a chi-square test was used for categorical variables and ANOVA for continuous variables. Then, a multilevel Poisson regression model with a random intercept was used to estimate the association between the number of convenience stores and the number of caries in permanent teeth among elementary school children in Japan. The following covariates were included in the adjusted models: maternal age, education, paternal education, household income, marital status, parental psychological distress, child sex, birth order, baseline number of caries in permanent teeth (in 2015) and number of dental clinics and land prices in a school district. Dummy variables for missing values were created for these covariates, except for the baseline number of caries in permanent teeth (in 2015).Further, while convenience stores pose the advantages for many people due to easy geographical access with most being open 24 h a day, products are usually sold at a fixed price without discount, except for discount for some food products that are approaching their expiry date . Therefon = 3,136). Although the age of the mothers was similar among the three groups, the group with the highest number of convenience stores in the school district had the highest percentage of mothers with college or more education . There were no differences in paternal education, household income, marital status, parental psychological distress, child gender, or birth order among the three groups. The group with the highest number of convenience stores in the school district had the highest percentage of dental clinics in the school district  and the highest land prices. The group with the lowest number of convenience stores had an average land price of 288,773  JPY/m2, the medium group 278,288  JPY, and the highest group 399,491  JPY. The mean number of dental caries in the permanent teeth for children in school districts with the fewest, middle, and highest number of convenience stores was 0.31 (SD: 0.81), 0.21 (SD: 0.69), and 0.16 (SD: 0.58).p for trend was 0.042, suggesting that there was a dose–response relationship.p < 0.1).In this study, we found that children in the school districts with higher number of convenience stores had fewer caries in their permanent teeth. Further, the inverse association between the number of convenience stores and caries status in permanent teeth was observed for children from non-low-income households, but not for children from low-income households.Previous studies have examined the association between community level exposures, such as area-level deprivation , school-Interestingly, an inverse association between the number of convenience stores and dental caries was observed in children from non-low-income households but not in children from low-income households. Previous studies conducted in Japan and the US suggested that people in low-income households are more sensitive to the price of goods than to the distance to the store, and thus tend to go to distant discount stores to purchase goods at cheaper prices instead of buying goods at neighborhood stores, especially so in large cities , 31. ThuThis study has several limitations. First, this study was conducted in only one area of Tokyo. It is possible that the effect of convenience stores was underestimated because Tokyo has many stores other than convenience stores and has good access to public transportation, so people buy goods at discount stores other than at convenience stores. Second, in this study, the number of convenience stores in the school district was used to determine people’s access to convenience stores, but the distance from home to a convenience store was not considered. However, since the school district coincides with people’s daily living range , the numNonetheless, our study has several implications. We found that a large number of local convenience stores are protective against dental caries. If future research can identify products sold in convenience stores that are protective against dental caries, it may be possible to reduce dental caries in the community by promoting the sale of these products not only in convenience stores, but also in other stores. Since dental caries not only leads to malnutrition and poor quality of life in children , but alsIn conclusion, we found that children in school districts with high and middle number of convenience stores had fewer caries in their permanent teeth, respectively, than children in school districts with low number of convenience stores. Further study is needed to clarify the mechanism that explain the association between the number of convenience stores and dental caries in children.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving humans were approved by the Ethics Committee at the National Center for Child Health and Development (Study ID: 1147) and Tokyo Medical and Dental University (Study ID: M2016-284). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from caregivers.NN: conceptualization, data curation, methodology, formal analysis, and writing – original draft. HN: data curation and writing – review and editing. YM: methodology and writing – review and editing. SD and AI: resources and writing – review and editing. TF: supervision, conceptualization, validation, and writing – review and editing. All authors contributed to the article and approved the submitted version.