Pregabalin has received wide clinical attention as a new type of analgesic. We undertake a systematic review and meta-analysis to evaluate the effect of pregabalin on postoperative pain in patients undergoing cardiac surgery.  We searched PubMed, Embase, and Cochrane Library (from inception to July 2020) for eligible studies. The primary outcomes were the total morphine consumption at 24 h. A secondary outcome was intraoperative fentanyl consumption, extubation time postoperative, and length of stay in hospital. We calculated pooled weighted mean difference (WMD) or odds ratio (OR) and 95% CIs using random- or fixed-effects models. P = 0.03). We found that there is no significant difference between the two groups in intraoperative fentanyl consumption. Compared with the control group, the length of stay in hospital in the pregabalin group was significantly shorter . And we found that there were no significant differences between the two groups in extubation time .  Seven trials involving 463 patients were listed. Meta-analysis showed that the total morphine consumption at 24 h in the pregabalin group was significantly less than the control group (WMD: -5.44, 95% CI: -10.42–0.46,  Oral pregabalin for cardiac surgery patients can effectively reduce the patient's 24-hour morphine consumption after surgery, shorten the patient's hospital stay, and is more conducive to early postoperative recovery. In recent years, the application scope of enhanced recovery after surgery(ERAS) has become more and more extensive, and at the same time, it has been applied in many clinical departments including cardiothoracic surgery and has received good results , 2. AmonPregabalin, one of the options of analgesics, was initially used clinically as an antiepileptic drug. Depend on its central analgesic effect, it has been widely favored by clinicians in recent years due to its effective analgesic effect. Pregabalin is often used clinically to assist analgesia after surgery , 6. In oCRD42020203862). We followed the methods of Wang et al. 2017 [This systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . We prosal. 2017 .PubMed, Embase, and Cochrane library databases were searched from inception to July 2020 for relevant studies investigating the effect of pregabalin in cardiac surgery. The following search terms were used: Pregabalin, Cardiac surgery, “Coronary artery bypass”, Valve replacement, “Ventricular septal defect repair”, and “Atrial septal defect repair.” A hand search in reference sections of included trials, published meta-analyses, and relevant review articles was conducted to identify additional articles. If duplicated data were presented in several studies, only the most recent, largest, or most complete study was included.P: adult patients undergoing cardiac surgery; (b) I and C: pregabalin and blank control, respectively; (c) O: opioid use, length of hospital stay, and extubation time; and (d) S: only randomized controlled trials (RCTs) were included. Only English was set.Original studies included were based on PICOS  as the following: (a) Characteristics of patients and trials design were also recorded. If the data mentioned above were unavailable in the article, the corresponding authors were contacted for missing information. All data were independently extracted using a standard data collection form by 2 reviewers (XX Wang and HJ Guo), and then the collected data were checked and entered into Review Manager analyses software (RevMan) Version 5.3. All discrepancies were checked, and a consensus was reached by discussion with a third author (XG Hu) involved. A record of reasons for excluding studies was kept.A critical evaluation of the included studies quality was performed by 2 reviewers (XX Wang and HJ Guo) by using a 5-point Jadad scale . The maiTwo reviewers (XX Wang and HJ Guo) independently evaluated the risk of bias according to the recommendations from the Cochrane Collaboration . The maiI2 value was used to estimate statistical heterogeneity. When I2 < 50%, heterogeneity could be accepted, and the fixed-effects model was adopted. Otherwise, the randomized-effects model was adopted and sensitivity analysis used. Whenever heterogeneity was present, several sensitivity analyses were carried out to identify potential sources. We also investigated the influence of a single study on the overall pooled estimate by omitting one study in each turn. Owing to the limited number (below 10) of studies included in each analysis, publication bias was not assessed. A P value < 0.05 was considered statistically significant. Risk-of-bias assessment was conducted by using Review Manager, version 5.3 . Power analyses of individual studies and meta-analysis were all conducted by the software, version 4.1.0.Risk ratio (RR) with 95% CI was used as a common measure of the effect between spinal anesthesia and general anesthesia. The A total of 153 potentially relevant abstracts were identified. After reading the abstracts, nine publications seemed to meet the inclusion criteria. For the remaining 9 articles, two of them were excluded for the reason: meta-analysis . FinallyThe characteristics of all included studies were presented in These studies were published between 2011 and 2019. The sample size of included studies ranged from 40 to 100. All were randomized controlled trials, and primary end points were morphine consumption, intraoperative fentanyl consumption, extubation time, and length of stay in hospital. All were cardiac surgery, and four of the studies were coronary artery bypass grafting –20. The I2 = 97%; P < 0.00001), and a randomized-effects model was selected. Compared with the control group, the total morphine consumption at 24 h in the pregabalin group was significantly lower   .I2 = 0%; P = 0.70), and a fixed-effects model was chosen. After examined the studies by meta-analysis, we found that there were no significantly different between two groups of intraoperative fentanyl consumption   .I2 = 20%; P = 0.29), and a fixed-effects model was selected. When compared with the control group, pregabalin was not associated with a significant reduction in extubation time   .I2 = 0%; P = 0.93), and a fixed-effects model was chosen. The results suggest that the length of stay in hospital in the pregabalin group was significantly shorter than the control group   .P = 0.44), , , , and . There was no statistically significant difference between the two groups of patients in the number of four antihypertensive drugs used, respectively: beta-blocks , Ca channel antagonist , ACE inhibitors , and diuretics   .Postoperative pain is part of the common complications in heart surgery patients. The occurrence of pain is affected by many factors; so, a reasonable choice of analgesic drugs can achieve a good postoperative analgesic effect. Based on a meta-analysis of the included literature, this article found that oral pregabalin during the perioperative of cardiac surgery can significantly reduce the 24-hour postoperative morphine consumption and shorten the patient's hospital stay. However, the intraoperative fentanyl usage and extubation time postoperative in patients who used pregabalin did not show an advantage.α2-δ subunits of voltage-gated calcium channels to reduce the excitability of nerve synapses and reduces the release of various excitatory neurotransmitters, thereby inhibiting patients with hyperalgesia [After heart surgery, the incision site often exhibits severe pain and long-lasting. Intense pain can cause changes in the patient's neuroendocrine and circulatory system, which will hinder early postoperative recovery, extend the patient's hospital stay, and increase the economic burden of patients. Therefore, effective analgesia after cardiac surgery can effectively improve the prognosis and promote rapid recovery of patients after surgery, which has important clinical significance. Pregabalin, as a new structural analog of gamma-aminobutyric acid (GABA), was used in clinical practice as an antiepileptic drug in the early stage and gradually began to be used in patients with pathological pain . In receralgesia , 26. ThiThis study included a meta-analysis of a randomized controlled study of the effects of pregabalin on the prognosis of different groups of cardiac surgery patients. It is our objective understanding of the application of pregabalin in cardiac surgery patients. The advantages of pregabalin in cardiac surgery provide a further direction for our next research. On the one hand, we can use this clue to observe its long-term impact on patients and analyze the quality of life; on the other hand, we can expand to other patient application research. The meta-analysis of this study included the baseline data of patients in the literature. It was found that the basic conditions of patients in the included literature were comparable and no significant difference. The heterogeneity between the literature was mostly 0%. Although qualitative exists, they are all relatively small and within acceptable limits. It shows that the consistency of the included literature in this study is good, and the credibility of the literature data is high.While several limitations should be taken into account, first, the time point and dosage of pregabalin used are different, which affect the comparison of results. Second, most of the literature does not report the relevant scores of postoperative pain, which difficult to directly assess the postoperative pain of the patient, and the postoperative morphine can only be used to indirectly reflect the postoperative pain of the patient. Third, ours were mainly based on studies published in the English language, and bias might be existed. Forth, the sample sizes of individual trials included were small or moderate. Fifth, only selected published studies and many studies were not registered with clinical trials databases; so, the scope of the unpublished literature could not be obtained and may lead to bias.Oral pregabalin for cardiac surgery patients can effectively reduce the patient's 24-hour morphine consumption after surgery, shorten the patient's hospital stay, and is more conducive to early postoperative recovery.


Substance P (SP) is a neuropeptide that is released from sensory nerve endings and is widely present in nerve fibers. It acts on bones and related tissues by binding to receptors, thereby regulating bone metabolism, cartilage metabolism, and fracture healing. SP has attracted widespread attention as a signaling substance that can be recognized by both the immune system and the nervous system. Previous studies have shown that bone and chondrocytes can synthesize and secrete sensory neuropeptides and express their receptors, and can promote proliferation, differentiation, apoptosis, matrix synthesis, and the degradation of target cells through autocrine/paracrine modes. In this paper, we review the research progress made in this field in recent years in order to provide a reference for further understanding the regulatory mechanism of bone and cartilage physiology and pathological metabolism. Bone is a complex and dynamic tissue with a mineralized extracellular matrix and the ability to adapt to its functional demands and repair itself. Bone is abundantly innervated by small diameter sensory nerves in the periosteum, bone marrow, and vascular canals , 2. TherThe balance between osteoclastic bone resorption and osteogenic bone formation processes in bone metabolism is the key to maintaining normal bone mass . Osteoclin vitro culture of bone marrow cells, the number, and size of bone marrow cell colonies increased with SP concentration, indicating that SP could stimulate bone formation. Paradoxically, SP slightly stimulated thymidine incorporation and strongly inhibited calcium accumulation in bone noduli, which was associated with a small decrease in ALP activity   and requactivity . SP promactivity . Althoug−/− BMMs/osteoclast cultures. Takaaki et al.  to establish a fracture healing model to study the effect of SP loss on the process of fracture healing. At day 13 post fracture, they observed a decrease in the area covered by hypertrophic chondrocytes in Tac1−/− mice, indicating that SP deficiency can delay the terminal differentiation of hypertrophic chondrocytes. This research suggested that SP is essential in the process of cartilage ossification during fracture healing. Furthermore, absence of SP reduces pain sensitivity and the mechanical stability of the bone after fracture in general. Guo et al. (SP is considered to be a regulator of angiogenesis that is important for bone repair and remodeling. Ding et al.  built a o et al.  showed to et al. , 54. BasSP is a neuroinflammatory mediator produced by sensory nerve fibers and local inflammatory cells, such as macrophages, lymphocytes, and dendritic cells , 55. SP in vivo and in vitro. The addition of 1 μmol/L SP to cultured chondrocytes or 0.33 Hz of mechanical stimulation caused hyperpolarization of the cell membrane, suggesting that SP is involved in the mechanical transmission process in chondrocytes. Blockade of SP signaling by a chemical antagonist of Nk-R1 inhibited chondrocyte responses to mechanical stimulation. To sum up, SP secreted by human articular chondrocytes can mediate chondrocyte mechanotransduction via Nk-R1 in an autocrine and/or paracrine manner. Karaha et al. (SP seems to be extremely important for cartilage health because it participates in mechanical transduction through Nk-R1 –64. Milla et al.  revealedin vitro and found that SP significantly promoted the gene expression of type I, IX, X collagen, and mmp-13, which are closely associated with the terminal differentiation of chondrocytes. In addition, SP also promoted chondrocyte proliferation in a dose-dependent manner. It was also found that the NK1 antagonist L733060 could exert dose-dependent inhibition on the proliferation of chondrocytes, indicating that endogenous synthesis and secretion of chondrocyte SP could also regulate proliferation through autocrine and paracrine effects. Tanja et al. (Opolka et al.  conductea et al.  found ata et al. , and thea et al. , 69, 70.Osteoarthritis, also known as degenerative joint disease, is characterized by synovial inflammation, cartilage destruction, and subchondral bone sclerosis associated with aging. Joint replacement is still the only treatment for patients with advanced osteoarthrosis. Recent studies have shown that SP plays an important therapeutic role in the process of OA cartilage degeneration. Higher concentrations of SP were found in the synovial fluid of OA patients, indicating the catabolic effect of SP on articular cartilage , 72. IncAlthough studies have shown that SP receptor antagonists can help reduce arthritis pain and swelling , blockinPrevious studies have confirmed that SP and Nk-R1 are widely present in bone and cartilage tissue and actively participate in bone and cartilage metabolism. Sensory nerve endings can release SP, and SP-positive nerve fibers are distributed in bone and cartilage tissue. SP binds to Nk-R1 to initiate a signal transduction pathway and regulates pathophysiological processes in bone and cartilage tissue.Due to the current lack of detailed knowledge about the effects of SP on bone, we are still unable to explain the pathophysiology of the most common bone diseases. Although previous studies have shown that SP is involved in bone metabolism, especially in bone resorption, the effect of SP on osteoblast formation is not fully understood. It will be a challenge to elucidate the relationship between bone metabolism and neural regulation. As a substance that can be synthesized by the human body, SP can produce a rapid and efficient response at very low levels. It remains to be determined whether it could be a potential therapeutic agent in osteoporosis and fracture repair. The exact mechanism by which SP is involved in the pathophysiology of bone and related tissues, the interaction of SP with other neuropeptides, cytokines and hormones, and the potential role of SP or Nk-R1 antagonists as effective preventive and therapeutic agents need to be fully determined.SP plays an important regulatory role in the mechanical response of cartilage, fracture healing, and the pathological degeneration of cartilage by promoting chondrocyte proliferation, adhesion, and secretion and accelerating chondrocyte terminal differentiation. Although cartilage metabolism involves multiple pathways, and SP is not the main pathway that plays a regulatory role, it has been proposed that through SP, NK-R1 antagonists may be promising for the treatment of OA in the future.in vivo or in vitro. Research on SP, the NK1 receptor and the Nk-R1 antagonist will be useful for exploring the mechanism of action of drugs, developing new drugs, and finding new treatments for bone diseases.Future research should explore areas related to the changes in SP and its receptors in cell proliferation and differentiation, cell signal transduction pathways, and protein and gene expression levels after SP treatment of animals/cells L-QY conceived and designed the manuscript. F-X-ZL, FX, XL, FW, J-YZ, YW, BG, M-HZ, and S-KS analyzed the data. L-QY and F-X-ZL wrote the paper.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.


Meat intake has been linked to increased risk of colorectal cancer (CRC) and mortality. However, diet composition may affect the risks. We aimed to estimate associations between red and processed meat and poultry intake and risk of CRC and all-cause mortality and if they are modified by dietary quality using Cox regression analyses. Baseline dietary data were obtained from three survey rounds of the Danish National Survey on Diet and Physical Activity. Data on CRC and all-cause mortality were extracted from national registers. The cohort was followed from date of survey interview—or for CRC, from age 50 years, whichever came last, until 31 December 2017. Meat intake was analysed categorically and continuously, and stratified by dietary quality for 15–75-year-old Danes at baseline, n 6282 for CRC and n 9848 for mortality analyses. We found no significant association between red and processed meat intake and CRC risk. For poultry, increased CRC risk for high versus low intake  was found, but not when examining risk change per 100 g increased intake. We showed no association between meat intake and all-cause mortality. The association between meat intake and CRC or mortality risk was not modified by dietary quality. In October 2015, the International Agency for Research on Cancer concluded that processed meat could be classified as “carcinogenic to humans”, and red meat could be classified as “probably carcinogenic to humans” . PoultrySome, but not all, prospective, population-based studies from different countries have associated high red and processed meat intake with increased risk of mortality, in particular in American cohorts ,5,6,7,8.Since composition of diets is complex and persons with different diets may differ on other characteristics, cohort studies on associations between meat intake and health have many confounders. However, it is possible to have a high meat content in a healthy diet . TherefoThe aim of the study is to evaluate the associations between the intake of red and processed meat and poultry and CRC and all-cause mortality risk, both in an adult study population in general and in subgroups with different dietary guideline compliance, minimising the influence of diet-related confounding.We defined red meat as unprocessed muscle tissue from mammals such as beef, veal, pork, and lamb. A small intake of unprocessed edible offal, e.g., liver and heart was included. The meat could be minced and/or frozen. It was usually eaten cooked.Processed meat was red meat or poultry that undergoes a transformation and contains approved ingredients and may be subject to some form of preservation; in other words: smoking, drying, curing or fermentation.Poultry included meat from chicken, hen, turkey, goose, dove, duck, and pheasant. However, only the intake of chicken and turkey was at a sizable level among Danes.Values for meat intake were expressed as cooked meat.The analyses were based on information from adults, who participated in The Danish National Survey on Diet and Physical Activity in any of the three survey rounds . Invited individuals were randomly drawn from the Danish Civil Registration System and comprised non-institutionalised free-living Danish citizens . Data foThe diet of each participant was assigned a Dietary Guideline Compliance Score (DGCS) based on how well the diet complies with the five quantitative official Danish dietary guidelines. The recommended dietary contents are 600 g fruit and vegetables/10 MJ, 350 g fish/10 MJ, 75 g whole grain/10 MJ, saturated fatty acids max 10% of total energy intake (E%), and added sugars max 10 E%. For each dietary guideline, a score of 0–1 was given by dividing the dietary content of the actual component with the recommended dietary content (scores > 1 were truncated at 1). The five scores were added to yield the total score between 0 and 5. We designate participants with a low DGCS (<3.1) as low-compliers and participants with a high DGCS (≥3.1) as high-compliers in analyses of the CRC cohort (see description of the cohort below). In the all-cause mortality cohort, low, medium, and high DGCS were <2.4, 2.4–3.7 and >3.7, respectively.Outcomes were identified through linkage of the study population with information from registers using the unique personal identification number . InformaInformation on age, sex, ethnicity, and emigration were obtained from the Danish Civil Registration System . EducatiFrom information on primary diagnosis in the National Patient Register, colorectal polyps up to 10 years before baseline (ICD-10: K62.1 and K63.5) were identified. Screening for colorectal cancer was not introduced in Denmark until 2014, and information on colorectal polyps was so rare in the study population (n = 5) that they were not included as a confounder in the analyses.In analyses of CRC, the aim was to study incident cases of disease, and, therefore, individuals were excluded if they had been diagnosed with CRC before baseline (n = 31). In addition, participants younger than 50 years of age before end of follow-up were excluded (n = 3535), as CRC was almost absent among this part of the study population. The CRC cohort (n = 6282) was followed from baseline (date of survey interview) or from age 50 years for those not 50 years old at baseline (delayed entry). Follow-up ended at first CRC event (first diagnosis or death due to CRC) or at emigration, death due to other causes or end of follow-up (31 December 2017), whichever came first. The mean time of follow-up was 8.7 years. For analyses of all-cause mortality, the cohort (n = 9848) was followed from baseline, and follow-up ended at death, emigration, or end of follow-up (31 December 2017), whichever came first. The mean time of follow-up was 10.8 years. In both analyses, there was no loss to follow-up.Missing information on country of origin (0.01%) was imputed as Danish origin, missing educational level (1.5%) was imputed as short education, missing BMI (1.0%) was imputed as normal BMI (18.5–25), missing smoking status (1.1%) was imputed as never smoker, and missing information on physical activity (0.4%) was imputed as the most common category (moderate/hard).We use the designation “categorical” when we compare groups with different intake, while we use “continuous” for analyses on increments per 50 or 100 g/day. Intake of red meat, processed meat, and poultry was analysed on both a continuous and categorical scale. For analyses of all-cause mortality, the measures of meat intake were categorised in three groups . Due to the small number of CRC cases in some groups, it was not possible to perform the statistical analyses with such categorisation. Therefore, meat intake was categorised in two groups  in CRC analyses. The intake of different types of meat  was almost identical in the CRC cohort and all-cause mortality cohort (data not shown). Therefore, and to eliminate categorisation of meat intake as reason for the differences in the analyses, we used intake in the all-cause mortality cohort to categorise meat intake in both CRC and all-cause mortality analyses. For analyses of all-cause mortality and CRC, the measures of dietary guideline compliance (DGC) were categorised in a similar way as meat intake. For analyses of associations between meat intake as a continuous variable and outcomes, red meat, and poultry were expressed per 100 g increments per day, and processed meat per 50 g increments per day.The associations between meat intake and outcomes were estimated as hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression analyses. As all studied outcomes were strongly associated with age, we used age as the underlying timescale in the analyses. Different measures of meat intake were included in different regression models with adjustment for sex, educational attainment (the year before baseline), ethnicity, smoking, physical activity, alcohol, BMI, and total energy intake. To test if non-linear effects better represented the associations between meat intake and outcomes compared with linear effects, quadratic and cubic terms were included in the regression models. However, all non-linear effects were non-significant, so meat intake was only included linearly. Valid results from Cox regression analyses require that the hazard ratio between groups does not change with age, i.e., the assumption of proportional hazards. To evaluate if the assumption of proportional hazards was fulfilled, we estimated the Schoenfeld residuals for each of exposure variable. We then tested in a linear regression model whether these residuals were correlated with age . These analyses indicated that the assumption of proportional hazards was fulfilled. We also visually inspected the log-negative-log survival curves for each of the exposure and outcome variables. These plots did not indicate violation of the proportional hazard assumption.The associations between DGC and the studied outcomes were estimated using the same methods as for meat intake, but DGC was only included categorical.To evaluate whether the association between meat intake and disease outcome differed depending on DGC, associations stratified by DGC were estimated using Cox regression analyses with age as the underlying timescale. In these analyses, the statistical significance of an interaction between meat intake and DGC was tested by including both meat intake and DGC as separate main effects and as an interaction term with each other. These tests were performed both on analyses with meat intake as a categorical and a continuous variable.p-value <0.05 was considered statistically significant.All analyses were performed using SAS 9.4 . A We ascertained 127 incident CRC cases, and 640 persons died during follow-up.Characteristics of the CRC study population stratified by DGC and red meat intake are shown in In the total study population, 51.7% were women, most had a medium educational level and were of normal weight, more than half of the population were either former or current smokers, and half of the population had a moderate/hard level of physical activity.Most characteristics seemed to differ when groups with different DGC and meat intake were compared. For example, men made up a large proportion of those with a high meat intake and low compliance with dietary guidelines, whereas the women dominated the low-meat groups. In the groups with high DGC, more participants had a long education, and fewer were current smokers compared with groups with low DGC. Participants in groups with high DGC were more physically active in their leisure time compared with groups with low DGC, but this was not reflected in the weight status of the groups.The intake distribution of the types of meat analysed is shown in p for trend = 0.34).No significant associations were found between red meat and processed meat intake and CRC risk . High poThe total meat intake did not significantly affect CRC risk in our study (data not shown).No significant associations were found between red meat, processed meat, and poultry intake and all-cause mortality .p for trend = 0.66)  .p for trend = 0.13)  .p for interaction = 0.53 and p for interaction = 0.45, respectively). Similarly, the CRC risk for high versus low processed meat intake and per 50 g processed meat per day was not affected by DGC . DGC was not found to significantly modify the association between poultry intake and CRC risk .The associations between meat intake and CRC stratified by DGC are shown in p for interaction = 0.98 and p for interaction = 0.85, respectively). Similarly, for high versus low intake and per 50 g per day of processed meat, DGC did not affect all-cause mortality risk . For poultry, DGC did not affect the risk of all-cause mortality for high versus low intake (p for interaction = 0.88), or per 100 g per day (p for interaction = 0.21).There was no significant association between meat intake and all-cause mortality stratified by DGC for any of the meat types . For redWe found no significant association between red meat or processed meat intake and CRC risk. For poultry, however, high compared with low intake increased CRC risk significantly by 62%, but we found no increased CRC risk per 100 g poultry per day.In accordance with our result on red meat, several prospective cohort studies representing more than 10 European countries, including Denmark, found no association between red meat intake and CRC risk ,17,18,19It is difficult to obtain and compare information about actual meat intake (g/day) for different types of meat in different cohorts, which affects the possibility to compare outcomes in studies of effects of high versus low meat intake. For example, high red meat intake in an Asian cohort may be similar in magnitude to low red meat intake in some Western cohorts.In contrast to our results on processed meat, others found positive associations between processed meat intake and CRC risk in American, Australian, Asian, and European cohorts ,21,22,23Studies on the effects of meat intake from different countries and continents can be difficult to compare because the proportions of the different types of red and processed meat differ significantly between regions. The types of meat—both red and processed meat—constitute different hazards due to their structure and composition. Moreover, certain meat subtypes may be more prevailing in unhealthy diets than others, which can affect the risk estimates. Therefore, analyses on effects of meat subtypes can contribute to our understanding of differences observed in different cohorts and are warranted in future studies.In a meta-analysis comparing the highest versus lowest red meat intake in Asian and European cohorts, Carr et al.  found thFor poultry intake, our results were in contrast with what others have found. No association between poultry intake and CRC risk was reported by the World Cancer Research Fund Continuous Update Project  or seen A pronounced difference in meat content in high-meat diets with different healthy eating indices was found by Kappeler et al. . Thus, cNorat et al.  found thWe found no significant associations between red meat, processed meat, and poultry intake and all-cause mortality.Similar results were found for red meat in a large American cohort  but not In contrast to our results, in a European cohort including Denmark, intake of processed meat was positively associated with all-cause mortality , which wIn a recent meta-analysis, Han et al. found a small, positive association between red and processed meat intake and cancer mortality, but the evidence was rated to be of low certainty .White meat  intake was not associated with all-cause mortality in meta-analyses of prospective cohort studies ,28. Likep for trend showed no significant effect of DGCS.In our study, a diet composition that did not comply well with the official, quantitative Danish dietary guidelines (independent of meat content) was significantly associated with mortality risk in the least adjusted model (adjusted by sex and age) . However, DGCS was not significantly associated with mortality risk in the multivariate model , and Kappeler et al.  found a Our study had several strengths. The studied outcomes were based on national registers with high validity and completeness, and we included complete information on migration and death ensuring complete follow-up of the study cohort. The linkage also enabled us to include only incident cases of disease and to minimise the risk of reverse causality as we excluded those with disease before baseline. The study included comprehensive information on dietary components, which made it possible to evaluate if associations differed with DGC. The diet registration for each participant included seven days including weekend days, and the data collection process in the study population covered all seasons to allow for seasonal variations in dietary data on study population basis.However, the study also had limitations. The dietary surveys were representative regarding gender and age. However, in the latest surveys, participants with short education were under-represented, which may limit the generalisability of the findings. In addition, the study only included one dietary registration for each individual. Therefore, it was assumed that the diet composition did not change during follow-up, but if the population had large variations in DGC during follow-up, this would influence the estimated associations. Finally, as mentioned previously, the size of the study population affected the power to identify statistically significant associations, especially in analyses on interactions between meat intake and DGC, where the numbers of participants in groups were low.In the analyses, BMI was included as a confounder, as is common practice in similar studies. However, it is likely that BMI is a mediator instead of a confounder in the presented associations, implying that the presented results have been over-adjusted. Analyses without BMI in the model (data not shown) showed that inclusion of BMI only mildly attenuated the estimates, and that the results on low DGCS did not become significant when BMI was not included in the model.We did not find statistically significant associations between meat intake and CRC or mortality risk. However, the ability to reach statistically significant results is influenced by many factors. For example, since the study population was 15–75 years at baseline, a large proportion of the population was too young to be at real risk of developing CRC. This is why we only studied CRC risk among individuals aged 50 years and older. Thus, the number of outcomes could be an explanation why the associations between meat intake and the CRC risk was non-significant. Similarly, a large proportion of the population were too young to be at an appreciable mortality risk.Analyses of dietary patterns in our cohort showed that a low dietary content of one type of meat, e.g., poultry, was associated with a high dietary content of other types of meat, e.g., red meat . Thus, dAnother limitation was that the size of the study population restricted our opportunity to study differences between those with very low and those with a very high meat intake. In analyses of CRC risk, we were only able to divide the population’s meat intake into two groups instead of quartiles. This introduced some arbitrariness around cut-off values of meat intake since we split the population into two groups without having a meaningful difference for meat consumed around the median. However, in the interpretation of results, we also focused on estimates of associations with meat intake on a continuous scale, which did not suffer from this limitation.We showed no significant associations between red and processed meat intake and risk of CRC and all-cause mortality. A significant increase in CRC risk, but not in all-cause mortality, was found for high versus low poultry intake but not for risk change per 100 g increment per day. None of these associations were modified by dietary guideline compliance.


Planning population care in a specific health care setting requires deep knowledge of the clinical characteristics of the target care recipients, which tend to be country specific. Our area virtually lacks any descriptive, far-reaching publications about institutionalized older people (IOP). We aimed to investigate the demographic and clinical characteristics of institutionalized older people (IOP) ≥65 years old and compare them with those of the rest of the population of the same age.Grupos de Morbilidad Ajustada)—, mortality, use of resources, and medications taken. All data were obtained from the administrative database of the local healthcare system.Retrospective analysis  of clinical and resource-use characteristics of IOP and non-IOP older than 65 years in Catalonia (North-East Spain). Variables analysed included age and sex, diagnoses, morbidity burden—using Adjusted Morbidity Groups , IOP showed a higher annual mortality (20.46% vs. 3.13%), a larger number of chronic diseases , higher multimorbidity (15.2% vs. 4.2% with GMA of maximum complexity), and annual admissions to acute care (47.6% vs. 27.7%) and skilled nursing facilities (27.8% vs. 7.4%), mean length of hospital stay (10.0 vs. 7.2 days) and mean of medications taken (11.7 vs. 8.0).This study included 93,038, 78,458, 68,545 and 67,456 IOP from 2011, 2013, 2015 and 2017, respectively. In this interval, an increase in median age (83 vs. 87 years), in women (68.64% vs. 72.11%) and in annual mortality (11.74% vs. 20.46%) was observed. Compared with non-IOP (There is a growing gap between the clinical and demographic characteristics of age-matched IOP and non-IOP, which overlaps with a higher mortality rate of IOP. The profile of resources utilization of IOP compared with non-IOP strongly suggests a deficiency of preventive actions and stresses the need to rethink the care model for IOP from a social and health care perspective. The persistently announced “epidemiological tsunami” of a great number of people of advanced age with multiple comorbidities, chronic conditions, and complex care needs is already a reality in our setting . BesidesBeyond the fact that health systems need to keep promoting strategic measures to prevent or delay the occurrence of chronic diseases and disabilities , it is aBesides a higher global demand of nursing home beds, analysing the epidemiological and clinical characteristics of institutionalized people and assessing their needs, values and preferences are increasingly becoming central in the care model design for nursing homes. In 2013, Morley et al. already pointed out the need to research the care and characteristics of institutionalized people . Since tFaced with this scenario, some authors have stressed the need to gather country-specific information about institutionalized patients to better understand the factors that influence mortality and morbidity and, therefore, the needs of these care models . In respIntegrated medical care model for older people residing in nursing homes”, promoted by the local health authorities, the term “nursing home” was defined as any permanent or temporary place for people ≥65 years that do not have a sufficient degree of autonomy to perform daily activities, need constant supervision and live in a social-family situation requiring the replacement of their home.This was a retrospective analysis of an administrative database that included all people ≥65 years in Catalonia (northwest of Spain) between 2011 and 2017. IOP were identified by using pharmaceutical dispensing coding data, which are necessary and specific to these people. Those subjects that in the year of inclusion had been living in a nursing home were considered IOP. Within the context of this study, and based on the consensus of the “Sociodemographic and clinical data were obtained from the Catalan Health Surveillance System (CHSS) that, since 2011, collects detailed information about the use of health care of the entire population of Catalonia. This record, which has been analysed in previous publications in other areas , 11, colGrupos de Morbilidad Ajustada), which considers the type of disease—acute or chronic—, number of systems affected, and complexity of each disease, enabling to classify people in four strata based on their morbidity-associated risk: 1) Initial risk , with a GMA score up to the 50th percentile of the total population; 2) Low risk, with a GMA score between the 50th–80th percentiles; 3) Moderate risk, with a GMA score between the 80th–95th percentiles; and 4) High risk, with a GMA score above the 95th percentile [Age and sex were the demographic variables used in the study. Clinical variables included diagnoses, as they appear in the CHSS database based on the normal course of clinical practice, and coded according to the International Classification of Diseases, ninth revision, Clinical Modification (ICD-9-CM). The comorbidity burden was stratified based on the Adjusted Morbidity Groups  and the median and interquartile range . Categorical variables were compared using the chi-square test. After confirming that all continuous variables followed a non-normal distribution (Kolmogorov-Smirnov test), we used the non-parametric Mann-Whitney U test for investigating between-group differences in these variables. The threshold of statistical significance was set at a bilateral alpha value of 0.05. All analyses were performed using the SPSS statistical software .During the seven-year interval analysed 2011–2017), the number of IOP tended to decrease, with a 27.5% reduction. IOP demographic, morbidity and mortality characteristics, summarized in Table 1–2017, tThe analysis—narrowed down to 2017—showed age and sex distribution differences between IOP and non-IOP , which suggest lack of preventive actions by the latter. This fact might explain, at least partially, IOP higher use of resources in acute care. However, the great variability of care models in our setting makes it difficult to draw conclusions in this sense, so studies that specifically investigate the difference regarding preventive actions between IOP and non-IOP would be necessary .The results of this study must be interpreted in the context of some methodological limitations. On the one hand, it is very likely that isolated diagnoses collected in the normal course of clinical practice (and therefore subject to heterogeneous criteria), as well as morbidity groupers, do not properly capture the seriousness of clinical processes, mainly in fragile patients with comorbidity. Deepening the knowledge of the severity degree and progression of the diseases described, as well as other chronic conditions (primarily geriatric syndromes and cognitive decline), would enable to give a more accurate clinical description of IOP. Given the descriptive and population approach of the study, comparative analyses have not considered the likely more heterogeneous clinical characteristics of non-IOP—from healthy adults to those in end-of-life transitions—compared with IOP. It would be interesting to analyse paired cases with IOP and non-IOP in the future, for example, in home care programs. Finally, being a large-scale, database-dependent epidemiological study, one key element of the person-centred care process could not be addressed , namely Our analysis shows that older people institutionalized in nursing homes tend to be increasingly older and more complex than the rest of the population of the same age. This growing gap between the two groups translates into higher mortality of IOP, which in our area was four times higher than that of non-IOP. Furthermore, the higher use of resources by acute care  and medications of IOP suggests a deficiency of preventive actions. Taken together, our findings stress the need to rethink the care model for IOP from a social and health care perspective.Additional file 1. Appendix. Figures. A1 and A2, which show the age and sex distribution of IOP and non-IOP, and the frequency of comorbidities of IOP


Background: The present study was aimed at developing nomograms estimating the overall survival (OS) and cancer-specific survival (CSS) of endometrial cancer (EC)-affected patients.Patients and Methods: We retrospectively collected 145,445 EC patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors were identified via univariate and multivariate Cox analyses. These risk factors were used to establish nomograms to predict 3- and 5-year OS and CSS rates. Internal and external data were used for validation. The predictive accuracy and discriminative ability were measured by using concordance index (C-index) and risk group stratification.Results: A total of 63,510 patients were collected and randomly assigned into the training cohort  and the validation cohort . Age at diagnosis, marital status, tumor size, histologic type, lymph node metastasis, tumor grade, and clinical stage were identified as independent prognostic factors for OS and CSS  and were further used to construct the nomograms. The area under the receiver operating characteristics (ROC) curve was greater than that of International Federation of Gynecology and Obstetrics (FIGO) staging system for predicting OS  and CSS  in the training cohort. The stratification into different risk groups ensured a significant distinction between survival curves within different FIGO staging categories.Conclusion: We constructed and validated nomograms that accurately predicting OS and CSS in EC patients. The nomograms can be used for estimating OS and CSS of individual patients and establishing their risk stratification. Endometrial cancer (EC) is the most common gynecologic malignancy in the United States , with anThe most commonly used classification system in EC patients is the International Federation of Gynecology and Obstetrics (FIGO) staging system, in which patients with non-metastatic cancer are stratified based on the depth of myometrial invasion, cervical stromal invasion, as well as the extent of lymph node involvement . HoweverNomogram is a statistical prediction tool that incorporates all prognostic factors to calculate the risk score of each patient and estimate the survival outcome for the individual, as has been widely demonstrated in other cancers such as breast cancer, gastric cancer, and ovarian cancer –8. ThereThe Surveillance, Epidemiology, and End Results (SEER) database collects data from 18 cancer registries and covers about 30% of the US population . Using t*Stat software . We identified patients who underwent primary surgery for FIGO 2009 staging system that were diagnosed between 2004 and 2015. The inclusion criteria included the following: age at diagnosis > 18 years; endometrial cancer pathologically confirmed by histology . For patients who had a history of prior malignancy and/or radiotherapy before surgery, were excluded. Clinical pathological features including patient age, year of diagnosis, marital status, tumor size, histological type, myometrial invasion, cervical stromal invasion, lymph node metastasis, tumor grade, clinical stage, chemotherapy, radiotherapy, time of survival, OS, and CSS were collected in the study. In addition, cases were excluded from the study if they had incomplete information on any of these characteristics. Age of the patients was stratified into five groups from 41 to 70 with a 10-year interval. Marital status was classified as married, single, and others (including widowed and divorced). The histological types were classified as endometrial endometrioid adenocarcinoma , serous endometrioid adenocarcinoma , and other types. Tumor size was categorized as ≤ 2, 2.1–5, 5.1–10, and >10 cm. Race was excluded because ethnicity proportions in the SEER database was uneven, which would bring bias to the nomogram. The eligible patients were randomly divided into the training cohort and the validation cohort according to the ratio of 2–1.Patients information was acquired by the National Cancer Institute SEER database, which was accessed via the SEERUnivariate and multivariate Cox regression analyses were used to identify the prognostic factors of the OS and the CSS in the training cohort. The independent risk factors were used to build the nomogram for the OS and CSS, respectively. The nomogram performance was assessed in both the training and validation groups by calculating discrimination and calibration criteria . An indeIn addition to numerically comparing the discrimination ability of the nomogram, we evenly grouped the patients into five risk groups according to the risk score calculated by the nomograms (from the highest to the lowest) in the training set. These values were then applied to the validation set and the respective Kaplan-Meier survival curves were determined.p-value < 0.05 were selected for the multivariate analysis. Hazard ratios (HR) and corresponding 95% confidence interval (CI) of variables were also calculated. The independent factors were used to build the nomograms for 3- and 5-year OS and 3- and 5-year CSS. Calibration curves were constructed to compare consistency between predicted and observed survival. Construction of the nomogram, calibration, and survival curves were performed using the rms, foreign, and survival packages in R, version 3.5.1 (http://www.r-project.org).All the categorical variables were described as frequencies and percentages. Baseline of the clinical and the pathological characteristics of the patients were compared between the training and the validation cohort using a Chi-square or Fisher exact tests as appropriate. Univariate and multivariate Cox regression analyses were performed using the SPSS 22.0 . All variables that in univariate analysis showed a n = 42,340) and the validation cohort . The demographic characteristics of the patients were listed in During the 2004–2015 time period, a total of 145,445 patients with endometrial cancer were identified from the SEER database. Of these, 63,510 patients were enrolled in this study according to the inclusion criteria and exclusion criteria listed in p = 0.004; 61–70, HR = 2.17, 95%CI: 1.82–2.58, p < 0.001; >70, HR = 4.01, 95%CI: 3.37–4.77, p < 0.001), marital status , tumor size , histological type , lymph node metastasis , tumor grade , clinical stage  were independent risk factors to predict OS in the training group. The analysis of the validation group showed similar results (p < 0.01) according to the multivariate analysis for CSS  and 0.850 (95%CI: 0.846–0.855), respectively. Similarly, the corresponding C-index values in the external validation cohort were 0.812 (95%CI: 0.806–0.819) and 0.847 (95%CI: 0.841–0.854). These results confirmed that our prognostic nomograms were reasonably accurate. The calibration curves estimating the 3- and the 5-year OS and CSS rates showed accordance between the nomogram-predicted and observed values in both the training and the validation groups . FurtherWe determined the cutoff values by dividing the patients in the training cohort evenly into five subgroups after sorting by the total OS score  and the total CSS score , and each group represented a distinct prognosis . As showThe clinical staging system is the most common method to predict the prognosis in endometrial cancer. The 2009 FIGO staging system included many of the known risk factors for OS and CSS, such as myometrial invasion, cervical stromal invasion, and lymph node metastasis. However, other important risk factors including age at diagnosis, tumor grade, and histologic type that may affect the survival, are not currently included in the FIGO system. Furthermore, in order to predict the individual survival probability, a single prognostic index may impose limitations on the individual prognosis. Accurate individual prognosis helps to avoid oncological under-treatment or over-treatment in EC patients.Nomogram is a common graphic prediction tool that can provide a more precise and acceptable accuracy and robustness to predict an individual patient's survival probability. In this study, we developed prognostic nomograms to predict the OS and CSS using univariate and multivariate Cox analyses by a large population-based database. Several clinicopathological characteristics have proven to be independent from other risk factors such as age at diagnosis, marital status, tumor size, histological type, lymph node metastasis, tumor grade, and clinical stage. Our nomograms identified these seven independent risk factors to determine the survival of EC patients and provided with an internal validation for the nomograms predicting the 3- and the 5-year OS and CSS in EC patients. Abu-Rustum constructed the first nomogram based on 5 variables to predict the OS and the study was based on 1,735 patients who received the treatment at the MSKCC in New York City . The intA previous study demonstrated that large tumor size was an important risk factor for a multitude of tumors including bladder , lung 1, and proThe validation of the nomogram is essential to avoid overfitting of the model and determine the scope of its application. In this study, calibration plots revealed an ideal accordance between the prediction and the actual observation in both the training and the validation groups, which illustrated the repeatability and reliability of the OS and the CSS nomograms. Patient differentiation was determined through a significantly higher AUC of the nomogram as compared to the FIGO staging system in both the cohorts. Historically, the FIGO staging system helped to standardize the therapeutic management and predict the OS. Our prognostic nomograms attempted to combine the FIGO staging system with other determinant clinical factors in order to predict the individual's survival outcome in all EC stages. Therefore, our nomogram represented a more accurate individual performance predicting prognosis as compared to the 2009 FIGO staging systems for EC. Our study revealed that the AUCs of the nomograms for OS and CSS were both greater than the AUCs as determined by the FIGO staging system, suggesting that the nomograms were more accurate in predicting the OS and CSS in EC patients. We also found that the MSKCC nomogram was more accurate than the 2009 FIGO staging system in predicting the OS .For a more detailed validation of the nomograms, we calculated the total scores for each patient and divided the patients into 5 subgroups  according to the total scores. According to our data, the survival rate of patients in the low score subgroup was always higher than patients belonging to the high score group, either for the OS or the CSS. The scoring system could also precisely differentiate patients in the same clinical stage but with a worse prognosis, which could be determinant in the context of an individualized treatment and of the precise therapy.This study constructed a nomogram predicting both OS and CSS based on a relative large population with a long term follow-up, and the nomogram outperformed in different layers of clinical characteristics. However, some limitations might affect our study. First, we developed and validated the nomograms using retrospective data. Although we collected the largest cohort using the SEER database which represented ~30% of the US population, the nomograms needed to be validated in a randomized controlled trial for a better reliability. The second limitation was that several recognized prognostic parameters, such as lymph-vascular space invasion (LVSI), serum CA-125 level, and chronic disease history, were unavailable in the SEER database. The external validation of the nomogram in this study also needed to be explored using prospective datasets.Above all, we developed and validated nomograms which predicted the 3- and the 5-year OS and CSS in EC patients based on a large, population-based cohort. The nomogram demonstrated a higher predictive accuracy than the FIGO staging system. Through this model, gynecologic oncologists could estimate the survival of individual patients more precisely and identify subgroups of patients needing a specific treatment strategy.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JW and XinL: conceptualization. YF and YD: methodology. YF: software. YD and YC: formal analysis. JZ: investigation. XiaL: resources. ZW: data curation. XinL: writing – original draft preparation. YF and JW: writing – review and editing. JW and YC: funding acquisition. 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.


The highest correlations in UCP group were found between proprioceptive processing and daily activities and mobility (r = −0.39); auditory, visual and tactile information and school environment ; behavioral and social-emotional responses and psychological well-being . Conclusions: UCP children have greater difficulty in sensory processing than TD children. Difficulties in proprioceptive processing contribute to poorer functional performance. Auditory, visual and tactile processing is associated with participation in the school environment and behavioral and social-emotional responses related to sensory processing are associated with the psychological well-being.Background: The study of children with unilateral cerebral palsy (UCP) has traditionally focused on motor aspects. The extent to which sensory processing disorders can affect their functional performance and quality of life (QoL) is uncertain. This study aimed to explore the differences in sensory processing between UCP and typical development (TD) children and to analyze the relationship of sensory processing with functional performance and QoL. Methods: Fifty-three children aged from 6 to 15 years  were recruited. The Child Sensory Profile 2, Pediatric Evaluation of Disability Inventory—Computer Adaptive Test and Kidscreen were used to evaluate sensory processing, functional performance and QoL. Results: UCP children showed sensory processing difficulties (avoidance:  Unilateral cerebral palsy (UCP) affects approximately 30% of children with cerebral palsy (CP) . UCP chiAccording to the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) , valid aThe quality of the sensory input provides adequate feedback and guidance needed to correct the error in a motor action, being essential for successful motor task performance ,14. UCP Sensory processing is a neurobiological process involving the registration and modulation of sensory information by neural systems. Moreover, the sensory input coming from the environment or the body itself has to be organized internally and integrated appropriately, thus the person can deliver a successful and adapted response to the demands of the environment. This allows the person to perform functional abilities of daily living and to engage in meaningful occupations . The linDifferent terminology can be found in relation to sensory processing. Dunn developed a theoretical model, Dunn’s sensory processing framework (DSPF) , which pThe sensory processing patterns proposed by Dunn are present in children with developmental conditions, such as autism spectrum disorder (ASD) and attention deficit and hyperactivity (ADH), being more likely to experience some challenges in occupational performance . AlthougGreater and more comprehensive knowledge is needed about how UCP children handle sensory information and the relationship between this processing and the functional performance, participation and QoL. This knowledge can provide important insights into the adaptations of both activities and environmental demands to promote the participation of UCP children with families and practitioners.Therefore, the aims of this study were (a) to describe the sensory processing, functional performance and QoL of UCP children compared to TD children and (b) to analyze the relationships between sensory processing, functional performance and QoL in both UCP and TD children.A cross-sectional study was performed. The study agreed with the STROBE statement . The stuFifty-three children (29 in the case group and 24 in the control group) took part in the present study. Participants were selected using non-probabilistic convenience sampling and they were recruited in the Region of Aragon and in the Region of Madrid, Spain. The groups of cases were recruited from AIDIMO (Association for Research in Motor Disability) and Hemiweb (Childhood Hemiparesis Association). Both entities sent an explanatory letter via email to their databases. In the control group, the sample selection method was convenience type, including professional and personal contacts from the context of the researchers being associated in pairs to the cases by age and sex. Family socio-economic factors were not taken into account in the pairing. In order to recruit the control sample, the project was disseminated through an explanatory document via email. Those families who volunteered to participate and met the inclusion criteria signed an informed consent prior to participation. All the participants were recruited and assessed between October 2019 and February 2020, with the assessments being done on two different days so that the possible fatigue of the families when answering the questionnaires would not influence the results. On the first day, a therapist experienced with the use of the measurement tools explained how to complete the Child Sensory Profile 2 to the families. On the second day, the Pediatric Evaluation of Disability Inventory—Computer Adaptive Test and Kidscreen questionnaire (proxy and self-report versions) were completed.The inclusion criteria for the UCP group were as follows: UCP diagnosis ; aged between 6 and 15 years; Manual Ability Classification System (MACS)  level I-CSP-2 is an 86-item parent-report measure of a child’s sensory processing characteristics. The CSP-2 measures four sensory processing patterns based on quadrants of DSPF : seekingThe PEDI-CAT is a clinical assessment for children and youth from birth to 20 years of age and can be used across all diagnoses, conditions and settings. It was developed in 2011 as a revision and updated version of the PEDI and it was designed to be a parent-report measure to examine the functional performance of children across four domains: (1) daily activities; (2) mobility; (3) social/cognitive, and (4) responsibility .The PEDI-CAT conceptual model was developed according to the ICF-CY framework, and activities and participation are strongly represented by the PEDI-CAT . The actThe PEDI-CAT has shown good reliability, validity and responsiveness in rehabilitation environments ,40. FurtThe Kidscreen questionnaire measures health-related quality of life (HRQoL) in healthy and chronically ill children from 8 to 18 years old . This inAdditionally, the Kidscreen-10 self-report version (KS-10) was included in this study to assess children’s perceptions of their global HRQoL, including physical, psychological and social aspects of HRQoL. Conceptually and psychometrically, KS-10 has demonstrated to be a good option for CP children .r effect size of 0.45 between cases and controls in the domains of the CSP-2 for a one-tail difference between a two-group analysis . Previous research comparing cases and controls reported an r effect size of 0.6 [The sample size was calculated using G*Power . Expecting a correlation from moderate to large (0.3 to 0.7) between questionnaires, with an alpha value of 0.05 and a beta value of 0.1 (power 90%), the a priori calculation for a two-tails bivariate correlation analysis indicated that a sample of 36 participants was needed. This sample size was enough to detect an e of 0.6 ; howevert test for parametric or Mann–Whitney test for non-parametric quantitative variables, and a Chi-squared test for qualitative variables). Depending on parametric or non-parametric data distribution, Cohen’s d effect size and r, respectively, were used to interpret the magnitude of the differences  [p < 0.05.Data analysis was conducted using SPSS . Data were examined for normality using the Shapiro–Wilk test. Descriptive statistics are represented as means and standard deviation (SD). In order to compare the sensory processing, functional performance and QoL between UCP and TD children, a comparison of means was conducted (using a ference) . A Pearsference) . The levAs can be seen in p = 0.02, p = 0.00, with a small (r = 0.32) and moderate effect size (r = 0.52), respectively) (p = 0.00) with a moderate effect size (r = 0.61) and oral (p = 0.02) with a small effect size (r = 0.32); and no statistically significant differences were found between groups in auditory, visual, touch and movement. Finally, in the social-emotional domains, the UCP group showed significantly higher scores as compared to the TD group (p = 0.01) with a small effect size (r = 0.33).The statistical differences between groups found in CSP-2, PEDI_CAT, KS-27 and KS-10 can be observed in ctively) . Regardip = 0.00), there was a large effect size (d = 2.21) and in mobility (p = 0.00) there was a moderate effect size (r = 0.70).The PEDI-CAT showed statistically significant differences between groups in all domains, except in responsibility; especially in daily activities (p = 0.00) with a large effect size (d = 1.06). Additionally, a moderate effect size (d = 0.534) was found for the dimension of school environment, although the difference found was not statistically significant. Regarding the KS-10, no statistically significant differences between groups were found.The KS-27 only showed a statistically significant difference in the physical well-being domain (Correlations showed a significantly negative moderate to large relationship between the avoidance and registration sensory profile patterns and daily activities and mobility domains (r = −0.41–−0.58). In the TD group, these relationships were maintained for daily activities but not for mobility. However, in the UCP group, they disappeared. In sensory systems, the highest significant correlations were found between body position and daily activities (r = −0.70), mobility (r = −0.67) and social/cognitive (r = 0.41) for the entire group. In the UCP group, these relationships were maintained for daily activities and mobility, although they were moderate and less significant. Regarding behaviors related to sensory processing, despite finding a significant negative relationship between social-emotional and daily activities (r = −0.46) and mobility (r = −0.44) for the entire group, no significant relationship was found in the UCP group .The correlations between the CSP-2 and the Kidscreen-27 and -10 domains can be observed in To the authors’ knowledge, this is the first study aimed to analyze the sensory processing of UCP children compared to TD children and to examine its relationship with functional performance and QoL. Our results showed that UCP children present, more frequently, the avoidance and the registration sensory profile pattern compared to TD children. Significant differences were found in the body position, oral sensory systems and in the socio-emotional responses, showing that UCP children have greater difficulties in sensory processing than TD children, as well as presenting greater difficulty in functional performance related to daily activities, mobility and social/cognitive function. However, our results exhibited that the UCP children in this sample can take control over major life tasks that enable independent living. The HRQoL perceived by the UCP children’s families was similar to that perceived by TD children’s families, except in the physical well-being domain. The HRQoL perceived by the children was also similar in both groups. Although there was a higher proportion of girls in the UCP group in the sample of this study, no statistically significant differences were found between the two groups, so this was not considered to influence the results. There was a significantly higher proportion of right-handed children in the TD group than in the UCP group due to the distribution of damage, so dominance was not considered as a covariate in this study.Little et al.  shows thp = 0.14), visual (p = 0.80) and vestibular (p = 0.29) information in a way that is comparable to TD children. However, other studies, such as Prakash et al. [Regarding sensory systems, our results revealed that UCP children process auditory . It seems, however, that their difficulties are more related to the registration and discrimination phases. In fact, 40% of UCP children presented deficits in registration and perception of tactile information in the affected UL and 37% presented deficits only in perception [Our results, according to Pavão et al. , indicatrception .p = 0.00). This has also been reported by Prakash et al. [p = 0.02) might be related to the prevalence of the avoidance profile in the UCP group, as these children often show avoidance responses related to certain foods and textures. Finally, our results indicated significant differences in the social–emotional responses related to sensory processing (p = 0.01) shown by the UCP group, which is common to all types of CP [UCP children have greater difficulty in modulating proprioceptive input , our results indicated that, even though they have functional performance problems, children with UCP participate equally to their TD peers. McManus et al. [Similar to our findings, Van Zelst et al.  found ths et al.  and Michs et al.  agreed wp = 0.29). These results coincide with those found by Dickinson et al. [p = 0.00). This makes sense considering the important motor consequences of the brain damage.Of note, despite low scores on functional performance, our results indicated that children with UCP perceive their HRQoL in the same way as typically developing peers , followed by the avoidance , and finally the sensitive profile . The more children present these profiles, the worse they perform. Proprioceptive processing has a large negative relationship with this performance  as well as the social-emotional responses , meaning that the more difficulties they have in processing sensory information, the worse their performance is. This confirms, as previously reported, that adequate sensory processing allows the person to perform functional abilities of daily living [When the entire group is analyzed, the patterns of sensory profiles are negatively associated with functional performance, especially the registry  and Mobility (r = −0.39 p < 0.05). This highlights the importance of unconscious proprioceptive information in posture and anticipatory control, and how this can influence movement planning [In UCP children, the sense of body position has a negative association with functional performance of ADL . This supports the idea that if children present sensory processing difficulties, this can affect the development of their executive functions [p < 0.05). This could be explained by the association between sensory sensitivity (low threshold in the avoidant profile) and attention difficulties [p < 0.01 and r = −0.49 p < 0.05, respectively).The processing of auditory and visual information negatively correlates with the HRQoL perceived by the families of the whole group regarding school environment (r = −0.53 unctions ,73. Moreunctions , visual iculties . FinallyOur study is subject to some limitations. First, the sampling of participants was non-probabilistic. Therefore, generalizing the results to a large population may be difficult, and these are only applicable to UCP children without moderate or severe cognitive impairment. Second, the PEDI-CAT is translated but not validated for the Spanish population, thus, it may not be able to identify some limitations and/or restrictions in the participation of Spanish children. Third, although none of the TD children had a diagnosis of sensory processing disorder, they were not screened prior to the study, so some of them could have sensory processing issues to a certain extent. Ultimately, we have not included an assessment that would detect deficits in the somatosensory discrimination of the UL. Despite this, our study is the first to expose and clarify sensory processing disorders in UCP children. Therefore, future lines of research should deepen into analyzing somatosensory discrimination deficits in UL, including a complete somatosensory assessment battery given its important contribution to motor control, and examine both their relationship with functional performance and the influence that the affected side, age or gender may have on their prevalence.Children with UCP have greater difficulty in sensory processing than TD children. The processing difficulties of proprioceptive input related to the handling of their body in space contribute to poorer functional performance. The processing of Auditory, Visual and Tactile information is associated with participation in the school environment and behavioral and social-emotional responses related to sensory processing are associated with the psychological well-being of UCP children. This study has clinical implications for both the families and practitioners, showing that knowing how UCP children process sensory information can provide important insights into the adaptations of both activities and environment demands to promote their participation.


Steelmaking slags are a promising resource as artificial seaweed beds for the reconstitution of marine environments. To grow seaweed well, the formation of biofilms is an essential process in biofouling. This study focused on the formation of initial biofilms on steelmaking slag samples and analyzed the resulting bacterial communities using the next-generation sequencing technique. Three types of steelmaking slag were submerged in an area of Ise Bay in Mie Prefecture, Japan, for 3 and 7 days in the summer and winter seasons to allow the formation of biofilms. The bacterial communities of these biofilms were richer in sulfur-oxidizing bacteria compared to the biofilms formed on polyurethane sponges. It was found that Helicobacteraceae dominantly grew on the biofilms formed on the slag samples. This shows that steelmaking slags have potential to be used as artificial seaweed beds and marine water purifiers. Fe), and magnesia (MgO) [2O5), and alumina (Al2O3). Fe, S, and SiO2 are essential elements for phytoplankton, however, Fe tends to be scarce in marine environments [Almost all iron and steel slags are used as a raw material for cement production, concrete aggregates, ground improvements, and so on . Japan pia (MgO) , along wronments . Thereforonments . In JFE ronments ,7,8. Addronments , which sronments  has goodronments . Yamamotronments ,13,14. WBiofouling is a vital process in the (re)generation of seaweed beds in marine environments. It involves the growth and attachment of organisms from bacteria to macroalgae and shellfish . The firIn this study, we investigated the relatively early stage  of biofilm formation in three types of steelmaking slag submerged in a live marine environment. First, the slag samples were immersed in an area of Ise Bay in Japan, where biofilm formation was observed by Raman spectroscopy. Then, next-generation sequencing (NGS) technology was employed to analyze the formed biofilms, where both the culturable and unculturable bacteria could be detected. In marine environments, the formation of biofilms on a steel substrate takes one month . The earBiofilms can be detected by crystal violet staining. Crystal violet dye is bound to negatively charged compounds of EPS components such as polysaccharides and nucleic acids ,20. Howe–1. The peak at around 1510 cm−1 is attributed to a C=O stretch vibration of peptide linkages [−1 corresponds to C–O–O stretching vibrations of lipid [−1, which correspond to the P–O stretch of nucleic acid [–1, corresponding to the C–O–O stretching vibration of lipid [linkages , and thaof lipid  and fattof lipid . These pof lipid ,34. Thereic acid  in slag of lipid  in slag Unfortunately, Raman spectroscopy failed to detect any specific Raman peaks corresponding to the biofilms in the winter-immerged samples. This could be attributed to the fact that the amount of biofilm formed on these samples were very small (below the detectable level).Eight main families were observed in each sample: Alteromonadaceae, Desulfobacteraceae, Desulfobulbaceae, Flavobacteriaceae, Helicobacteraceae, Piscirickettsiaceae, Rhodobacteraceae, and Saprospiraceae. It can be observed that the bacterial flora of the sponge samples (control) on days three and seven were significantly different from that of the slag samples. Even in the same porous material, bacterial flora varied. The reason for the remarkable difference in the bacterial flora is still unclear, however, each bacterial flora could be characterized by the variations in the slag content.Sulfurimonas, a newly discovered genus of Helicobacteraceae, can oxidize sulfides [Sulfurimonas autotrophically oxidizes sulfides in their experiment using sulfide, sulfur, thiosulfate, and hydrogen as electron donors and nitrite, nitrate, and oxygen molecules as electron acceptors [Sulfurimonas paralvinellae can perform denitrification in an anaerobic or microaerobic environment using carbon dioxide as a carbon source [A detailed comparison of the bacterial florae of the control and slag samples revealed that Helicobacteraceae was the most prevalent family in the slag samples. Nakagawa et al. reported that Helicobacteraceae is involved in the oxidation of sulfides in the ocean, and it is likely to contribute to the detoxification of sulfide compounds . In addisulfides . Furthercceptors . Addition source . Desulfobulbaceae was observed as the second typical family in the slag samples. The members of this group were identified as organic acid oxidizers, which help in bacterial water purification. When in contact with water, they transport electrons from hydrogen sulfide-rich sediments to oxygen-rich sediments . DesulfoPiscirickettsiaceae was also discovered as one of the typical families in the slag samples. These bacteria have been intensively studied for various applications, including water treatment, bioleaching, and bioremediation. Recent investigations revealed that these bacteria are S-oxidizing compounds .Saprospira has both a high sulfide-oxidizing activity and an ability to degrade sulfate compounds in shallow-water gas vents [Interestingly, all the samples, including the control samples, contained Saprospiraceae, under which 14 known bacteria have been classified . The memas vents .Sulfurimonas was the only identified main genus in all the three slag samples, however, it was not observed in the sponge samples. For the Desulfobulbaceae family, all bacteria were unassigned in all the samples. On the other hand, Lewinella was the main genus in Saprospiraceae in all the samples, and the dominance was higher in all the slag samples than in the sponge samples. Lewinella sp. are long rod-shaped heterotrophic bacteria, which belong to Bacteroidetes, and they mainly live in the bottom mud. They can degrade organics, such as organic acids and polysaccharides [Lewinella agarilytica can degrade agar and xylan (polysaccharides) [charides , and conharides) .This study elucidates the dominance of sulfide-oxidizing bacteria in seawater-immerged slag samples. In particular, Helicobacteraceae was found as the typically dominant biome even though its rate in the samples tested in the winter was less than that of the summer. Considering that biofouling (biofilm formation) in the summer season proceeded faster than that in the winter season, then Helicobacteraceae would grow dominantly on the steelmaking slag samples . Helicobacteraceae is considered to play a significant role in the oxidization of sulfides and denitrification around the immerged slag environment. In the summer season, slag types II and III showed more abundant Helicobacteraceae and Desulfobulbaceae than slag I. Moreover, in the winter season, Helicobacteraceae was more abundant in slag II, suggesting that type II is most suitable for applications in seawater purification. Pseudoalteromonas species  isolated from biofilm were formed in the soil of the tideland [Iijima et al. reported that some tideland . In thisIn this study, we focused on the early stage of biofouling, i.e., the biofilm formation (within one week), on steelmaking slag in a marine environment. Based on the constituents of steelmaking slags, previous studies, and experimental results of the bacterial biomes from biofilms formed on steelmaking slags, we propose the mechanism of  biofilm formation as follows :   were used as the reference specimens.Slag types I, II, and III were provided by Professor Ryo Inoue of Akita University, Japan. The compositions are summarized in Each type of slag and reference specimen (10 units) was packed in a polyethylene mesh sack . The packed sacks were tied to a steel sample holder with a polypropylene rope, and the holder was suspended on two thick polyethylene ropes a. This a−1. The measurements were performed for 10 s. Sixteen measurements were performed each, of which the average was recorded as the biofilm spectrum.Microscopic Raman spectroscopic analysis of the slag samples after the marine immersion test for 3 or 7 days was conducted using a laser Raman spectrophotometer . The measurement points were selected using a microscope attached to the spectrophotometer, and these points were irradiated by the laser. The measurement range was 657–1688 cmg). The supernatant was collected and centrifuged for 20 min at 15,000× g to recover the microbial cells. The bacterial genomic DNA on each sample was extracted using a Promega DNA purification system  according to the manufacturer’s instructions.Each sample was pooled into a tube and homogenized using Beads Crusher  for 1 min at 4000 rpm. The debris was removed by quick centrifugation . The first step of the polymerase chain reaction (PCR) was performed using the universal primers 27F (5′-ACACTCTTTCCCTACACGACGCTCTTCCGATCTAGRGTTTGATYMTGGCTCAG-3′) and 338R (5′-GTGACTGGAGTTCAGACGTGTGCTCTTCCGATCTTGCTGCCTCCCGTAGGAGT-3′). Thermal cycling was maintained for 24 cycles. The PCR products were purified using the Wizard SV Gel and the PCR Clean-Up System (Promega). The second step of the PCR was amplified using the purified products from the first PCR (12 cycles). A second PCR was performed, following the same method as those of the first PCR, using 27F and 338R primer-added barcodes for each sample. After the second PCR, the products were treated as described above for the first PCR products.The samples were sequenced on an Illumina MiSeq platform. After using a FASTQ barcode splitter (FASTX toolkit)  to excluThis study focused on the relatively initial formation of biofilms on steelmaking slags in a marine environment since it is a crucial step in biofouling in the establishment of seaweed beds. Three types of steelmaking slags, two hot metal pretreatment slags (slag I and slag II) and a converter slag (slag III), were immersed in a marine environment, and biofilms were successfully formed. Compared with the biofilms formed on the polyurethane sponge foams as a control specimen, those formed on the slag samples were rich in the S-oxidizing bacteria of Helicobacteraceae and Piscirickettsiaceae as well as in organic acid-oxidizing bacteria of Desulfobulbaceae. These bacteria can purify marine waters, therefore, the biofilms formed on the steelmaking slag could be suitable for marine water treatments. Furthermore, the biofilms on slag samples II and III were richer in Helicobacteraceae and Desulfobulbaceae than those on slag I, which indicates that slag samples II and III are superior to slag sample I in marine water treatments. However, the relationship between the components of the various slag types and the trends of the biofilm formation suitable for water treatment remains unknown. Thus, there is a need for more investigation on these in future research, which will focus on the components of steelmaking slags, particularly, the sulfur and calcium contents.