Although several studies have investigated the associations of neck circumference (NC) with arterial blood pressures (BPs) and hypertension, no such studies have been conducted among Northern Chinese population. Between April and June 2015, a total of 2631 subjects aged ≥35 years old were recruited from Northeastern China. NC and arterial BPs were measured by trained personnel. Generalized linear and logistic regression analyses were applied to examine the associations of NC with arterial BPs and hypertension risk. The optimal cut-off points of NC for predicting hypertension were assessed by the receiver operating characteristic analysis. We found that NC was significantly associated with arterial BPs and hypertension risk in the Northeastern Chinese adults, even after adjusting for many covariates including body mass index, waist circumference or waist-to-hip ratio. The optimal cut-off values for NC to predict hypertension differed with sex, age, and body mass index. Our study suggests that NC may play an independent role in predicting hypertension beyond the classical anthropometric indices, and that it could be used as a valuable anthropometric measurement for routine assessment in primary care clinics and future epidemiological studies. The causes of hypertension are complex and are correlated with numerous environmental and genetic factors. Among them, adiposity is a well-documented modifiable risk factor. Body mass index (BMI), waist circumference (WC) and waist-to-hip (WHR) are the most used anthropometric indices to reflect the total body adiposity or visceral adiposity, and to predict hypertension risk4. However, several recent studies reported that the regional deposition of fat, especially in the upper body segment, is more pathogenic than total body adiposity and visceral abdominal fat6.Hypertension is a leading risk factor for many disorders including coronary heart disease and stroke, and contributes to approximately 12.8% of annual deaths worldwide8, obstructive sleep apnea syndrome8, and cardiovascular diseases14. However, only a few studies have investigated the relationships of NC with arterial blood pressures (BPs) and hypertension14, and the results were often inconsistent. In a systematic literature review, we found 3 human epidemiological studies on NC and arterial BPs or hypertension in Chinese population. Specifically, Zhou et al. investigated the relationships of NC with cardio-metabolic syndrome risk in 4201 middle-aged Chinese southerners, and found that NC had significant associations with arterial BPs and hypertension12. Similarly, a more recent study conducted in 1943 Central Chinese reported that the positive predictive of NC for discriminating hypertension were 77.58% in males and 71.36% in females13. However, another study on 1709 adults from central China, showed that NC was not associated with systolic blood pressure (SBP) and the association with diastolic blood pressure (DBP) was very weak14.Neck circumference (NC), a simple, cheap, time-saving and practical anthropometric parameter, has been used as a surrogate measure for the upper body subcutaneous adipose tissue distribution. In the past decade, accumulating evidence showed that NC was independently associated with metabolic syndrome17. However, the 3 prior studies mentioned above were all performed in Southern and Central China, and, to the best of our knowledge, no such study had been performed in people living in northern China. In addition, several prior studies conducted in other countries have applied receiver operating characteristic (ROC) analysis to assess the accuracy of NC as diagnostic tests for hypertension20 and indicated that NC may be a valuable anthropometric parameter to predict hypertension risk. However, no study to date has explored the optimal cut-offs of NC in discriminating hypertension in Chinese adults.In China, the distribution of hypertension and obesity prevalence rates show a large geographical imbalance and people living in north areas usually have higher prevalence of the two disorders than the southerners, presumably due to differences in environmental exposure, dietary patterns, life habits, and genetic backgroundsTherefore, we conducted a large community-based cross-sectional study in Northeastern China to explore (1) the potential relationships of NC with arterial BPs and hypertension; (2) the optimal cut-points of NC for predicting hypertension risk.p < 0.05).Figure p values for age, gender, fasting blood glucose (FBG), salt consumption, family history of hypertension, smoking and drinking status, physical activity and history of hypertension were less than 0.2. Thus, these variables were included in the final multivariate regression model. Further, we made additional adjustments for BMI, WC and WHR one by one due to close collinearity between them. For all subjects, NC was significantly associated with increased SBP and DBP levels in all the 5 models. For females, after further adjustments for BMI (model 3) or WC (model 4), the effect sizes were attenuated but still significant. For males, NC was associated with SBP in all the 5 models. However, for DBP, its association with NC became insignificant after additional adjustments for BMI or WC .We also performed univariate and multivariate logistic regression models to estimate the relationships of NC levels with hypertension risk Table , and fouSubsequently, we used the areas under the ROC curves (AUCs) to evaluate the predictive values of NC for hypertension susceptibility Table . The AUCFurthermore, we assessed the associations between NC categories based on cut-off values and the risk of hypertension by gender Table . TherefoIn this study, we found that NC was associated with arterial BPs and hypertension risk in the Northeast urban Chinese adults, even after adjusting for many covariates including BMI, WC or WHR. In addition, we estimated the optimal cut-off value for NC to predict hypertension, and found that the values differed with gender, age and BMI.et al. reported that NC was strongly associated with SBP and DBP levels21. In a cross-sectional study of 4201 Chinese adults, Zhou and colleagues found that NC had positive correlation with SBP, DBP and hypertension12. Additionally, Lee et al. compared the predictive power of anthropometric indices for hypertension in a Korean population, and found that NC was a valuable index in distinguishing hypertension and normotension19. Consistent with these prior findings, our current study found that NC was significantly associated with both arterial BPs and hypertension.In recent years, a growing number of studies have been performed to estimate the associations of NC with arterial BPs and hypertension. For instance, in a longitudinal cohort study of 431 Israeli individuals, Ben-Noun 18. For example, in the Framingham Heart Study in 3307 participants, Preis et al. found that NC were related with SBP and DBP levels and hypertension risk in both males and females after adjusting for several potential covariates. However, after further adjustments for BMI, NC was positively related to DBP in males only9. Likewise, in a cross-sectional study of Caucasion population, Assyov et al. observed that NC was associated with hypertension in univariate analysis. However, when adjusted for WC and age, the association lost its statistical significance in females18. Contrary with these studies, our study showed that the significance of the associations of NC with arterial BPs and hypertension were not changed after additional adjustments for BMI or WC, although the magnitudes of the associations were slightly attenuated. The inconsistencies between those prior studies and ours may be caused by differences in genetic backgrounds, dietary habits, adjustment factors, and the effects of other confounding factors.Due to the close link of NC with BMI and WC, several previous studies found that after further adjustments of BMI or WC, the associations of NC with arterial BPs and hypertension became insignificant18. Additionally, Zhou et al. reported that NC was a valuable index for discriminating hypertension in Chinese adults 12, which further corroborated by the subsequent studies among Korean population 19 and American children 20. In our study, the AUCs for males and females were 0.583 (95% CI = 0.546–0.621) and 0.577 (95% CI = 0.550–0.604), respectively, which were relatively lower than those observed in the previous studies. However, in the current study we observed that both the discriminative values in distinguishing hypertension were statistically significant . Additionally, applying binary logistic regression analyses, we explored the association of NC with hypertension risk based on the calculated cut-off values of ROC analysis, and observed that participants with NC above cut-off values had an approximately 1.70-fold increased risk of hypertension than those with NC below cut-off values. In sum, although there exists heterogeneity in the diagnostic value of NC in discriminating hypertension among different populations, evidence from our and those previous studies consistently support that NC is a valuable index for discriminating hypertension.We further used the ROC analysis to determine the predictive validity of NC and evaluated optimal cut-off values for identifying hypertension, and found that a NC of more than 32.75 cm in females and 35.75 cm in males is suitable for assessing the likelihood of hypertension. In a systematic MEDLINE search, we found 4 relevant human epidemiological studies on the accuracy of NC as diagnostic test for hypertension. A study of 255 Caucasian adults found that the cut-off values of NC for the prediction of hypertension in females and males were 35 cm and 38 cm, respectively, which were relatively greater than those observed in our analysisBecause of the links of age and BMI with NC, we further assessed the optima cut-offs of NC by age and BMI groups, and found that the cut-off values were relatively higher in the younger and those with higher BMI. To our knowledge, this is the first study to determine the age- and BMI-specific predictive validity of NC in identifying hypertension, thus it is difficult to directly compare our results with other findings. Future studies with large sample size and longitudinal design is needed to validate our findings.26. Additionally, NC is an important predictor of obstructive sleep apnea syndrome. Obstructive sleep apnea syndrome can cause hypertension by increasing sympathetic activity, which influences vascular resistance and cardiac output27, as well as the potential for fluid retention29. Thus, the association of NC with arterial BPs and hypertension may also be mediated by its relationship with the severity of sleep-disordered breathing.The precise mechanisms underlying the relationships of NC with arterial BPs and hypertension are not fully understood. Several investigators have proposed that upper-body subcutaneous fat might affect the arterial BPs and the development of hypertension via releasing large amounts of systemic free fatty acid, which may induce insulin resistance, vascular injury, provoke endothelia cell dysfunction, and increase oxidative stress and very-low-density lipoprotein cholesterol production32. Thirdly, NC is a proxy for upper-body subcutaneous fat, we did not perform radiographic measures to directly quantify the depot of fat. Despite these caveats, our study still has several advantages. First, to the best of our knowledge, it explored the associations of NC with arterial BPs and hypertension risk for the first time in the Northern Chinese adults, and reported the optimal sex-, age-, and BMI-specific NC cut-off points in the population. Second, all participants were of Han nationality and from the same district, which reduce the selective bias and improve the validity of statistical analysis.In interpreting the findings of the current study, three main limitations should be acknowledged. Firstly, the cross-sectional nature of the present study may limit the interpretation of causality of associations between NC and arterial BPs and hypertension. Secondly, self-reported information such as smoking and drinking status, and physical activity might have caused recall biases. In addition, we used questionnaire method to evaluate salt intake, which might have caused underestimation of actual salt intakeIn conclusion, this is the first study to explore the relationship between NC and BPs in Northern Chinese. Our findings suggest that NC may play an independent role in predicting hypertension beyond the classical anthropometric indices including WC, BMI, and WHR, and that the optimal cut-offs of NC for distinguishing hypertension differs with sex, age and BMI. The measurement of NC is inexpensive and easier to obtain, thus it could be used as an important measure to consider for routine assessment in primary care clinics and other health care settings as well as for large-scale epidemiological studies on obesity-related diseases. However, considering the limitations of our study, further large prospective population-based studies and mechanistic studies are still needed to validate our finding, and to explain how NC contributes to the elevated arterial BPs and the development of hypertension.The cross-sectional study was conducted in Shenhe district between April and June 2015. The district locates in the center of Shenyang city and consists of 14 blocks. A total of over one million people reside in this district, of whom 73.00% are registered residents. A 3-stage sampling method was applied to select participants in this study. In the first stage, we selected all the 14 blocks of the district, and from each of these, 8 communities were randomly identified. In the second stage, we selected 25 households from each of the residence community using systematic sampling. In the third stage, one participant, aged ≥35 years old and lived in the district for at least 2 years, was selected from each household without replacement. The sampling frame resulted in the selection of 2800 potential participants, of whom 2761 individuals agreed to participant in the investigation and filled out the questionnaire, yielding a response rate of 98.61%. All of the participants are registered residents of the district. Inclusion criteria included: (1) without thyroid diseases, neck masses and deformity, malignant diseases, and secondary hypertension; (2) without pregnancy, lactation and weight control; (3) Han nationality. Finally, a total of 2631 individuals met these criteria and were included in the present analysis. The study was in accordance with the World Medical Association Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects and was approved by the Ethics Committee of China Medical University. A written informed consent form was obtained from all participants after they had been informed of the objectives, benefits and confidentiality of personal information.2). NC was measured at the level of the laryngeal prominence using a flexible tape, with the subjects in the standing position and the head held erect and eyes facing forward. WC was measured at the level of the midpoint between the lower rib margin and the iliac crest. HC was measured at the level of maximal protrusion of the gluteal muscles. WHR was calculated as WC divided by HC.The anthropometric indices were measured using standard techniques and equipments with the subjects in light clothing after an overnight fast. BMI was calculated as weight in kilograms divided by the square of height in meters -minutes/week, or ≥7 days of any combination of walking, moderate- or vigorous intensity activities achieving ≥3000 MET-minutes/week), moderate , and low (not meeting any of the above mentioned criteria) categories36.All participants underwent a self-administered questionnaire delivered by a face-to-face interview. The questionnaire had two parts: the first section elicited baseline information of demographic characteristic; the second section elicited information on tobacco use, alcohol consumption, salt consumption, and physical activity as well as other health-related information. Smoking and drinking status were categorized as current-, former- and non-smoking or drinking, which were detailed in our previous paperAll participants were asked for permission to collect a blood sample after an overnight fast of >8 hours. The concentrations of TC, TG, HDL-C, LDL-C, and FBG in samples were determined using a Mindray Autoanalyzer  in local community health service centers as well as environment and non-communicable diseases research centers, China Medical University. All assays were performed according to the manufacturer’s instructions.p < 0.2 in the univariate analysis were included in the multivariate model. Additionally, to avoid the problem of multi-collinearity, BMI and WC were included in the models as categorical variables, because multicollinearity between categorical variables was thought to be not as strong as that between continuous variables37. Normal weight was defined as a BMI < 24, overweight was defined as 24 ≤ BMI < 28, and obesity was defined as a BMI ≥ 2838. Abdominal obesity was defined based on WC . Therefore, model 1 included only NC. In model 2, we adjusted for age, FBG, salt consumption, smoking and drinking status, physical activity and family history of hypertension. In model 3, we adjusted for the covariates in model 2 as well as BMI categories. In model 4, we adjusted for the covariates in model 2 as well as WC categories. In model 5, we adjusted for the covariates in model 2 as well as WHR. Subsequently, ROC analysis was performed to assess the accuracy of NC as diagnostic test for hypertension, and determine optimal sex, age and BMI-specific cut-offs of NC for predicting hypertension. Logistic regression models were also used to assess the associations of NC (per unit increases of NC) and NC categories  with hypertension risk. All statistical analyses were performed using SPSS software . A two tailed p value < 0.05 was taken as statistically significant.As human body shape differs according to gender, the data for females and males were treated separately. All of the continuous variables were tested for normality by Shapiro-Wilks W test before Student’s t-test, and those non-normally distributed variables were log-transformed to reach normality and variance homogeneity. Differences in the distribution of baseline characteristics between males and females were tested using student’s t-test for continuous variables  and chi-square test for categorical variables . Generalized linear regression models were used to examine the associations of NC with SBP and DBP. Univariate and multivariate logistic regression models were used to assess the association between NC and hypertension risk. We performed univariate regression analysis to evaluate the potential risk factors of arterial BPs and hypertension, and those with Supplementary Tables


BICs of the HE- and H-treated samples were significantly higher than that of the control. Metal ion diffusion towards the bone was also evaluated to examine the adverse effect of metal ions. No metal ion diffusion was observed, indicating the safety of our solution processed implant materials.Simulated Body Fluid (SBF) has served as a useful standard to check the bioactivity of implant materials for years. However, it is not perfectly able to imitate human serum; sometimes disparities between the SBF test and animal test were confirmed. Therefore, to ensure the reliability of the results of the SBF test obtained from our previous study, an animal study was performed to check osteoconductivity of surface modified implant materials. Three types of solution processes, hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE), were performed on the Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) to improve its bioactivity, and their bioactivities were measured  To evaluate bioactivity in a simple and inexpensive way, the simulated body fluid (SBF) test was developed by Kokubo et al. . This teaterials . A recenivo test . These divo test . Human sIn our previous study, the SBF tests were conducted on a surface modified Ti-29Nb-13Ta-4.6-Zr (TNTZ) alloy . This al2-heat-water treatment for the application of implant material.To improve its biocompatibility, three types of surface modification processes were performed in the previous study: hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE) processes . One of in vivo environment, in which blood flow and proteins such as collagen exist. Therefore, in this paper, bioactivity of the TNTZ alloy surface modified by the three processes mentioned above was evaluated in vivo based on bone-implant contact (BIC). Moreover, we conducted a non-parametric statistical analysis on the BIC data of the TNTZ samples to provide a new insight into the treatment effects of these solution processes. It is noted that the statistical analysis presented in this paper is applicable to a wide range of biomedical studies where only small numbers of observations are available. Lastly, in addition to the BIC measurements, electron dispersive x-ray spectrometer (EDX) mapping was also performed to observe metal ion diffusion towards the bone region since metal ions were reported to cause bone resorption [Our previous report revealed that the order of apatite inductivity for the three processes was HE > H > E without impairing adhesive strength between alloy surface and apatite layer , 10. Howsorption .The material used in this study was a forged TNTZ bar. The forged TNTZ bar was solutionized at 1073 K for 3.6 ks followed by water quenching. TNTZ samples with a thickness of 5 mm and a diameter of 2 mm were machined from the forged TNTZ bar subjected to solution treatment. The TNTZ samples were then degreased prior to the experiment by sonication in acetone and distilled water  for 10 min each and air-dried at ambient temperature.4F for 1 h. For the H and HE processes, the hydrothermal temperature was set at 90°C, and for the E and HE processes, the applied current density was set to 15 mA/cm2 [H, E, and HE processes were then performed on the TNTZ samples. All the samples were treated with 5 M NaOH solution containing 0.17 wt% of NH5 mA/cm2 . All of 5 mA/cm2 .The TNTZ samples subjected to each solution treatment mentioned above and untreated control were implanted in the tibia metaphysis of seven-week old Sprague Dawley rats  weighing 330–360 g. Bioactivities were evaluated from new bone formation. Before surgery, all the TNTZ samples were cleaned with distilled water. Rats were kept in quarantine for seven days. Prior to surgery, the rats were anesthetized with pentobarbital (25–30 mg/kg), and the operation region was shaved and cleaned with povidone-iodine solution and ethanol. Holes with a diameter of 0.5 mm and a length of 2 mm were created at the middle of the tibia metaphysis using a slow speed rotary drill, and then the TNTZ samples were inserted in the hole. To prevent festering of the operation site, Penicillin G was administered. Then, the skin was sutured and cleaned with povidone-iodine solution.After surgery, the rats were kept individually in polycarbonate cages and reared for two weeks. No complications or ill effects were observed while rearing. Rats were then sacrificed by exsanguination being anesthetized with 2–3% isoflurane and the implanted TNTZ samples with surrounding tissues were explanted. The TNTZ samples were fixed in 10% neutral buffered formalin solution followed by rinsing with distilled water. Then, the rinsed TNTZ samples were dehydrated in a graded series of ethanol, followed by acetone, and embedded in methylmethacrylate. Subsequently to polymerization, each TNTZ sample was mechanically sliced to be 20 μm thick using a microcutting machine  and a microgrinding machine . The sliced sample was then stained with toluidine blue and observed by light microscopy to determine BIC. This experiment was carried out at the laboratory of Hamri Co., Ltd. , which has been approved by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) International. The experimental protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Hamri Co., Ltd. .BIC was determined by the linear measurement of direct bone contact with the implant surface, which was calculated using the following formula:BIC was measured separately in cancellous and cortical bone regions using a fluorescence microscope  (n = 3-6/group). Statistical analysis was then performed to determine the treatment effects of different solution processes.Statistical analysis was performed on the BIC data of the TNTZ samples with and without each alkali solution treatment in the cancellous bone region and is detailed below in the following subsections.Due to small sample sizes, outlier detection was performed by R using Hampel’s identifier ; the staWith such small sample sizes, it was not possible to assume any underlying distribution of the data. Therefore, a robust non-parametric rank-based multiple contrast testing procedure  was perfp1 and p2 are the relative effects of the two samples being compared. the Hasselblad-Hedges effect size allowed us to interpret the magnitude of effects easily due to its similarity to one of the most widely used effect sizes called Cohen’s d. Specifically, the common cut-off values of 0.2, 0.5, and 0.8 in absolute values were respectively used as small, medium, and large effects in this study. Statistical significance was determined at p < 0.05, where p denotes the adjusted p-value.Effect sizes, which are used to supplement the results from statistical tests, are reported to provide a more intuitive understanding of the magnitude of differences between samples. To facilitate the understanding of its magnitude, we employed the Hasselblad-Hedges effect size, which is useful for relative effects . Specifi+ sputter gun. MaltiPack software was used for the analysis.The interface region of bone and TNTZ on the sliced implanted sample was observed using a scanning electron microscopy (SEM)  with an acceleration voltage of 15 kV. To confirm any metal ion diffusion from the TNTZ alloy into surrounding tissue, the interface region of the bone and TNTZ alloy on the sliced implant was analyzed using an energy-dispersive X-ray spectrometer . Then, elemental mappings of Ca, Ti, Nb, Ta, and Zr were conducted. For surface chemistry analysis, X-ray photoelectron spectroscopy (XPS) was performed in a PerkinElmer 5500MT spectrometer. XPS data were acquired using Al Kα X rays with pass energy 8 kV. Sputter cleaning was done with ArNo significant differences were observed in the cortical bone region, while significant differences were detected in the cancellous bone region between samples-Box plots of BICs of the TNTZ samples without the alkali solution treatment (referred to as raw) and with each alkali solution treatment in the cortical bone and cancellous bone region are shown in In the cortical bone region, there were only minor differences in the BIC among the TNTZ samples without and with alkali solution treatments, and the median of each TNTZ sample was between 20–50%. On the other hand, BIC in the cancellous bone region showed clear differences among the TNTZ samples with and without alkali solution treatments. The TNTZ samples subjected to the HE, H, and E processes had much higher median values of 78, 62, and 51%, respectively, than the raw TNTZ sample (15%). Such a different tendency in the BIC values between the cortical and cancellous bone regions may arise from blood flow differences in these two regions. It is widely known that the blood flow is much faster in the cancellous bone than in the cortical bone [Pairwise and effect size comparisons clearly show the difference in each treatment- No outlier was detected using Hampel’s identifier. As such, all of the observations were used in the analysis. Specifically, there were 5, 5, 6, and 3 observations from the TNTZ samples subjected to H, E, and HE processes, and the raw TNTZ sample for the cancellous bones, respectively.p-values for the all-pairwise differences in the BICs of the cancellous bones. The p-values were adjusted appropriately for multiplicity using the multivariate t-distribution, and statistical significance was determined at p < 0.05. In particular, statistically significant evidence of alkali solution treatment effects was found when the TNTZ sample subjected to the H process (H) and the raw TNTZ sample (Raw) were compared, and also when the TNTZ sample subjected to the HE process (HE) and the raw TNTZ sample (Raw) were compared.C and the corresponding magnitude of effect for the six all-pairwise comparisons were reported. Several medium and large effects were observed by using the effect size C. For the cancellous bones, the difference between the TNTZ samples subjected to H and Raw, E and HE, E and Raw, and HE and Raw, were considered either medium or large.A question that arose from these findings was if there was any practical difference between the TNTZ samples subjected to H and E, HE and E, and H and HE. Even though the pairwise comparisons above revealed no statistically significant difference, this may be due to the low power of detecting any statistically significant difference for very small sample sizes. As a remedial measure, the Hasselblad-Hedges effect size was also calculated for measuring the practical magnitude of pairwise differences. The analysis above suggested advantages of some methods, which were not clear from the statistical tests. In particular, the effect size of -0.681 for the pair E and HE showed a medium advantage of HE over E. Moreover, the comparison between H and HE resulted in the effect size of -0.224, indicating a small advantage of HE over H. From these observations, some advantage of the HE treatment over H and E was suggested. In addition, the ones that showed statistically significant differences (H vs. Raw and HE vs. Raw) had large effects , implying substantial advantages of the H and HE treatments over the untreated TNTZ sample.No alloying elements diffused into bone- Figs p < 0.01) while the BIC value of the TNTZ sample subjected to the E process was not significantly different from that of the raw TNTZ sample. These differences could be attributed to the chemical composition of the sample surface. Our previous experimental results suggested that the sample surface with higher Nb oxide is likely to inhibit apatite formation, and a higher amount of Nb was found on the surface of the TNTZ subjected to the E process [4+ ion was coordinated with oxygen and stable with some Na+ ions. When the TNTZ samples were subjected to the H and HE processes, their surfaces were mainly composed of the Na-contained amorphous titanium oxide. However, for the TNTZ sample subjected to the E process, Nb oxides took up spaces where Na-containing amorphous titanium oxides existed, as shown in +. As a result, the total amount of Na+ ions decreases. Therefore, the TNTZ sample subjected to the E process contained less Na+ ions on its surface, which releases less Na+ ions in blood plasma, resulting in a less negatively charged surface as compared to those of the TNTZ samples subjected to the H and HE processes. As a result, the surfaces of the TNTZ samples subjected to the H and HE processes were very much negatively charged and could attract Ca2+ ions easily. Once Ca2+ ion is adsorbed on the surface, fibronectin, which is considered as an important cell adhesion molecule, binds with the surface via a Ca2+ site by its carboxyl group [in vitro experiment, which analyzed osteoconductivity using an SBF immersion test [in vivo experiment and supported the usefulness of the immersion test in SBF solution as an indicator of osteoconductivity.In the cancellous bone region, statistical analysis of BIC indicated that the TNTZ samples subjected to the H and HE processes had significantly higher BIC values than that of the raw TNTZ sample  gene expression, which caused bone resorption at the interface of dental implant and tissues [Several studies showed adverse effects of the Ti tissues . Other r tissues . Therefo tissues . The thi tissues , 26. Acc tissues , fabricain vivo based on the bone-implant contact (BIC) test and deemed as safe biomaterials. The HE process, in particular, is a very promising surface modification process for TNTZ as it results in high osteoconductivity and corrosion resistance. Specifically, the degree of osteoconductivity in vivo matched with the results from the in vitro experiment [In summary, the bioactivity of TNTZ, whose surface was modified by alkali solution treatments , was evaluated periment , support


There is a need to examine the issue of childhood obesity from a systems perspective. This study aimed to describe the baseline characteristics of children attending pediatric multidisciplinary weight management services and understand how this information will inform future service delivery. A total of 51 children and adolescents who were overweight and obese  and aged between two and 16 years participated. Body size measures such as body mass index (BMI) and body fat percentage were collected. Participants and their parents/guardians also completed questionnaires on dietary intake, behaviors and habits, physical activity and health-related quality of life. A total of 72% of participants were classified as morbidly obese. Adolescents had significantly lower scores for overall diet, physical activity and particular health-related quality of life scores. No significant correlations were found between BMI z-scores and diet, physical activity and health-related quality of life. In adolescents, correlations were detected between dietary scores and health-related quality of life. Results confirm the need to critically examine the current context to adapt and tailor interventions to individual circumstances, and when combined with focused referral, triaging and screening processes, should assist in delivering the right care at the right time. There is a clear need to understand the issue of childhood obesity from a systems perspective. Overweight and obesity in childhood and adolescence remains a critically important health care issue, both in Australia and internationally ,2. ObesiCurrent literature highlights the need for a systems approach to the issue of childhood obesity. The World Health Organization (WHO) Commission on Ending Childhood Obesity recently released a report which details actions required to address the issue of childhood obesity worldwide . The plaHealth services research, with a focus on implementation science, is a systems approach that enables researchers to understand the strengths and weaknesses of a health care system, and how research findings and evidence can be translated and integrated into changes in health care policy and practice ,11. MoreThere are currently limited public health services in Australia for children who are overweight or obese, and these services are not always delivered in a consistent, integrated way. The majority of children do not receive evidence-based care, despite our knowledge of what works . To inveThis prospective cross-sectional study was part of a larger project investigating the expansion, evaluation and sustainability of a public multidisciplinary pediatric weight management service in Queensland, Australia. Ethics approval was obtained from the Human Research Ethics Committees at both Children’s Health Queensland Hospital and Health Service (CHQ HHS) and Bellberry Limited respectively. The study is registered under the Australian New Zealand Clinical Trials Registry (ID: ACTRN12616000101482) and is a pragmatic research trial. Written informed consent was provided by all parents/guardians and obtained from participants where appropriate. Data collection occurred between June 2016 and June 2017 at two clinic locations: Lady Cilento Children’s Hospital (LCCH), a large central service and at a satellite site, The University of Queensland (UQ) Ipswich Nutrition and Dietetics practice (IPSWICH), both situated in Queensland, Australia. All children and their parents/guardians attending the clinic were invited to participate in the study. Inclusion criteria for acceptance in the clinics were the following: (i) referred by a pediatrician, primary care provider (PCP), member of the education department or allied health and aged between 0 and 18 years; and (ii) participants less than two years of age were required to be above the 97th percentile on the WHO weight-for-age growth charts . ChildreThe multidisciplinary weight management clinic offered the same service to children, adolescents and families across the two sites, and involved a medical practitioner (pediatrician or endocrinologist), dietitian and psychologist. It was an intensive, clinical management program in a real-life setting, and all advice and guidance provided was individualized and evidence-based, following recommendations from the Clinical Practice Guidelines for the Management of Overweight and Obesity in Adults, Adolescents and Children in Australia . Advice 2) was calculated using the above information and BMI z-score for age and gender was determined via US-CDC or WHO z-score data files [Height was measured to the nearest 0.1 cm using a stadiometer  and weight to the nearest 0.1 kg was collected using digital scales  with participants wearing light clothing and no shoes. BMI  questionnaire . This toPhysical activity (PA) was assessed via paper-based questionnaires and completed by participants or parent/guardian depending on age and capacity. The validated pre-school age physical activity questionnaire (Pre-PAQ) was used to assess young children who were not yet of school age . For thiHealth-related Quality of Life (HRQOL) was measured using the paper-based PedsQL™ Measurement Model for the Pediatric Quality of Life Inventory™ questionnaire, validated for ages 2–18 years . PedsQL™t-tests and Mann-Whitney U tests (for variables compared across two age groups only) or via ANCOVA with post-hoc multiple comparisons, adjusted for the Index of Relative Socio-Economic Disadvantage Score (IRSD). Differences between child-reported and parent proxy-reported quality of life scores were calculated using paired samples t-tests and Wilcoxon signed rank test. Relationships between key variables were assessed using partial correlation, controlling for the effect of IRSD scores.Statistical analyses were performed using Statistical Package for the Social Sciences version 23 (IBM SPSS Statistics 23.0). Standard diagnostics tests such as normality and homogeneity of variance were performed. All tests were two tailed and statistical significance was set at an α value of 0.05 apart from Mann-Whitney U tests to identify differences between the three age groups and here it was set at 0.017 to avoid Type 1 error. Participants were grouped according to age: 0–4.99 years (young children), 5–11.99 years (children) and 12–17.99 years (adolescents) and descriptive statistics determined. Differences in variables between groups were assessed using either one-way ANOVA with the post-hoc Tukey tests, Kruskal Wallis tests with post-hoc Mann-Whitney U tests, n = 7) were classified as overweight, 14% (n = 7) as obese and 72% (n = 37) as morbidly obese [n = 18 participants, 35%), followed by paediatricians within the LCCH , external general practitioners , external dietitians , obesity specialists within the LCCH  and external paediatricians . All participants were either Anglo-Celtic or East Asian in ethnicity.Fifty-one children and adolescents  ranging in age from 1.6 years to 16.3 years participated in the study over a one-year period (July 2016 to June 2017). At the time of assessment, 53% of the participants attended the LCCH clinic, and 47% attended the IPSWICH clinic. Based on the IOTF classification for BMI for age and gender, 14%  were aged between 0 and 4.99 years (young children), 45% (n = 23) were aged between 5.00 and 11.99 years (children), and 43% (n = 22) were aged between 12.00 and 17.99 years (adolescents). Comparisons were made between the three age groups for anthropometric variables (p < 0.006), and there were no significant differences between BMI z-scores for children and adolescents. No differences in body fat percentage were found between children and adolescents, and median body fat percentage results for both groups were considerably higher than the 98th centile for all ages and genders on current reference curves [When grouping participants according to age, 12% . Young children had the highest scores for dietary behaviors and eating beliefs, significantly greater than scores for adolescents . Dietary intake scores were similar across all age groups  = 6.6, 95% confidence of interval (CI) = 0.24–13.0, e groups .p = 0.014)  .p < 0.05) and social scores . Within the adolescents, parent proxy-reported HRQOL was lower overall  and for both physical  and social scores (f (18) = 2.55, p < 0.05) . No other significant differences were found between the age groups for child or parent proxy-reported HRQOL. When comparing the child and parent proxy-reported HRQOL scores within groups, parent scores were generally lower overall and for each section. For the children, parent proxy-reported HRQOL was lower for overall (f (20) = 2.75,  < 0.05) .p < 0.01), dietary intake score  and dietary behaviors and eating beliefs score . A medium to strong correlation was found between parent proxy-reported HRQOL and dietary practices or habits score  in the adolescent aged group. No relationships between HRQOL and dietary measures were evident in the children and young children age groups.BMI z-score was compared to HRQOL, dietary overall and PA scores across age groups, but no obvious significant relationships were found. The relationship between HRQOL and dietary measures was investigated, with significant findings in the adolescent age group . A stronn = 7) of children or adolescents were referred by an external general practitioner, compared to 65% (n = 33) referred by a specialist or pediatrician within the LCCH. Of these 33 children and adolescents, data regarding their contact with the public or private health care system was not collected, so it is unclear why concerns regarding weight were not flagged earlier. Ideally, this should be happening at the primary care level. Additionally, the sample size did not include children or adolescents of ethnicities considered to be at higher risk of overweight and obesity in Australia, such as Indigenous Australians or those from Maori and Pacific Islander cultures [The aim of this study was to describe the baseline characteristics of children attending a pediatric multidisciplinary weight management clinic in Queensland, Australia, in the context of health services implementation research. The authors wanted to understand, at the systems level, what strategies are working to support the prevention and management of pediatric overweight and obesity in Queensland, and what needs to change. Results showed that children entering the clinics were not assessed on parameters of diet, physical activity or HRQOL prior to referral, and were considerably overweight as per international definitions, with 72% of participants classified as morbidly obese. This may have been due, in part, to triaging practices within the system, where children classified as overweight were generally placed into a dietitian-only clinic, rather than a multidisciplinary clinic. These results may also reflect referring practitioner decisions, who may only be referring children and adolescents when their BMI is within the obese category and other concerns are apparently obvious. This is supported by the data which show that only 14%  increased as self-reported HRQOL scores increased, highlighting an important relationship that was not evident in the children in the study. This has been described previously in the literature in a large prospective study in Australia by Jacka et al.  who founThe absence of any significant relationships between BMI z-score and diet, PA and HRQOL measures was unexpected. It was thought that these results may have provided an interesting insight into what to target in multicomponent interventions for specific age groups. These findings may be due to the fact, that 72% of the cohort were classified as morbidly obese, and the variation in BMI z-scores across all age groups was small.Clearly, more research is required to understand why children and adolescents are not being identified and referred to services in a timely manner, and what can be done from a systems perspective to change this practice. This is important, given that recent evidence from similar multidisciplinary clinics in real-life settings on an international level suggests that treatment outcomes are better when children were younger  and thatThe main limitation of this study is the small sample size potentially causing insufficient power to detect correlations. The population of interest is difficult to recruit, and attrition is high, resulting in small sample sizes which may not be representative of the larger population of children and adolescents who are overweight or obese. Missing data was also a common theme as a result of unavoidable reasons such as child age or behavior. Another limitation was that outcome measures for dietary intake, behaviors and habits and physical activity were self-reported rather than objectively measured. Given the pragmatic nature of the study, and the limitations when embedding research into clinical practice, this was a necessary compromise. Furthermore, the E-KINDEX tool has, at this stage, only been validated for children aged 9 to 13 years . Lastly,There is no single solution to the problem of pediatric overweight or obesity, however it remains a significant health problem and a focus on timely identification of concerns, appropriate referral systems, and dedicated services is critical. Results of this study found that adolescents are already experiencing detrimental consequences related to being overweight or obese, such as lower scores related to diet and dietary practices or habits, and lower levels of PA. Results identified that system referral processes are not effective, and confirm the need to critically examine the current context to further investigate these processes and adapt interventions to individual circumstances, supported by focused triaging and screening processes to enhance the opportunity for individual success. There is a clear need to implement these research findings for system-wide change to enable efficient, effective service delivery options at all levels of health care that can be up-scaled throughout the public health system.


M = 14.07, SD = 1.39). Results showed that girls and 14–16 adolescents were more involved in a problematic use of online social networking sites. Furthermore, adolescents with high problematic use of online social networking sites were more involved in overt—reactive and instrumental—and relational—reactive and instrumental—aggressive behaviors, and self-reported higher levels of overt—physical and verbal—and relational victimization. Even though boys indicated higher levels of all types of victimization, girls with high problematic use of online social networking sites scored the highest on relational victimization. Relating to age, early adolescents (aged 11–14) with higher problematic use of online social networking sites reported the highest levels of overt verbal and relational victimization. Overall, results suggested the co-occurrence of problematic use of online social networking sites, peer aggression and victimization. In addition, results showed the influence that gender and age had on peer victimization. This study highlights the continuity between offline and online domains with regard to maladjustment problems in adolescence.The problematic use of social networking sites is becoming a major public health concern. Previous research has found that adolescents who engage in a problematic use of social networking sites are likely to show maladjustment problems. However, little is known about its links with peer aggression and victimization. The main goal of this study was to analyze the relationship between problematic use of online social networking sites, peer aggression –overt vs. relational and reactive vs. instrumental–, and peer victimization –overt physical and verbal, and relational–, taking into account gender and age (in early and mid-adolescence). Participants were selected using randomized cluster sampling considering school and class as clusters. A battery of instruments was applied to 1,952 adolescents' secondary students from Spain  (50.4% boys), aged 11 to 16 ( The use of Internet and Online Social Networking Sites (SNS) is an increasingly popular leisure activity in many countries around the world  and, in particular, problematic use of SNS  four dimensions or subtypes of aggressive behavior are obtained: overt -reactive and proactive-, and relational –reactive, and proactive. This classification has been validated ecologically and these dimensions, although interrelated, have shown important differences  and the functions (reactive vs. proactive) of aggressive behavior, and as a function of gender and age. Second, despite the empirical evidence on the excessive use of Facebook and other SNS and cyber-victimization, no studies have been found that explore the link between the problematic use of the Internet or SNS and peer victimization. Since the virtual and the non-virtual settings are interrelated , enrolled in nine compulsory secondary education centers (ESO) in Andalusia (Spain). The participants attended public (56.4%) and semi-private (43.5%) schools. Two age groups corresponding to different stages in adolescence were established: early adolescence  and middle adolescence .The study was ex post facto transversal and descriptive. In this study, the initial sample consisted of 2,083 adolescents of both sexes aged 12–16 years. A total of 81 adolescents were excluded for the following reasons: not having attended one of the three phases of the study, normally due to illness (56%), mistakes in the answers  (28%), difficulties in understanding Spanish (foreign students) (12%), and students who voluntarily abandoned the study or who responded systematically in the same way to all scales (4%). Finally, 1,952 adolescents (50.4% boys) participated, aged 11–16 years  , overt proactive aggression  , relational reactive aggression   and relational proactive aggression  . The confirmatory factor analysis [CFA] performed showed the measurement model had a good fit with the data . Taking into consideration the following values, the overall reliability of the scale was acceptable   , verbal overt victimization  , and physical overt victimization  . The CFA performed showed a good fit of the measurement model to the data . The overall reliability of the scale was acceptable  ]. The scale showed an acceptable reliability   to 4  it measures the problematic use of SNS . The CFA showed a good fit of the proposed measurement model . Girls were overrepresented in the group with high problematic use of SNS ; whereas boys were overrepresented in the low problematic use group , and the percentages of boys and girls were similar in average problematic use group . As for age, results also showed significant differences among groups . Adolescents aged 14 to 16 were overrepresented on average , as well as in high problematic use of SNS , while adolescents from both groups were similar in low use of SNS . This data coincides with results obtained from previous studies in the Spanish context  = 64.41, p < 0.001, η2p = 0.178], age  and problematic use of the SNS . A statistically significant interaction effect was also obtained between problematic use of SNS and gender  and problematic use of SNS and age .In the calculated MANOVA, statistically significant differences were found in main effects of gender variables [Λ = 0.822, Regarding sociodemographic variables, in the ANOVA, statistically significant differences were obtained with respect to gender in the variables overt reactive, overt proactive, and overt instrumental aggression. As shown in Table Concerning the problematic use of SNS, results of the ANOVA showed significant differences in all dimensions analyzed  = 17.75, p < 0.001, η2p = 0.044. As seen in Table post-hoc contrasts performed with the Bonferroni test (α = 0.05) indicated that girls, particularly those with greater problematic use of SNS, obtained the highest scores in relational victimization, compared to the remaining groups  = 12.07, p < 0.001, η2p = 0.030. Results of the post-hoc contrasts performed with the Bonferroni test showed that adolescents aged 11–13 with a higher problematic use of SNS reported higher overt verbal victimization, compared to the remaining groups  = 2.42, p < 0.001, η2p = 0.034. As shown in Table A statistically significant interaction effect was also obtained between problematic use of SNS, age and overt verbal victimization, F5, 196 = 12.07F5, 196 = 12.07The general goal of the present study was to analyze existing relationships between the problematic use of SNS, peer aggression and victimization in adolescents, taking into account gender and age. In addition, the forms  and the functions (proactive vs. reactive) of aggressive behavior were considered to evaluate peer aggression. Forms of victimization were considered as well. Overall, results confirmed that the problematic use of SNS was associated with greater involvement in all dimensions of analyzed peer aggression and with higher levels of overt  victimization and relational victimization. Likewise, gender and age were shown to have an important role in the relationship between problematic use of SNS and relational victimization and verbal expression.The first specific objective of this study was to examine the relationship between peer aggression and the problematic use of SNS, by gender and age. We hypothesized that adolescents with a problematic use of SNS would be more involved in all the subtypes of aggressive behavior measured. As expected, results showed that adolescents with greater problematic use showed a greater involvement in overt and relational aggression, with both a reactive and a proactive purpose. These results are compatible with those obtained in previous studies in which the PIU has been linked to Internet addiction with greater hostility and greater expression of aggressive behaviors in adolescents . All participants gave written informed consent. The required authorizations from the education authorities, the schools, and the children's families were obtained.BM-F, DM, and GM had participated in the intellectual content, the analysis of data, and the writing of the work. BM-F, DM, and GM had reviewed the final version of the work and they approve it for publication.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.


In a clinical science-based profession such as physiotherapy, research is mandatory to update knowledge and to provide cost-effective, high quality treatments. This study aimed to provide point prevalence of Italian physiotherapists who are academics, holding a PhD degree, or being authors of scientific papers. The scientific journal productivity of physiotherapists was also thoroughly analyzed.A descriptive cross-sectional study was carried out on all Italian physiotherapists. Academics, postdoctoral research fellows, and PhD graduates were identified by searching the Italian Ministry of Education, University and Research (MIUR), Italian Society of Physiotherapy, and university websites. Then, authors of articles indexed in Scopus were searched. The following data were extracted: type of affiliation, authorship order, H-index, number of publications and citations, name of journals, year of publication, and journal’s Impact Factor.p < 0.001). There was a significant difference between researchers and clinicians in both publication productivity (p < 0.01), citations (p < 0.01), and H-Index (p = 0.05). Articles were published in 359 different journals, receiving a total of 13,373 citations.The prevalence of academics, physiotherapists holding a PhD, or being author was 0.01%, 0.05%, and 0.56%, respectively. We identified 1083 papers co-authored by Italian physiotherapists, and their number has progressively increased over the years , the quantity and quality of journal productivity is growing fast, and an increasing number of physiotherapists are involved in research activities. The credibility and professional development of physiotherapy is growing fast, thanks to the scientific knowledge produced by their members and the clinical application of proven research findings . In a heLaurea Magistrale’) was introduced in late 2004, and the first physiotherapists graduated in 2008. Since then, a few programs have begun offering the Doctor of Philosophy (PhD) degree to physiotherapists in our country. Moreover, in 2012 the Italian Ministry of Education, University and Research  introduced a new process for the appointment of professors, which has been described elsewhere [In a previous study , the sciThe primary aim of this study was to provide point prevalence of Italian physiotherapists who: a) have university roles; b) holding a PhD degree; and c) have written at least one article published in peer-review journals indexed in the Scopus database. The secondary objectives were to describe the profile of academics and educational programs, and to analyze the scientific journal productivity of authors.This was a descriptive cross-sectional study.The study population was represented by all Italian physiotherapists with a bachelor’s degree (3 years), working either in Italy or abroad. Foreign professionals working in Italy were excluded.The number of Italian professionals was recently estimated by the MIUR and the Italian Association of Physiotherapists (AIFI) in a survey conducted to establish the national educational needs . In thisSettore Scientifico Disciplinare, SSD) tag was used to retrieve positions in the sector “Sciences of nursing, rehabilitation and neuropsychiatric techniques” (MED/48). The MED/48 filter option was selected, and academics were classified as: full professors, associate professors, and researchers. The curriculum of each person was then carefully analyzed to identify those who were physiotherapists. The same strategy was used to find postdoctoral research fellows and the university educational programs  offered in Italy.To identify those who have university roles - i.e. professors and postdoctoral research fellows - the MIUR website  was searTo find physiotherapists holding a PhD, three strategies were used. First, all PhD programs offered to physiotherapists in the last 5 years were extracted from the MIUR database. Each PhD program’s website - if available - was then searched to find information on students and former students, and physiotherapists were identified. Second, the list of PhDs and PhD students available on the Italian Society of Physiotherapy (SIF) website was downloaded . Third, Italian physiotherapists who published in peer-review journals indexed in the Scopus database were then searched with a previously described strategy .Istituti di Ricovero e Cura a Carattere Scientifico, were termed ‘researchers’, while those working in hospitals, hospices, retirement homes, or professional studies were termed ‘clinicians’), total number of publications per author, number of citations received per author, authorship order , and H-index. The H-index  was proposed in 2005 to quantify the productivity and the impact of researchers, and it is used also by the MIUR to evaluate the activity of researchers.For each author the following data were extracted: type of work based on affiliation . The IF is a measure reflecting the yearly average number of citations of recent articles published in that journal. In this study, the Web of Science 2015 IF values were used.Counts, percentages, and ratios were used to summarize the data. A Mann-Whitney U test was used to analyze differences between researchers and clinicians in H-Index, number of publications and citations received per author. The correlation between year and number of published articles was estimated by the Spearman rank-order correlation coefficient (rho). For all tests, the level of statistical significance was set at 0.05.In 2017, the Italian population of physiotherapists was estimated at about 65,000 professionals [To date, 7 physiotherapists - 1 full professor, 1 full temporary professor, and 5 researchers - are listed in the MED/48 section area of Italian university faculty members, wich resulted in a prevalence of 0.01%. The full professor was appointed in 2005, and the associate professor in late 2016. Besides the academics, the MIUR website currently lists 4 postdoctoral research fellows among physiotherapists.A total of 85 bachelor (undergraduate) programs of physiotherapy are currently being taught in Italy, to which must be added 16 master (graduate) programs and 5 doctorate programs  accessible to physiotherapists. Thirty-one Italian physiotherapists holding a PhD have been identified , with a prevalence of 0.05%. At least 14 more physiotherapists are currently in training, either in Italy or abroad .Up to 2016, 363 Italian physiotherapists were identified as having been involved in scientific journal publication , citations received (p < 0.01), and H-Index (p = 0.05) between researchers and clinicians.Overall, they appeared as authors 1820 times and, after deleting duplicates generated by collaborations, they produced a total of 1083 different articles published in journals indexed in the Scopus database. The distribution of H-Index, number of articles published, and number of citations received by researchers and clinicians are shown in Table In the sequences of authors, Italian physiotherapists were listed as authors in first, second, or last position  54% of times.p < 0.001)  Fig. .Fig. 2NuThe 1083 papers identified received a total of 13,373 citations. In 74% of the articles accounting for 71% of citations researches featured as authors; in 16% of the articles accounting for 21% of citations clinicians featured, while in 10% of articles receiving 8% of the total citations the authors represented a collaboration between the two  of physiotherapists who are professors or academic researchers in Italy has already been described in the recent past , 8. HoweItalian physiotherapists holding a Doctoral degree are about 0.05%. This prevalence is still very low, but it is in line with emerging countries such as Brazil  and it iDespite the small number of academics and PhDs in physiotherapy in Italy, the national scientific output in the rehabilitation area has achieved important bibliometric indicators worldwide: in the SCImago Country rank for number of published articles Italy was 9th, with 301 papers in 2016 and 4183 in the decade 1996–2016 . Of notep = 0.05), they were the profile most often involved in publishing (p < 0.01) and they received more citations (p < 0.01) than clinicians. While it was not surprising that researchers had a greater scientific output (Table In this study, more than 1000 articles were found to be co-authored by at least 363 physiotherapists, who most often had a scientific affiliation. In a previous review [ut Table . This maCriteria for authorship have been discussed at length, but a simple way to determine credit associated with the sequence of authors’ names is still missing . In multSince the first publication co-authored by an Italian physiotherapist appeared in 1981 , the numArchives of Physiotherapy - will get Scopus indexing. This could finally promote development of physiotherapy leadership and governance of university programs.Journal productivity is a complex issue reaching beyond the existence of research degree programs , and theThe conclusions that we can draw from this investigation may be limited by some factors. First, the approach used to find authors was not exhaustive because no database provides search options by both profession and country. Second, only the journals indexed in the Scopus database were considered. Although this choice may have underestimated the results, we believe that it was justified since Scopus provides a strong coverage of the physiotherapy literature  and it iThis study presented an updated point prevalence of Italian physiotherapists who are academics, holding a PhD degree, or being authors of scientific papers. The scientific journal productivity of physiotherapists was also thoroughly analyzed. Results indicate that faculty members among physiotherapists are still very low, and there are insufficient PhD programs to meet the demand. However, the quantity and quality of journal publication productivity is growing fast, with an increasing number of physiotherapists involved in research activities.


In Control group nutritional status was stable during observation. The performance status and quality of life were stable in both groups. No statistical differences between groups (ONS vs. Control) in the numbers for disqualification, resignation, delay in treatment, or dose reduction were observed. Conclusions: Results of the study did not indicate that nutritional support in precachectic oncologic patients influenced the toxicity of systemic therapy. High protein nutritional support improved nutritional status assessed by SGA, VAS for appetite, albumin, and prealbumin. The performance status and quality of life were stable throughout the observation and were not changed under the supplementation.Background: Cancer disease is usually associated with impaired nutritional status, which is one of the factors contributing to deterioration of the results of surgery, chemotherapy or radiotherapy. Objectives: The aim of the study was to determine whether nutritional support with high protein (ONS) in adult oncologic patients in the first step of cancer cachexia—asymptomatic precachexia, has an influence on the toxicity of systemic therapy. However, secondary endpoints were established: to determine whether high protein ONS influences the nutritional status, the quality of life, and the performance status. Materials and Methods: A total of 114 persons aged 40–84 years old with colorectal cancer were examined. Based on the randomization, 47 patients were qualified to the interventional group (ONS group) and 48 to Control group. To evaluate the nutritional status NRS-2002 , SGA , SCRINIO  Working Group classification, VAS  for appetite was used. FAACT  questionnaire was used for assessment of the quality of life. The health status of patients was evaluated based on the Karnofsky Performance Scale. Anthropometric measurements were done. Results: Severe complications of chemotherapy, which caused the end of treatment, a slight complication of the gastrointestinal tract such as diarrhea grade 2 according to ECOG (Eastern Cooperative Oncology Group) score regardless of the studied group, were observed. There were no statistical differences in the number and severity of the observed complications, i.e., neutropenia, leucopenia, thrombocytopenia, anemia, abdominal pain, nausea and vomiting, and diarrhea. During the follow-up the significant changes of SGA, VAS, albumin and prealbumin were observed between groups. In the ONS group an improvement in nutritional status was noticed (increased appetite VAS,  Cancer is a systemic disease, since even in the early stages malignancies are accompanied by homeostatic imbalance, including metabolic deregulation and increased catabolism. These abnormalities may initially seem poorly discernible in the clinic, but with disease progression they may aggravate; and may cause overt cancer-related cachexia. It is known that cachexia is an independent negative prognostic factor, a leading cause of impairment of the quality of life, and that it produces functional deterioration of oncologic patients. Various frequencies of cachexia in different malignancies are also well described, and may result from their different biology or, presumably, from unknown individual factors ,6,7,8,9.However, according to the international consensus, cancer-related cachexia is a complex multifactorial syndrome defined by an ongoing loss of lean body mass  that cannot be fully reversed by conventional nutritional support as a single intervention, and leads to a progressive functional impairment of the whole organism . The pathogenesis of cachexia is not completely elucidated, yet negative protein and energy balances are its crucial elements: these being the consequence of deregulation of multiple intermediate metabolic pathways, latent inflammatory state and anorexigenic action of multiple biologically-active factors ,2. Moreover, it should be stressed that clinical pictures of metabolic disorders in cancer form a continuum; beginning from precachexia (stage I), through cachexia (stage II) and ending with refractory cachexia (stage III) ,10 or acThe cancer cachexia could be associated with increased toxicity of cytotoxic treatment, and frequently necessitate premature termination of therapy. Furthermore, cachectic patients have poor performance status. So, a vicious cycle develops: cachexia reduces the possibility of use of cytotoxic agents, thus leading to disease progression, and this in turn promotes the development of resistant cachexia. The result is not only an unfavorable prognosis, but also poor quality of life for patients. Unfortunately, a sole nutritional intervention is inefficient in these cases, and its support with targeted pharmacotherapy requires further research. Thus, it is important to undertake actions aimed at prevention of developed cachexia (stage II and III) or postponing its occurrence ,2,12,13.Cancer-related precachexia—the first step of cancer-related cachexia—requires special attention. The optimal nutritional management of patients with precachexia could contribute to improvement of tolerability of oncologic therapy; as well as administration of due dose density, translating into higher treatment efficacy and improvement or preservation of the current nutritional and metabolic status. A positive impact on the quality of life and performance status is also proposed ,8,10,13.The patients with precachexia may have particular benefits from the implementation of nutritional support. Nevertheless, such data is lacking in the literature. Of course, maintaining or improving nutritional status in patients undergoing chemotherapy or chemo-radiotherapy is extremely important, as it is associated with improved prognosis. And indeed, this is the primary endpoint of many clinical trials. However, it seems that both the nutritional status and the toxicity of chemotherapy are closely related. However, the optimal nutritional management of precachectic oncologic patients, remains unclear. Presently, no nutritional support leading to an increase of nutrient delivery is routine use in asymptomatic precachectic patients. Furthermore, there are no specific guidelines on the requirements for nutritional support in these persons. Oral nutritional supplements (ONS), however, may be of some importance. Unfortunately, currently there are no standards for nutritional management in precachectic stage., It is especially unclear whether nutritional support should be implemented in preemptive strategy in the first step of cancer cachexia—asymptomatic precachexia. Furthermore, an unresolved question concerns the clinical justification of ONS use, which could also have economical consequences. The discussed products allow for delivery of nutritional elements in amounts covering the demand, in small volumes and in a form convenient for consumption. It should be noted that such a supply is often difficult to assure with nutrition using natural products only. Nevertheless, lack of data regarding the tolerability of ONS/intake ONS compliance remains another unsolved problem. Many products are characterized by high nutritive density and high osmolarity, which are associated with a potential risk of the induction of gastrointestinal disorders or paradoxical anorexia. Elucidation of the discussed issues seems especially important in view of possible improvements to tolerance of chemotherapy, quality of life, nutritional status and prognosis in cancer patients; as well as potential savings of healthcare funds.The aim of the study was to determine whether nutritional support with high protein ONS in adult oncologic patients in the first step of cancer cachexia—asymptomatic precachexia, influences the toxicity of systemic therapy.However, secondary endpoints were established: to determine whether high protein ONS influences the nutritional status, the quality of life and the performance status.The study received approval of the Ethics Committee of the Medical University of Gdansk (no. NKBBN/412/2014). Informed consent was obtained from all individual participants included in the study. The study was conducted in the Department of Oncology and Radiotherapy in the Medical University of Gdańsk. Patients were treated by oncologists, nutritional assessment was performed by an internal medicine physician and clinical dietitian.A total of 114 persons aged 40–84 years old were examined. Based on the randomization  47 patients were qualified to the interventional group (ONS group) and 48 to Control group  in clinical stage II-IV according to TNM UICC 2010.-Successful qualification to first line chemotherapy according to protocols with: 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX-4) or 5-fluorouracil, leucovorin, irinotecan (FOLFIRI); 100% dose of chemotherapy (no dose reduction).-Performance status at least 80% according to Karnofsky scale.-Cancer-related asymptomatic precachexia diagnosed according to SCRINIO Working Group.-Absence of contraindications to oral nutrition and practicable realization of oral nutrition.-Absence of severe, decompensated concomitant diseases—e.g., diabetes, hepatic insufficiency, renal insufficiency (K/DOQI stage ≥ 2).-Signed informed consent for participation in the study.-Diagnosis of a malignant neoplasm in clinical stage I according to TNM UICC 2010.-Disqualification from oncologic treatment.-Cancer cachexia or cancer anorexia–cachexia syndrome.-Poor performance status—Karnofsky scale < 80% or WHO/ECOG  2–4.-Contraindications to oral nutrition or to high protein nutrition .-Regular nutritional support at the moment of qualification to the study.-Patient incompliance at the moment of qualification to the study.All patients had histopathologically confirmed diagnosis of colorectal cancer. On the basis of the TNM classification 30 persons had the fourth stage (31.6%), 50 persons (52.7%)—third stage, and 15 persons (15.8%)—the second stage. Metastases to lymph nodes were diagnosed in 28 persons. Distant metastases: lung, ovary, liver, bladder, kidney, adrenal glands were found in 21 persons. -caecum—4.0%-ascending colon—58.6%-sigmoid colon—16.0%-rectum—21.3%.71 patients (74.7%) were in the second clinical stage (G2), 20 patients (21.1%)—in the third stage (G3), and 4 patients (4.2%)—in the fourth stage (G4). The location of the tumor was as follows:Patients were qualified to receive the treatment with chemotherapy. A total of 41.0% patients in the study were qualified to receive FOLFOX regimen and the rest of the patients were qualified to the following regimens FOLFIRI, LF, CLF, XELOX.The full 12 weeks follow-up period was completed by 72 patients. The shorter observation period was associated with resignation from the study, early termination of chemotherapy because of severe complications, transfer to another center. In the ONS group, 6 patients resigned from the study (gave up on taking supplements). In Control group, 2 patients moved to another oncology center, 1 patient resigned from the oncology treatment, 5 patients resigned from the study . The above data are presented in There were no statistical differences between groups (ONS vs. Control) in the number of resignation from the nutritional treatment.Chemotherapy-related toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0).Every 4 weeks, on every visit, data on toxicity of chemotherapy such as neutropenia, leukopenia, anemia, thrombocytopenia, diarrhea, vomiting, abdominal pain, and sepsis or other symptoms were noted.In addition, delayed chemotherapy and dose reduction due to toxicity were recorded.The following methods for determination of the nutritional status were used in the study:Body mass measurement with the use of the scale (Tanita BC 420).Body mass index (BMI) calculation on the basis of the following formula:2 (kg/m2)BMI = body weight/height<18.5—underweight18.5–24.9—normal body weight25.0–29.9—overweight<30.0—obesity BMI classification was adopted:-unintentional weight loss in the past six months <10%-no anorexia.The precachexia was diagnosed on the basis of SCRINIO Working Group Classification i.e.,The cachexia was diagnosed when the weight loss was >10% in the past six months.Also, the following scores were used:Nutritional Risk Screening (NRS-2002)—method is based on the evaluation of unintentional weight loss, BMI, consumption quantity, clinical condition and age. Gaining three or more points means the risk of malnutrition.Subjective Global Assessment (SGA)—on the basis of this method consisting of an interview, unintentional body weight loss, clinical status and physical examination patients are qualified to the following groups: well-nourished (7 or 6 points), moderately malnourished  and severely malnourished (1 or 2 points).Visual Analog Scale for Appetite (VAS) was completed by patients on the basis of a patient’s feelings regarding appetite during the previous seven days. VAS for appetite is a 100-mm line where 0 mm means “I had no appetite at all”, and 100 mm means “My appetite was very good”. VAS score is obtained by measuring the distance (in millimetres) from 0 point “I had no appetite at all” to the point selected by a patient. The lower the score—the worse appetite. It was assumed that below 70 mm appetite is moderately reduced, and below 50 mm—severely reduced (weak).Functional Assessment of Anorexia/Cachexia Therapy (FAACT) is a measure of the quality of life, and it is completed by the patient, it has a total of 42 questions. Patients mark 0 (none)—4 (very much) for each question. This tool consists of five subscales: functional well-being (7 items), physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items) and other aspects, including appetite (13 items). The maximum score is 168. The lower the score, the lower the overall quality of life.Karnofsky scale allows one to quantify the overall state, and quality of life, of a patient with neoplastic disease who qualifies to receive chemotherapy. The score has a range from 0 to 100, where 100 represents the ideal state and 0 represents death.At each visit, all participants were measured in serum concentration of albumin, prealbumin, triglycerides, total cholesterol, C-reactive protein (CRP), ferritin, complete blood count .Patients were treated by high-energy, high-protein, oral liquid nutritional supplements; dosage: A total of 2 × 125 mL per day, 7 days per week for 12 weeks (3 months). One drink contained 300 kcal, 18 g of protein. It contained carbohydrates, lipids, minerals, trace elements and vitamins. It is clinically free from lactose and gluten-free. Patients were given a choice of 4 flavours and could change them during supplementation.p-value < 0.05 was considered to be statistically significant. To assess correlations among the evaluated variables, Pearson’s correlation coefficient (r) was used. A multifactorial regression method was used to establish relationships between variables . Results are expressed as percentages , mean and standard deviation. The assumption of normality was verified with the Kolmogorov-Smirnov test. A t-test or a Mann–Whitney test, as appropriate. Compared also were the incidence of events  in study groups. Basic inference was based on the Fisher–Boschloo double-sided test, Chi-square test (with Yates’ correction). The change in value between the first and fourth visits  was compared between groups. The comparison was made using the two-sided Welch test .In the whole study group the mean unintentional body weight loss during the previous six months was 6.7 kg (median 6 kg) and ranged from 1.1 kg to 15.0 kg. The mean BMI was within normal limits and was 24.5. In NRS-2002 assessment: 76% in the study group received three or more points—which indicates the risk of malnutrition, or malnutrition, and indicates the need for nutritional intervention. Similarly to NRS-2002—in SGA 73.3% of patients were classified as presenting mild/moderate malnutrition. 37.0% of patients had moderate decreased appetite and 6.0% had poor appetite. Results of the Karnofsky scale indicated the state of normal activity, minor signs and symptoms of the disease among the majority of the patients. FAACT—average score (median 78.5 points) indicated a reduction in the quality of life of the patients in all aspects of functioning.p = 0.04), prealbumin (p = 0.02) and lower body mass and BMI (p = 0.04)  .The comparisons between the 1st and 4th visits in the study groups are presented in the p = 0.05; increased points in SGA, p = 0.015, and increased levels of albumin and prealbumin, p = 0.05). During the follow-up the significant changes of SGA, VAS, albumin and prealbumin were observed between groups. In ONS group improvement in nutritional status was observed ; the appetite significantly increased in the ONS vs. Control group after 8 weeks of observation  and also after 12 weeks   see .p = 0.01, this change was maintained during the 4th visit .During the 3rd visit there was a difference in albumin concentration . Concentration of prealbumin was correlated positively with albumin level  and negatively with CRP .Prealbumin was statistically significantly higher in the ONS group in comparison to Control during the 4 visit  in the ONS group and 10 subjects (13 cycles) in the Control group.-in the number and severity of the observed complications, ie neutropenia, leucopenia, thrombocytopenia, anemia, abdominal pain, nausea and vomiting, and diarrhea-p = 0.30), delay of chemotherapy cycle (p = 0.24) or disqualification from continuation of chemotherapy.in the number of dose reductions :In ONS group compliance was high—80% of patients made recommendations in excess of 75%. Also, tolerability of the ONS treatment was good. There were no differences between the groups (ONS vs. Control) in number and severity of nausea, vomiting, diarrhea, abdominal pain.An extremely important clinical issue in oncology is the problem of malnutrition or high risk of deterioration of nutritional status, lack of appetite and subclinical inflammation.High percentages of patients with significant weight loss have already been diagnosed early as onset of cancer—depending on the location of the cancer, and the stage of the disease, it ranges from 40 to over 80% ,15,16,17Both subclinical inflammation, as well as metabolic disorders and abnormal nutritional status as a consequence, are highly unfavorable prognostic factors. In addition, the negative impact of the above on quality of life and functional independence of patients at various stages of cancer have also been found.It is known that nutritional interventions in patients with malnutrition is unequivocally indicated, although it may not be fully effective due to co-existing metabolic abnormalities with increased catabolic processes. It would be prudent to undertake earlier nutritional interventions, for example, already at the stage of precachexia.This study included the population of patients who met the criteria for diagnosis of cancer precachexia. They were patients with colorectal cancer in stage II–IV according to the TNM classification.In the study group, despite the normal or elevated BMI, it was found that the majority of patients were at high risk of malnutrition, or mild malnutrition criteria were met. The assessment of nutritional status was done comprehensively. Recommended scales for assessment of nutritional status and biochemical indicators as mentioned above. It is worth stressing that such a comprehensive assessment is necessary to obtain adequate results, since the measurement of body mass and BMI itself is insufficient and not entirely reliable.At the start of the study, appetite in most patients was moderate (median VAS was 6.5 mm). However, it should be noted that the study program excluded patients with fully symptomatic anorexia. Despite the differences in BMI and body mass between study groups, at the beginning of the study unintentional body mass lost in both groups were similar and less than 10%.Unfortunately, in the ONS group albumin and prealbumin concentration were significantly higher in comparison to the Control group at the beginning of the study, but statistical analysis after 3-months of observation considered the degree of changes during follow-up. But we can not exclude that in the case of patients with lower albumin and prealbumin a positive effect of supplementation would be even more noticeable. Statistically significant improvement in nutritional status was observed on the third visit in ONS group; while in the Control group, at the same time, a decrease of albumin and prealbumin levels was observed. Moreover, after completion of follow-up in the ONS group, compared to the Control group, patients presented statistically better appetite and higher albumin and prealbumin levels.Thus, the implementation of oral high protein diet support already at the stage of precachexia appears to be significant and clinically relevant. In this study, it was found to improve the nutritional status of patients receiving ONS. In addition, the use of a high protein supplement did not negatively affect appetite. On the contrary, patients from the ONS group presented an improvement in appetite as compared to the Control group.It is also worth emphasizing the significantly higher serum albumin and prealbumin levels in patients receiving ONS, which may have a long-term beneficial prognostic significance. The literature highlights the significant role of these nutritional markers in patients with cancer of various organs, including those with colorectal cancer ,18,19.Higher serum albumin levels are associated with improved prognosis, fewer complications after oncological treatment, and longer survival time. In a large retrospective analysis of more than 40,000 patients with colorectal cancer, hypoalbuminemia (<3.5 g/dL) was a strong correlator with longer hospitalization time and greater complications after surgical management of colorectal cancer . In anotProbably, in our study the too short observation time made it impossible to find a similar relationship—better prognosis in better nourished patients.As mentioned above, subclinical inflammation, which occurs in a significant proportion of patients with solid tumors, contributes to many metabolic disorders , anorexia and, consequently, to abnormal nutritional status.Indeed, the investigated inflammatory marker—C-reactive protein (CRP) indicated the presence in most of the subjects of chronic inflammation, although no clinical evidence of infection was observed. Moreover, what was extremely important was the negative correlation between CRP and biochemical parameters of nutritional status  and appetite assessed by VAS. It is also worth noting that after 2 months of observation CRP levels have decreased in the ONS group, and regression indicates that CRP was a statistically significant factor affecting albumin concentration.The above observation also seems to be very clinically relevant. It appears that the implementation of high-protein oral nutritional support in patients with precachexia reduces the expectations of subclinical inflammation while contributing to improved nutritional status.In both study groups, patients with mild to moderate complications (systemic adverse events) were the most commonly reported. Diarrhea, as well as nausea and lack of appetite, were observed in grade 1–2 (acc. NCI CTCAE) several days after receiving the drug. These are the most frequently mentioned in the literature, the adverse effects of chemotherapy primarily due to the gastrointestinal toxicity of cytostatics.Laboratory results  were stable during follow-up—delayed administration of the next chemotherapy cycle, or half-dose reduction due to thrombocytopenia, leucopenia or neutropenia were similar in both groups.There were no direct statistically significant differences in chemotherapy related toxicity between the two study groups. However, it seems highly likely that such a difference would occur in the case of longer follow-up times, and more chemotherapy cycles. This indicates an improvement in nutritional status and a reduction in inflammatory parameters in patients receiving nutritional support.Our study is one of the first studies of early nutritional support during chemotherapy, and the first in CRC. The monthly visits with extensive data collection in both groups, including a strong focus on nutrition status, helped minimize placebo effect. The high compliance is also a strength of the study. The limitation of this study is primarily the short observation period, as well as patient resignation during the study. Patients most often reported lack of time, fatigue, malaise, and in ONS group, difficulty maintaining the recommended dose of the supplement, bad taste of the supplement. However, it is worth emphasizing the good tolerance of dietary treatment, the absence of differences in gastrointestinal symptoms between groups, and the high level of compliance of patients with recommendations for nutritional treatment.It appears that the implementation of high-protein oral nutritional support at an early stage of metabolic disorders and nutritional status  is a good method to reduce the risk of deepening malnutrition. It is also worth stressing that such action reduces the exponents of subclinical inflammation, which is the main pathophysiological cause of the development of malignant anorexia-cachexia syndrome. Taking into account the results of the study, the main endpoint should be the nutritional status rather than toxicity. Determining the effect of supplementation on chemo-toxicity has resulted in much longer follow-up and more patients.Further studies, and longer follow-up time, are advised to answer the question—does the use of high-protein dietary support at the stage of precachexia involve a prolongation of overall survival in patients with colorectal cancer? We are still looking for new therapies that will help to improve the prognosis of patients with cancer. It is also worth to pay attention to nutritional aspects, and their possible role in the prognosis.Results of the study did not indicate that nutritional support with high protein ONS in adult oncologic patients in the first step of cancer cachexia—asymptomatic precachexia, had an influence on the toxicity of systemic therapy.High protein dietary support improves nutritional status in colorectal cancer patients with precachexia.The performance status  and quality of life were stable throughout the observation, and was not changed under the supplementation.Tolerability of the ONS treatment was good. There were no differences between the groups (ONS vs. Control) in number and severity of nausea, vomiting, diarrhea, abdominal pain.