The Patient Activation Measure (PAM) is a recognized measure of how active patients are in their care, and has been translated into several languages and cultural contexts. Patient activity, self-care, and health literacy have become increasingly important aspects of health care, and thus reliable measures of these are needed. However, a Swedish translation of PAM is currently lacking. The aim of the study was to translate and assess the validity and reliability of the Swedish PAM-13.A self-report questionnaire was handed out to 521 patients at ten medical, geriatric, and surgical wards, and one Virtual Health Room. The Rasch model was employed, using the partial credit model, to assess the functioning of the PAM scale, item fit, targeting, unidimensionality, local independence, differential item functioning (DIF), and person-separation index. Evidence of substantive, content, structural, and external validity was examined.Of the 521 patients who were consecutively handed a questionnaire, 248 consented to participate, yielding a response rate of 47.6%. The average measure for each category advanced monotonically. The difficulty of the PAM items ranged from − 1.55 to 1.26. The infit and outfit values for the individual items were acceptable. Items 1, 2, and 4 showed disordered thresholds. The mean person location was 1.48 (SD = 1.66). The person-item map revealed that there were no item representations at the top of the scale. The evidence for unidimensionality was ambiguous and response dependency was seen in some items. DIF was found for age. The person separation index was 0.85.The Swedish PAM-13 was reliable, but was not conclusively found to represent one underlying construct. It seems that the Swedish PAM-13 lacks strong evidence for substantive, content, and structural validity. Although valid and reliable measures of ability for activation in self-care among patients are highly warranted, we recommend further development of PAM-13 before application in everyday clinical care. Patients’ active involvement in their own health is a key feature for successful health care. Living with long-term conditions can be highly demanding, and requires that patients manage their symptoms, disabilities, and complex medical regimens , as wellThe transition of patients across institutional borders imposes a responsibility on the health care system to engage patients in taking an active role in follow-up treatments and care plans. Discharge from hospital care is an important part of the patients’ preparation to manage their health at home. However, when information is given hastily, patients leave the hospital with an incomplete understanding of their diagnoses, medication changes, and plans of care , meaningThe PAM was developed through a series of studies, in order to measure levels of patient activation. The first version, developed in 2004, comprised 22 items , and in Each item of the PAM has five response categories with scores from 1 to 4: strongly disagree (1), disagree (2), agree (3), agree strongly (4), and not applicable (no score). The overall score is calibrated into a metric from 0 to 100, where a higher score indicates greater patient activation . The scoPrevious studies indicate that patient activation is associated with improved health outcomes and care experiences, reduced health care costs and health care utilization , 19, 20.The translation and adaptation followed the recommendations of the World Health Organization . First, The aim of the present study was to translate the Patient Activation Measure (PAM-13) into a Swedish version and assess its validity and reliability among patients at discharge from hospital and in primary care, using Rasch analysis.This cross-sectional study was approved by the Regional Ethical Board in Stockholm, Sweden, no. 2014/1498–31/2. Participants were recruited at one Virtual Health Room (VHR), and ten wards  in five hospitals. One of these was a university hospital, and four were county hospitals representing three different regions of Sweden. The VHR included patients in rural areas of Sweden. The inclusion criteria were patients ≥18 years, who understood Swedish and managed their own health in their private homes. Patients with known psychiatric diagnosis and cognitive impairment were excluded. In total, 521 questionnaires were consecutively handed out by nurses and team leaders at the study sites to patients, at the time of hospital discharge or when they visited the VHR. In all, 248 individuals consented to participate in the study and completed the questionnaires, generating a response rate of 47.6%.Information about the study was given to adult patients, fulfilling the inclusion criteria by the time of hospital discharge, or after the health care service at the VHR. Persons who were willing to participate got a closed envelope comprising the PAM-13-S and questions on socio-demographics , diagnosis, and self-rated health. Education was divided into four ordinal categories, university level being the highest. Diagnosis was divided into six nominal options, and self-rated health was measured on a 5-point scale from excellent to poor. The patients also received a stamped, addressed return envelope. No reminder was sent out. Consent to participation was confirmed by a written consent form that was completed together with the questionnaire  in WINSTEPS, version 4.0 . SPSS for Windows version 25.0 software  was used to analyse descriptive statistics.We evaluated the functioning of the PAM-13-S and the presence of theoretically congruent item hierarchies to provide evidence of substantive validity –24. Subsprincipal component analysis of the residuals (PCAR) was performed [Structural validity was addressed by evaluating unidimensionality and local independence , 25. To erformed . The evaerformed –30.Local independence of PAM-13-S items was examined using standardized residual item correlations. Negative or zero standardized residual item correlations suggest that the items reflect local independence , 29. Whep value was used. Linacre recommended that the DIF contrast should be at least 0.5 logits and statistically significant for DIF to be noticeable (p ≤ .05).In addition, differential item functioning (DIF), , and person-separation index was investigated. DIF was assessed across the dichotomous categories of age, sex, self-reported general health status, educational level, and main diagnosis. The magnitude of uniform DIF was evaluated using the non-parametric Mantel-Haenszel statistic and a Bonferroni corrected The person-separation reliability represents the ability of the measure to separate patients into distinct levels of activation. A person reliability of 0.80 with a person separation index of 2.0 is considered acceptable for a scale to distinguish between three or more levels . There iThe median age of respondents was 70 years, range 20–96 years, and 127 (51.2%) were males. About half of the respondents had primary school education or lower, and one-fifth (19.4%) had a university education. The most common diagnoses were heart failure (21%) and chronic obstructive pulmonary disease (16.9%). The largest group was that of surgical and acute patients with various diagnoses , the response alternative ‘strongly disagree’ was scarcely used by the participants  among the PAM items. This means that many of the patients do not have any corresponding PAM item.Unidimensionality of the PAM-13-S was examined using PCAR analysis. The first component explained 48.9% of the total variance and the eigenvalues of the first contrast was > 2.0. The two items with the strongest positive loadings on the first contrast were item 1 (0.60) and item 2 (.56). The three items with the strongest negative loadings were item 13 (− 0.57), item 10 (− 0.56), and item 12 (− 0.53). It was found that the disattenuated first contrast person-measure correlations on the item clusters were 0.73 (item cluster 1–3), 0.84 (item clusters 1–2) and 0.94 (item clusters 2–3). Overall, the evidence for unidimensionality is ambiguous.p = 0.015) and item 4 . Also, self-reported general health status revealed significant differences for items 1, 4 , 9 , and 10 , between the group with poor health and the group with good health. DIF was also found in item 10 between having poor health and having very good health . Main diagnosis was categorized into two major diagnostic groups: long-term illnesses and acute surgical procedures. However, the statistical significance was not retained when using the Bonferroni correction (p < 0.0038) for any of the variables above. Dividing the sample into two age groups, 44 to 64 years and 65 years and older, a statistically significant difference was observed for item 8 , where the lower age group had a higher DIF score, indicating that item 8  is more difficult for that group.We did not observe statistically significant differences in DIF for sex. The DIF test for education using the polytomous MH test showed statistically significant differences between educational levels for item 1 . Both the infit and outfit MnSq values for the 13 PAM items fulfilled the criterion for item goodness-of-fit (0.5 to 1.5). Findings from different European countries have demonstrated that PAM-13 has acceptable infit and outfit values , has preThe second threat is construct irrelevance, which refers to the presence of unrelated and irrelevant dimensions . Our res required a higher level of activation  than items 4, 6, 7, and 8. Item 4 (‘I know what each of my prescribed medications does’) was perceived as easier than item 2 . This might affect the classification between levels 1 and 2 in PAM-13-S and create uncertainty about a patient’s actual ability to participate and act. Consistent with the original American version, items 9, 10, 11, 12, and 13 were the most difficult of the scale, yet their order differed slightly in the Swedish version . Scaling variations seem to be a common problem with PAM-13 in European countries [Concerns related to PAM-13 scaling arose from our results. The original PAM-13 not only provides a classification based on total score, but the score is also connected to specific items. Level 1 encompasses items 1 and 2, level 2 encompasses items 3–8, level 3 encompasses items 9–11, and, lastly, level 4 encompasses items 12 and 13. The distributions of responses in our study indicated for example that item 3 ountries , albeit ountries . Hibbardountries , 38. In ountries  highlighountries .Patient activation might be influenced not only by knowledge, skills, and confidence related to self-management, but also by the health system itself . Our finp value 0.0019. Small sample sizes could affect the magnitude of DIF and therefore be misleading, while large magnitudes should always be investigated further. A possible shortcoming of the DIF analysis is that Mantel-Haenszel was used, since only uniform DIF can be detected with this approach. Further investigations of non-uniform DIF could be carried out by visual inspection of empirical item-scale regressions, but we refrained from doing that at this point.The findings revealed presence of DIF in some items. However, DIF is only evidence of bias in cases where the factor causing it is irrelevant to the underlying construct. Age, which should not be of relevance for the construct, showed uniform DIF for item 8, i.e., the group showed a consistent systematic difference in their response to the PAM item, across the whole range of the attribute being measured. To support unidimensionality, it is generally accepted that no more than one item on a scale, or 5% of the items, should demonstrate DIF . In addiThe use of modern test theory  offers a number of advantages by modelling the relationship of individual items to the construct being measured. The method provides a much richer description of the performance of each item and greater detail on a measure’s precision than the classical test theory (CTT) . The posAnother major strength of the study is the systematic translation using input from patients, researchers, and health care professionals, which ensured that the items were worded in an easily understood and comprehensible way. The present study had a response rate of 47.6%. There is no direct correlation between response rate and study validity. A low response rate merely indicates a greater risk of low validity . We chosAs shown in Table As we wanted to gather data from multiple hospital settings in various regions, questionnaire distribution was delegated to nurses and team leaders at different wards. This may have caused a selection bias, in that the professionals might unintentionally have hesitated to invite patients with low health literacy, due to limited time for providing information. This could lead to underrepresentation of patients with low patient activation.The Swedish version of PAM-13 had high reliability, but was not found to represent one underlying construct conclusively. Furthermore, the order of items differed from that in the original PAM-13, as seen previously in European studies. It is possible that differences in health care systems and culture influence how patients perceive the items, explaining the varying order of items between countries. Problems with targeting were noticed, which might indicate construct under-representation.Although there is a great interest in measuring patient activation across Europe –15, 39, Additional file 1. The questionnaire used at data collection.


The visual analogue scale (VAS) was used; pain scores were measured four times: during local anesthesia, probe insertion, sampling procedures, and at 15 min post procedures. No significant differences were observed in VAS scores during local anesthesia  or during probe insertion . Similarly, no differences in VAS scores were detected during the sampling procedures  and at 15 min post procedures . No major complications were noted in either group. Both PPB and PNB are comparably effective and safe methods for PBx related pain relief, and PPB is not superior to PNB. Local anesthetic method could be selected based on the preference and skill of the operator.We evaluated whether pelvic plexus block (PPB) is superior to periprostatic nerve block (PNB) for pain control during transrectal ultrasonography (TRUS)-guided prostate biopsy (PBx). A prospective, double-blind, randomized, controlled study was performed at a single center; 46 patients were enrolled and randomly allocated into two groups: PPB ( Prostate cancer (PCa) is the most frequently occurring malignancy in men worldwide, with approximately 1.1 million new cases diagnosed each year . NotablyRecently, various local anesthetic methods have been developed to reduce PBx-related pain. These involve multiple types of anesthetic agents and sites of injection, and when used either alone or in combination, most were found to be effective for control of PBx-related pain . During Pelvic plexus block (PPB), which involves injecting lidocaine directly lateral to the tip of the seminal vesicles, was first described by Wu et al. . Becausehttp://clinicaltrials.gov . This prospective, double-blind, randomized, controlled study was performed at one institution  from September 2018 to February 2019. Ethical approval was obtained from the Institutional Ethical Committee , and the study is registered at Patients with an abnormal prostate finding during digital rectal examination (DRE), a serum prostate-specific antigen (PSA) level >2.5 ng/mL, and/or an abnormal lesion detected with TRUS were included in this study. Those under 50 years of age or with a history of previous TRUS-guided biopsy, chronic prostatitis/pelvic pain, neurological conditions , bleeding diathesis, anticoagulation/antiplatelet therapy, active urinary tract infection, hemorrhoids/anal fissure/anal fistula, or a known allergy to lidocaine were excluded from the study. Before the biopsy procedure, patients with active urinary tract infection and prostatitis were excluded by investigation of current symptoms and past history and urine analysis. Written informed consent was obtained from all patients prior to study enrollment.Using pain scores reported in the literature , we estiEnrolled patients were randomly allocated by computer randomization into the PPB and PNB groups. The former received PPB and the latter received PNB. All patients took levofloxacin  prior to the procedure, for a total of five days, and received intravenous third-generation cephalosporine on the day of the procedure, according to the institutional protocol. A cleansing enema was also performed on the morning of biopsy. All block procedures were performed by a single well-experienced urologist who was accustomed with five years of experience with performing the block procedure. Another single urologist, with more than seven years of prostate biopsy experience, conducted all the biopsy procedures using a BK 3000 scanner , with a 4- to 14-MHz endorectal triplane transducer. During the procedure, patients were placed in a right lateral decubitus position. EMLA cream  was applied first around the anal ring and 10 mL 2% lignocaine jelly was instilled into rectum 10 min before the introduction of the TRUS probe. Nerve block (either PPB or PNB), with 2.5 mL 2% lidocaine, was injected into both sides of the prostate , using a 21 G, 15 cm Chiba needle . In the PPB group, lidocaine injections were administered to the pelvic neurovascular plexus, located at the end of the seminal vesicle, under Doppler-guided ultrasound, on each side ,12,13,14All study participants were blinded to their treatment group assignment, and the urologist who conducted the biopsy procedures was blinded as to the type of nerve block given. A physician’s assistant, who was also not aware of the type of nerve block administered, explained the visual analog scale (VAS) to the participants and requested they rate their degree of pain or discomfort from 0 to 10 at four time points: (1) VAS-1, during the local anesthesia procedure, (2) VAS-2, during ultrasound probe insertion, (3) VAS-3, during the sampling procedure, and (4) VAS-4, 15 min after finishing all procedures. In addition, the physician’s assistant recorded the time it took to complete all procedures. The patients recorded VAS scores themselves, without assistance. The patients were observed for 4 h after the procedures and were counseled about the possibilities of mild hematuria, self-limiting rectal bleeding, mild fever, and/or hematospermia. They were advised to go to the emergency room if they experienced a high fever, syncope, massive hematuria, or urinary retention. All patients were reviewed again after one week to monitor for any late complications.p-values were calculated using SPSS version 23 , and p < 0.05 was considered statistically significant. The primary outcome of the present study was VAS scores at the time of biopsy. Pain scores  and the time to complete all procedures were compared between the two groups using the Mann–Whitney test. n = 46). These 46 patients were randomized into two groups, PPB (n = 23) and PNB (n = 23).Overall, 53 patients were assessed for eligibility and provided consent to be included in the study. Of these, seven patients did not meet the inclusion criteria : four hap = 0.154) (p = 0.537). Mean pain scores at ultrasound probe insertion after anesthetic procedure (VAS-2) were 2.83 ± 2.21 for the PPB group and 2.39 ± 1.90 for the PNB group (p = 0.569). There were also no differences in mean pain scores during the sampling procedure , and for those measured 15 min after finishing all procedures . There were no significant differences in age, prostate volume, and serum PSA between the two treatment groups. The total time for all procedure was 12.52 ± 3.39 min for the PPB group and 13.78 ± 2.91 min for the PNB group (= 0.154) . Table 2There were no major complications, including urinary tract infection, sepsis, or significant rectal or urethral bleeding, reported by any of the patients. Pain during PBx is caused by the introduction and manipulation of the ultrasound probe into the anal canal and rectum, as well as by penetration of the needle into the prostate capsule, which is rich in autonomic sympathetic and parasympathetic fibers ,17. In gPPB was first described as an alternative to PNB by Wu et al.  in 2001 Recent meta-analysis by Li et al.  found thThe characteristics and outcomes of this present study, as compared to previously published studies, are summarized in We conducted a study of 46 patients; 23 across two groups. The total number of participants may be considered too small when compared to the previous studies ,13,14. HNotably, all studies being compared were designed as double-blind investigations; however, we speculate that the current study may have less bias in the blinding step, due to the fact that clinicians performing the anesthesia, the biopsy procedure, and the access of the VAS scores were different and the physicians performing PBx and accessing the VAS score were blinded to the type of local anesthetic method. Other differences include the fact that Akpinar et al.  performeWe note, however, that the present study was not designed to evaluate the pain scores based on the site of biopsy, and therefore it remains unclear whether PPB may help in controlling pain associated with apex biopsies, due to the blocking of the anterior nerve fibers that might be missed by PNB. Further studies will thus be needed to clarify this issue. Lastly, VAS is widely used for epidemiological and clinical studies, and its strengths and weaknesses are well appreciated . In partWe found that despite the theoretical advantage of PPB, this technique did not show superiority for PBx-related pain control as compared to PNB. Thus, our data suggest that both PPB and PNB are comparably effective and safe methods for pain control in patients undergoing PBx, and as such, the local anesthetic method utilized in this procedure could be selected based on the preference and skill of the operator.


Background: The association between body mass index (BMI) and colorectal cancer is unique. There are several patient- and tumor-related factors that affect this and associations are not entirely clear. The primary aim of this study is to examine the association between BMI and survival after colorectal cancer diagnosis.Methods: Among 26,908 Mayo Clinic patients diagnosed with colorectal cancer between 1972 and 2017, 3,799 patients had information on BMI within 6 months prior to cancer diagnosis. Multivariable Cox regression models were used to assess the differences in overall survival between BMI groups in each cancer stage, controlling for age, gender, year of diagnosis, and cancer location. The impact of change of BMI at 30, 60, and 90 days on survival afterwards were also analyzed.Results: Among 3,799 patients included in the study, there were 29% normal weight, 2% underweight, 36% overweight, and 33% obese patients. With all stages combined together, the overall 5-years survival rates for underweight, normal weight, overweight, and obese patients were 33, 56, 60, and 65%, respectively (p < 0.001). The results show that, the difference in overall survival was not statistically significant when underweight, overweight, and obese patients were compared to normal weight patients in stage 1 and stage 2, although there was a trend that overweight patients had better survival than normal weight group in stage 2 cancer patients . In stage 3 and 4 patients combined, underweight group demonstrated a significant disadvantage  for overall survival compared to the normal weight group. Additionally, post-diagnosis BMI drop more than 10% from either a previous time  or pre-diagnosis time  was associated with worse overall survival after adjusting for baseline variables.Conclusions: BMI is an important consideration in patients with colorectal cancer. Outcomes are stage-dependent where in some situations obesity maybe an advantage. More importantly, being underweight is a significant negative predictor of outcome. The impact of drop in BMI or weight, on survival of CRC patients, needs to be studied further since this is potentially an actionable variable and a dynamic biomarker that may help improve outcome in these patients. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the United States –3. AccorIn this study, our aim was to examine the association between BMI and outcomes in patients who are diagnosed with CRC at our institution, and to estimate their survival patterns. We also tried to study if change in BMI, specifically fall in BMI, was a negative predictor of outcome.Institutional review board approval was obtained. The Mayo Clinic, 3-site single institution , cancer registry was queried for all patients seen with a diagnosis of CRC between 1972 and 2017. Twenty-six thousand nine hundred eight patients were identified. The Mayo Clinic Colon and Rectal Cancer Registry is an institutional dataset comprising of patients seen at all of the 3 Mayo Clinic Sites. Patients are identified through the ICD coding, which is subsequently verified based on clinical notes and pathology. This forms the basis of reporting data to other datasets as well. Since this represents data from 3 major academic sites in the country of Mayo Clinic, patients tend to represent population based registries and dataset from other tertiary care institutions in United States. For this particular study, 3,814 patients were found to have either BMI, or height and weight data available to calculate BMI within 6 months prior to cancer diagnosis. To allow for comparisons across patients to be similar and minimize confounding and other disease/treatment variables, we restricted the BMI data to what was available within 6 months of the diagnosis. After excluding patients with BMI < 10 or >80 (likely due to inaccurate data entry), a total of 3,799 patients were included in this analysis.2), underweight (<18.50 kg/m2), overweight (25.00–29.99 kg/m2), and obese (≥30.00 kg/m2). Continuous variables were compared between BMI groups using Kruskal-Wallis test and categorical variables were compared using Chi-squared test. Overall survival rates after diagnosis at 5, 10, and 15- years were estimated using Kaplan-Meier method and compared between groups using log-rank test. Multivariable Cox regression models were used to assess the differences in overall survival between BMI groups in each cancer stage, controlling for age, gender, year of diagnosis, and cancer location. Since proportional hazard assumption was violated for BMI category in stage 2 patients, it was included in the model for stage 2 patients with time dependent coefficients. When analyzing post-diagnosis BMI in stage 4 patients, BMI data was sorted in a way to accommodate the counting process model for time-dependent covariates. BMI was assumed to stay the same between two dates of measurements, as well as from the last BMI measurement to last survival follow up date. The impact of change of BMI at 30, 60, and 90 day on survival afterwards were also analyzed. Again, these cutoffs were chosen arbitrarily to minimize confounding and allow similar comparisons to be made across patients post-diagnosis. The reasons for choosing the BMI change 30, 60, and 90 day was mainly because of expert opinion on what would be clinical meaningful in patients with stage-4 cancer. SAS 9.4 was used for statistical analysis.Summary statistics for continuous variables are reported as mean (standard deviation) and median (range) while categorical variables are reported as frequency (percentage). The international classification guideline for adult BMI was used to create the following BMI groups: normal  and 54% patients were male. The majority of patients (78.3%) were diagnosed with CRC in year 2000 or later (Q1–Q3: 2000–2010). Demographic and baseline variables are demonstrated in Table 3.6 and 518.6% patients had tumor stage 4 at time of diagnosis. Cancer/tumor-related information are shown in Table p < 0.001). The median survival for underweight, normal weight, overweight and obese was 38, 80, 106, and 114 months, respectively. To examine if these effects were stage-dependent, Kaplan-Meier estimates of overall survival since cancer diagnosis by BMI category and stage were done and are demonstrated in Table With all stages combined together, the overall 5-years survival rates for underweight, normal weight, overweight and obese patients were 33, 56, 60, and 65%, respectively p < 0.00. The medp = 0.007) for overall survival compared to the normal weight group. In all the analyses, HR reported is in reference to the normal weight group. The unadjusted KM survival curves for BMI groups in stage 3 and 4 patients are displayed in Figure Multivariable model as shown in Tables p < 0.001) was a significant predictor for worse survival. Post-diagnosis BMI drop more than 10% from either a previous time  or pre-diagnosis time  was associated with worse overall survival after adjusting for baseline variables. Similar trends were also noted for a post-diagnosis BMI drop by 5–10% from previous time  or pre-diagnosis time , respectively. Multivariable model predicting overall mortality is demonstrated in Tables When post-diagnosis BMI was analyzed as time-dependent covariates for stage 4 patients, being underweight  . Our stuResearch has indicated that several lifestyle modifications including exercise and weight loss are protective against development of CRC , 23. Onen = 3,799), availability of stage-specific data and estimation of CRC survival with serial drop in BMI. This study is limited by its retrospective design and lack of information about the comorbid and confounding factors which might have played role in survival. Furthermore, there is potential of reporting bias since only 14%  patients, out of total  seen at our institution, were included in the analysis whose BMI information was available. We adjusted for this as whenever BMI values were not available and instead height and weight information was available, we calculated BMI manually. Additional limitations include the smaller subset of individuals with serial BMI data that we used for the weight loss or drop in BMI analyses. Furthermore, therapy that these patients got was likely heterogeneous. With BMI being a dynamic variable, the same question posed by our study group can potentially be studied and analyzed through other approaches as well. However, more of value would be to studying these variables in prospective studies, especially intervention studies e.g., improving BMI or reducing rate of weight loss in malnourished patients e.g., with nutrition counseling.Strengths of our study include large sample size .Abstract submitted to American Society of Clinical Oncology (ASCO) meeting in June 2018. This was published as an online only abstract but not presented at the meeting (J Clin Oncol 36, 2018 (suppl; abstr e15631; available online: Authors PK and AM thought of the study based on clinical experience. The research team with authors PK, FS, AM, and DC, formulated the design and the plan for the study. Statistical analysis was conducted by statisticians ZL and JC. This was in close discussions and revisions with authors PK, FS, and AM. All the authors approved of the final analysis and results. Authors FS and PK drafted the initial draft of the paper with ZL and JC outlining the methodology and results. These were edited and approved by all authors prior to submission of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Psychological stress is a ubiquitous subjectively negative emotional experience, but excessive psychological stress has adverse effects on the happiness in our lives and physical and mental health, and may cause many health problems. Studies have found that probiotics have a certain role in alleviating negative emotions, reducing abnormal behaviors, improving cognitive function, and also showing the great potential of probiotics in relieving psychological stress. At present, many clinical trials have been carried out to intervene in populations with psychological stress with probiotic supplements, but there still lack of targeted systematic review and meta-analysis.The Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Psycoinfo, Cumulative Index to Nursing and Allied Health Literature will be searched to obtain the eligible randomized controlled trials published up to March 1, 2019. Meanwhile, the references to relevant publications will also be reviewed to identify other studies, and will re-search before finial summary for analysis. EndNote X7 will be used as a document manager for duplicate checking and screening of literature. The risk of bias will be assessed and the date of included studies will be analyzed by Revman V5.3.5.The primary outcome will be subjective stress level, general mild psychiatric symptoms of participants. The secondary outcome will be cortisol level and adverse effects likely to be related to treatment.The systematic review and meta-analysis will provide evidence to assess the efficacy and safety of probiotics in relieving psychological stress.PROSPERO CRD42019122930. Generally, stress response is important for enhancing adaptability and coping with threatening situations. However, excessive psychological stress is negative, not only increases the risk of diseases, included hypertension, cardiovascular diseases, digestive system diseases, and most neuropsychiatric disorders,9, but also may cause reduced happiness in life, job burnout, unhealthy lifestyles,,13 and other consequences. Statistics showed that in the UK, at least one-third of work-related diseases are caused by stress, resulting in a large loss of working time. Therefore, finding an effective means to prevent stress, relieve stress, and reduce the adverse effects of stress on individuals, families, and society has become a hot issue in the present research, especially in the medical field.When an individual perceives that demands from society, work and study tax, or exceed his or her adaptive capacity, psychological stress unavoidably occurs.1.2,16 Studies have found that–19 intestinal microbes can regulate the mood, cognition, and nervous system function of the host through various means such as nerve, immunity, and endocrine . Stress is an important factor in the intestinal micro-ecological disorders, and may cause more health problems.A large number of diverse intestinal microbes are planted in the human gut, which are symbiotic with the host and participates extensively in the life activities of the host. Animal and human studies have confirmed that in some cases, probiotics can increase or decrease the synthesis of certain neurotransmitters and biologically active factors such as serotonin, brain-derived neurotrophic factor, cortisol, thereby alleviating the subjective stress level of the participants, as well as related mental symptoms such as anxiety and depression. Because probiotics have a positive role in mood, cognition, and other psychological processes, probiotics are also known as “psychobiotics”,25 and may be a potential therapy or auxiliary means for stress-related mental disorders.Probiotics are active micro-organisms. When applied in sufficient quantities, probiotics can play a beneficial role by improving the intestinal tract for ecological balance.1.3So far, a large number of clinical studies on the application of probiotic supplements to intervene in stress response have been carried out worldwide. However, the Cochrane Database of Systematic Reviews, Embase, and MEDLINE databases were searched, and evidenced reviews or protocols on “whether probiotics have effects on relieving psychological stress in healthy participants” were not found. Therefore, this systematic review is urgently needed.22.1The protocol has been registered in PROSPERO, the International Prospective Register of Systematic Reviews with registration number CRD42019122930 on February 21, 2019.2.2Ethical approval is not necessary as this paper is a reanalysis of the original study, which does not involve participations’ privacy issues. The results of this study will provide information on the effectiveness and safety of probiotics supplements to alleviate psychological stress in healthy populations. This protocol will be disseminated by a peer-reviewed journal, thus providing evidences for clinical practice.2.3The healthy participants with no known major health issues, regardless of age, gender, ethnicity, and region will be included. Pregnant women will be excluded in the selection criteria for this study due to potential adverse effects.2.4Studies that use oral probiotic supplements as interventions will be included. The probiotics can be in the form of tablets, powders, capsules, soft capsules, fermented milk, or fortified foods containing probiotics. Studies in which probiotics do not survive,  or use prebiotics as intervention alone will be excluded.Trials will be included if they use placebo as a control. If compared with the control group, the effect of probiotics alone can be used in the treatment group, for example using probiotic yogurt and normal yogurt as comparison, will also be eligible.2.5All randomized controlled trials that reporting subjective stress level of participants will be included. If mean deviation and standard deviation of the study results cannot be obtained, then the study will be excluded. If the results of a study are reported multiple times, we will combine these reports and consider them as 1 study.2.62.6.1(1)Subjective stress level: measured using the Perceived Stress Scale, Berocca Stress Index, Personal Strain Questionnaire of the Occupational Stress Inventory-Revised, or Visual Analog Scales, and so on.(2)General mild psychiatric symptoms: measured using the General Health Questionnaire, Psychological General Well-Being Schedule, State/Energy Visual Analogue Scales, Hospital Anxiety and Depression Scale, Hamilton Anxiety Rating Scale, Depression Anxiety Stress Scale, Visual Analog Scales, Geriatric Depression Scale, or Hopkins Symptom Checklist-90, and so on.2.6.2(1)Cortisol level ;(2)Adverse effects likely to be related to treatment.2.7Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature will be searched, and the references to relevant publications will also be retrieved to identify additional studies. The searches will be re-run before the final analyses. The detailed search strategy is seen in Tables 2.82.8.1The retrieved literature will be imported into EndnoteX7 and the duplicate data will be removed. Preliminary screening of the literature will be conducted by 2 authors independently through reading the title and abstract. The full text of these potentially eligible studies will be retrieved and independently assessed for eligibility by those 2 authors. Any disagreement between them over the eligibility of particular studies will be resolved through discussion with a third reviewer. The specific process of the selection procedure is presented in a preferred reporting items for systematic reviews and meta-analyses flow chart Fig. .2.8.2A standardized, pre-piloted form will be used to extract data from the included studies for assessment of applicability of the data extraction form. Extracted information will include: study design, study population and participant demographics and baseline characteristics, details of the intervention and control conditions, study methodology, recruitment and study completion rates, measurement methods, measurement times and results for each outcome measure included, as well as information for assessment of the risk of bias. Two review authors will extract data independently, and discrepancies will be identified and resolved through discussion (with a third author when necessary).2.8.3Review Manager V5.3.5 software will be used for all bias risk assessments. The risk of bias in the included study will be assessed by considering the following characteristics:(1)Random sequence generation (selection bias);(2)Allocation concealment (selection bias);(3)Blinding of participants and personnel (performance bias);(4)Blinding of outcome assessment (detection bias);(5)Incomplete outcome data (attrition bias);(6)Selective reporting (reporting bias);(7)Other bias.Disagreements between the review authors over the risk of bias in particular studies will be resolved by discussion, with involvement of a third review author when necessary.2.8.4For continuous variable, if the measurement tool is same, we will use the mean difference with 95% confidence intervals (CIs) to analyze the treatment effect. If the measurement tool is different, we will use standardized mean difference to eliminate the effects of different measurement units of the multiple studies. For dichotomous variable, we will use the relative risk with 95% CIs to analyze the effects of treatment.2.8.5If the research report cannot provide all data in the data extraction form, we will try to contact the corresponding author or first author to obtain the data by e-mail. If the data cannot be obtained, the available data will be analyzed.2.8.6I2 value is less than 50% and P value is >.10, it is considered that the heterogeneity between multiple studies is acceptable. A range of 0% to 40% of I2 indicates the heterogeneity might not be important; a range of 30% to 60% indicates possible moderate heterogeneity among multiple studies; a range of 50% to 90% indicates substantial heterogeneity; a range of 75% to 100% indicates considerable heterogeneity. We will select models based on the heterogeneity between studies. If heterogeneity exists between multiple studies, we will perform sensitivity analysis and subgroup analysis to process heterogeneity and analyze heterogeneity sources.We will use tests for heterogeneity to assess the heterogeneity of the statistics of multiple studies. If 2.8.7It should be noted that this is a qualitative synthesis and while subgroup analyses may be undertaken. It is not possible to specify the groups in advance. If the necessary data are available, subgroup analyses might be done according to the age of participants, length of intervention, or the type of probiotics (including single-strain probiotics formulation and multi-strain probiotics formulation).2.8.8We will eliminate the studies with more than 1 risk of high bias, or 2 or more risks of unknown bias by item. It will be observed that whether the quality of the study will affect the results of the study.2.8.9If more than 10 studies are included, we will use Review Manager V5.3.5 software to assess potential reporting bias. If there is a clear reporting bias, we will assess the impact of bias on the outcome.3,27 As an important type of “spiritual microbes,” probiotics show good prospects in relieving stress and preventing stress-related health problems. Although many animal experiments and clinical studies have been conducted, the efficacy of probiotic supplements for relieving stress has not been scientifically and systematically evaluated. The purpose of this systematic review is to assess the effectiveness and safety of probiotics in relieving stress in healthy populations, and we hope that this study will provide additional evidence. Through preliminary search, we found that there are still many clinical studies underway. These studies are very important for the conclusion, so we consider updating the systematic review after 5 years.As we are concerned, excessive stress is threatening our physical and mental health and triggering more and more public health problems.Conceptualization: Ning Zhang, Weiguang Wang, Shuangqing Zhai.Data curation: Ning Zhang, Yanan Zhang, Menglin Li.Formal analysis: Xing Liao, Yanan Zhang, Menglin Li.Investigation: Yanan Zhang, Menglin Li.Methodology: Xing Liao, Weiguang Wang.Project administration: Shuangqing Zhai, Xing Liao.Software: Ning Zhang.Supervision: Shuangqing Zhai, Xing Liao.Validation: Shuangqing Zhai, Xing Liao.Visualization: Shuangqing Zhai, Ning Zhang.Writing – original draft: Ning Zhang, Shuangqing Zhai, Yanan Zhang.Writing – review and editing: Shuangqing Zhai, Xing Liao, Ning Zhang.


Alzheimer’s disease patients are reported to have higher survival rate compared to patients with vascular dementia or dementia with Lewy bodies. There is a paucity of studies investigating survival including persons with cognitive decline and dementia of various aetiologies.We aimed to compare survival for patients with subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease, vascular dementia, mixed Alzheimer’s/vascular dementia, dementia with Lewy bodies/Parkinson’s disease, and other dementias compared to the general Norwegian population, taking into account the role of gender, cognitive function, function in everyday activities, comorbidity and education.Patients (N = 4682), ≥65 years, in the The Norwegian register of persons assessed for cognitive symptoms (NorCog) during 2009–2017 were followed for mortality in the National Registry until January 2018. Flexible parametric survival models were applied to estimate relative survival, life expectancy and years of life lost for diagnostic groups compared with the general population.Patients with vascular dementia or dementia with Lewy bodies/Parkinson’s had the shortest survival, followed by mixed dementia, Alzheimer’s disease, unspecified dementia, mild cognitive impairment and subjective cognitive decline. At age 70 years, men with vascular dementia or dementia with Lewy bodies/Parkinson’s had life expectancy of 4.7 years, which corresponded to 10.3 years of life lost compared to the general population. Years of life lost for other diagnoses were 10.0 years for mixed dementia, 9.2 years for Alzheimer’s disease, 9.3 years for other dementias, 5.2 years for mild cognitive impairment and 2.2 years for subjective cognitive decline. Corresponding years of life lost in women were: 12.7 years, 10.5 years, 9.8 years, 10.6 years, 7.8 years, and 2.6 years. Poor relative survival among dementia patients was associated with male gender, comorbidity, low cognitive function, and low function in activities of daily living.Compared with the general population, patients with subjective cognitive decline had no significant loss in life expectancy, while patients with mild cognitive impairment and all dementia subtypes had large losses, especially those with a diagnosis of vascular dementia or dementia with Lewy bodies/Parkinson’s. Dementia is caused by a variety of brain disorders, which substantially shortens the life span , and we Unfortunately, the Swedish study lacked inclusion of patients with milder cognitive impairment, not fulfilling dementia criteria. AD is usually diagnosed at the dementia stage, but as AD is a progressive disease it can present both at the mild cognitive impairment (MCI) stage and at the even earlier preclinical subjective cognitive decline (SCD) stage . A revieSeveral studies report a male survival disadvantage for people with a dementia diagnosis , 4, 14, In the current study, we aimed to quantify survival for the included dementia types, as well for incident SCD and MCI, expressed as relative survival, life expectancy and years of life lost compared to the general Norwegian population. We also aimed to investigate the role of gender, cognitive function, function in everyday activities, comorbidity and education in relation to survival.st 2018, whichever occurred first. Those emigrating were censored at date of emigration (n = 5). Apart from this, none of the participants were censored. Patients were followed for maximum seven years.Clinical data on 4,682 persons ≥65 years from the Norwegian Register of Persons Assessed for Cognitive Symptoms (NorCog) , in the NorCog is a national register and includes clinical data for patients referred for a dementia workup in outpatient clinics . At the The study population comprised subjects with one of the following diagnoses: SCD, MCI, AD, VaD, mixed AD/VaD, DLB, PDD, unspecified and other dementias (hereby denoted other dementias). DLB and PDD was treated as one group due to high degree of clinical overlap . In someYears of education was dichotomised . Performance in instrumental activities of daily living (IADL) was assessed with the scale published by Lawton and Brody , with a Mortality rates were compared to those in the general Norwegian population using yearly national life tables from Statistics Norway based on the middle population and number of deaths by gender and one-year ages for each year 2009–2016. For 2017, the life table for 2016 was used. Mortality rates were smoothed using multivariable regression spline models.Unadjusted survival curves by diagnosis and gender were estimated using the Kaplan-Meyer method. Furthermore, Flexible parametric survival models were applied , 25 to eWhen comparing survival of several diagnose groups, (let’s say diagnoses A and B) it is feasible to calculate excess mortality rate ratios (RER), which is the absolute excess mortality rate for diagnose A divided by the absolute excess mortality rate for diagnose B. These measures of excess mortality and relative survival are widely used in cancer epidemiology, but should be applicable to other disease groups as well .Another advantage of the flexible parametric model is the possibility to estimate life expectancy and years of life lost for the patient group of interest . Years oThe flexible parametric models were modelled with five knots for the baseline hazard, with default knot location, and a base model was fitted using diagnosis group as a categorical variable adjusted by age at diagnosis, gender and the interaction diagnosis by gender. Age at diagnosis was first modelled as a restricted cubic spline with three degrees of freedom, but treating age linearly provided equally good fit, so this simpler model was preferred. Further adjustment was done sequentially by adding the covariates to the model. Regression analyses were performed on the study population with non-missing values for all covariates. A similar regression model was applied for the estimation of relative survival, life expectancy, and years of life lost, using smoothed mortality rates from the general Norwegian population as the reference population. In the estimation of life expectancy and years of life lost, year of diagnosis was included in the model as a restricted cubic spline with three degrees of freedom, but also in this setting the simpler linear term had equally good fit, and therefore chosen. Since there were no signs of violation of proportionality of hazards, and models with such effects gave similar results, no time-dependent effects were included in the models. All analyses were performed in Stata version 14.0 . The project is approved by the Regional Committees for Medical and Health Research Ethics (2015/1510/REK vest) and by the registry owners . Written informed consents were obtained from patients.The mean follow-up time for the study participants was 3.5 years (median 3.2 years). Total follow-up time was 16,601 person years. Mean age at baseline was 77.1 years (SD 6.7), min age was 65 years and max age was 97 years. Mean age at exit was 80.7 years (SD 6.7) .The most prevalent diagnoses were MCI (35%) and AD (30%), followed by mixed AD/VaD (9%), other dementia (9%), SCD (9%), VaD (6%) and DLB/PDD (4%) . The AD Predicted median survival at age 75 years ranged from 4.5 and 4.6 years for male DLB/PDD and VaD patients, respectively, to 12.0 years for female SCD patients , Table 2The survival of the SCD group was not significantly different from the general population , S3 Fig;By dividing the excess mortality rates for each diagnosis by the excess mortality for AD, we get estimates for excess mortality rate ratios (RER). Thus, RER for AD was set to 1, and a RER value less than 1 indicates that the excess risk of death for that diagnosis was less than that of AD, and vice versa. In the age and gender adjusted model, with AD as reference group, MCI had RER 0.38  0.25, 0.56). Thus, the absolute excess mortality rate for MCI was significantly less than that of AD. For VaD the RER was 2.66  and for DLB/PDD it was 2.46  . Thus, sFemale life expectancy at age 70 years in the general population in 2016 was 17.3 years, while for women with a dementia diagnosis it was 6.5 years . Thus, aIn this registry based prospective open cohort study, a dementia diagnosis was associated with substantial years of life lost compared with the mortality in the general population, especially for patients with a diagnosis of VaD or DLB/PDD. AD, mixed AD/VaD, other dementias and MCI were also associated with significant loss in life expectancy, while survival for SCD did not differ from that of the general population. Among dementia aetiologies, AD had significantly better survival than VaD and DLB/PDD, also after adjustment for age, gender, education, MMSE, and IADL.Among the patients who developed dementia after age 75 years, we found median survival times of 5.2 years in males and 6.8 years in females. These survival times are comparable to those reported in a systematic review covering the period 1987–2010 , a perioOur findings of AD having a survival advantage over patients with other dementia diagnoses fits with the conclusion in a review, which included 42 studies, of which 16 compared AD with either VaD or other dementia disorders , while aStudies on survival of MCI are generally in line with our findings of increased mortality in MCI patients compared with the general population , 10. OurFor SCD, the survival did not differ from that of the general population, which was also reported in two previous studies , 13, whiSurvival after a dementia diagnosis has generally been reported to be in favour of females , 4, 14. A limitation of the present study is that patients diagnosed in primary health care were not included, who in general are diagnosed at a later stage of dementia than in a memory clinic. Also patients, who were not competent to give informed consent were not included . FurtherAll dementia disorders were associated with substantial years of life lost. AD patients had the most favourable survival pattern among those with dementia. MCI was also associated with reduced survival, while SCD did not affect life length significantly. Differences across aetiologies in disease progression and severity, physical and cognitive function and comorbidity were important for the survival differences, but a large part of survival differences between aetiologies remained unexplained.S1 FigShaded areas are 95% confidence bands. Modelled using flexible parametric models including diagnosis, age, gender and diagnosis by gender interaction terms. N = 4,682.(TIF)Click here for additional data file.S2 FigN = 4,682.(TIF)Click here for additional data file.S3 FigShaded areas are 95% confidence bands. Modelled using flexible parametric models including diagnosis, age, gender and diagnosis by gender interaction terms. N = 4,682.(TIF)Click here for additional data file.S1 TableModelled using flexible parametric models.(DOCX)Click here for additional data file.


Background: Crohn’s disease (CD) is a chronic inflammatory bowel disease frequently associated with malabsorption and secondary protein-energy malnutrition (PEM). Methods: Biochemical and clinical data of 63  patients with PEM due to CD sent to our outpatient unit for nutritional evaluation were retrospectively analyzed. Patients were divided into two groups, according to disease activity. Thirty-eight patients (group A) had the active disease, and 25 patients (group B) suffered from malabsorption resulting from past intestinal resections due to CD. After a physical and hemato-biochemical evaluation at the first visit, all patients received disease-specific personalized dietetic indications. When indicated, oral nutritional supplements, oral/parenteral vitamins, micronutrients, and electrolytes, up to parenteral nutrition, were prescribed. Results: After 1, 3, and 6 months of nutritional therapy, body weight, body mass index (BMI), and serum butyryl-cholinesterase significantly improved in both groups. In 8 out of 13 (61.5%) patients with a cutaneous stoma, intestinal continuity was restored. Conclusions: This study confirms the effectiveness of nutritional rehabilitation and provides information on the time required for nutritional treatment in patients with CD, both during the acute phase and after malabsorption due to intestinal resection. Crohn’s disease (CD) is a chronic inflammatory bowel disease that can involve all segments of the gastrointestinal tract. During the acute phases of the disease, malabsorption and catabolic effects of acute inflammation cause weight loss and malnutrition with an incidence of 25–80% ,2,3,4.Patients with CD can develop chronic intestinal failure (CIF) as a result of reduced absorption due to the inflammatory involvement of intestinal mucosa, mechanical obstruction, or wide intestinal resections. These factors may act alone or in combination, impairing the ability of the gut to maintain protein-energy, fluid, electrolyte, or micronutrient balance, particularly in the presence of a stoma (jejuno or ileostomy) ,6.Documented malnutrition in patients with Inflammatory Bowel Disesses should be treated appropriately, as it worsens the prognosis, complication rates, mortality, and quality of life .For these reasons, CD patients often require personalized dietetic advice, oral or parenteral macro-and micro-nutrients, and fluid and electrolyte supplementation, according to their clinical and nutritional conditions, as well as their absorptive capacity .The study evaluates the types, modalities, and durations of nutritional interventions in patients with malnutrition secondary to CD.Biochemical and clinical data of 63  patients followed at a specialized outpatient unit for Clinical and Artificial Nutrition of Federico II University Hospital in Naples , from January 2016 to December 2017, were retrospectively analyzed.At the first visit, accurate medical history, a physical exam with particular attention to nutritional status , and anthropometric measures ) were collected. A dietetic inquiry by a specialized dietitian was included.Blood samples was taken for routine hemato-biochemical exams; in particular, albumin, transferrin, prealbumin, butyryl-cholinesterase (BChE), and lymphocyte count.Clinically, disease severity was defined by the Crohn’s disease activity index (CDAI), consisting of eight variables: number of stools, presence and severity of abdominal pain, general well-being of the patient, presence of extra intestinal manifestations of disease, presence of abdominal masses, use of antidiarrheal drugs, and presence of anemia and weight loss. Patients with CDAI <150 were classified as being in the clinical remission phase, while patients with CDAI ≥150 were considered to have the active disease.The patients were divided into two groups: Patients with malnutrition/malabsorption due to active disease (Group A) and patients in clinical remission with malnutrition/malabsorption due to intestinal resection (Group B). Malabsorption was testified by diarrhea, low nutritional indicators, weight loss, and remnant bowel length.After baseline evaluation and according to their nutritional status, all patients received personalized dietetic advice.In the case of protein energy malnutrition (PEM) and underweight condition, oral nutritional supplements (ONS) were prescribed for a supplementary intake of up to 250–300 kcal/day , enriched with vitamins and micronutrients according to the RDA.In the presence of protein malnutrition and normal to overweight, a modular protein powder (12 g/day) was chosen.Hydro-electrolytic parenteral supplementation was generally necessary in the acute phase of CD with severe diarrhea and dehydration; parenteral nutrition was reserved for cases of associated malabsorption and malnutrition or during remission phases in patients with a short bowel and/or high-output intestinal stoma. The prescribed parenteral supply considered the patient’s nutritional status, oral intake, and losses; for guidance, the energy supply (expressed per kg body weight/day) was approximately 25–30 kcal  was <30 mL/min; and lipid/CHO ratio, 30/70% or 40/60% of the total energy supply), with vitamin and micronutrient enrichment according to the RDA [Patients were followed up monthly or biweekly, according to their baseline clinical conditions.For each patient group, baseline data were compared with evaluations at 1, 3, and 6 months.The study was approved by the Ethics Committee of Federico II University (protocol number: 102/16).The data obtained were processed using a specific software for statistical analysis .p value < 0.05.Values were expressed as the mean ± standard deviation (SD), median, min, and max. For the comparison between means, the T test was used for non-paired data, and the chi-squared test was used for categorical variables. Finally, analysis of variance (ANOVA) was used for the comparison among the groups. Differences were considered significant for The baseline characteristics of the 63 CD patients, subdivided into the two groups, are reported in A total of 26 out of 38 (68.4%) patients in group A and 24 out of 25 (96.0%) patients in group B had undergone one or more intestinal resections, and 13 (20.6%) patients had an intestinal stoma—4 patients in group A (1 with a jejunostomy and 3 with ileostomies) and 9 patients in group B (4 with jejunostomies and 5 with ileostomies) .No differences emerged in the evaluated clinical and biochemical parameters between group A and B patients.2. Additionally, 8 out of 38 (21.0%) patients in group A and 8 out of 25 (32.0%) patients in group B had lost at least 5%–10% of their body weight in the previous 6 months. Similarly, in both groups, the main hemato-biochemical exams were lower than normal values in a considerable percentage of patients  patients in group A and 11 out of 25 (44.0%) patients in group B had BMI ≤18.5 kg/mpatients .All patients received detailed and personalized dietetic indications.Fiber-and lactose-free diet in the acute phase of the disease;Fiber was gradually reintroduced into the diet, based on individual tolerance, during the phase of slight/moderate activity;Milk and dairy products were gradually reintroduced in patients who did not report a pre-existing lactose intolerance before the acute phase onset; otherwise, lactose-free products were suggested, according to the individual’s tolerance.All dietary advice had the following characteristics ,8,9:FibeAlmost all patients received multivitamin and mineral tablets. A total of 21 out of 38 (55.3%) patients in group A and 11 out of 25 (44%) patients in group B received the prescription of a modular gluten -and lactose-free protein powder and/or ONS for a supplementary intake of up to 250–300 kcal/day , enriched with vitamins and micronutrients according to the RDA.Nine (23.7%) patients in group A needed parenteral (i.m. or i.v.) multivitamin complexes and intravenous electrolytes and micronutrients. In particular, i.m., B1–B6–B12 vitamins, folic acid, and vitamins A, D, and E were prescribed, following measurement of blood levels.Rehydration therapy consisted of the prescription of intravenous electrolytic solutions . In addition, 9 out of 25 (36%) patients in group B received parenteral iron.Due to moderate to severe protein-energy malnutrition and severe malabsorption, 7 out of 38 (55.3%) patients in group A and 13 out of 25 (52%) patients in group B required parenteral nutrition: through peripheral venous access in 6, and through central venous access in 14. The prescribed parenteral supply considered the patient’s nutritional status, oral intake, and losses. For guidance, energy supply (expressed per kg body weight/day) was approximately 25–30 kcal , with vitamins and micronutrients according to RDA.The mean duration of therapy was 149 ± 236  days for oral supplements, 45 ± 21  days for hydration, and 203 ± 202  days for Home Parenteral Nutrition (HPN).As shown in At present, all patients are still being followed up at our outpatient unit.At baseline, 13 patients (20.6%) had an intestinal stoma: 5 had undergone jejunostomy and 8 had undergone ileostomy. All of these patients were referred to our outpatient unit soon after discharge from the surgical ward and, since then, they have all received home parenteral nutrition. In 8 out of 13 (61.5%) of these patients (4 with jejunostomies and 4 with ileostomies), intestinal continuity was restored after a median of 8 months  of HPN. In 5 out of 13 (38.5%) patients, the persistence of disease activity did not allow for surgical rehabilitation. The 8 rehabilitated patients were completely weaned off of HPN; among the 5 patients with a persisting stoma, 1 still received daily HPN, 2 received electrolytic infusions three times a week, and 2 (with ileostomies) were completely weaned off HPN due to intestinal adaptation.In this study, the effectiveness of nutritional intervention in a group of patients with malnutrition due to CD was retrospectively evaluated.To this end, study patients were divided into two groups according to disease activity, the mechanisms responsible for malnutrition, and the resulting nutritional needs: a group of patients (Group A) with malnutrition/malabsorption due to active disease, and another group of patients (Group B) in clinical remission with malnutrition/malabsorption due to intestinal resection.The type and modalities of the nutritional support were personalized—according to the patient’s clinical conditions —and modulated during follow-up visits.In each phase of the disease, appropriate dietary advice is an essential component of CD care: In the active phase, specific dietary indications may control the number and consistency of stools, consequently reducing dehydration, as well as electrolyte and nutrient losses .Oral nutrition supplements (ONS) were prescribed as a minor supportive first-step therapy, in addition to normal food. Hydro-electrolytic parenteral supplementation was generally necessary in the acute phase of CD, with severe diarrhea and dehydration. Parenteral nutrition was reserved for cases of associated malabsorption and malnutrition or during remission phases, in cases of short bowels and/or high output intestinal stoma .In patients with a stoma, the rapid gastric emptying, small bowel transit, and exclusion of the colon compromise the absorption of water, electrolytes, and/or macronutrients. If the condition is left untreated, undernutrition and/or dehydration will result. In these cases, parenteral nutrition represents a lifesaving therapy and contributes to the surgical restoration of bowel continuity, when indicated ,10,11.After the first basal evaluation, follow-up visits were performed at 1, 3, and 6 months of nutritional support. During the first months of observation in the analysis of our data, only an increase in body weight and BMI, but not a significant improvement in biochemical parameters (except for BChE), were observed in both groups; possibly due to the improved hydration status and consequent hemodilution .On the other hand, the increased BChE levels after 1, 3, and 6 months of nutritional support testify to the recovery of nutritional status and liver protein synthesis. Several studies have shown that BChE levels reflect amino acidic substrate availability and, in the case of malnutrition (with or without inflammation), the impaired synthesis of visceral proteins; as well as reduced levels of other classical nutritional indicators .Malnutrition, a disease within the disease, may negatively influence a patient’s prognosis. To our knowledge, it has not been clearly demonstrated whether a good nutritional status can reduce the number of disease relapses.  CertainlEven with the several reported limits, to our best knowledge, the literature lacks studies with detailed step-by-step descriptions for nutritional intervention in CD patients.According to the ESPEN guidelines, patients with CD are at risk and should be screened for malnutrition at the time of diagnosis and thereafter on a regular basis (grade of recommendation 3A) . The reqIn patients with active CD, nutrition—particularly, enteral nutrition—can act as a primary therapy to treat intestinal inflammation, particularly in children and adolescents, and/or as a supportive therapy in the case of secondary malnutrition ,14,15,16During remission, the most frequent nutritional abnormalities principally result from malabsorption for past intestinal resections, which differ according to the presence of a jejuno-/ileostomy or of the colon in continuity.Despite the division in two groups (A and B), the patient characteristics remained quite heterogeneous; due to the small number of patients, further divisions seemed inconvenient.Patients with the active disease received several treatments, ranging from corticosteroids to azathioprine to biological drugs. To our knowledge, the direct effects of specific drugs on nutritional parameters have not yet been fully described in the literature. On the other hand, the active disease influences nutritional parameters due to systemic inflammation, as well as nutrient and fluid malabsorption. Undoubtedly, disease treatment may also improve nutritional status by reducing inflammation and increasing nutrient and fluid absorption. In our opinion, etiological therapy and treatment for malnutrition are two inseparable entities.The main purpose of this manuscript was to testify the global effectiveness of nutritional intervention in patients with CD, regardless of the activity and evolution of the disease.With this study, we intend to motivate research into more efficient and effective nutritional therapeutic strategies for these patients in the future.Unfortunately, our data represent the experience of a single specialized center for clinical and artificial nutrition. Further studies in more homogeneous groups of patients, clinical conditions, and pharmacological protocols could be useful in evaluating whether an adequate nutritional status favorably affects the clinical course of Crohn’s disease and/or the quality of life of these patients.


Getah virus (GETV) is a mosquito-borne virus that was first determined in Malaysia in 1955, and can infect humans and multiple other mammals. GETV infection in horses has been reported in Japan and India, and causes great economic losses. In China, GETV has been identified in mosquitoes, pigs, foxes, and cattle with a wide geographical distribution, but has not been detected in horses. In August 2018, a sudden onset of fever was observed in racehorse in an equestrian training center in Guangdong Province in southern China. Blood samples were collected from the sick horse, and PCR/RT-PCR analysis was performed to screen for equine viral pathogens associated with fever. The results indicated that the samples were GETV RNA positive. After RT-PCR, sequencing, and assembly, the genome of the first Chinese horse-derived GETV strain, GZ201808, was obtained. Compared with the genome sequences of other GETV strains, twelve unique nucleotide substitutions were observed in GZ201808. The genome of GZ201808 had the highest genetic identity (99.6%) with AH9192, which was detected in pigs in China in 2017. Phylogenetic analysis indicated that GZ201808 clustered in Group III, and was located in an independent branch distant from other horse-derived GETV strains, indicating a unique evolutionary pattern of GZ201808. This study first determined and described the disease course of horse infected with GETV in China, sequenced and characterized the genome of the field horse-derived GETV strain, and therefore presented an unequivocal report of GETV infection in horses in China. Alphavirus genus of the Togaviridae family. Its genome is linear, positive-sense ssRNA and contains a 5′ terminal cap, two large open reading frames (ORFs), and a 3′ terminal poly(A) tract. The two ORFs encode nonstructural (nsP1 to nsP4) and structural polyproteins , which are flanked by a 44 nt 26S junction region associated with transcription of an intracellular subgenomic 26S RNA (The species Getah virus (GETV) belongs to the  26S RNA .Culex sp. mosquitoes in Malaysia in 1955  and Japanese encephalitis  vaccines each year. After collection, the samples were immediately transported to our laboratory in an icebox for further use.In the present study, a total of 16 serum samples were collected from racehorses in the equestrian training center. Among them, two samples were collected from the sick horse on day 1 and 13, respectively. The remaining samples were collected from 14 other healthy racehorses on day 13 .Total RNA/DNA of 200 μl of the samples collected from the sick horse on day 1 was extracted using a MiniBEST Viral RNA/DNA Extraction Kit  following the manufacturer’s recommendations, and finally diluted in 30 μl of nuclease-free water. A total of 6 μl of RNA was then used for reverse transcription into cDNA using a HiScript 1st Strand cDNA Synthesis Kit  with random primers. Conventional or nested PCRs targeting the conserved regions of the viral genome were then performed to detect nucleic acids of equine arteritis virus, African horse sickness virus, equine infectious anemia virus, Japanese encephalitis virus, equid herpesviruses 1 and 4, and GETV using previously published PCR primers and procedures , and GenE. coli DH5α competent cells . After culture for 10 h, the bacterial clones were picked and detected by PCR, and the positive samples were sent for Sanger sequencing from both ends .After 1.5% agarose gel electrophoresis, the PCR products with the expected size were considered positive for the corresponding viruses . The DNA1 with the Clustal W method, and a total of 14 primer pairs covering the near complete genome of GETV were designed using Oligo 7.02 based on the conserved region among all of the GETV strains (3) and the genome of GZ201808 was assembled.The genome sequences of all of the GETV strains available in the NCBI database were obtained. The sequences were aligned using BioEdit 7.0.9.0 strains . PCR was3; The genome of the first GETV strain detected in horses in China, GZ201808, was aligned with 34 other GETV strains detected in mosquitoes, pigs, horses, foxes, and cattle from China, South Korea, Japan, Mongolia, and Russia . The nuc4 based on the GETV genome sequence, the nonstructural and structural polyprotein coding sequences, and the E2 gene. By “Find Best DNA Models,” the phylogenetic trees were inferred using general time reversible + gamma distributed or Tamura-Nei + gamma distributed models, based on a bootstrap value of 1,000 replicates.Maximum likelihood phylogenetic trees were constructed using MEGA 7.0EDTA-treated blood samples collected from the sick horse on day 1 were processed for virus isolation, as described previously . BrieflyTo understand whether archived horse serum samples in our laboratory contained GETV RNA, a total of 320 samples collected during 2014–2018 in our previously studies were processed for GETV detection by RT-PCR , 2018.In August 2018, a sudden onset of fever was observed in a racehorse  in an equestrian training center in Guangdong Province in southern China. Blood sample from the sick animal was collected after the onset of illness (day 1) , and tesAfter agarose gel electrophoresis, only two PCR products testing for the Cap and nsP1 gene of GETV showed the expected band. The subsequent sequencing and BLAST results also indicated GETV, with the highest genetic identity of 99.6% with a Chinese swine-derived GETV strain  and 99.7% with three Chinese mosquito-derived GETV strains , a Korean mosquito-derived GETV strain [KorL915 (JN410944)], and a Korean swine-derived GETV strain [South Korea (AY702913)] when analyzing the Cap and nsP1 genes, respectively. This GETV strain detected in a racehorse in our study was designated GZ201808, and was used for further genomic sequencing and analysis.To acquire the genome of GZ201808, a gap-filling PCR strategy was used based on 14 primer pairs covering the genome of all of the published GETV strains in the NCBI database . After sThe nucleotide identity of the genome between GZ201808 and other GETV strains was calculated . The resWhen analyzing the nonstructural polyprotein coding sequence, it was found that GZ201808 had the highest nucleotide identity (99.6%) with AH9192 and the highest amino acid identity (99.5%) with three GETV strains, GETV-V1, HNJZ-S2, and South Korea, detected in pigs in China or South Korea. When analyzing the structural polyprotein coding sequence, it was observed that GZ201808 had the highest nucleotide (99.7%) and amino acid (99.8%) identity with AH9192.The genome sequence, E2 gene, and the nonstructural and structural polyprotein coding sequences of GZ201808 and other GETV strains were used to construct four maximum likelihood phylogenetic trees to understand their genetic relationship . The phyIn the four phylogenetic trees, it was observed that GZ201808 was located in Group III, always had the closest relationship with AH9192 and had a closer relationship with the recently determined Chinese GETV strains than with the first Chinese strain (M1).Among the horse-derived GETV strains, it was observed that the Japanese strains detected during 2014-2016  and those in GETV outbreaks in 1978  were located in two distant branches. The Chinese horse-derived GETV strain GZ201808 was located in an independent branch, clustered together with the pig-derived GETV strain AH9192 detected in China in 2017. In addition, the Japanese horse-derived GETV strains determined during 2014–2016 had a closer relationship with the pig-derived GETV strain 15-I-1105 detected in Japan in 2015. It indicated the horse derived GETV strains had a close relationship with the locally prevalent strains in other animals, exhibiting a distinct geographical pattern.To date, there has been no reported effective antiviral treatment for horses infected with GETV. During the acute and recovery stages of the disease, routine training programs were terminated, and an increase in rest time was prescribed for the sick animal.In this study, a rectal temperature of ≥38.9°C was considered as the reference for fever in horses, which was observed in the following 10 days after day 1, with transient drops below the fever threshold applied on days 4 and 8 . The higNo apparent clinical sign of GETV infection was observed in other racehorses in the equestrian training center. Blood samples from the other 14 racehorses were collected on days 1 and 13, and were confirmed to be GETV negative by RT-PCR.After serial passages, no CPE were observed in cultured cells, and no clinical signs caused by GETV were found in suckling mice. In addition, no GETV RNA was detected in the cultured cells or mice by RT-PCR.After RNA extraction, cDNA synthesis, and PCR, all the 320 archived horse serum samples were negative for GETV RNA.Previously, GETV infection in horses was only recorded in Japan and India. In this study, GETV was detected for the first time in a racehorse with fever in China, which is the first description of disease caused by GETV infection in horses outside Japan and India. It has been reported that horses infected with GETV could recover spontaneously within 1 week without special treatment , and the–3 substitutions/site/year  was developed and used for preventing GETV infection in racehorses. In China, there is a large number of horses, and the racehorse industry is developing rapidly. To our knowledge, domestic horses in China have not been vaccinated against GETV infection. GETV is a potential threat to the racehorse industry in China. Developing a GETV vaccine using a field-prevalent strain as antigen components will help to prevent and control GETV in horses in China.All datasets generated for this study are included in the manuscript and/or the supplementary files.The blood sample collection method was conducted under the guidance of the South China Agricultural University Experimental Animal Welfare Ethics Committee. All procedures associated with the animal experiments were also approved by the South China Agricultural University Experimental Animal Welfare Ethics Committee.SL: conceptualization, writing – review and editing, supervision, project administration, and funding acquisition. GL: methodology, software, formal analysis, resources, writing – original draft preparation, and visualization. JO, JJ, ZR, XH, and CW: validation. GL, JO, JJ, ZR, XH, and CW: investigation.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.


To analyse the short-term adverse effects (AEs) of propranolol in the treatment of infantile hemangiomas (IHs) and their relevant factors, as well as the relationship between child growth and propranolol.  A total of 506 patients with confirmed or suspected IHs were enrolled, and a total of 439 cases were included in the study. Short-term AEs were analysed using single-factor analysis and binary logistic regression. Out of 439 patients, 292 were enrolled to examine the effect of propranolol on 2-year-olds' height and body weight (BW), by comparison with reference range and among groups. Spearman rank correlation analysis was used to determine the relationship between BW, height, and duration of propranolol treatment.  Among 439 patients, 70 (16.0%) experienced AEs. Among them, 48 had gastrointestinal (GI) symptoms, 23 had central nervous system (CNS) symptoms, 8 had both symptoms above, and 7 had other symptoms. Most of the AEs occurred on the starting day (day 0), and 6 children's AEs were transient. Starting age of no older than 3 months led to more CNS symptoms, and starting age of older than 3 months was a protective factor against CNS symptoms, with an OR value of 0.303 (0.117–0.783). Height and BW of 292 two-year-old children were no less than the reference levels, although those of 3 females and 1 male were less than the average −2 standard deviation (−2SD). The height and BW of the children at the age of two was not related to the length of time of propranolol treatment.  Oral propranolol has a good tolerance in the treatment of IHs. Oral propranolol exerts more adverse effects on the CNS of lower age children, and it has exhibited no effect on the growth of two-year-old children. As a serendipity, propranolol has become the first-line drug for the treatment of infantile hemangiomas (IHs) since 2008 [Propranolol, a nonselective nce 2008 , with hince 2008 . IHs neence 2008 . AlthougThe general adverse effects (AEs) of propranolol include nausea, vomiting, diarrhea, and other gastrointestinal symptoms. Severe adverse events include inhibition of cardiac function, Raynaud's phenomenon, aggravating bronchospasm, hyperkalaemia, depression, somnolence, and insomnia, which can result in serious consequences , 4–7. AtTherefore, we performed a prospective study to document short-term adverse events in a large number of children receiving oral propranolol and analyse factors that may be associated with these adverse events; follow-up measurements of body length and weight were conducted when the children reached two years of age to elucidate the impacts of propranolol on the growth and development of young children.This study was approved by the Institutional Ethics Review Board of Shandong Provincial Hospital Affiliated to Shandong University (No. 2016-308). The study was a part of a project, so the ethical number might also be used in other articles. Written informed consents were signed by the guardians of the children.First, the patients were subjected to history talking, examination of the affected part and color Doppler imaging. A total of 506 consecutive outpatients with confirmed and suspected IHs at the Department of Plastic Surgery were recruited from September, 2016 to July, 2018.Inclusion Criteria. (1) patients diagnosed with proliferating IHs and requiring systemic treatment ; (2) patients suspected to have IHs, but their guardians disagreed to biopsy or watchful waiting and agreed to try oral propranolol as a diagnostic treatment; and (3) patients with normal results of routine examination, and if the children had congenital deformities, abnormal electrocardiogram (ECG) or routine blood test and thus could be treated with propranolol orally, following consultation with pediatricians. At least one of the first two criteria must be satisfied, whereas the third criterion must be met.Exclusion Criteria. (1) children whose guardians refused to sign the written informed consent; (2) children who showed contraindications to oral propranolol ; and (3) patients who needed or insisted to receive other treatments at the same time. Patients who met any of these 3 criteria were excluded.Among the screened cases, children who were 2 year old by February, 2019 were enrolled for a follow-up measurement to elucidate the effect of propranolol treatment in infants. See details in Figure 1.The routine examination conducted before administration of the medicine included physical examination, ECG test, routine blood test, and blood glucose test. Propranolol was administered every 12 hours during feeding or within half an hour after feeding. Dose of the starting day (day 0) was 0.5 mg/kg/day, and then the dose was gradually increased according to the reaction of the child. Generally, the dose was increased to 1 mg/kg/day on day 2 or day 3, then to 1.5 mg/kg/day on day 7, and finally to 2 mg/kg/day on day 14.Parents could report their children's conditions to the investigators by telephone or WeChat, and routinely visit the outpatient care. The guardians were trained to recognise adverse reactions, so that they could promptly report these adverse reactions to the researchers and deal with the adverse reactions accordingly. The AEs were recorded and consulted with pediatricians when not sure if the AEs were caused by propranolol. Follow-up of short-term AEs lasted for 6 months. The height and body weight (BW) of the children were followed up by the age of 2.M ). The enumeration data were expressed as the number of cases and the percentile (N (%)).SPSS 22.0 was used to analyse the data. Double-cross recording and checking were used to ensure the accuracy of data entry. Normality of measurement data was tested by the moment method. The data with normal distribution were expressed as mean ± standard deviation . Otherwise, two samples were compared using the Mann-Whitney U-test. Spearman rank correlation analysis was used to determine the relationship between height, BW, and total duration of propranolol administration. The significance level (α) was set at 0.05.Chi-squared tests, Fisher's exact test, or the Mann-Whitney Out of the 506 patients screened, 439 were included in this study. Among the 439 patients, the starting age was 3.20 1.97, 5.37) months; 301 (68.6%) patients were females; 32 (7.3%) patients were premature; 234 (53.3%) patients had IHs on the head and neck; and 70 (16.0%) patients experienced AEs. Among the patients who experienced AEs, 48 had gastrointestinal (GI) symptoms, 23 had symptoms in the central nervous system (CNS), 8 had both GI and CNS symptoms, 7 showed other symptoms, and 4 withdrew treatment owing to AEs. In children showing both GI and CNS symptoms, the AEs occurred simultaneously, except for in 1 child who had diarrhea following propranolol administration at 1 mg/kg/day and hypoprosexia following dose increase to 1.5 mg/kg/day. Therefore, it was possible that the child's mood and sleep disorders were due to factors such as diarrhea .Among the 48 GI cases, 39 (81.3%) occurred on day 0, whereas the remaining 9 (18.8%) occurred when propranolol was increased to 1, 1.5, or 2 mg/kg/day; among the 23 cases of CNS symptoms, 22 (95.7%) occurred on day 0 and 1 occurred when propranolol was increased to 1 mg/kg/day. There were 6 cases that had transient adverse effects, 4 of which were GI symptoms and 2 were CNS symptoms see . The trap > 0.05), but it could be considered that patients with starting age of no older than 3 months showed more total AEs than patients with a starting age of older than 3 months (p = 0.007). Logistic regression based on total AEs occurrence as a dependent variable, whereas age, sex, medical history, and location as independent variables, revealed that starting age of older than 3 months was a protective factor against AEs, with an OR value of 0.508 (0.301–0.857). Statistical analysis with the same methods above showed that it could not be considered that GI symptoms were different in different starting age, gender, medical history, and location (p > 0.05), and no variable entered the regression model. In addition, it could be considered that patients with starting age of no older than 3 months showed more AEs in the CNS (p = 0.010), as determined by single-factor analysis, and starting age of older than 3 months was a protective factor against AEs in the CNS, with an OR value of 0.303 (0.117–0.783). See details in Tables Single-factor analysis showed that it could not be consider that total AEs occurrence was different in different gender, medical history, and location p > 0.0, but it One case of lip cyanosis occurred sporadically within 10 months of propranolol treatment, but the symptom improved after termination of treatment. There were 2 cases of shortness of breath when the children got cough, but the symptoms also disappeared after treatment termination. One child showed no weight gain after 4 months of treatment (when he was 6 months old), and this state lasted for 4 months until the child finished the propranolol treatment. One case of hair-thinning occurred at 3 months after propranolol initiation; by the end of follow-up, the child had been treated for 8 months and the symptom had lasted for 5 months. Furthermore, 2 cases of cold and sweaty hands and feet occurred within 3 days of propranolol administration, which might have occurred due to hypoglycaemia because their parents administered propranolol to the children on an empty stomach; after the method of propranolol administration was corrected, the symptoms disappeared.A total of 4 children withdrew the treatment owing to AEs, which all happened on day 0 and generally improved after treatment discontinuation; however, the guardian of one child reported that the symptom of decreased total sleep time gradually improved after 8 weeks of drug termination see . TherefoAmong the 439 patients under oral propranolol therapy, 305 patients were 2 year old by the end of the follow-up period, and 292 cases were qualified for data analysis. Among the 292 patients, 199 (68.2%) were females and 93 (31.8%) were males; the starting age of 82 females and 35 males was no more than 3 months; 15 females and 10 males were preterm birth; and 162 females and 76 males experienced AEs see .Groups were divided according to starting age, premature birth, and AEs. Some of the groups' values were higher than the reference standard, whereas others showed no statistical significance. There were 3 females and 2 males whose height and BW were more than +2 standard deviations (+2SD). In the values of less than −2SD, there were 2 females who had normal BW but lower height, and 1 female whose height and BW were lower, while 1 male showed both values less than −2SD. In brief, the height and BW of population represented by 292 two-year-old children were no less than the reference levels, whereas 9 (3.1%) were not within the average ± 2SD.p > 0.05).According to group comparisons, it could not be considered that the height and BW of children whose starting age were no older than 3 months were different than the children who started to take propranolol in older age. Similarly, preterm birth and AEs did not affect the average of height and BW. It could not be considered that height and BW not within ±2SD were different in different starting age, full-term or premature birth, and with or without AE .The height and BW of the 2-year-old children was not related to total duration of propranolol treatment. The Spearman correlation coefficient was 0.019, 0.042, −0.021, 0.015, respectively, in height of female, BW of female, height of male, and BW of male. It could not be considered that there was a positive or negative correlation between BW/height in female/male and total duration of propranolol treatment (Propranolol is a representative of conventional drugs that have been used to treat cardiac dysrhythmias, angina pectoris, myocardial infarction, hypertension, thyrotoxicosis, anxiety, glaucoma, alcoholism, and muscle tremor . In recePropranolol has been used in clinical treatment for a long time and for a wide range of diseases. There are many reports on the side effects of propranolol, principally in adult volunteers; these side effects include sleep disturbances, increased dream recollection, nightmares, and diarrhea , 20. WitIn literature on propranolol as a treatment of IHs, AEs occurred at a frequency of 8.8–18%, with sleep problems, respiratory disorder, and asymptomatic hypotension as relatively common AEs; however, other types of AEs also occurred –26. In oAlthough some doctors previously did not advocate using propranolol as a treatment of IHs in premature infants, recent studies indicated that oral propranolol is safe for preterm and low-birth-weight infants , 33, 34.In clinical setting, oral administration of montmorillonite powder and probiotics showed no obvious effect in children who showed GI symptoms following oral propranolol. Therefore, if diarrhea does not cause emotional fluctuations, dehydration, or affect sleep in children, observation treatment should be performed. With respect to sleep disorder and mood change, hydrophilic atenolol is a good alternative in cases of IHs that cannot be treated by other ways .In this study, the reference BW and height values were derived from published tables, not from an untreated control group. Thus, there may be a certain discrepancy between this standard and the actual situation, especially considering improvements in nutrition levels during the past 10 years in China. Moreover, this study only followed the height and weight of children at the age of two; therefore, further evaluation of neuropsychological development in children, such as Denver Development Screening Test, Japanese SM Social Life Test, or other behavioural and psychological follow-up, are needed to reflect the long-term effects of propranolol on the CNS of children.The study analysed short-term AEs of 439 children under maximum 2 mg/kg/day propranolol treatment, and the height and BW of 292 two-year-old children. A hair-thinning case was observed, which has not been reported in infants before. In the treatment of younger children with oral propranolol, especially those aged 3 months or less, special attention should be paid to their CNS symptoms. When AEs occur, the method of administration must be reconfirmed first. If the AEs are not life-threatening, observation can be taken, and the AEs which are difficult to tolerate can be replaced with atenolol. Moreover, based on our findings, propranolol may be regarded as a safe drug which does not impair the growth of children aged 2 year old or less.