Accumulating evidence supports the use of virtual reality (VR) as an effective pain and anxiety management tool for pediatric patients during specific medical procedures in dedicated patient groups. However, VR is still not widely adopted in everyday clinical practice. Feasibility and acceptability measures of clinicians' experiences are often missing in studies, thereby omitting an important stakeholder in VR use in a clinical setting. Therefore, the aim of this mixed-methods study was to investigate the feasibility, acceptability, tolerability (primary outcomes), and preliminary effectiveness (secondary outcome) of Relaxation-VR in both pediatric patients aged 4–16 years and clinicians. Relaxation-VR is a VR application prototype aimed to provide distraction and relaxation for a variety of patient populations and procedures and is used to reduce anxiety, stress (tension) and pain for children in hospital. Multiple measures of acceptability, feasibility and tolerability, and pre-to-post changes in measures of pain, anxiety, stress and happiness were assessed in pediatric patients. At the end of the study, acceptability and feasibility of VR use was assessed in clinicians. Results indicate that VR use  for both distraction and relaxation is acceptable, feasible and tolerable for a variety of pediatric patients aged 4–16 years, as assessed in both patients and clinicians, and can reduce anxiety, pain and tension (stress), and increase happiness in a hospital setting. Virtual reality (VR) is a form of human-computer interaction technology that immerses an individual in a computer-generated environment. While earlier versions of VR have included the use of large screens or 3-D glasses (semi-immersive VR), nowadays, VR environments are mainly experienced through advanced head-mounted displays  with built-in motion tracking (immersive VR). The specific immersive nature of this technology has made VR an interesting distraction method in pediatric pain and anxiety management (research) for over 20 years. Seminal work by Hoffman et al.  assessinTo improve translation from research to practice, more knowledge on implementation factors is needed. A group of 21 international VR experts  reported recommendations for research methodology on using VR in healthcare and defined three phases of VR clinical study designs: VR1, VR2, and VR3 . VR1 stuRelaxation-VR is a VR application (prototype) aimed to provide distraction and relaxation for a variety of patient populations and procedures, that is used to reduce anxiety, stress (tension) and pain for children in hospital. Also, no specific medical procedure, treatment or patient population is chosen in order to increase the generalizability of the findings and, therefore, the potential usability in clinical practice.This mixed-methods study was performed at the University Hospital Brussels  and the General Hospital Sint-Maarten  to assess the acceptability, feasibility, tolerability and preliminary effectiveness of Virtual Reality (VR) as a relaxation and distraction tool for children admitted to the hospital. To do so, we used the Relaxation-VR app, a VR application (prototype) aimed to provide distraction and relaxation for a variety of patient populations and procedures. Before and after one VR session with Relaxation-VR, multiple measures of acceptability, feasibility and tolerability were assessed in pediatric patients. In addition, pre-to-post changes in measures of pain, anxiety, stress and happiness were assessed in pediatric patients. At the end of the study, after using Relaxation-VR with multiple patients, acceptability and feasibility of VR use was assessed in clinicians. Written informed consent was obtained from all participants prior to the study. Consent forms and study design were approved by the Medical Ethics Committee of the University Hospital Brussels (EC-20202-305) as well as by the local ethical committee of the AZ Sint-Maarten in accordance to the Code of Ethics of the World Medical Association (Declaration of Helsinki). The trial was registered at ClinicalTrials.gov (NCT04666506).M = 10.88, SD = 3.17, median = 11.00, minimum = 4, maximum = 16) were recruited between January and May 2021 from the UZ Brussel (N = 39) and AZ Sint-Maarten (N = 12) pediatric departments. Patients were included according to the following criteria: age between 4 and 16 years, normal or corrected-to-normal vision and hearing, in- or outpatient in one of the study sites and in need of relaxation or distraction before treatment of medical procedure, as assessed by the clinical staff. Exclusion was based on the following criteria: history of seizures, physical impairment that precludes VR intervention, need for medical procedures considered unsuitable in combination with the use of a VR headset, non-Dutch native patient or caregiver, or previous enrolment in the current study . Data from four participants were not included in the final analyses due to drop-out  or a mistake in the informed consent procedure (N = 1). Final analyses were therefore performed with data of 51 pediatric patients. Regarding clinicians, twelve women  employed at the pediatric departments of UZ Brussel and AZ Sint-Maarten have participated in the study after informed consent was obtained. Demographic information of the study sample is described in Fifty-five pediatric in- and outpatients aged 4–16 years . By using the VR headset, participants are immersed in a novel, calming and distracting environment where they are asked to perform tasks that will help them to relax when distressed before and/or during a medical procedure or during their stay in hospital. The Relaxation-VR app consists of three modules or VR environments. The first module comprises breathing exercises; the second comprises meditation exercises  and the third module presents a scene with different interactive animations and objects   . Dependivia a tablet for demographic and background data collection and a paper questionnaire to collect baseline data on anxiety, pain, tension (stress) and happiness. If needed, parents were allowed to help their child to fill in the questionnaires. Participants then received the VR intervention. Participants were seated on a hospital bed or chair and also remained stationary in the virtual environment. The user was able to look around in the virtual environment by moving his/her head and was able to interact with virtual objects by staring at them for a few seconds, but did not move around in the different environments (modules). Modules 1 and 2 took ~6–7 min to complete, whereas participants were allowed to use module 3 for as long as needed. Afterwards, participants were asked to fill in the same paper questionnaire assessing anxiety, pain, tension (stress) during use of the VR intervention, as well as a self-composed paper and online questionnaire assessing acceptability, feasibility and tolerability of the intervention. Finally, at the end of the study , the involved clinicians were asked to fill in an online questionnaire assessing acceptability and feasibility of the use of VR.After initial screening procedures by the clinical staff, pediatric patients and their parents were approached by the clinicians involved in the study at the pediatric departments of the study sites. Subsequently, interested patients and parents received the informed consent form (for parents and children aged 12 years and older) and assent form (for children aged 4–12 years old). Study procedures and legally and ethically required information were presented and explained in an informative video that was shown on a tablet in the hospital, any questions were answered by the local investigators. After the informed consent was obtained, participants filled in an online questionnaire Outcome measures were based on the recommendations of the Virtual Reality Clinical Outcomes Research Experts (VR-Core) for development and evaluation of therapeutic virtual reality, specifically on the recommendations for VR2 trials focusing on acceptability, feasibility, tolerability (primary outcomes) and initial clinical effectiveness (secondary outcome) . Data weIn the context of this study, acceptability refers to the patient's and clinician's willingness to use the Relaxation-VR app . In pediIn the context of this study, feasibility refers to the degree to which the VR intervention (Relaxation-VR) can be successfully integrated in the hospitals' usual care . In pediTolerability refers to the evaluation of adverse events in pediatric patients, related to either hardware or software components . In pediIn order to explore the potential clinical effects of the VR intervention on pain, anxiety, tension (stress) and happiness, the Revised Faces Pain Scale (FPS-R) was used, a VAS to measure anxiety and the Self-Assessment Manikin (SAM) to measure tension and happiness. The FPS-R scale is used to assess the intensity of a child's acute pain from the ages of four or five onwards . The scat-tests. All statistics were executed with SPSS version 27 . The significance level was set at p < 0.05. Cohen's d effect sizes are reported with 0.2, 0.5, and 0.8 indicating small, moderate and large effect sizes, respectively , a parent (N = 6) or both (N = 2)] refused to participate for reasons including fear of side effects (N = 3), willingness to see the procedure (N = 1), risk of overstimulating the child (N = 2), too much paperwork (N = 2), disinterest (N = 3), lack of time (N = 1), absence of need (N = 2), or an overlooked exclusion criterion (N = 1). Reasons for willingness to try the application and enroll in the study, range from a need for distraction or relaxation to boredom and curiosity. Future use of VR in a hospital context was favorably scored with a median score of 3.00 . Also, most pediatric participants would recommend the use of VR to others with a median score of 4.00 . Acceptability data is reported in The majority of recruited patients (55/70) were willing to enroll in the study. Fifteen individuals [either the child (N = 2), while 19 out of 51 participants used the app for periprocedural distraction: blood draw (N = 9), (veni)puncture (N = 3), tube placement (N = 2), lactose test (N = 1), wound care (N =1), circumcision (N = 1) and unknown procedure (N = 2). The majority of participants used all three modules (28/51), 15 out of 51 participants only used module 3 (minigames) . Most participants (33/51) used the VR application until the end, whereas 10 participants quit prematurely for reasons including discomfort (N = 2), disliking the application (N = 1), technical issues (N = 1), willingness to see the medical procedure being performed (N = 2), termination by nurse (N = 1), wanting to change the VR module (N = 1) . Five out of 51 participants reported technical issues including start-up issues and low battery levels . Most participants (33/51) did not suggest any changes to the application, whereas 18 participants suggested changes regarding content  or hardware . Ease of use of the Relaxation-VR application was favorably scored with a median score of 4.00 . Also, likeability of the Relaxation-VR application was favorably scored with a median score of 2.50 . Data concerning ease of use of two participants is missing as well as likeability data of one participant.With respect to the specific use of the VR application, 30 out of 51 participants used the Relaxation-VR app as a relaxation tool during hospitalization and 19 participants used the application during a medical procedure   and a mean total SUS score of 70.83 , indicating good usability .Concerning the Peds SSQ, reported simulator sickness was limited as mean item scores per subscale ranged between 0.76 and 1.12 (with 0 indicating no discomfort and 6 indicating a lot of discomfort) . Note, hPre-to-post changes in pain, anxiety, happiness and tension are visualized in M = 2.65, SD = 2.37), pediatric participants reported less pain after using Relaxation-VR , t(50) = 3.80, p < 0.001 (d = 0.53). Results indicate a significant decrease in reported anxiety after using Relaxation-VR  as compared to baseline , t(49) = 5.53, p < 0.001 (d = 0.78). Pediatric participants also reported significantly less tension after using Relaxation-VR  as compared to baseline , t(49) = 7.28, p < 0.001 (d = 1.03). Finally, results indicated that pediatric participants reported significantly higher levels of happiness after using Relaxation-VR  as compared to baseline , t(50) = 4.99, p < 0.001 (d = 0.70). Note that for the VAS and the SAM tension scale data of one participant are missing.Compared to baseline  as both a relaxation and distraction tool for pediatric patients in a hospital setting. To do so, data from both patients and clinicians were collected. With respect to acceptability, most patients aged 4–16 years and/or their parents were willing to use VR with the aim of lowering their own (or their child's) anxiety or pain, out of mere curiosity, or due to boredom during a longer stay in hospital. Our findings indicate that pediatric patients accept the use of VR as a distraction and relaxation tool in a hospital. They wanted to use VR again during future hospital visits and would recommend it to others. These findings are in line with prior research indicating that participants  would like to use VR distraction again during future procedures , 14, 21.Concerning feasibility, results revealed that the use of Relaxation-VR as a distraction and relaxation tool in pediatric clinical practice is feasible. Patients liked using VR and thought it was easy to use, which is in line with previous findings , 8, 23. With respect to (preliminary) clinical effectiveness, results revealed that pediatric patients reported less pain, anxiety and tension (stress) and higher happiness during VR use as compared to baseline measurements. Although different study designs have been adopted across the aforementioned studies, our findings are in line with prior research showing that the use of VR as a pain and/or anxiety management tool reduces periprocedural pain and anxiety levels in pediatric patients with various conditions and during various medical procedures –17. EvidTaken together, our results indicate that the use of VR is acceptable, feasible and tolerable, as assessed by both pediatric patients and clinicians, for providing both relaxation and distraction in a variety of pediatric patients as well as for periprocedural use and as a relaxation tool for children admitted to hospital for a longer period of time. The findings of this study confirm prior research indicating that VR is a relevant tool in a pediatric hospital setting and add to the evidence-base that VR use is also feasible and acceptable from clinicians' perspectives. Future research should, therefore, focus on potential barriers and facilitators to adoption of this innovation in clinical practice. Considering VR use was assessed in a varied population, during various procedures and for multiple purposes in one study, these findings also highlight that VR use in a hospital should not be limited to periprocedural distraction or specific patient groups, which might encourage adoption in clinical practice.The presented findings should be considered in view of the following limitations. The study was unblinded and no control group was included. In addition, the nature of the participant-reported and clinician-reported outcomes may have introduced bias and subjectivity. The combination of these factors may have lead both patients and clinicians to provide more pleasing answers when completing the questionnaires and scales.Concerning tolerability measures, we noticed that some pediatric participants had difficulties in discerning symptoms of VR use from symptoms related to their hospitalization. We therefore advise, researchers to include measures at multiple time points  to assess potential changes in VR sickness.As the current study was not designed to assess the impact of potential moderators on the included outcomes, we cannot provide reliable information on the potential impact of age, gender, VR usage, type of medical procedures or other factors on study outcomes such as acceptability, feasibility and tolerability. Researchers are encouraged to design and conduct studies to explore the potential impact of these factors.Note that this study was performed during the COVID-19 pandemic. All Belgian hospitals were subjected to national, regional and local regulations. These regulations may have influenced the number or type of patients available at the study sites. Regulations did not allow external researchers to visit the study sites to educate the clinical staff in study procedures, nor in VR use, so that the necessary education and support was provided online. Guidelines were developed to guide clinical staff in working with the technology and performing the research steps as planned.Study results indicate that VR use  for both distraction and relaxation is acceptable, feasible and tolerable for a variety of pediatric patients aged 4–16 years, as assessed in both patients and clinicians, and can reduce anxiety, pain and tension (stress), and increase happiness in a hospital setting.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the University Hospital Brussels as well as by the Local Ethical Committee of the AZ Sint-Maarten. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.SB and IG have coordinated the study design. IG has coordinated data collection. SB has written the first and final versions of the paper. BB, JD, RS, DS, and WV have provided feedback on both the study design and the manuscript. All authors contributed to the article and approved the submitted version.This study has been conducted as part of the Immersive Care Project funded by the TETRA Program of the Flemish Government in Belgium .The virtual reality prototype used in the study was developed by the Dutch company Psylaris. Psylaris was not involved in the study design, data collection or writing of this article. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inner Mongolia Arbas white cashmere goats is a dual-purpose breed for producing cashmere and meat. In recent years, its meat has become more and more popular among consumers because of rich nutrients and delicious flavor. Therefore, it is particularly important to study the genetic and non-genetic factors affecting the early growth traits and estimate variance components of pre-weaning growth traits of Inner Mongolia Albas white cashmere goats. A total of 37487 kidding records such as birth weight (BWT), weaning weight (WWT), average daily gain from birth to weaning (ADG) and Kleiber ratio (KR) from 343 sires and 7296 dams were used in this study. The most appropriate model was chosen on the basis of likelihood ratio test by fitting six models which excluding or including maternal genetic, maternal permanent environmental effects. The parameters were estimated under the most appropriate model using AIREML method by WOMBAT software. With the best model (Model 6), heritability estimates were 0.0435, 0.0911, 0.0932 and 0.2339 for BWT, WWT, ADG and KR traits, respectively. Maternal heritability estimates were 0.0143, 0.0246, 0.0220 and 0.0186 for BWT, WWT, ADG, and KR traits respectively. The correlation between different traits was estimated with the most suitable model by using bivariate analysis method. The direct additive genetic correlation among the traits ranged from −0.026 (BWT~KR) to 0.772 (ADG~KR). The maternal permanent environment correlation is between −0.289 (BWT-KR) ~0.900 (WWT-ADG). Results indicated that maternal effects and direct-maternal genetic covariance should be considered in any program aimed at improving pre-weaning growth traits to have an accurate genetic evaluation. In addition, positive and medium to high genetic correlations generally exist among WWT, ADG and KR due to the existence of genetic variation for early growth traits. The results showed that the genetic progress of these traits could be slowly through selection except for KR. As is well-known, goats are important multipurpose economic animals. Cashmere goat is a breed mainly raised for cashmere production. Cashmere goats live primarily in the arid and semi-arid areas of China  is a dual-purpose breed for producing meat and cashmere, which is mainly distributed in Ordos, Inner Mongolia, China. Traditionally, IMWACGs mainly produced high-quality cashmere, supplemented by meat production. In the last decade, cashmere profits have fallen whereas mutton profits have gradually increased. Goat meat is valued as a high-protein and low-fat food that contains fatty acids and amino acids necessary for the human body . TherefoAn understanding of the influencing factors and the genetic principles affecting the growth traits is necessary to implement optimal breeding and selection programs . PreviouEarly growth is influenced by several factors, including environmental variables such as herd, grassland quality, direct genetic effects of the kid, and the maternal additive genetic and permanent environmental effects of the dam . SeveralThis study aimed at estimating the genetic parameters for preweaning body weight traits and Kleiber ratio and also the genetic correlations among these traits to consider these traits in the genetic selection program.x indicates the observational value of traits) and records from animals from an unknown dam were omitted. Finally, 37,487 kidding records from 343 sires and 7,296 dams were used in this study. The kids were weighed and ear-tagged at birth and weaned for about 90 days. The kids were fed with hay freely during the day and suckled with the grazed dams during the night until 30 days of age. 2 months after birth, the kids suckled their mothers two times a day, morning and evening, until weaning. The maiden does were mated by artificial insemination at about 18 months of age. In the present study, the birth weight (BWT), average daily gain from birth to weaning (ADG), weaning weight (WWT), and preweaning Kleiber ratio (KR) were analyzed. The Kleiber ratio is an indirect selection method for measuring feed conversion. The data used in the analysis are given in The IMWACG population is mostly raised in Ordos , the environmental details of which have been described by Zhou et al.  and Bai The fixed effects of each trait were determined by a general linear model (GLM) procedure using SAS software . The fixyijklmn is the observation of nth kids that belonged to the ith year, the jth herd, the kth type of birth, the lth sex, and the mth dam age. μ is the overall mean, (PH)ij is the interaction between the ith year and the jth herd, (TS)kl is the interaction between the kth type of birth and the lth sex, and eijklmn is the random error.where −8. The models are as follows:The (co)variance components were estimated for each trait by the restricted maximum likelihood (REML) method using the WOMBAT program . Six dif1, Z2, and Z3 are the design matrices associating the fixed effects, the direct additive genetic effects, the maternal additive genetic effects, and the maternal permanent environmental effects to the y vector. For WWT, we also considered the days between birth to weaning as the covariate for quadratic regression in the model.where y is a vector of observations on the different traits; and b, a, m, c, and e are the vectors of the fixed effects, the direct additive genetic effects, the maternal additive genetic effects, the maternal permanent environmental effects, and the residual effects, respectively. X, ZA is the additive genetic correlation matrix, Id and In are the identity matrices that have an order equal to the number of dams and kids, respectively, and σam denotes the covariance between the direct additive genetic and the maternal additive genetic effects.The direct additive genetic effects, the maternal additive genetic effects, the maternal permanent environmental effects, and the residual effects are assumed to be normally distributed with mean 0 and To create the most suitable model for the traits, a likelihood ratio test (LR) was performed to obtain the appropriate model as given below :1 and L2 are the maximum likelihood function values of model 1 and model 2, respectively. Model 1 is a sub-model of model 2. LR obeys the chi-square distribution. The degree of freedom is the number of parameters considered in model 2 minus the number of parameters in model 1.where LFurthermore, the genetic and phenotypic correlations between the traits were obtained using bivariate animal models based on the most appropriate model for each trait.From 2) estimated by model 1 were the highest. With the inclusion of the maternal genetic effect, the maternal environmental effect, or the individual additive and maternal additive genetic covariance in other models, the direct additive genetic variance and heritability estimates decreased.The variance groups of BWT, WWT, ADG, and KR estimated by the six models are listed in The likelihood ratio test results of the different models are listed in The variance components and genetic parameters of different models for each trait were estimated and are shown in It was estimated that the correlation of WWT heritability is between 0.0841 (model 4) and ~0.2737 (model 1), maternal heritability is between 0.0246 (model 6) and ~0.0752 (model 3), the variance ratio of the maternal permanent environmental effects is between 0.0272 (model 6) and ~0.0509 (model 2), and that of direct genetic effect with maternal heritability is 0.6396 (model 4) and 0.6710 (model 6). They have a high positive correlation.The ADG heritability estimated by different models was between 0.0856 (model 4) and 0.2776 (model 1), the maternal heritability range was between 0.0220 (model 6) and 0.0713 (model 3), and the variance ratio of the maternal permanent environmental effects was between 0.0246 (model 6) and 0.0467 (model 2). There was a highly positive correlation between the direct additive effect and maternal genetic correlation, which was estimated to be 0.7497 by model 4 and 0.7906 by model 6.The KR heritability estimated by different models was between 0.2080 (model 3) and ~0.3075 (model 1). The variance ratio of maternal heritability to maternal permanent environmental effect was low, ranging from 0.0168 (model 5), ~0.0501 (model 4), 0.0308 (model 5), and ~0.0396 (model 2), respectively. The direct additive effect had a low negative correlation with the maternal genetic effect, ranging from −0.0103 (model 4) to approximately −0.0874 (model 6).As presented in The correlation between different effects was estimated with the most suitable model of traits using the bivariate analysis method. The results are shown in The phenotypic correlations between BWT and other traits were both low negative and positive correlations  and the phenotypic correlations between other traits were highly positive correlations .p < 0.01) in the present study and were in agreement with the previous reports on Sirohi goats , which was consistent with that reported by Menezes et al.  for BoerThe heritability, maternal heritability, and direct maternal genetic correlation of the same traits between breeds were different. The main reason may be that the breeds were different, and their breeding directions and schemes were also inconsistent, resulting in different micro-effect polygenes affecting the quantitative traits carried inside or outside the nucleus of each breed, thus leading to the genetic diversity of the same quantitative trait among different breeds.Estimates of different correlations between the investigated traits are shown in The WWT had a positive and medium genetic correlation with ADG (0.614). Zhou et al.  reportedHowever, the maternal genetic correlation was negative between WWT and KR but positive among other traits. The BWT-WWT (0.388), BWT-ADG (0.406), and WWT-ADG (0.577) maternal genetic correlation was medium, while it was high for ADG-KR. The results were significantly lower than those of Dige et al.  for JamuThe different genetic correlations between the same traits of different breeds and between different traits of the same breed can be attributed to the following aspects: first, the genes that affect the quantitative traits are mostly micro-effect polygenes that are vulnerable to environmental effects. Different breeds have different breeding environments and selection pressures, resulting in differences in gene expression although they carry the same genes; therefore, the genetic effects of various traits are different in different breeds. Second, according to the principles of genetics, the mechanisms of genetic correlation are pleiotropism and linkage inheritance. Therefore, the number of common genes, the genes for different traits, and the strength of linkage between the genes are the main reasons for the difference in genetic correlation between traits. Finally, the models, data volume, and estimation methods used in statistical analysis are also some important reasons for the differences in parameter estimation between the same traits of different breeds and different traits of the same variety.The estimates of maternal permanent environmental correlation range from −0.366 (BWT-KR) to 0.957 (WWT-ADG) among early growth traits. The estimates of environmental correlation among WWT, ADG, and KR were positive and high and range from 0.739 for WWT-KR to 0.957 for WWT-ADG, which were probably due to the greater similarity of the environmental and management conditions. The differences in uterine space during pregnancy, nutrients during pregnancy and lactation, maternal behavior, and the mothering ability of the dam may be the main reasons for the variabilities in maternal permanent environmental effects.The phenotypic correlation estimates among WWT, ADG, and KR changed from −0.294 for BWT–KR to 0.927 for WWT–ADG, which were in agreement with the estimates of environmental correlation for the same traits. The phenotypic correlation estimates between the traits indicated the presence of a desirable association among pre-weaning traits.These results indicated that environmental factors have a significant impact on pre-weaning growth traits and hence should be considered while accurately modeling genetic evaluation. The low-to-moderate estimates of direct heritability for pre-weaning growth traits indicated the presence of genetic variabilities within the IMWACGs, and the genetic progress of these traits can be achieved by selection.The maternal genetic effects and the maternal permanent environmental effects seemed to have a significant effect on early growth traits. Thus, in addition to the direct genetic effect, the maternal genetic effects and maternal permanent environmental effects were found to be important for the genetic evaluation of early growth traits in this breed. The moderate-to-high estimates of genetic correlation among WWT, ADG, and KR indicated that the selection of one of these traits would probably bring out a positive response for the selection from the correlated one. Therefore, selection for early growth traits should only consider one of them when designing a breeding program for this variety.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.All animal experiments were performed in accordance with the Guidelines for Experimental Animals of the Ministry of Science and Technology  and were approved by the Scientific Research and Academic Ethics Committee of Inner Mongolia Agricultural University and the Biomedical Research Ethics of Inner Mongolia Agricultural University . Written informed consent was obtained from the owners for the participation of their animals in this study.RW, YLiu, and JL conceived the idea and designed the study. RW, ZW, YS, YQ, and YLi analyzed the data. RW and YLiu wrote the draft. YZhan, RS, and YZhao finalized the manuscript. All authors read and approved the final manuscript.


Inadvertent intravascular injection of local anesthetics (LA) during regional anesthesia causes Local Anesthetic Systemic Toxicity (LAST). Theories of lipid rescue in the case of LAST proved that the administration of lipids in LAST has beneficial effects. One possible mechanism of action is based on the lipophilic properties of LA which allow plasma-free LA to be bound by the molecules of Lipid Emulsion (LE). The association LA–LE is shuttled towards organs such as liver and the kidneys, and the half-life of LA is shortened. The main objective of this experimental study was to assess the possible cardio-prophylactic effect of LE administration before the induction of LAST by intravenous administration of Ropivacaine. This was an experimental, interventional, prospective, and non-randomized study. The subjects were divided into groups and received, under general anesthesia, LE 20% first 0.3–0.4 mL, followed by 0.1 mL Ropivacaine 2 mg/mL, or Ropivacaine alone. At the end of the experiment, the subjects were sacrificed, and tissue samples of kidney, heart and liver were harvested for histopathological examination. LE, when administered as prophylaxis in Ropivacaine-induced LAST, had protective cardiac effects in rats. The LE known side effects were not produced if the substance was administered in the low doses used for LAST prophylaxis. Local anesthetics (LA) are a class of pharmacological agents widely used in current medical practice, ranging from small surgical interventions to more complex procedures, such as wound sutures, or reconstructive hand surgery. The inadvertent intravascular injection of LA during regional anesthesia causes Local Anesthetic Systemic Toxicity (LAST). This syndrome includes seizures, malignant arrhythmias to cardiac arrest, hardly responsive to resuscitation .These modifications might affect the patient’s sensory and vision and determine muscular stimulation with convulsions. Through the negative influence they have upon the resting membrane potential, LA affects the normal conduction within the heart cells at the cardiac level. The corresponding EKG modifications are prolonged PR, ORS, and ST intervals, re-entrant tachyarrhythmias, and bradyarrhythmia leading to a prolonged QR interval . The mecAlthough the occurrence of LAST is not very frequent, with a number of 459 cases being reported in a 5-year period, by the National Poison Data System (NPDS)-USA, the catastrophic manifestation of this event - seizures, malignant arrhythmias, cardiac arrest resistance to resuscitative measures - maintains the severity of this condition [In the past two decades, theories of lipid rescue in the case of LAST emerged and proved that the administration of lipids in LAST has beneficial effects ,6,7. MorAlthough the exact mechanism by which lipids are useful in the case of LAST is not fully understood, some cases of LAST were successfully treated by LE administration during the toxic event ,9. (LA) Among LE side effects, the ones worth mentioning are acute kidney injury, metabolic acidosis, acute lung micro embolism, or cardiac arrest ,14. The The main objective of this experimental study was to assess the possible cardio-prophylactic effect of LE administration before the induction of LAST by intravenous administration of Ropivacaine.Secondly, we aimed to observe whether lipids, prophylactically administered, induce histological changes upon heart, liver, and kidney.The study was approved by the Ethics Commission of the University of Medicine, Pharmacy, Science and Technology “George Emil Palade” of Targu-Mures, Tirgu Mures, Romania .This was an experimental, interventional, prospective, and non-randomized study.The study comprised Wistar male rats aged 10–12 weeks and weighing between 200 and 300 g.The subjects were divided into 4 groups:n = 10)—LA Ropivacaine 2 mg/mL 0.1 mL was administered every 2 min and cardiac activity was monitored after 4 administrations. Tissue samples were harvested from the kidney, heart, and liver.Group A—(n = 9)—LE 20% 0.3–0.4 mL was administered 2 min prior to 0.1 mL Ropivacaine 2 mg/mL. Cardiac activity was monitored and, after 4 administrations of Ropivacaine, the subject was sacrificed, and tissue samples were harvested from the kidney, heart, and liver.Group B—(n = 8) which only received Lipid Emulsion 20% under general anesthesia. Cardiac activity was monitored and tissue samples from kidney, heart, and liver were harvested.Group C—(n = 8) which received none of the studied substances. Subjects were anesthetized, the cardiac activity was monitored and tissue samples from kidney, heart, and liver were harvested.Group D—control group  0.3–0.4 mL 2 min prior to Ropivacaine—were administered via inferior vena cava puncture. The dosages were adjusted to weight. The invasive maneuvers and the exact dosage calculation were performed as previously described by the authors Lazar, A. et al. Acta Medica 2021; 67(2) 90–94 [Four hours before the experiment, the subjects were fasted for water and food. The experiments were performed entirely under general anesthesia, using Isoflurane . The studied substances—Ropivacaine 2 mg/mL concentration 0.1 mL repeated at 2 min intervals  and Lipid Emulsion 20%  90–94 . AccordiThe cardioprotective effect of LE 20% was assessed by rhythm analysis of the cardiac tracings of the subjects. A protective effect was considered when the normal cardiac rhythm was maintained longer or the EKG components (length of the QRS complexes or the heart rate) were maintained after Ropivacaine was administered.At the end of the experiment, the subjects were sacrificed by exsanguination and tissue samples from the heart, liver, and kidney were harvested for histopathological assessment. Groups C and D were included for the secondary objective, in the assessment of possible histological changes induced by LE in various organs. Electrophysiological investigations were not performed in these groups.The tissue samples from the heart, liver, and kidney were preserved in neutral buffered formaline solution 10%, embedded in paraffin, and stained with Hematoxylin Eosin. Two experienced pathologists  examined the possible histological changes of the examined tissues, in a blind manner.cran.r-project.org, accessed on 1 September 2021). Normal distribution of quantitative data was verified using the Shapiro–Wilk test, whereas statistical hypothesis testing regarding the differences in biological parameters between the experimental groups was performed using Student’s two-sample t-test for paired/unpaired data, as required. A statistical significance threshold of 0.05 was considered.Data were centralized in Microsoft Excel spreadsheets and analyzed in the R statistical environment ; in the second group, intravenous LE 20% was used before Ropivacaine . The third group  received only LE 20%, and the fourth  was the control group. The baseline values of cardiac activity in groups A and B were similar for both heart rate (p = 0.073) and QRS duration (p = 0.715)  .p = 0.085, paired t-test) or the QRS interval duration .In rats from group B, intravenous LE did not change either the heart rate (p < 0.001) and prolonged QRS duration (p < 0.001) in both experimental groups . The relative change of QRS duration was similar in the two groups .Intravenous administration of Ropivacaine significantly reduced heart rate  current .Regardless of the safety measures taken to avoid LAST—ultrasound usage, echogenic needles, aspiration before injecting the LA—accidents can happen, and the LA can reach the systemic circulation.There are several theories about how LE helps in LAST, none of them concluding an exact mechanism of action. The most popular is the “lipid sink” theory, which is based on the liposolubility of local anesthetics . AlthougTo induce LAST, we used Ropivacaine, a relatively recent LA first produced as a pure enantiomer. Ropivacaine is a long-acting amide LA extensively metabolized by the liver .To our knowledge, this is one of the few experimental studies which evaluated the protective effects of LE in Ropivacaine-induced LAST.The results support the hypothesis that LE has beneficial effects against the cardiac manifestations of LAST.The maintenance of heart rate and QRS duration close to baseline range for a longer period in rats prophylactically treated with LE prior to LA administration suggests the cardioprotective effects of LE. Our results are concordant with those from other studies ,21.The histopathology samples of the main organs showed that LE administered in the low dose used as a prophylactic measure in this study does not induce any organ abnormalities, at least in the immediate term. Along with the already-known safety of LE administration, our observations support the introduction of LE as prophylaxis before regional anesthesia, to reduce even more the risk of cardiac arrest caused by a possible inadvertent intravascular administration of LA.This experimental study has several limitations. One of them is the unknown plasma level of LE or the LA, although the administration was according to international guidelines for lipid rescue in LAST. However, the time interval between LE and LA administration in our setup (2 min) was much shorter than the half-life of long-chain triglycerides, the main constituent of Intralipid administered in rats, which was reported to be more than 30 min . We can The next phase of this study contains the prospect of LE and LA plasma level measurement. In the phase presented herein, we aimed to observe the influence upon clinical signs.Another limitation that can be considered is the use of general anesthesia in our subjects, given the available evidence in the literature that neurological manifestations in LAST appear earlier, and at lower doses of LA, than the alteration of cardiac function. In our setup, we only explored the case wherein the LA concentration was high enough to trigger anomalies in heart activity, while the potential neurological impairment could not be assessed.These limitations will be addressed in future experimental models.In present clinical practice, LE is only used in LAST as a treatment after the onset of symptoms. The novelty of our study is the introduction of LE as a prophylactic agent in Ropivacaine-induced LAST, instead of a treatment for an already-diagnosed toxicity. Although not sufficient for supporting the routine prophylactic use of LE in all procedures requiring LA, our results are encouraging, showing a cardioprotective effect and negligible toxicity of LE in our experimental model. Further safety and efficacy studies are warranted to explore the benefit of this prophylactic approach.Lipid Emulsion, when administered as prophylaxis in Ropivacaine-induced LAST, has protective cardiac effects in rats, illustrated by sustaining the heart rate and QRS duration for a longer period.The Lipid Emulsion known side effects are not produced if the substance is administered in the low doses required for LAST prophylaxis.


The subjects were categorized into the ChEI only group and the ChEI and nootropics combination group. The primary outcome measure was the change in cognitive function, as assessed by the mini-mental state examination (MMSE) from baseline to 300–400 days after the first ChEI prescription. Subsequent analyses were conducted in consideration of the dementia type, medical adherence, and type of nootropics. The changes in MMSE scores from baseline to endpoint were not significantly different between the two groups. In Alzheimer’s dementia, the combination group showed significantly less deterioration in MMSE language subscale scores compared to the ChEI only group , and the difference was consistent in the highly adherent subjects . The choline alfoscerate and the ginkgo biloba extract subgroups in Alzheimer’s dementia showed more significant improvements in the MMSE language subscale scores compared to the other nootropics subgroup . The present study showed that the effectiveness of ChEI and nootropics combination on cognition may appear differently according to the dementia type. This emphasizes the need for well-controlled studies to generalize the effectiveness of nootropics across various clinical settings.The clinical benefits of nootropics in the treatment of cognitive decline has been either limited or controversial. This study aimed to observe the effectiveness of cholinesterase inhibitor (ChEI) and nootropics combination in the treatment of cognitive impairment in dementia. Data were based on electronic medical records in a university health system. Patients with mild-to-moderate dementia and no history of prior cognitive enhancer use were included ( Dementia is one of the most rapidly growing syndromes in aging societies, and it is also the leading cause of disability and caregiver dependency among older adults. Currently, more than 55 million people worldwide are affected by dementia, and nearly 10 million new patients are diagnosed with dementia every year ,3.Nootropics, which were originally described as compounds with similar pharmacology to piracetam, are now generally accepted as any and all compounds that are expected to improve learning and memory in experimental and clinical paradigms . In KoreThis study aimed to elucidate whether the concomitant use of nootropics with ChEIs is effective in the treatment of cognitive impairment in patients with dementia. We hypothesized that dementia patients treated with both ChEIs and nootropics would show less deterioration in cognitive function as assessed by mini-mental state examination (MMSE) over a 1-year follow-up period compared to dementia patients treated with ChEIs only. We further hypothesized that this trend would be more evident in the neurodegenerative forms of dementia, particularly Alzheimer’s dementia.n = 583) (n = 410) and the ChEI and nootropics combination group (n = 173). Subjects in the ChEI and nootropics combination group were prescribed at least one of the following nootropics during the follow-up period: choline alfoscerate, ginkgo biloba extract, acetyl-L-carnitine, nicergoline, and oxiracetam. MMSE total scores and its six-subscale scores  were collected at the baseline (within 30 days of the first ChEI prescription of ChEI) and at the endpoint (300–400 days after the first ChEI prescription), respectively. Baseline data on age, sex, weight, height, body mass index (BMI), blood pressure (BP), education, alcohol use, tobacco use, concomitant psychiatric medications, and comorbid diagnoses were collected during the study period. Subjects were categorized by the type of dementia according to their main diagnosis in the highest order: Alzheimer’s dementia (n = 447), vascular dementia (n = 80), and other dementia (n = 56). For subgroup analysis, the ChEI and nootropics combination group of the Alzheimer’s dementia patients were further classified as follows: choline alfoscerate group (n = 74), ginkgo biloba extract group (n = 39), and other nootropics group (n = 21). Other nootropics included acetyl-L-carnitine, nicergoline, and oxiracetam.The present study aimed to observe the effectiveness of the concomitant administration of nootropics with ChEIs for the treatment of cognitive deficits in patients with dementia. Data were collected and extracted via the clinical data warehouse of a university health system consisting of three general hospitals with 4050 beds in total. Patients with any diagnosis of dementia, defined according to the International Statistical Classification of Disease and Related Health Problems 10th Revision (ICD-10) diagnostic codes F00, F01, F02, F03, F10.7, G23.1, G30, G31.0, G31.1, and G31.8, between the ages of 60 and 89 years were selected. We extracted all diagnostic codes of the patients regardless of whether they were the main or sub-diagnoses. After screening the entire prescription histories registered on the clinical data warehouse, which was over 7 years of record, only the patients who had their first ChEI prescription between 2012 and 2015 were included in the study. Subjects were further narrowed down to only those with mild-to-moderate dementia, as defined by their baseline MMSE total scores from 10 to 26 (n = 583) . SubjectThis research protocol was exempt from an ethics review and informed consent was waived by the Institutional Review Board of Yongin Severance Hospital (9-2020-0108). This study adhered to the doctrine of the Declaration of Helsinki for Biomedical Research.The main outcome measure was the change in cognitive function from baseline to endpoint, as assessed by the MMSE total score and its six subscale scores. Since the primary analysis did not differentiate the dementia type, subsequent analysis was conducted by comparing the changes in cognitive function between the ChEI only and ChEI and nootropics combination groups for each type of dementia separately. Further analysis was conducted in consideration of adherence to ChEI and nootropics. We defined the proportion of days covered (PDC = (Number of days in period “covered” by prescription) × 100/(Number of days in period)) ≥ 0.7 to be highly adherent, based on previous studies on adherence . In the t-test for continuous variables and χ2 test or Fisher’s exact test for categorical variables. Two-sample t-tests were utilized to compare the two treatment groups at baseline and endpoint, as well as the change from baseline to endpoint. In order to adjust for critical covariates such as time and other relevant factors, including sex, age, hypertension, diabetes mellitus, stroke, Parkinsonism, visual disturbance/hearing loss, hemiplegia/paraplegia, mood/anxiety disorder, we further used linear mixed-effect model analyses with time, treatment group, and their interaction to test the difference of the change in MMSE total score and its six-subscale scores from baseline to endpoint between the two treatment groups. The analysis of variance (ANOVA) with Bonferroni multiple comparisons test was conducted to compare the changes in MMSE total score and its six-subscale scores among the three ChEI and nootropics combination subgroup of Alzheimer’s dementia .Baseline demographic and clinical characteristics between the two groups were compared by independent p < 0.05 (two-tailed).All statistical analyses were conducted using IBM SPSS ver. 26 for Windows , and statistical significance was determined at p = 0.446 for donepezil, p = 0.334 for rivastigmine, p = 0.092 for galantamine) (ntamine) .t-tests at baseline and endpoint showed no difference between the two groups in terms of the MMSE total score and any of its six subscale scores. A linear mixed-effects model analysis with the MMSE total score as the dependent variable also revealed no significant treatment-by-time interaction . None of the six-subscale scores showed any significant treatment-by-time interaction, albeit the change in language subscale score showed a trend of less deterioration in the nootropics combination group than in the ChEI only group .Results for the primary outcome measure are shown in p = 0.148 for Alzheimer’s dementia, F = 0.38, p = 0.540 for vascular dementia, F = 0.04, p = 0.906 for other dementia). Within the subjects diagnosed with Alzheimer’s dementia, the ChEI and nootropics combination group showed a significantly less deterioration in the MMSE language subscale score compared to the ChEI only group, revealing a significant treatment-by-time interaction , while in the vascular dementia subjects, the ChEI and nootropics combination group showed a significantly less deterioration in the MMSE attention and calculation subscale score compared to the ChEI only group, with a significant treatment-by-time interaction . None of the six-subscale scores showed any significant treatment-by-time interaction in the other dementia patients.Comparison of the change in cognitive function for each of the three types of dementia is shown in p = 0.002) (p = 0.046)  . Apart f= 0.046) .p = 0.006) compared to other nootropics combination  (p = 0.001) as well   . Highly s group) .Our study findings suggest that the effectiveness of nootropics combination with ChEI may be different according to the type of dementia. The difference in change in the MMSE total scores from baseline to endpoint between the ChEI only group and the ChEI and nootropics combination group was not evident, but the results implied a positive impact of ChEI augmentation with nootropics on some domains of cognitive function in certain types of dementia, particularly Alzheimer’s dementia. The impact of nootropics augmentation on ChEI in Alzheimer’s dementia was consistently depicted on the language domain after consideration of medical adherence and nootropics type.Previous studies on nootropics revealed nootropics to have minimal, if any, effects on the prevention of cognitive decline. Most studies were either examined over a relatively short follow-up time or conducted with a limited number of subjects, and many of them focused on nootropic monotherapy rather than concomitant use with ChEI ,23,24,25Choline alfoscerate is a derivative of phosphatidylcholine that enhances cholinergic transmission by upregulating acetylcholine (ACh) synthesis or release in the hippocampus ,27; thusThe strength of this study lies in the methodological aspects of real-world data utilization. Many studies in Korea are actively conducted using the national claims database in an attempt to perform large-scale research . HoweverThe study had some limitations. Due to its retrospective nature, we were not able to control the treatment settings in terms of medication dosage, treatment duration, the overlapping periods of concomitant nootropic and ChEI use, and adherence monitoring. In order to compensate for these factors, we calculated and considered PDC, the number of days covered by the prescriptions in the total prescription periods, to reflect and consider drug adherence. Moreover, we only included subjects with MMSE scores within 300–400 days after the baseline, which might have excluded certain patients who could not take the annual MMSE test either due to a deleterious progression of dementia or because they no longer sought help or changed hospitals. In the near future, it seems that these limitations can be solved by conducting research based on a large database that combines real-world data from numerous hospitals . Finally, analyzing the six subscale domains of the MMSE may raise the issue of multiple comparison. However, through subsequent analyses, we induced consistent results at least in the Alzheimer’s dementia group, of which nootropics combination could have a subtle positive impact on the language domain. Surely, further studies that more deliberately focus on the separate cognitive domains should be performed with other more qualified neuropsychological tests. Still, this study would be of best effort to observe the effectiveness of nootropics utilizing the accumulated real-world data.In conclusion, our results demonstrated partial effectiveness of nootropics with ChEIs on some cognitive domains in Alzheimer’s dementia. The reliability of the current study was further strengthened by its 1-year follow-up period, consideration of treatment adherence, and adjustments for confounding comorbid diagnoses. This study emphasizes the need for future well-controlled studies to generalize the effect of nootropics on cognitive function across various clinical settings or cause of dementia.


This study assessed the validity of a hypothesized model predicting that physical activity improves health-related quality of life (HRQOL) in older Japanese adults with pain, dysesthesia, and kinesiophobia following lumbar surgery.  We included 431 elderly patients who underwent surgery for lumbar spinal stenosis at two hospitals. The frequency of physical activity, pain, dysesthesia, kinesiophobia (somatic focus and activity avoidance), and HRQOL were investigated using a questionnaire. Missing values were complemented by the stochastic regression imputation. We constructed the following model. (i) physical activity affects pain, dysesthesia, and kinesiophobia. (ii) pain, dysesthesia, and kinesiophobia separately affect HRQOL. This hypothetical model was tested by structural equation modeling. The model was improved based on a modified index. Discussion. Our hypothesized model predicting that physical activity improves HRQOL in terms of pain, dysesthesia, and kinesiophobia in older Japanese adults after lumbar surgery was validated using cross-sectional data. Interventional studies on physical activity based on this model are required to establish the model. Of the 431 respondents, 297  were analyzed (68.9%). The fit of the model improved based on the modification index and was acceptable comparative fit index, 0.948; Tucker–Lewis index, 0.919; root mean square error of approximation, 0.048 , and standardized root mean square residual (0.046). The paths by which physical activities reduced pain or dysesthesia  and somatic focus (−0.301) and consequently improved HRQOL were significant .  The Japanese population is aging, with the percentage of older adults (≥65 years) at 27.6% in 2017, the highest in the world, and is projected to rise to as high as 38.4% by 2065 [In a review comparing the outcomes of conservative and surgical treatment for patients with LSS and neurogenic intermittent claudication, conservative treatment was observed to have a smaller effect on pain than surgical treatment . Due to A review of previous research on the relationship between pain and dysesthesia and HRQOL demonstrated that pain and dysesthesia directly affect HRQOL and that cognitions of pain act as mediating variables that affect HRQOL. Such mediation by cognitions of pain is consistent with the framework of the fear-avoidance model (FAM) . VariousTreatments for chronic pain using physical activities have been attempted . It has Therefore, this study aimed to assess the validity of our hypothesized model, predicting that physical activity reduces kinesiophobia along with pain and dysesthesia and consequently improves HRQOL in older adults who underwent surgery for LSS more than 1 year previously. We used structural equation modeling to examine whether our hypothetical model fits the cross-sectional data.This was a cross-sectional, observational study and extension of a previously published study series . In the A questionnaire-based survey was conducted between October 2019 and August 2020. The respondents were required to mention their names in the questionnaire to combine the questionnaire with the medical records at the medical facilities.The study protocol was approved by the Ethical Review Committees of Sapporo Maruyama Orthopedic Hospital and Harunaso Hospital .The research description and consent forms were distributed to the participants, and informed consent was obtained from all participants. In addition, a consent withdrawal form was provided to the participants to ensure that they had the option to withdraw from the study after participation. If a withdrawal form was submitted, data obtained from the respondents were deleted.A total of 422 individuals aged ≥65 years underwent surgery for LSS at Sapporo Maruyama Orthopedic Hospital and Harunaso Hospital at least 1 year ago, and whose current address was known were included. In this study, lumbar disc herniation and degenerative lumbar spondylolisthesis were considered LSS types [Age, sex, date of surgery, and surgical technique (decompression fixation or decompression) were obtained from the medical records. The number of postoperative days was defined as the number of days between the date of the surgery and the postmark on the return envelope.Using a 5-point Likert scale, participants were asked how often they performed five types of physical activities , muscle strength exercises (MSE), maintenance tasks of the house and garden, including kitchen garden (MTH/G), and paid works)  often peThe average intensities of lower back pain (LBP), leg pain (LP), and leg dysesthesia (LD) that continued postoperatively in the last month were assessed using an 11-point numerical rating scale (NRS) (0 points for “no pain or dysesthesia” and 10 points for “intolerable pain or dysesthesia”). The validity of the NRS as a scale for assessing pain intensity has been validated .The Japanese version of the original TSK  was usedThe self-administered EuroQol-5 Dimension-5 Levels (EQ-5D) was used to assess HRQOL . ValidatThe EQ-5D consists of five questions related to mobility, self-care, daily living, pain/discomfort, and anxiety/depression, and the participants answered each question on a five-point scale based on the degree of disability and symptoms. In this study, the participants were asked to look back over the last month and answer questions. The EQ-5D index value  was calcU test. In addition, descriptive statistics were calculated for each item.First, missing values were complemented by stochastic regression imputation. The datasets before and after the completion of missing values were compared using the Mann–Whitney Pain/dysesthesia was created as a latent variable, and the NRS scores for LBP, LP, and LD were set as their components. Pain/dysesthesia, a latent variable, drew a path toward SF and AA, which are subconcepts of kinesiophobia. The covariance was set for SF and AA .The EQ-5D received a direct path from pain/dysesthesia and an indirect path from SF and AA, respectively. Therefore, pain/dysesthesia directly affects the EQ-5D and indirectly via kinesiophobia .Physical activity, a latent variable consisting of walking, S/LIE, MSE, MTH/G, and paid work, was created. Physical activity added a path toward pain/dysesthesia, as well as SF and AA .A hypothesis model based on FAM was developed (see the following for details):The aforementioned hypothetical model was tested for validity using structural equation modeling. The weighted least squares mean variance (WLSMV) estimation developed for ordinal scales was used , 35. TheR  was used for all statistical analyses, and a risk rate of 5% was set as the level of statistical significance.A complete set of questionnaires was mailed to 431 participants who met the inclusion criteria. A total of 322 respondents (74.7%) responded. Of these, 25  were excluded, resulting in a total of 297 participants  included in the analysis (68.9%) . The medSince the number of survey items per person was 30 , the total number of questionnaire items collected from 297 people was 8910. Among these, there were 318 with missing values (3.6%). Missing values were obtained using MICE. When the original dataset with missing values was compared with the complete dataset after completion, no significant difference was observed.The descriptive statistics of the survey items are summarized in The goodness-of-fit indices obtained from the hypothetical model of this study were 0.840 for CFI, 0.768 for TLI, 0.084  for RAMSEA, and 0.072 for SRMR. Because only SRMR revealed acceptable values, three covariances were added between walking, S/LIE, and paid work and between S/LIE and MSE with reference to the modification indices . After m`The purpose of this study was to clarify the clinical significance of maintaining and improving physical activity in older adults who had undergone surgery for LSS more than 1 year earlier. To achieve this goal, we tested whether the model that physical activities can reduce kinesiophobia, as well as pain and dysesthesia, and consequently improve HRQOL, is valid.Older adults who had undergone surgery for LSS >1 year earlier were included. The median NRS scores for LBP, LP, and LD were low. In contrast, the EQ-5D index values were comparable to the mean of the Japanese individuals aged ≥50 years who complained of nonspecific LBP and were lower than the mean of those without nonspecific LBP . The mosBased on the FAM, pain and dysesthesia directly affected HRQOL and indirectly through the mediation of kinesiophobia , 40. In According to the modification indices, the covariance between walking and S/LIE, walking and paid work, and S/LIE and MSE improved the goodness-of-fit to a level that made the model acceptable. A significant positive covariance was observed between walking and S/LIE, and between S/LIE and MSE. It has been reported that people with personality traits, such as extroversion and conscientiousness, are more active , and thaAs hypothesized in this study, the paths by which physical activity reduced the intensity of pain and dysesthesia and consequently improved HRQOL were significant. This result is consistent with the findings of Nambi et al., who reported that yoga successfully reduced the intensity of chronic LBP and improved HRQOL . As it hFurthermore, the path by which physical activity reduces kinesiophobia and consequently improves HRQOL is significant. This suggests that physical activities affect psychological factors in addition to their effects on pain. These paths from physical activity to HRQOL via kinesiophobia are supported by the following two reports. Patients with nonspecific LBP at low levels of physical activity had strong kinesiophobia . MoreoveWhen considering two aspects of kinesiophobia, “tendency to focus on physical symptoms” and “avoidance beliefs about physical activities” had a direct effect on HRQOL in our model, while “avoidance beliefs about physical activities” had only an indirect effect on HRQOL in relation to “tendency to focus on physical symptoms.” In a study of women with patellofemoral joint pain, both “avoidance beliefs about physical activities” and “tendency to focus on physical symptoms” affected HRQOL . FactorsTo the best of our knowledge, this is the first study to validate a model predicting HRQOL improvement due to physical activity in older Japanese adults with pain, dysesthesia, and kinesiophobia who had undergone surgery for LSS. The model is consistent with a report that physical activity improves HRQOL in patients with chronic pain  and is nThis study has two main limitations. First, our cross-sectional data in this study may contain recall and dropout biases. Participants were asked to recall their pain and health status in the last month, but it is not guaranteed that participants' self-reports will match their true status. In addition, approximately 30% of the participants were excluded from the analysis. It is possible that the 30% dropout rate may have biased our data. These biases limit the generalizability of the findings in this study. Second, the hypothetical causal model assessed in this study fits well with our cross-sectional data, but causal relationships between physical activity and HRQOL in terms of kinesiophobia, pain, and dysesthesia have not been determined. Moreover, it does not consider factors that may influence pain, kinesiophobia, and physical activities, such as sex, season, or region of residence. The prevalence and severity of chronic pain are reportedly higher in women , and sexWe assessed the validity of our hypothesized model that physical activity affects HRQOL in older Japanese adults who underwent surgery for LSS more than 1 year previously. Structural equation modeling using WLSMV, a statistically robust method, revealed that physical activities were significant both in the path of improving HRQOL by reducing the intensity of pain and dysesthesia and improving HRQOL by reducing kinesiophobia. Although the hypothetical causal model was validated in our cross-sectional data, intervention studies on physical activity are required to confirm the causal relationships.


I2 = 60.6%). Alcohol consumption resulted in a non-significant decrease in the risk of sarcopenia in men  and in women . The subgroup analyses by age and alcohol consumption were significantly associated with an increased the risk of sarcopenia in <65 years . This meta-analysis of observational studies indicated that alcohol consumption was not significantly associated with sarcopenia risk. However, there are factors influencing the association between alcohol consumption and sarcopenia, such as smoking and dietary patterns. Additional study of these confounding factors is needed for the systematic analysis of the association of alcohol consumption with sarcopenia in future studies.Sarcopenia is a common disease defined as the loss of skeletal muscle mass, strength, and physical performance. Alcohol consumption is an uncertain risk factor for sarcopenia. Previous observational epidemiological studies have reported inconsistent results regarding the association between alcohol consumption and sarcopenia risk. This study aimed to investigate the association between alcohol consumption and sarcopenia. A literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed, EMBASE, and the Cochrane Library through April 2022 using keywords related to alcohol consumption and sarcopenia. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using a random effects model meta-analysis. The risk of bias of the studies was assessed using the Newcastle–Ottawa scale. Nineteen observational studies that reported 3826 sarcopenia patients among 422,870 participants were included in the qualitative analysis. Alcohol consumption was not significantly associated with sarcopenia risk (OR, 1.00; 95% CI, 0.83 to 1.20;  Sarcopenia refers to a progressive and generalized disorder of the skeletal muscle that is associated with an increase in negative health outcomes such as falls, fractures, physical disability, and death . AlthougPrevious studies have examined the association between sarcopenia and anti-inflammatory dietary factors among many muscle function-related dietary factors, including omega-3 fatty acids and flavonoids, which are associated with inadequate protein intake, inadequate energy intake, micronutrient deficiency, malnutrition, and inflammation ,6,7. TheAlcohol consumption causes various diseases, such as liver disease, cancer, and cardiovascular disease, possibly resulting in malabsorption of various micronutrients. In earlier studies of the association between alcohol consumption and muscle health, ethanol inhibited skeletal muscle protein synthesis in an in vivo animal model and cell experiments ,11, and One meta-analysis of the association between alcohol consumption and sarcopenia has been reported. The results of the meta-analysis, including 13 studies, showed that the pooled odds ratios (ORs) of sarcopenia in subjects consuming alcohol was 0.77 , indicating that alcohol consumption was not a risk factor for sarcopenia , a more This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines . We searTwo reviewers independently screened the titles and abstracts, and selected full-text studies were subsequently assessed. Disagreements were resolved through consensus. Inclusion criteria for the selection of studies were based on the following: (1) all observational studies; (2) the definition of sarcopenia based on AWGS (Asian Working Group for Sarcopenia), AWGS 2019 (Asian Working Group for Sarcopenia 2019), EWGSOP (European Working Group on Sarcopenia in Older People), EWGSOP2 (European Working Group on Sarcopenia in Older People2), and FNIH ; and (3) information on sarcopenia with the corresponding OR and 95% CI. The following exclusion criteria were applied: (1) sarcopenia defined only by muscle quality and quantity; (2) data from the same study; (3) review, case report, and animal articles; and (4) studies that were not published in the English language. The most comprehensive study was included if it was reported in the same study.Data extraction was performed through two independent reviewers. Extracted information included first author, publication year, country of included participants, sarcopenia definition, body composition assessment method, sarcopenia prevalence, sex, age, definition of alcohol consumption (highest vs. lowest category), OR with 95% CI, and adjusted variables.We investigated the association between alcohol consumption (highest vs. lowest category) and the risk of sarcopenia using adjusted ORs with 95% CIs in the main analysis. We used the groups with the highest levels compared to lowest levels of alcohol consumption among the various groups in each study. We also performed subgroup analyses according to sex, age, definition criteria of sarcopenia, and geographical region of the included participants.The Newcastle–Ottawa Scale (NOS)  for crosI2, which measures the percentage of total variation across studies [I2 was calculated as follows:We used the adjusted OR and 95% CI reported in individual studies to calculate the pooled OR with 95% CI. We evaluated the heterogeneity in results across studies using Higgins  studies . I2 was Q is Cochran’s heterogeneity statistic and df indicates the degrees of freedom. Negative values of I2 were set at zero; I2 lies between 0% (no observed heterogeneity) and 100% . An I2 value of >50% indicated substantial heterogeneity. We used a random effects model meta-analysis based on the DerSimonian and Laird method, because individual studies were conducted in different populations [p-value was less than 0.05 as determined by Egger’s test. We used the Stata SE version 16 software package  for the statistical analysis.Where ulations . We alsoA total of 587 studies were retrieved from the preliminary search of all data . We exclI2 = 60.6%). I2 = 0.0%; n = 4). In addition, alcohol consumption was not significantly associated with an increased risk of sarcopenia in women . Publication bias was assessed using funnel plots and Egger’s test. Begg’s funnel plot revealed a symmetric result (p for bias = 0.69).c result . TherefoI2 = 0.0%; n = 4), but a significantly increased risk of sarcopenia in <65 years . In the subgroup analyses according to the definition of sarcopenia, alcohol consumption was not significantly associated with an increased risk of sarcopenia in AWGS 2019  and EWGSOP , but with a decreased risk in AWGS  and EWGSOP2 .Subgroup meta-analyses were performed to determine the influence of age, definition of sarcopenia, and geographical region on the included participants. To the best of our knowledge, this is the first systematic review and meta-analysis of population-based studies that focus on the association between sarcopenia and alcohol consumption. A total of 19 observational studies, representing data from 422,870 participants, of which 3826 patients had sarcopenia, were included in the meta-analysis. As a result, it was found that alcohol consumption was not significantly related to the risk of sarcopenia. However, when we conducted the subgroup meta-analyses by age group, alcohol consumption in participants aged 60 years and older decreased the risk of sarcopenia .Even with the use of subgroup meta-analysis by age group and sarcopenia diagnosis criteria, which are important factors related to the onset and diagnosis of sarcopenia, our study results should be interpreted with caution. The main results of this study were slightly different from the previously reported results of a meta-analysis performed by Steffl et al. . In theiOur findings indicate that the association between alcohol consumption and sarcopenia was not significant in men and women. Previous research has suggested that sex differences in the association between muscle health and alcohol consumption are linked to hormones . EstrogeAlthough alcohol consumption has been reported to induce muscle atrophy in animal models , the assOur meta-analysis has several limitations. First, this meta-analysis included only cross-sectional studies on alcohol–sarcopenia, and cross-sectional design studies provide a lower level of evidence than cohort studies. Second, there was a possibility of recall bias due to the data collection method used in cross-sectional studies. This meta-analysis included only cross-sectional studies because there are few reliable cohort studies on the association between alcohol consumption and sarcopenia. Third, our study data did not allow us to specify variables to measure alcohol consumption, although the type and amount of alcohol consumed by each individual were very different. Alcohol is a type of food that can be consumed and an individual’s health is greatly affected by the amount of alcohol consumed. A small amount of alcohol consumption may not be closely related to health; however, as alcohol consumption increases, the health risk increases exponentially. Therefore, it is very important to accurately estimate the amount of alcohol consumed in studies of alcohol consumption. All the studies included in the present meta-analysis asked participants to self-report their alcohol consumption using survey questions regarding alcohol consumption variables. Nevertheless, given the previous study by Del Boca et al. , in whicOur study has several strengths. This meta-analysis contributes to our understanding of the effects of alcohol consumption on sarcopenia by conducting a subgroup meta-analysis according to sex, age, diagnostic criteria for sarcopenia, and region. As sarcopenia accelerates with age, and the patterns of alcohol consumption change with age, this study analyzed the association between alcohol consumption and sarcopenia by subgroups based on age. Moreover, there are various diagnostic criteria for sarcopenia, such as AWGS, AWGS 2019, EWGSOP, and EWGSOP2. There are many diagnostic indicators of sarcopenia, including grip strength, physical performance, five-time chair stand test, and muscle mass , and cut-off values for muscle mass for evaluation of muscle mass loss differ by race. Therefore, the diagnostic criteria for sarcopenia are diverse and continue to be updated. In this study, to clarify the association between alcohol consumption and sarcopenia, we analyzed the association between alcohol consumption and subgroups according to the diagnostic criteria for sarcopenia and found no significant association. Age, dietary patterns, socioeconomic factors, and physical activities are expected to influence the association between sarcopenia and alcohol consumption. One of the characteristics of original papers in this meta-analysis is the adjustment for various factors such as age, smoking status, physical activity levels, body mass index (BMI), and education levels .In conclusion, the results of this meta-analysis of 19 studies showed that alcohol consumption was not significantly associated with sarcopenia risk. However, the association between sarcopenia and alcohol consumption may differ according to age. An implication of this is that the association between alcohol consumption and sarcopenia may be different in a particular group by sex and age. The effects of alcohol use on health-related outcomes have been analyzed using various variables for alcohol consumption, such as alcohol consumption, frequency, and amount of alcohol consumed. However, there are few studies on alcohol consumption and sarcopenia considering various alcohol use variables. Future studies on alcohol–sarcopenia are needed to systematically assess alcohol consumption in various subjects. Considering the variety of diagnostic indicators of sarcopenia, such as grip strength and physical performance along with appendicular skeletal muscle mass, detailed studies on the association between alcohol consumption and the various sarcopenia indicators are anticipated.


Cross-cultural psychosis research has typically focused on a limited number of outcomes . It is unknown if the purported superior outcomes for psychosis in some low- and middle-income countries extend to fundamental treatment processes like trust. Addressing this gap, we studied two similar first-episode psychosis programs in Montreal, Canada and Chennai, India. We hypothesized higher trust in healthcare institutions and providers among patients and families in Chennai at baseline and over follow-up.Upon treatment entry and at months 3, 12 and 24, trust in healthcare providers was measured using the Wake Forest Trust scale and trust in the healthcare and mental healthcare systems using two single items. Non-parametric tests were performed to compare trust levels across sites and mixed-effects linear regression models to investigate predictors of trust in healthcare providers.The study included 333 patients  and 324 family members . Across all timepoints, Chennai patients and families had higher trust in healthcare providers and the healthcare and mental healthcare systems. The effect of site on trust in healthcare providers was significant after controlling for sociodemographic characteristics known to impact trust. Patients’ trust in doctors increased over follow-up.This study uniquely focuses on trust as an outcome in psychosis, via a comparative longitudinal analysis of different trust dimensions and predictors, across two geographical settings. The consistent differences in trust levels between sites may be attributable to local cultural values and institutional structures and processes and underpin cross-cultural variations in treatment engagement and outcomes. It hOverall, trust is known to be an essential ingredient in therapeutic relationships and considered the foundation of patient-centered care . It is aPrevious studies have reported conflicting and at times inconclusive results regarding the association between patients’ sociodemographic characteristics and their trust in healthcare institutions and providers , 15. WheConsidering the long history of fear and stigma associated with psychiatric institutions and the specificities of mental health disorders and their treatment, trust building is especially important – and may be particularly challenging - in the context of mental healthcare , 33, 34.The present study is part of a larger cross-cultural research project , 44 condIn this study, our focus was on differences in the level of trust in healthcare providers among patients and families in Chennai and Montreal. This line of enquiry was sparked by the finding from pilot phase focus groups that patients and family members in Chennai trusted their providers and program more than their Montreal counterparts did . Since f2.Our primary aim was to compare the trust levels of patients and their family members receiving care at two early intervention services in Chennai and Montreal.At baseline, we predicted that trust in the medical profession (without reference to any specific doctor), and in the healthcare and mental healthcare systems  would be higher among Chennai patients and families compared to their Montreal counterparts, after accounting for sociodemographic factors associated with trust levels  and for institutional trust levels.At follow-up, we predicted that patients’ and families’ trust in their doctors and case managers and in the mental healthcare system (now after experiencing care in EIS) would be higher in Chennai than in Montreal, after accounting for sociodemographic factors associated with trust levels  and for baseline trust levels.As exploratory analyses, considering that continuity of care has been previously associated with higher trust levels –37, we a3.3.1.This study was conducted in two McGill University-affiliated early intervention services in Montreal, Canada (Prevention and Early Intervention Program for Psychosis/PEPP), and one early intervention service in Chennai, India (Schizophrenia Research Foundation/SCARF). PEPP is a publicly funded program that is part of the healthcare system and SCARF is a non-governmental non-profit organization and a World Health Organization (WHO) collaborating center. Both programs follow international guidelines for early intervention services –53, work3.1.1.Primary diagnosis of a schizophrenia-spectrum or affective psychotic disorder (DSM-IV classification)Age between 16–35 years oldAbility to communicate in Tamil or English (Chennai) and in French or English .3.1.2.Treatment with antipsychotic medication for more than one monthPrimary diagnosis of a pervasive developmental disorder, organic psychosis or substance abuse/dependence. Patients with concurrent diagnoses of substance abuse/dependence were not excluded.IQ below 70Family members recruited for this study included parents, legal guardians, grandparents, siblings, spouses/partners, extended family members, friends and roommates.3.2.Assessments were administered by staff who went through similar training, using measures that had been previously administered at both study sites . SeveralInterpersonal trust levels were measured using the Wake Forest Trust in Medical Profession Scale and the Wake Forest Physician Trust Scale , 56  and the other to assess trust in the mental healthcare systems . While the former has been applied in previous studies , 61, theWe evaluated the psychometric properties of the modified Wake Forest scales and the single self-rated item on trust in the mental healthcare system. Overall, we found that reliability and internal consistency estimates were adequate for patients and families, in Montreal and Chennai (suppl. table 2).Patients and family members completed the trust measures at different time points. At baseline (entry into the early intervention service), the self-reported trust measures included the Wake Forest Trust in Medical Profession Scale and the two additional questions on institutional trust . During follow-up , the Wake Forest Physician Trust Scale, its adapted version for case managers and the single-item questionnaire on trust in the mental healthcare system were distributed.3.3.2) coefficients, classified as small: (η2 = 0.01), medium (η2 = 0.06) and large (η2 = 0.14) [As different trust measures were administered at baseline and during follow up, data analysis was performed both cross-sectionally and longitudinally. Descriptive data were presented using proportions for categorical variables and means, standard deviations, medians and IQRs (interquartile ranges) for continuous variables. Total scores from 5-item trust scales were standardized to a scale from 1 to 5 to facilitate comparisons. Chi-square statistics were performed to examine differences between sites regarding categorical variables and t-tests were computed to assess site differences for continuous and normally distributed sociodemographic variables. To assess whether continuous sociodemographic variables were associated with trust measures, Spearman correlations were used, due to the right skewness of the trust data. In order to analyse differences in trust levels between sites and stakeholder groups, non-parametric Mann-Whitney tests were performed. Effect sizes were calculated using eta squared (ηp = 0.14) .Linear regression models were fitted to assess predictors of trust in the medical profession at baseline and linear mixed effects models (autoregressive covariance structure) were fitted to assess predictors of trust in doctors and trust in case managers during follow-up . Independent variables were chosen based on study hypotheses. The choice of models was based on theoretical assumptions and likelihood criteria (Bayesian Information Criterion). Statistical analyses were executed using SPSS 21.0 for Windows.4.4.1.4.1.1.The total baseline sample included 333 patients with first-episode psychosis from Montreal (N = 165) and Chennai (N = 168), and 324 family members from Montreal (N=128) and Chennai (N=168). At baseline, at both sites, most patients were in their mid-twenties, had completed high school level education and lived with their families. Participants from Montreal were significantly younger, more often male and single. Most family members belonged to the age group between 50–60 years old, were female, patients’ parents, and had high school (or higher) education. Family members from Chennai were more likely to be female, to have less than high school education and to be older than Montreal family members .4.1.2.2 = 0.015).At Baseline, 82/165 patients from Montreal and 4/168 patients from Chennai did not complete the trust scales. Within the family members’ group, 61/128 participants from Montreal and 4/168 participants from Chennai did not complete the trust scales at baseline. During follow-up, 36/165 patients and 21/128 family members from Montreal; and 3/168 patients and 33/168 family members from Chennai did not respond to both the scale on trust in doctors and the scale on trust in case-managers at any of the follow-up times. Overall, there were no significant differences between respondents and non-respondents on any of the assessed sociodemographic variables (baseline and follow-up) and in terms of previous assessments of trust (follow-up) except for family members in Chennai, among whom follow-up respondents had reported higher trust in the mental healthcare system at baseline , and institutional trust  ranging between 4 and 5. An exception to this was patients’ trust in the medical profession at baseline, with a lower median at 3.8 (suppl. tables 3 and 4). At baseline, at both sites, correlations between trust measurements were strong for both stakeholder groups. At each follow-up time point, trust levels in doctors and in case managers were strongly correlated and moderately correlated with trust in the mental healthcare system   compared to patients. In Montreal, no statistically significant differences were found between patients’ and families’ trust levels in institutions and in the medical profession . During 4.4.4.4.1.1 = 0.22; p < 0.001), trust in the healthcare system  and trust in the mental healthcare system . The effect of site  on trust in the medical profession remained significant when variables of institutional trust and sociodemographic variables  were added to the model. In the final model for family members  = 97,18; p<0,001; adjusted R squared: 0.58) trust in the medical profession was significantly associated with site  , trust in the healthcare system  and trust in the mental healthcare system . The effect of site  remained significant when the variables of institutional trust and sociodemographic variables  were added to the model (suppl. table 8).In the final model for patients  = 58.73; p<0.001; adjusted R squared: 0.43) trust in the medical profession was significantly associated with site  , baseline trust in the medical profession  and time  were found to be significant predictors of trust in doctors during follow-up. These effects remained significant even when other sociodemographic variables  were added to the model. Among family members, site (Chennai as the reference category) , baseline trust in the medical profession  and age range (higher trust for older family members) were found to be significant predictors of trust in doctors. These effects remained significant even when other sociodemographic variables  were added to the model. The effect of site  was sustained when baseline trust in the medical profession was added to the model. Trust in doctors did not change significantly over time, among family members, both in simple and multinomial models (suppl. table 9).In the patients’ group, site (Chennai as the reference category)   and baseline trust in the mental healthcare system  were found to be significant predictors of trust in case managers during follow-up. These effects remained significant even when other sociodemographic variables were added to the model. Among family members, site (Chennai as the reference category) , baseline trust in the medical profession  and age range  were found to be significant predictors of trust in case-managers. These effects remained significant even when other sociodemographic variables and baseline trust in the medical profession were added to the model. Trust in case managers did not change significantly over time for both stakeholder groups (suppl. table 10).5.As hypothesized, compared to their counterparts in Montreal, both patients and family members from Chennai scored higher on all self-reported measures of institutional trust  and interpersonal trust . The effect of site was still significant even when other variables , known to influence trust, were added to the models.Site differences in trust are likely to be influenced by the social, cultural and political contexts that underpin peoples’ realities at both sites . Sociocultural contexts also shape public opinion and determine previous experiences with healthcare services and providers by influencing the availability, access and quality of services received. All in all, contexts mould expectations regarding institutions and healthcare professionals, shaping the ways in which therapeutic relationships are conceptualized and enacted in the context of healthcare , 64, 65.It has been suggested that trust may be higher in collectivistic  societies, characterized by a higher sense of group and interpersonal cooperation, greater emphasis on hierarchy and authority, and less concern with avoiding uncertainty. Our study results align with this perspective, since Canada and India could arguably be placed at the opposite poles of the individualistic-collectivistic spectrum –68. HoweAt baseline, trust in the medical profession was associated with trust in the healthcare and mental healthcare system, for both patients and family members. Age was a significant predictor of trust for only family members, with older individuals having higher trust levels, as previously reported in the literature –21, suggWhen comparing stakeholder groups, results differed by site, with family members from Chennai reporting consistently higher trust levels in both institutions and healthcare providers. In Montreal, however, no differences were found between patients’ and families’ trust levels, at most timepoints. This is particularly relevant given that in other studies from this cross-cultural project, family involvement was found to be higher in Chennai than in Montreal, and valuable for both promoting engagement and better clinical outcomes , 44.This study has several strengths, which include its prospective design and well-defined inclusion and exclusion criteria, the similarity of the care models and protocols at both sites, the rigorous staff training, centralized data management and verification, and the strong psychometric properties of the instruments used. Furthermore, it is unique and innovative in its focus on trust in early intervention services for psychosis, while assessing trust across countries in a nuanced way, considering different trust dimensions , from different points of view . Several study limitations should also be noted. At both sites, all stakeholders reported high levels of institutional and interpersonal trust, with medians ranging between 3.4 and 5 , suggesting that responses could have been influenced to some extent by social desirability. However, both families and patients were asked to report their trust levels at an early stage of contact with services. Also, all trust scales showed good to excellent psychometric properties at both study sites. It should also be pointed out that not all chosen measures were developed specifically for this study and hence were not specifically adapted to the study populations who could conceptualize and evaluate trust differently. For instance, previous studies from South India have reported that, for doctors to be trusted, it is more important that patients experience respect, loyalty, comfort, personal involvement by the care provider, cultural competence and the assurance of being treated (regardless of the ability to pay), whereas the experience of individuality, shared responsibility and confidentiality tend to be emphasized in Western contexts , 73–75.