Acer truncatum resources. However, research on one of its by-products, namely seed oil residue (ASR), from seed oil extraction is seriously insufficient, resulting in a waste of these precious resources. We aimed to optimize the conditions of ultrasound-assisted extraction (UAE) using a response surface methodology to obtain high acetylcholinesterase (AChE) inhibitory components from ASR and to tentatively identify the active metabolites in ASR using non-targeted metabolomics. Based on the results of the independent variables test, the interaction effects of three key extracting variables, including methanol concentration, ultrasonic time, and material-to-liquid ratio, were further investigated using the Box–Behnken design (BBD) to obtain prior active components with high AChE inhibitory activity. UPLC-QTOF-MS combined with a multivariate method was used to analyze the metabolites in ASR and investigate the causes of activity differences. Based on the current study, the optimal conditions for UAE were as follows: methanol concentration of 85.06%, ultrasonic time of 39.1 min, and material-to-liquid ratio of 1.06:10 (g/mL). Under these optimal conditions, the obtained extracts show strong inhibitions against AChE with half maximal inhibitory concentration (IC50) values ranging from 0.375 to 0.459 µg/mL according to an Ellman’s method evaluation. Furthermore, 55 metabolites were identified from the ASR extracted using methanol in different concentrations, and 9 biomarkers were subsequently identified as potential compounds responsible for the observed AChE inhibition. The active extracts have potential to be used for the development of functional foods with positive effects on Alzheimer’s disease owing to their high AChE inhibition activity. Altogether, this study provides insights into promoting the comprehensive utilization of A. truncatum resources.The State Council of China has called for the comprehensive development and utilization of  Acer truncatum, a perennial deciduous arbor from the genus Acer (Sapindaceae), is native to China and has been widely cultivated around the world for its ornamental, ecological, edible, and nutritional values oxyphenyl]-2,3-dihydrochromen-4-one and D-Tryptophan, the other seven discriminative metabolites have been reported to display inhibitory effects on AChE or anti-AD. Studies have shown that ferulic acid was the most common active component for the inhibition of Aβ aggregation, and the protection of neurons from oxidative damage, but its interaction with AChE was not significant (<20% inhibition of AChE at 20 mM) oxyphenyl]-2,3-dihydrochromen-4-one are potential biomarkers. The extracts from ASR obtained through UAE could be used for the development of functional foods with positive effects on Alzheimer’s disease.The experimental results indicated that the optimized conditions for UAE were effective in extracting AChE inhibitory components from ASR. The extracts with the IC


Mobile technology can support HIV care, but studies in youth are limited. In 2014, youth receiving HIV care at several health care facilities in Nairobi, Kenya spontaneously formed peer support groups using the social media platform WhatsApp.Inspired by youth-initiated groups, we aimed to evaluate the use of WhatsApp to deliver a social support intervention to improve HIV treatment and psychosocial outcomes in youth. We developed a facilitated WhatsApp group intervention (named Vijana-SMART), which was grounded in social support theory and guided by the design recommendations of youth living with HIV. This paper evaluates the intervention’s acceptability and pre-post changes in health outcomes.The intervention involved interactive WhatsApp groups facilitated by study staff for 6 months, with each group having approximately 25 members. Study staff sent weekly structured messages, and the message content was based on social support theory and encouraged unstructured peer-to-peer messaging and support. We conducted a single-arm pilot among 55 youth living with HIV aged 14-24 years recruited from a government health care facility serving a mixed-income area of Nairobi. At enrollment and follow-up, self-report questionnaires assessed acceptability; antiretroviral therapy (ART) information, motivation, and behavioral skills (IMB); depression; social support; stigma; resilience; and ART adherence. All participants received the intervention. We used generalized estimating equations (GEEs) clustered by participant to evaluate changes in scores from baseline to follow-up, and correlates of participant WhatsApp messaging.P<.001). Stigma scores also increased , and resilience scores decreased . We found no significant change in ART adherence, social support, or depression. We detected a positive association between the level of messaging during the study and the resilience score, but no significant association between messaging and other outcomes. Once enrolled, it was common for participants to change their phone numbers or leave the groups and request to be added back, which may present implementation challenges at a larger scale.The median participant age was 18 years, and 67% (37/55) were female. Intervention acceptability was high. All participants reported that it was helpful, and 73% (38/52) sent ≥1 WhatsApp message. Messaging levels varied considerably between participants and were higher during school holidays, earlier in the intervention period, and among youth aged ≥18 years. IMB scores increased from enrollment to follow-up ; https://clinicaltrials.gov/study/NCT05634265 In 2021, an estimated 1.71 million adolescents aged 10-19 years were living with HIV globally, with 86% of them in sub-Saharan Africa . Youth lThe use of mobile communication technology for health  is a promising strategy to improve youth HIV outcomes. Access to mobile phones and social media has grown exponentially over the last decade in both high-income and low-income settings. In Kenya in 2021, of the total population of 54.4 million, there were 59.2 million mobile phone subscriptions (109% coverage) and 20.9 million mobile internet users (38% coverage) . Recent In 2014, youth receiving HIV care at several health care facilities in Nairobi, Kenya, spontaneously formed peer support groups using the social media platform WhatsApp. Interviews with participants in these youth-led groups indicated that the groups served to supplement in-person support groups and provide information, emotional support, and community to youth living with HIV . InspireThe study involving Vijana-SMART was a single-arm pilot study with pre-post longitudinal outcome assessment. This design was used in this initial pilot owing to funding and time constraints.This study was conducted at a level 3 government health care facility serving a mixed-income area of Nairobi including formal and informal housing, where no other social media peer groups were offered. Youth receiving HIV care were recruited in person by the study team and through paper flyers posted at the facility. Facility staff also shared information about the study and referred potential participants. Snowball sampling from enrolled participants was used to maximize recruitment of youth aged <18 years. Interested participants provided verbal consent for study staff to complete eligibility screening with a tablet-based electronic questionnaire administered using the Open Data Kit. Eligible participants were aged 14-24 years, were living with HIV and aware of their status, and had access to WhatsApp. Participants provided written informed consent prior to enrollment. In accordance with Kenyan regulations, parent or guardian permission was required for adolescents aged 14-17 years, unless they were considered emancipated minors due to being married, pregnant, or parenting. Ethical review boards additionally granted a waiver of parental permission for adolescents who were attending HIV care without a parent or guardian. Participants were enrolled between January 31 and March 26, 2019. Follow-up visits were completed between November 18 and December 14, 2019.The Vijana-SMART intervention involved a facilitated peer group for youth living with HIV, which was delivered through WhatsApp. The intervention was inspired by spontaneously developed youth-led WhatsApp support groups at other facilities in Nairobi and was designed based on youth guidance in 2 rounds of individual interviews and focus groups with youth living with HIV . InterveParticipants attended 2 in-person study visits at the study facility, at enrollment and 6 months. At each study visit, study staff administered self-report tablet-based questionnaires to assess ART information, motivation, and behavioral skills ; depresWe assessed individual participant-level changes from baseline to follow-up in the following primary outcomes: ART IMB, ART adherence, depression symptoms, social support, stigma, and resilience. Instrument scores at enrollment and follow-up were modeled by generalized estimating equations (GEEs) clustered by participant. Intent-to-treat analyses were performed, and they were conducted among all participants and among those who had data available at both enrollment and follow-up (complete cases) to explore possible biases due to loss to follow-up. The mode of HIV acquisition was determined based on self-report if the participant knew the mode of acquisition. If none was reported, age at infection or ART initiation was used as a proxy, with the age of ≤14 years considered perinatal. Participant satisfaction with the intervention was summarized descriptively.Participant engagement in the intervention was assessed as follows: (1) Boolean indicator of whether participants left the group during the intervention, (2) total number of messages sent per day, (3) Boolean indicator of whether the participant was active . We evaluated the association of baseline characteristics (as predictors) with each measure of engagement (as outcomes). Leaving the group was modeled using Poisson regression, the number of messages sent per day was modeled using linear GEEs clustered by participant, and being active each day was modeled using log-binomial GEEs clustered by participant. We evaluated the association of each measure of engagement (each as a predictor) with each behavioral outcome , using linear regression adjusted for the baseline score of the outcome variable. Analyses were conducted using Stata v13 (StataCorp) and RStudio v2022.07.1+554 .This research was approved by the ethics review boards at the University of Washington (STUDY00002554) and Kenyatta National Hospital/University of Nairobi (P296/06/2017), and performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. The study was registered at ClinicalTrials.gov (NCT05634265). Registration was completed after data collection because the study was not determined to require registration by the ethics review boards.P=.05) and fewer were employed  (Participant characteristics are summarized in  P=.004) .Intervention acceptability was very high among the 46 participants who completed follow-up . Among tAs empirical measures of intervention engagement, we examined participant messaging levels in the group. Messaging patterns varied considerably between participants . We obseWhen asked, no participants reported experiencing a confidentiality breach in which a third party accessed their Vijana-SMART messages. However, 3 instances of third-party access were reported during implementation or in-depth exit interviews: participant 21 exited the group and, when asked why, explained that their sibling had accessed their phone and exited the group; participant 39’s sibling accessed the group and had an exchange with another group member; and participant 42 reported messaging one-to-one with another participant and then realizing they were messaging with the participant’s spouse who had accessed the phone . All 3 pP<.001). Within the IMB score, the information and behavior skills elements both significantly increased at follow-up, with an increase in the score of 6.5  and 6.1 , respectively. The self-reported ART adherence score remained similar between enrollment and follow-up .P=.001). In particular, the subscale focusing on internalized stigma showed an increase of 10.1 . Additionally, we observed a decrease in the resilience score from 75.0  to 70.0 .We found no significant difference in depressive symptoms and social support scores . HoweverWe investigated whether participant engagement in the intervention was associated with a pre-post change in outcomes. In this pilot study, we evaluated the uptake, utility, and preliminary effect of a novel WhatsApp-based peer group intervention for youth living with HIV in Nairobi, Kenya. We found that participants expressed high satisfaction with the intervention. All eligible youth chose to enroll in the study, and the vast majority reported that the intervention was helpful for learning new information, gaining emotional support, and promoting ART adherence. The levels and patterns of participant engagement varied considerably between participants. Most participants messaged the group at some point, but typically on a minority of days during the intervention. Messaging was higher during school holidays in the group of ≥18-year-old individuals and declined over time. On comparing baseline and follow-up data among participants, we found a significant improvement in participants’ ART-related information and behavioral skills, which are indicators associated with ART adherence behavior , consistPrevious studies evaluating digital health interventions for ART adherence and virologic suppression have mostly focused on SMS text messaging connecting adults with health care workers, and have yielded mixed evidence ,13,27-32Our observation of increased stigma and decreased resilience scores was unexpected and requires further study. It is possible that hearing about peers’ lived experiences in the Vijana-SMART group led to heightened awareness of stigma and the challenges of living with HIV, or that discussion of stigma in the group increased participants’ ability to identify their experiences as stigma. Internalizing these ideas may also have led to decreased resilience scores. During in-depth interviews at the study exit, participants reported enhanced support as a result of participation and did not report any adverse impact . Our finTo shed light on potential intervention mechanisms, we analyzed the association of participants’ messaging levels with baseline characteristics and behavioral outcomes. mHealth intervention usage data (paradata) can explain mechanisms and optimize intervention targeting, but they have been understudied . We hypoOur study adds to the small but growing literature on the use of social media group interventions for youth living with HIV ,41. The This study presents a novel digital intervention offering youth living with HIV information and support from peers and a trained facilitator. The intervention design was grounded in guidance for youth living with HIV, leading to an acceptable and feasible intervention with promising initial findings. The findings may be especially relevant in the context of COVID-19–related disruption of in-person health care. Future research is needed to deepen the interpretation of these findings. In particular, a larger-scale randomized evaluation of Vijana-SMART with long-term follow-up will support more robust testing of the intervention’s efficacy. More detailed assessment of stigma and resilience is also needed, including longitudinal quantitative assessment and qualitative exploration of these constructs. Finally, the collection of more detailed paradata, such as reading of messages in addition to sending of messages, is needed to better understand the relationship between intervention engagement and outcomes.


Transjugular intrahepatic portosystemic shunt (TIPS) can be an effective treatment for cirrhotic patients who develop variceal bleeding and ascites. However, TIPS placement is associated with an increased risk of developing hepatic encephalopathy (HE). Recently, there have been efforts to use the typical medical therapies prophylactically in patients undergoing TIPS placement to prevent post-TIPS HE.We conducted literature searches in MEDLINE, Embase, CINAHL, Scopus, and Cochrane to examine studies that use prophylactic medical therapy for preventing post-TIPS HE. A narrative synthesis and grading of recommendations assessment assessment were done for all studies. Meta-analysis was performed for eligible studies using the Mantel-Haenszel method random-effects model. Nine hundred twenty-one articles were screened and 5 studies were included in the study after 2 levels of screening. The medications studied were rifaximin, lactulose, lactitol, L-Ornithine-L-aspartate (LOLA), albumin, and combination therapies.Narrative results showed that lactulose, lactitol, LOLA and albumin prophylaxis were not associated with reduction in HE occurrence or mortality. A combination of rifaximin and lactulose was found to be associated with lower occurrence of HE, and the results were not different when LOLA was added. Meta-analysis (n = 3) showed that rifaximin treatment was not associated with changes in HE occurrences.In conclusion, a vast majority of medications were not found to be effective post-TIPS HE prophylaxis when used alone. A rifaximin and lactulose combination therapy may be beneficial. Overall, there is significant limitation in the current data and more studies are needed to yield more robust meta-analysis results in the future. Indications for TIPS include variceal hemorrhage, refractory ascites, and hepatic hydrothorax. Studies have shown TIPS can increase liver transplantation-free survival rates of cirrhotic patients with refractory ascites.Transjugular intrahepatic portosystemic shunt (TIPS) is an artificial shunt that can be placed to reroute blood flow past the liver to reduce portal hypertension in patients with liver cirrhosis.,4 Up to 23% of post-TIPS patients develop HE. HE is thought to be primarily caused by a rise in ammonia levels after TIPS placement. This occurs due to decreased breakdown of ammonia as a result of bypassing liver parenchyma as well as increased intestinal ammonia production from upregulation of glutaminase. Clinically, HE carries a wide spectrum of presentations, ranging from covert HE to overt HE. Covert HE is detected via neuropsychological tests analyzing psychomotor speed/executive functions, while overt HE can result in mental changes such as lethargy, disorientation, confusion and coma. The West Haven criteria is a scale that differentiates HE into 4 grades ranging from inattention to coma.However, patients with TIPS are at increased risk of developing hepatic encephalopathy (HE). Nonabsorbable antibiotics such as rifaximin and neomycin can also be used because they are able to modulate the gut microbiota by decreasing the nitrogenous compound-producing bacteria in the colon, hence decreasing overall ammonia production. LOLA, a stable salt, is a key substrate in both the synthesis of urea and the synthesis of glutamine. LOLA is therefore able to reduce HE by inducing nitrogen metabolism to decrease blood and CSF ammonia levels. Lastly, studies have also demonstrated that albumin infusion may reduce occurrence of overt HE in patients with cirrhosis, as albumin has an established role in plasma expansion and decreases risks of cirrhosis-related complications related to circulatory dysfunction. Currently, the European association for the study of the liver (EASL) (2022) recommends that patients with covert HE be treated with nonabsorbable disaccharides. Following an episode of overt HE, the EASL recommend patients be treated with lactulose titrated to 2 to 3 bowel movements/day as secondary prophylaxis. In this case, rifaximin can also be added as an adjunct to lactulose therapy.The management of post-TIPS HE is similar to that of patients without TIPS. Methods of management include nonabsorbable disaccharides, specific antibiotics, L-ornithine-L-aspartate (LOLA), and albumin. Lactulose, a nonabsorbable disaccharide, is an osmotic laxative. In the case of HE, lactulose can be used to decrease the production and absorption of ammonia into the bloodstream. This recommendation was based on 1 study that demonstrated that the prophylactic use of rifaximin or lactitol did not reduce the incidence of post-TIPS HE. However, recent studies have been conducted that show drugs such as LOLA or combination of lactulose and rifaximin may offer some benefit in reducing post-TIPS HE.,11 The EASL (2022) recommends that in patients with cirrhosis and prior episodes of overt HE, rifaximin can be considered for prophylaxis prior to nonurgent TIPs placement. Other medication however, such as lactulose, require further studies.Despite the many options available for treating HE, no clear guidelines have been established if these drugs can be used as primary prophylaxis for HE in patients who have received TIPS. Currently, the American Association for the Study of Liver Diseases (2014) recommends no primary prophylaxis of HE in post-TIPS patients.To the best of the authors knowledge, there has not been a systematic review that examines the possibility of medical prophylaxis for post-TIPS HE in light of these new studies. To bridge this gap in knowledge, this paper aims to systematically review the randomized and non-randomized studies that examine the use of 1 or more medical therapies for prophylaxis of post-TIPS HE. The protocol of this review is documented on the International prospective register of systematic reviews (PROSPERO) registry (ID: CRD42022300004).This manuscript was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In addition, study design was limited to randomized-controlled trials, cohort studies, or case-control studies published in peer-reviewed journals. Conference proceedings and case studies were not included. Studies were also limited to those published in English to mitigate risk of mistranslation.Eligible studies examined patients 18 years or older who have undergone a TIPS procedure and have been given pharmacotherapies immediately before or after TIPS placement. Studies that include patients with preexisting hepatic encephalopathy or patients with preexisting neurological symptoms before TIPS placement were also included. No restrictions were placed on the comparator groups as there is currently no-treatment that is used for the prevention of hepatic encephalopathy post-TIPS. Eligible studies assessed the incidence of post-TIPS hepatic encephalopathy along with the grade of HE according to the West Haven Criteria if available, as well as secondary outcomes of patient hospitalization and mortality.http://links.lww.com/MD/J921).A research librarian was consulted in the development of the search strategies. Relevant documents were identified through literature searches conducted in databases MEDLINE, Embase, Cochrane Central Register of Controlled Trials , CINAHL and Scopus. Keywords and medical subject headings (MeSH) were used to identify all relevant studies and no date restrictions were placed on the searches. Manual citation screening of included trials was also conducted to ensure a comprehensive search. Complete search strategy is available in .Two reviewers (AL and SB) independently conducted a title abstract screening of the eligible retrieved articles using Covidence. Potentially relevant studies then underwent full-text screening by both reviewers independently. After each level of screening, conflicts were resolved during a consensus meeting between the 2 reviewers. Cohen kappa (K) coefficient was calculated for each level of screening to assess for inter-rater reliability in screening.Data was extracted from the included studies independently by 2 reviewers using Excel. Any discrepancies were resolved during a consensus meeting between the 2 reviewers. Extracted data pertained to study characteristics , participant demographics , intervention , and measured outcomes .The main outcome was to determine whether pharmacotherapies such as rifaximin and lactulose administered immediately before or after a TIPS procedure reduced the incidence of post-TIPS hepatic encephalopathy. Secondary outcomes evaluated whether the pharmacotherapies had any impact on patient mortality and hospitalization.For randomized studies, the second version of the Cochrane risk of-bias tool for randomized trials (RoB 2) was used to assess the risk of bias in all the studies analyzed in this paper. RoB2 will identify bias in the following domains: Risk of bias arising from the randomization process; Bias due to deviations from intended interventions; Bias due to missing outcome data; Bias in measurement of the outcome, and; Bias in selection of the reported result. Complete risk of-bias summary plots are in .For non-randomized studies, the risk of bias in non-randomized studies of interventions (ROBINS-I) tool was used to assess the risk of bias. ROBINS-I identified the following domains: Bias due to confounding; Bias in the selection of participants into the study; Bias in classification of interventions; Bias due to deviations from intended interventions; Bias due to missing data; Bias in measurement of outcomes, and; Bias in the selection of the reported result. Certainty of evidence was then assessed using the grading of recommendations assessment, development and evaluation (GRADE) across the domains of risk of bias, inconsistency, indirectness, and imprecision.Two reviewers (AL and SB) sequentially provided a narrative descriptive synthesis of data based on predefined criteria using synthesis without meta-analysis guidelines.P value of < .05 was considered statistically significant. Forest plots were generated for primary outcomes with 95% confidence intervals.Meta-analysis for data that was comparable across interventions and sufficiently homogenous was conducted using RStudio version 1.4.110. The meta and metasens function package was used to develop quantitative measurements and graphics. Mantel-Haenszel random-effects risk ratio (RR) was obtained. Ninety-five percentage confidence intervals were obtained and heterogeneity between trials were assessed by a chi-squared test for heterogeneity. A Ethical approval was not necessary as this study was a systematic review and did not involve patients.,11,18–20 The medical therapies examined were LOLA, rifaximin, lactulose, lactitol, albumin, and various combinations. The characteristics of the included studies are shown in Table The PRISMA flow diagram of screening process is shown in Figure P = .97).Seifert et al (2021) conducted a retrospective study where they found that all patients who had received rifaximin monotherapy (n = 6/233) developed post-TIPS HE. Patients were treated with rifaximin 72 hours prior to TIPS and for 12 months after TIPS. Riggio et al (2005) conducted a randomized-controlled trial (RCT) where they also found that patients treated with rifaximin for 4 weeks after TIPS and patients that received no-treatment had similar 1-month post-TIPS HE occurrence .However, Bureau et al (2021) also conducted an RCT where patients received rifaximin treatment 2 weeks before and 168 days after TIPS. They determined that post-TIPS HE occurrence for up to 6-month after TIPS did differ between the rifaximin and placebo group. An episode of overt HE was observed in 32 of 93 patients in the rifaximin group  and 49 of 93 patients in the placebo group , with an estimated risk difference of −18 percentage points . However, Riggio et al (2005) found that the number of grade 3 and 4 post-TIPS HE episodes in the patient groups treated with rifaximin remained similar to the no-treatment group .The effects of rifaximin monotherapy on the grade of post-TIPS HE remains unclear. Bureau et al (2021) found that when compared to patients in placebo group, patients treated with rifaximin developed less grade 2 (78% vs 69%) and grade 3 HE (16% vs 25%), but these results were not shown to be statistically significant . Riggio et al (2005) reported 2 patient deaths in the rifaximin group versus 1 death in the no-treatment group .Bureau et al (2021) reported incidences of gastrointestinal bleeding (1.1% vs 3.2%), acute kidney injury (24.7% vs 29.0%), hepatocellular carcinoma (2.2% vs 3.2%), liver transplantation (2.2% vs 5.4%) and all-cause mortality (11% vs 13%) in post-TIPs patients treated with rifaximin and placebo. The authors tested differences between groups for each event for significance using a x2 or Fisher exact test. They reported none of the differences were statistically significant (P = .808). They concluded that lactulose monotherapy did not have a prophylactic effect.In the retrospective review conducted by Seifert et al (2021), lactulose monotherapy was given as HE prophylaxis 3 days before and up to 12 months after TIPS placement. They found that prophylactic lactulose monotherapy did not affect that frequency of post-TIPS HE development within 12 months after TIPS placement when compared to the no-treatment group . The number of grade 3 and 4 HE episodes occurring in each group was also similar between the no-treatment and lactitol group .The RCT conducted by Riggio et al (2005) found that treatment with lactitol was not effective as prophylaxis against post-TIPS HE. Patients were given 60 mL of lactitol per day, for up to 4 weeks after TIPS placement. The 1-month incidence of post-TIPS HE in patients was similar in the no-treatment and lactitol group . They concluded no differences in the occurrence of HE were observed between the 2 groups.Riggio et al (2016) conducted an RCT where 23 patients admitted for TIPS were prophylactically treated with 1 g/kg body weight of albumin for the first 2 days post-TIPS followed by 0.5 g/Kg body weight on day 4, day 7, and then once a week for 3 weeks. The incidence of HE 1-month to 6-month post-TIPS was compared with the incidence of HE of patients from a previous RCT  following the same protocol except treated with no pharmacological treatment. In the albumin group, HE occurred in 34% (n = 8/23) patients 1-month post-TIPS, while in the control group, HE occurred in 31% (n = 14/45) patients 1-month post-TIPS  also found no statistically significant differences in survival between the 2 groups. In the albumin group, 22% (n = 5/23) of patients died and in the control group, 18% (n = 8/45) of patients died. Specific P = .001, P < .001, P < .001), serial dotting test  and line tracing test  compared to patients in control group. Fewer patients in the LOLA group had overt post-TIPS HE compared to control group . However, these differences in overt HE were not found to be statistically significant.Bai et al (2014) conducted a RCT where patients were randomized into the experimental group, received an infusion of LOLA, 30 g daily in 500 mL of 5% glucose, for 7 consecutive days. At days 1, 4, and 7, post-TIPS patients in the LOLA group had greater improvement in psychometric tests such as the number connection test (P = .004).Seifert et al (2021) conducted a retrospective review where a combination of lactulose and rifaximin (LR) was administered 72 hours before TIPS and for up to 12 months after TIPS. Lactulose was dosed individually with the aim of 2 to 3 loose stools per day. Rifaximin was administered twice daily at a dosage of 550 mg. Patients in the LR group had less occurrences of post-TIPS HE within 12 months than patients in the no medication group or the lactulose monotherapy group .Seifert et al (2021) showed that patients receiving a combination of lactulose, rifaximin and LOLA did not have significantly lower occurrences of post-TIPS HE within 12 months compared to patients receiving the combination of lactulose and rifaximin alone   which can arise from differences in settings and participants. The funnel plot also demonstrates potential publication bias or other small study effects  of the effects of rifaximin prophylaxis on incidence of HE. This analysis was possible in 3 studies  that included 325 patients. The Mantel-Haenszel test found that there was overall no significant difference between the rifaximin-treated group and the control group . The differences in the timeframe under which rifaximin prophylaxis was started may contribute to the differences in the conclusions made by the 3 studies.Five studies were reviewed in this systematic review. As the included studies investigated a number of different medications that are not comparable to each other, rifaximin was the only medication that was eligible for completion of meta-analysis. There were 3 studies that reported the effect of rifaximin on incidence of HE included in the meta-analysis. The data for the other medications and various combinations were therefore summarized narratively and their qualities were assessed using GRADE. Literature suggests rifaximin alone is not effective for primary prophylaxis of overt HE.Other than rifaximin monotherapy, the other monotherapies of lactulose, lactitol, LOLA, and albumin, were each reviewed in a single study. These studies results did not find significant difference in the occurrence of post-TIPS HE with prophylactic medication. Outside the context of TIPS, studies have shown lactulose to be an effective prophylactic medication to reduce HE occurrence in cirrhotic patients.A combinational therapy using rifaximin and lactulose may be beneficial for reducing post-TIPS HE as Seifert et al (2021) demonstrated that treating patients with lactulose and rifaximin reduced occurrence of post-TIPS HE. This finding is in-line with prior literature that has shown that the addition to rifaximin to lactulose reduces occurrence of overt HE and HE-related hospitalizations when compared to lactulose alone.To the best of our knowledge, our study is the first systematic review that examines different medical interventions for post-TIPS HE prophylaxis. Although the scarcity of current data meant a meta-analysis could not be completed for most of the medications, we aimed to make our qualitative analysis as objective and comprehensive as possible by adhering to predefined criteria using synthesis without meta-analysis guidelines when providing narrative descriptive synthesis, as well as using GRADE to assess the certainty of evidence. The studies analyzed in our review also had strong internal validity, with our quality assessment demonstrating that 2 RCTs had low risk of bias, and 1 RCT and 2 cohort studies had moderate risk of bias. That being said, the major limitation of this review is the limited number of studies currently available in literature. For all monotherapies other than rifaximin, there was only 1 study that met the inclusion criteria. Furthermore, some results reported were based on small sample sizes and did not report secondary outcomes such as all-cause mortality.Our study highlights the need to continue research into the area of medical prophylaxis against post-TIPS HE is an understudied topic. Although existing literature regarding medical treatment of HE is abundant, it is evident that their efficacy cannot be assumed when used prophylactically for patients post-TIPS placement specifically. Our review demonstrates that certain medications or their combination therapy, such as rifaximin and lactulose, would be worth investigating further to establish whether they truly have a role as a medical prophylaxis for post-TIPS HE. As most monotherapies investigated by the studies included in our review did not demonstrate efficacy, it would also be interesting to see if there are other unstudied pharmacotherapy that could play a prophylactic role for post-TIPS HE. One notable ongoing study is the hepatic encephalopathy prevention with polydextrose after TIPS (POEME) pilot study, which will investigate the role of prophylactic treatment with polydextrose, a nondigestible oligosaccharide often used as a prebiotic.As such, we hope that we will be able to make stronger recommendations in the future once the available data becomes more robust. The ongoing The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial will provide valuable data as it is a multi-center RCT that will have a total sample size is 238 patients.Our systematic review examined 5 studies that reported on the use of various medical pharmacotherapy for prophylaxis of post-TIPS HE. A meta-analysis was done for the 3 studies that examined rifaximin monotherapy. Narrative review of included studies did not find prophylaxis with any monotherapy  to be associated with reduction in HE occurrence. Our meta-analysis did not find a significance difference when using rifaximin monotherapy. However, only 3 studies were eligible to be included in the review. Further research would still be worthwhile to increase sample size. As well, a combination of rifaximin and lactulose could potentially be associated with lower HE occurrence based on 1 study by Seifert et al, making it another potential area of investigation. While the limitations in available data hinders any strong recommendations based on the results of this review, our review summarizes the extent of current research on this topic to highlight the current gaps in knowledge and identify medical therapies worth further investigations.Conceptualization: Aileen Liang, Sukhman Brar, Majed Almaghrabi, Anouar Teriaky.Data curation: Aileen Liang, Sukhman Brar.Formal analysis: Aileen Liang, Sukhman Brar.Investigation: Aileen Liang, Sukhman Brar, Majed Almaghrabi, Anouar Teriaky.Methodology: Aileen Liang, Sukhman Brar, Majed Almaghrabi, Anouar Teriaky.Project administration: Aileen Liang, Sukhman Brar, Majed Almaghrabi, Anouar Teriaky.Resources: Aileen Liang, Sukhman Brar.Software: Aileen Liang, Sukhman Brar.Supervision: Majed Almaghrabi, Anouar Teriaky.Validation: Aileen Liang, Sukhman Brar.Visualization: Aileen Liang, Sukhman Brar.Writing – original draft: Aileen Liang, Sukhman Brar.Writing – review & editing: Aileen Liang, Sukhman Brar, Majed Almaghrabi, Mohammad Qasim Khan, Karim Qumosani, Anouar Teriaky.


COVID-19 patients can report ‘brain fog’ and may exhibit cognitive symptoms for months after recovery (Cognitive COVID). However, evidence on whether and the extent to which SARS-CoV-2 infection impacts cognition irrespective of COVID-19 course and severity is limited to clinical samples and mainly comes from prognostic studies. We aimed to explore the association between serologically confirmed SARS-CoV-2 infection and cognitive functioning in community-based and institutionalized older adults, irrespective of COVID-19 symptoms.We conducted a case-control study nested into two cohorts in Southern Switzerland. Eligible subjects were Italian speaking older adults, without a previous diagnosis of dementia, who underwent serological testing for anti-SARS-CoV-2 antibodies between November 2020 and July 2021. We manually selected age-, sex- and education-matched cases , with seronegative controls, and we conducted in-person neuropsychological assessments using validated, highly sensitive cognitive tests.We completed 38 neuropsychological assessments in a mostly female sample of older adults . 17 were community dwelling individuals while 21 lived in a nursing home. As expected, socio-demographic characteristics of age, gender and educational level were similarly distributed between cases (n = 14) and controls (n = 24). In linear regression models, cases had significantly lower scores in cognitive tasks of memory , attention  and executive functions . We found no significant difference in tests of language and spatial-temporal orientation .SARS-CoV-2 infection was associated with cognitive impairment in memory, attention, and executive functions in older adults. Our findings are consistent with mechanistic evidence of the neurotropism of the virus and provide empirical support for the “Cognitive COVID” construct also in non-clinical samples. With nearly 800 million COVID-19 cases (in April 2023), and many more infections worldwide, the clinical and public health implications of Cognitive COVID due to SARS-CoV-2 infection may be massive and warrant further epidemiological investigations. •Cognitive assessment in non-hospitalized COVID-19 cases and seronegative controls.•SARS-CoV-2 seropositivity in community-dwelling and nursing home older adults.•Poor memory, attention, and executive functions in seropositive SARS-CoV-2 cases.•SARS-CoV-2 infection is associated with poor cognition irrespective of symptoms. AlthougCognitive COVID is important but difficult to investigate both from a clinical and public health perspective. As said, current evidence on Cognitive COVID remains limited, and it is mainly based on data collected in hospitalized patients in the post-acute phase of the infection , despiteOur aim was to study the association of SARS-CoV-2 infection with cognitive sequelae, overcoming the above listed limitations and reducing proneness to biases of previous studies. We conducted a case-control study at the community level and in a nursing home for older adults. We hypothesized that there is an association between serologically confirmed infections and cognitive impairment, irrespective of COVID-19 symptoms and severity. In order to provide empirical evidence to better define the Cognitive COVID construct, we also sought to describe the cognitive profile of people over the age of 65 previously affected by COVID-19.22.1We conducted a nested case-control study within the Corona Immunitas Ticino and Cov-risk nursing homes cohort studies in Southern, Italian-speaking Switzerland . Both studies have been previously described  and entaBetween July 2021 and January 2022, we drew cases  and manually matched them with controls  and conducted in depth, in-person neuropsychological assessments. Interviews lasted 45 min on average and were all conducted by a purposely trained junior psychologist (GR).The study was approved by the Ticino Cantonal Ethics Committee  and found to comply with the principles of research involving human people.2.2Participants were Italian speaking older adults (≥65 years) without a previous diagnosis of dementia, who underwent serological testing between November 2020 and July 2021.Simple Random Sampling technique. We manually matched seronegative controls with cases based on age, gender, and years of education, with a planned one-to-one control to case ratio. We included both community-dwelling older adults and residents living in a nursing home. The planned sample size was 35 participants, based on a priori power analysis implemented in Statulator (2014) (http://statulator.com/SampleSize/ss2M.html) using the following parameters: probability level (α) 0.05, and statistical power (1 - β) 0.80. We sampled and contacted 50 people, and 38 agreed to take part in the study.We selected cases (seropositives) in the source populations using a All participants  provided handwritten signing of the informed consent document before the interviews.2.3We collected socio-demographic characteristics , and information related to COVID-19 plausible symptoms  and severity of disease with online self-reported questionnaires. Healthcare staff could assist older adults in data collection based on need. For residents living in a nursing home a staff member completed the questionnaires on their behalf. For the cognitive assessment schedule, we assembled a battery of cognitive tests related to the Cognitive COVID construct . We usedTo minimize bias, the interviewer was blinded by design about grouping of participants .2.4We used IBM® SPSS Statistics version 25  for all statistical analysis and set statistical significance at 0.05.T-test for independent samples, or the Mann–Whitney non-parametric test, based on departure from normality.We computed summary statistics for normally distributed continuous variables as means ± standard deviation (SD), or medians with min/max ranges in case of a skewed distribution and conducted between groups comparisons using Student's Next, we ran separate linear regressions models to investigate the relationships between seropositivity (independent variable) and cognitive test performance (continuously distributed dependent variables of cognitive tests).TMT and Stroop test outcomes were considered as binary variables , based on their respective normative grids . For bin2.5bona fide uses.Anonymized data, including raw and analyzed data, and materials not published within this article will be made available by request from any qualified investigator for 33.1A total of 38 older adults took part in the study between July 2021 and January 2022; 21 were nursing homes’ residents, 17 lived in the community. Mean age was 83.13 (SD: ± 8.95), ranging between 68 and 99 years. Most of the study participants were women (86.8%). The characteristics of the actual sample cases (n = 14) and matched controls (n = 24) are summarized in 3.2We completed the full neuropsychological battery with all participants, except for one of them who could not complete the Trail Making Test Part A, and 10 participants who could not finish the Trail Making Test Part B. Because participants were not able to perform the tests, we coded missing values as impaired scores. In linear regression models, cases obtained considerably lower scores in attention , executive functions , and memory tasks . We found no significant differences between cases and controls in language and orientation tasks. Detailed neuropsychological test battery results, adjusted by age and years of education, are reported as mean ± SD in Age did not significantly modify the association of seropositivity with cognitive functions, for all cognitive tests.4Our observations seem to confirm that SARS-CoV-2 infection may lead to long-term sequalae and affect cognition. The cognitive effects of SARS-CoV-2 are common even if it is still not clear how cognitive impairment evolves after recovery from infection. In this nested case-control study, we assessed the association between serologically confirmed SARS-CoV-2 infection and cognitive functions in an older adults' sample. The study aimed at exploring if and which cognitive domains were affected by the virus up to several months following the infection and irrespective of COVID-19 symptoms in both community-dwelling and nursing homes’ residents older adults. The neurotropism of SARS-CoV-2 provides a solid mechanistic presumption for our research hypotheses.In a mostly female sample of asymptomatic to moderate COVID-19 older adults’ cases and matched seronegative controls, we found that previously infected individuals exhibited cognitive impairment entailing fewer words remembered in memory tasks and more time required to complete attention and executive functions tasks. Lower cognitive performance in cases was up to 4-fold compared to what we observed in controls, independent from the age of participants. The present findings are consistent with previous demonstration of the neurotropism of SARS-CoV-2 , which cComparisons with other studies are not straightforward because of the methodological heterogeneity. After the first pandemic wave, literature was largely dominated by case reports and small case series conducted in COVID-19 hospitalized patients with moderate to severe symptoms . We focuEpidemiological research on Cognitive COVID is in its infancy, but inconsistent results are likely attributable to measurement. Most of previous studies assessed cognitive deficits following COVID-19 based on self-reporting of both infection and perceived cognitive functioning  or used Our study has some worth noting limitations. First, the small sample size of our study may have hindered our ability to detect all true virus-cognition associations. Even if we used a multi-stage approach to contact and attempt to recruit one control per case from the source population, response rate was not high enough to maintain the anticipated ratio and matching of cases and controls in the study sample. Based on the limited number of cases, we selected more controls per case ended up with an almost 1:2 ratio, in order to maximizing the statistical power of the study . This isSecond, baseline measures of the study participants' cognitive functioning were not available. Issues of directionality may exist that limit any causal speculations for the association between SARS-CoV-2 infection and cognitive deficits. Nevertheless, reverse causality, that is cognitive impairment leading to infection, seems unlikely in our sample because we excluded people with dementia by design. We acknowledge that whether those with poorer cognition were at greater risk of infection because of general poor health may be difficult to disentangle, and evidence is lacking on the association of poor health with adherence to infection preventive measures. Furthermore, although the age difference between cases and controls was not significant and tests were all age-standardized, it cannot be ruled out that age played a role in subtle differences in neuropsychological performance.Third, most of our cases were nursing home residents, reflecting greater spread and circulation of infection in long-term residential settings compared to communities . HoweverAgain, we did not have and could not adjust our statistical models for dysmetabolic measures  or comorbid conditions  that may be associated with poorer cognition and cognitive decline . This isWe found that non-hospitalized, SARS-CoV-2 positive older adults had worse cognitive performance compared to immunonaive counterparts, across a variety of cognitive domains, including memory, attention and executive functioning, and visuospatial processing speed. Collectively, our findings extend previous observations in hospitalized COVID-19 patients and relate the cognitive sequalae of the disease to SARS-CoV-2 infection irrespective of symptoms. This provides empirical support for the “Cognitive COVID” construct, and it is consistent with mechanistic evidence of the potentially detrimental neurotropism of SARS-CoV-2 . Our resResearch on Cognitive COVID is in its infancy. We need basic sciences and clinical studies to advance knowledge on mechanisms, etiology, and timing of the phenomenon. The role of medical, psychological, and social/environmental variables that may modulate the risk and expression of Cognitive COVID deserves further investigation. Moreover, longitudinal studies may combine serological testing and objective cognitive assessments with neuroimaging techniques to explore brain structural damage. On the other hand, epidemiological evidence is needed to estimate the prevalence of Cognitive COVID in previously infected individuals, and study potential risk and protective factors.5Patients with COVID-19 may experience cognitive difficulties (Cognitive COVID) as they recover from the disease. Existing evidence comes mainly from clinical studies. Our data describe an association between serologically confirmed SARS-CoV-2 infection and cognitive impairment, in memory, attention, and executive functions in older adults. It provides empirical knowledge on the Cognitive COVID construct in a non-clinical sample of older adults, supporting the relationship between poor cognition and infection, irrespective of the severity of symptoms. With nearly 800 million COVID-19 cases, Cognitive COVID societal impact may be massive. We need more longitudinal data on the distribution, frequency, and impact of the cognitive post-infection manifestations, as well as on their determinants and modulators to address epidemiological and mechanistic gaps. This knowledge can inform future studies, and surveillance strategies for Cognitive COVID, as well as help in clinical practice in terms of timely diagnosis and treatment options.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors have no declaration of competing interest.


Previous research indicated outcomes among refractory out-of-hospital cardiac arrest (OHCA) patients with initial shockable rhythm were different in Singapore and Osaka, Japan, possibly due to the differences in access to extracorporeal cardiopulmonary resuscitation. However, this previous study had a risk of selection bias. To address this concern, this study aimed to evaluate the outcomes between Singapore and Osaka for OHCA patients with initial shockable rhythm using only population-based databases.n = 3088) and applied to the PAROS-SG data (n = 2905). We calculated the observed-expected ratio (OE ratio) for good neurological outcomes observed in Singapore and the expected derived from the data in Osaka by dividing subgroups with or without prehospital ROSC.This was a secondary analysis of two OHCA population-based databases in Osaka and Singapore, including adult OHCA patients with initial shockable rhythm. A machine-learning-based prediction model was derived from the Osaka data  and 57% (440/773), and among patients without prehospital ROSC were 10% (196/1963) and 2.8% . After adjusting patient characteristics, the outcome in Singapore was slightly better than expected from Osaka in patients with ROSC , conversely, it was worse than expected in patients without prehospital ROSC .This study showed the outcomes of OHCA patients without prehospital ROSC in Singapore were worse than expected derived from Osaka data even using population-based databases.(249/250 words).The online version contains supplementary material available at 10.1186/s13054-023-04771-5. Extracorporeal cardiopulmonary resuscitation (ECPR), which utilizes extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation, is an advanced procedure designed for OHCA patients who are unresponsive to standard resuscitation, especially those presenting with initial shockable rhythms like ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) –4. Our pThis was a secondary analysis of two population-based OHCA databases in Singapore and Osaka, Japan, which were the All-Japan Utstein Registry and the Singapore Pan-Asian Resuscitation Outcomes Study (SG-PAROS) , 6. Deta, patient characteristics, pre-hospital information, in-hospital procedures, and outcomes were described as continuous variables with median and interquartile range (IQR), while categorical variables were reported as numbers and percentages. In the main analysis, similar to the previous study, . Of the SG-PAROS database, 2905 patients with initial shockable rhythm were included in the analysis. The study flowchart is described in the Additional file For the Osaka Utstein Registry database, 3414 OHCA patients with an initial shockable rhythm were included in the analysis ) in patients without prehospital ROSC) between 2010 and 2019. The incremental number of one-month survival cases had a similar trend to neurological outcomes . The incremental one-month good neurological outcome in each year is described in the Additional file This population-based observational study showed that the outcomes of OHCA patients without prehospital ROSC in Singapore were worse than expected derived from Osaka data even using population-based databases. These results were consistent with our previous research, mitigating previous selection bias concerns.Similar to the previous study, we speculated that the outcome difference among patients without ROSC between Singapore and Osaka was related to the different availability of ECPR. First, outcomes were similar among patients with ROSC after adjusting the patients’ characteristics, which suggests the quality of post-resuscitation care after ROSC was comparable between Singapore and Osaka. In contrast, for patients without prehospital ROSC, ECMO was rarely performed 0.5%, 11/2,132) and hospital admission was considerably low  in Singapore while the percentage of ECPR cases was 30–60% and hospital admission was reported around 60–80% in the tertiary care hospitals in Osaka. ,132 and  In additSeveral limitations should be acknowledged in this study, similar to the previous study. It didn't directly examine the link between ECPR policies and outcomes but instead highlighted potential differences in in-hospital care before ROSC between Osaka and Singapore. Outcomes might also be influenced by unmeasured factors like past medical history, frailty, and quality of resuscitation. A lack of detailed data limited our comparison of resuscitation specifics. Moreover, there are risks associated with the prediction model, such as overfitting and regularization bias. , 13.This study using two population-based databases indicated that the outcomes of OHCA patients without prehospital ROSC in Singapore were worse than expected compared to Osaka. The results are consistent with our previous research. We speculate that the outcome difference among patients without ROSC between Singapore and Osaka was due to different availability of ECPR.(1455/1500 words).Additional file 1. Supplementary material.


Research on device-based physical activity in the oldest-old adults is scarce. We examined accelerometer-measured physical activity and sedentary behavior in nonagenarians. We also investigated how the accelerometer characteristics associate with nonagenarians’ self-reported physical activity, anthropometric, sociodemographic, health and cognitive characteristics.Nonagenarians from a population-based cohort study  used accelerometers during the waking hours for seven days. They also participated in a health survey and cognitive telephone interview. The Wald test and Pearson and polyserial correlations were used to analyze the data.The participants’ average day consisted of 2931 steps, 11 minutes of moderate-to-vigorous physical activity and 13.6 hours of sedentary time. Physical activity bouts less than 3 minutes per day and sedentary time bouts of 20–60 minutes per day were the most common. No sex differences were found. Many accelerometer-measured and self-reported physical activity characteristics correlated positively . The low levels of many accelerometer-measured physical activity characteristics associated with low education , dizziness  and fear of falling . Fear of falling was also associated with accelerometer-measured sedentary behavior characteristics (correlations -0.42 or ≥0.43).Nonagenarians were mostly sedentary and low in physical activity, but individual variability existed. Accelerometer-measured and self-reported physical activity had a good consistency. Education, dizziness and fear of falling were consistently related to accelerometer-measured characteristics in nonagenarians. Nonagenarians are the fastest growing population segment in many countries . Along wThe state-of-the-art supports the use of devices in physical activity studies because devices eliminate many of the limitations associated with self-reports . Most deThe results of number of daily steps in nonagenarians have been varying as well. The Swedish study reported 4818 steps per day for nonagenarian men and women together , while tGiven only few studies, some of which had highly selected samples, there is the need for more research that focuses on device-based physical activity in nonagenarians. The further need is justified by the fact that only one previous study has focused on the association between device-based and self-reported physical activity, indicating no significant association between these factors . FinallyIn the present study, we have taken many of the previous issues into account and provide novel information. By using a population-based sample, we investigated nonagenarians’ accelerometer-measured physical activity and sedentary behavior and their correspondence with nonagenarians’ own ratings of their physical activity behavior. We also examined anthropometric, sociodemographic, health and cognitive correlates of accelerometer-measured physical activity and sedentary behavior. We expected substantial individual differences but no sex differences in accelerometer-measured physical activity and sedentary behavior characteristics in nonagenarians. Additionally, we hypothesized that the accelerometer-measured and self-reported physical activity characteristics correlate at least moderately.Participants were from the ongoing NONAGINTA–Memory and Health in 90-year-olds–study that is aimed to investigate 90-year-old twins from the population-based older Finnish Twin Cohort study , 11. HowThe questionnaire-based assessment of physical activity behavior was based on the structured and validated questions, which were also used in the previous surveys of the older Finnish Twin Cohort study , 13. TheThe self-reported highest educational degree achieved was the measure of education. The level of education was classified into eight groups: 1) less than compulsory education, 2) compulsory education (six years in our participants), 3) compulsory education and at least one-year vocational training, 4) lower secondary education, 5) lower secondary education and at least one-year vocational training (or upper secondary studies), 6) upper secondary education, 7) upper secondary education and at least one-year vocational training (or tertiary education studies), and 8) tertiary education (university or polytechnic college).2). The participants also rated how they perceived their health in general and reported whether they ever feel dizzy or off balance. The given response options for the subjective health status were: 1) very poor, 2) poor, 3) fair, and 4) good. For dizziness and poor balance, the response options were: 1) never or hardly ever, 2) sometimes, causing some harm, and 3) often, causing great harm. Fear of falling was assessed with the question “Are you afraid of falling?” with the response options of 1) never, 2) occasionally, 3) often, and 4) constantly.The height and weight of the participants were self-reported. Based on the self-reports, body mass index (BMI) was calculated as the ratio between weight and height in meters squared (kg/mThe Center for Epidemiologic Studies–Depression (CES-D) scale was used to assess depressive symptoms . The CESIn the NONAGINTA study, two validated telephone interviews were used: 1) telephone assessment of dementia (TELE) –22 and 2Cognitive status was based on a validated Finnish TELE (score range 0–20 with 2 cut-off points): cognitively impaired (scores <16) and cognitively healthy (scores >17.5) . We alsoThe participants used a hip-worn tri-axial accelerometer  to monitor their daily physical activity and sedentary behavior . The accData from the accelerometers were recorded at a sampling frequency of 100 Hz. The analyses of raw acceleration data are based on algorithms that employ the mean amplitude deviation (MAD) of the raw acceleration signal and the angle for posture estimation (APE) of the body . These aWe pre-specified to report our nonagenarians’ daily step count and time spent in physical activity and sedentary behavior, including time spent in moderate-to-vigorous physical activity. Compared to younger adults, the impulse required to detect a step was set at a lower level  among these nonagenarian participants because of the common finding of a shortened step length in older adults . PhysicaBased on a consensus of the time criterion for adequate accelerometer data collection , we follWe reported questionnaire- and interview-based physical activity, anthropometric, sociodemographic, health, and cognitive characteristics as well as accelerometer-measured physical activity and sedentary behavior characteristics for men and women. Next, we used the Wald test to assess whether the characteristics differed significantly between sexes. The Wald test was also used to investigate whether selection bias occurred in accelerometer data collection. Regarding selection bias, we assessed whether questionnaire-based characteristics and cognitive functioning measured by telephone interview differed significantly between those who did and did not participate in the accelerometer data collection. Because there were four complete twin pairs in our dataset, we controlled for family structure by including the pair number as a clustering variable. Thus, standard errors and p-values were adjusted for the non-independency of twin data.To see whether self-reported physical activity, anthropometric, sociodemographic, health, and cognitive characteristics were associated with accelerometer-measured physical activity and sedentary behavior characteristics, we calculated correlations between these factors. We used Pearson correlation between continuous variables , whereas polyserial correlations were used to estimate the associations between ordinal and continuous variables . In all analyses, Stata 16.1 software  was used, and the threshold for the statistically significant p-value was set at p<0.05.The Ethics Committee of the Hospital District of Helsinki and Uusimaa approved the NONAGINTA study protocol on May 8, 2020  and December 16, 2020 (accelerometer data collection). All study methods were carried out in accordance with the approved guidelines and the Helsinki Declaration. All participants provided written informed consents for the main study  and for accelerometer measurements.2versus 24.4 kg/m2, p = 0.21). Most of the participants had a compulsory education only and they reported their health to be at least fair and having no dizziness or constant fear of falling. Men and women did not differ in immediate recall (men mean (M) = 12.2, women M = 12.6, p = 0.71), delayed recall , or semantic fluency performance . Based on the TELE, 6 of 37 participants (16%) were cognitively impaired and 14 of 37 participants (38%) had mild impairment in cognition. Altogether, 4 of 38 participants (11%) reported a clinically significant number of depressive symptoms. As shown in versus 1.5 MET hours/day, p = 0.10). The majority of participants reported that the intensity of their physical activity sessions was as tiring as walking .All participants wore the accelerometer for at least four days and for at least 10 hours a day. The mean time the participants carried the devices a day was 16:23:00 h:min:sec (men 15:54:44 and women 16:51:17). On average, the participants took 2931 steps a day during the measurement week: men 2924 (range 518–9878) and women 2936 (range 528–11190) steps. The average time of total physical activity was 111.4 minutes (men 116.0 and women 106.9). Out of this total physical activity time, 100.7 minutes (men 104.3 and women 97.1) were spent in light and 10.7 minutes (men 11.6 and women 9.8) in moderate-to-vigorous physical activity in a day. Physical activity bouts shorter than 3 minutes were the most often recorded amount of physical activity . The meaWe found that self-reported physical activity characteristics, except the intensity of physical activity, correlated significantly with the accelerometer-measured number of steps, moderate-to-vigorous physical activity and bouts of physical activity lasting more than 10 minutes . The parOur next analyses concerned the associations of accelerometer-measured physical activity and sedentary behavior characteristics with self-reported anthropometric, sociodemographic, health, and cognitive characteristics . The resThose who participated in the accelerometer data collection (N = 38) reported higher education , higher health status , felt significantly less dizzy or off balance , and had less fear of falling  than those who participated in the health survey but not in the accelerometer data collection (N = 117). Those wearing accelerometers also recalled more words immediately , had better semantic fluency , were more likely to be cognitively healthy  and had less clinically significant levels of depressive symptoms  than those who did not to participate in the accelerometer data collection. They also reported higher overall amount, duration, and intensity of physical activity  compared to those not wearing accelerometers.This study was set to examine accelerometer-measured physical activity and sedentary behavior in Finnish nonagenarians derived from a population-based sample. We investigated how the accelerometer characteristics associate with nonagenarians’ self-reported physical activity, anthropometric, sociodemographic, health, and cognitive characteristics. On an average day, the participants took 2931 steps and had 111 minutes of physical activity, of which nearly 11 minutes were moderate-to-vigorous physical activity. The average daily sedentary time was 13 and half hours. As expected, we did not observe differences in accelerometer-measured characteristics between sexes. However, in line with our hypothesis, substantial individual differences existed in all accelerometer-measured characteristics both in men and women.In general, nonagenarians were highly sedentary and their physical activity level was low in our study. The most common physical activity and sedentary behavior characteristics recorded during the measurement week were the very short bouts of physical activity and medium-length bouts of sedentary time. Moreover, our results indicated a significant correlation between most accelerometer and self-reported physical activity items. Highly educated nonagenarians were the most active based on the time of total and light physical activity but also based on the number of steps and short bouts of physical activity. High BMI and low subjective health indicated high overall sedentary time in nonagenarians. Not surprisingly, strong feelings of dizziness and fear of falling were clearly shown to be associated with a decreased level of physical activity. Moreover, those nonagenarians who had the greatest fear of falling were overall more sedentary and spent more time in prolonged bouts of sedentary behavior.versus 2931), whereas Swedish nonagenarians [versus 2931). Some of the discrepancies between these results could be attributed to differences in health status and sample characteristics but also due to devices and tracking times used. Moreover, it seems that hip- and thigh-worn devices are more consistent in their step number results  in the present study, the average number of steps taken by nonagenarians in a day i.e., 2931) was approximately half of the minimal number of steps a day found to be beneficial to health in adults  . Moreove1 was appal. 2020  numbers al. 2020 .Our results indicating no sex differences in any of the accelerometer-measured characteristics are in line with previous studies that found no differences in daily step count , 6, 7 orThe most interesting finding to emerge from our study was that nonagenarians’ own perception of their average physical activity behavior corresponds with a 7-day accelerometer measurement, except for the intensity of physical activity. According to our knowledge, there was only one previous study on this topic before our study , but thaOur results indicated that nonagenarians’ subjective impressions of the average intensity of their physical activity sessions do not correspond with the intensity of their accelerometer-measured physical activity. Most of our nonagenarians reported that the average intensity of their physical activity sessions was as tiring as walking. The impression the participants have of their physical activity intensity can partly be due to the fact that walking is the most common form of physical activity among older adults . We usedOur study further showed that those with a higher education had higher physical activity levels, partly supporting previous research showing that physical activity has a positive relationship with cognitive status  and healversus the participants’ self-reports on their average physical activity behavior). Questionnaire-based physical activity behavior and the telephone interview of cognitive status used in this study are based on validated measures [A major limitation of the current study was a limited sample size, although nonagenarian accelerometer data combined with survey and interview data, such as ours, is still unique. Our sample size was small but consistent with the sample sizes of previous studies in the field –8. Nevermeasures , 13, 21.measures –30.The dataset we used was drawn from a population-based study cohort with equal sex representation and moderate response rates in the mail survey and telephone interview, which contributes to fewer selection biases. Even though we did not automatically exclude those with chronic diseases, cognitive disorders, reduced mobility or a need for walking aids, some selection bias existed with regards to accelerometer data collection. Thus, our accelerometer data should not be regarded as a representative sample of all nonagenarians. On the other hand, the consistency of our findings with the previous population-based accelerometer study of Finnish participants aged 70–85 years  suggestsA great seasonal variation in Finland with very different circumstances for outdoor activities in summer and winter is also a factor that should be considered because it strongly affects the population’s physical activity behavior. Our accelerometer data collection was conducted in the spring, summer, and fall seasons. In winter, snow and ice on the walking paths may prevent some of the nonagenarians from moving outdoors. Given that walking is the most preferred type of physical activity among older adults , the lacTo conclude, our study provided novel information on device-based physical activity and sedentary behavior and their correlates in nonagenarians. A clinically important finding was that most of the accelerometer-measured physical activity characteristics correlated significantly with self-reported physical activity, indicating a good usability for many self-reported items in everyday settings. Our findings further suggested no sex differences in accelerometer-measured characteristics in nonagenarians, indicating that sexes behave similarly in the last decades of life. The evidence from this study indicated that there is a beneficial effect of higher education on physical activity, and that the high level of sedentary time seems to be associated with poor subjective health and high BMI still in late old age. The current data also highlight the relevance of feelings of dizziness and fear of falling as contributing factors in nonagenarian’s physical activity and sedentary behavior. However, given our limited sample size, caution is recommended when interpreting our results. Larger studies, including longitudinal aspects as well, can help in understanding the antecedents and underpinnings of both physical and mental health in this fast-growing understudied population segment.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


There is limited evidence regarding implementing organisational improvements in the cultural responsiveness of non-Aboriginal services. Using a pragmatic implementation process to promote organisational change around cultural responsiveness, we aimed to (i) identify its impact on the cultural responsiveness of participating services; (ii) identify areas with the most improvement; and (iii) present a program logic to guide cultural responsiveness. A best-evidence guideline for culturally responsive service delivery in non-Aboriginal Alcohol and other Drug (AoD) treatment services was co-designed. Services were grouped geographically and randomised to start dates using a stepped wedge design, then baseline audits were completed . After receiving feedback, the services attended guideline implementation workshops and selected three key action areas; they then completed follow-up audits. A two-sample Wilcoxon rank-sum (Mann–Whitney) test was used to analyse differences between baseline and follow-up audits on three key action areas and all other action areas. Improvements occurred across guideline themes, with significant increases between median baseline and follow-up audit scores on three key action areas  = 1.0–3.0) and all other action areas . All services completing the implementation process had increased audit scores, reflecting improved cultural responsiveness. The implementation process appeared to be feasible for improving culturally responsive practice in AoD services and may be applicable elsewhere. There are substantial inequalities in health status and health care access between Aboriginal and Torres Strait Islander people  and non-Aboriginal people in Australia , includiCultural responsiveness initiatives have been shown to improve healthcare worker cultural knowledge, awareness and sensitivity ,10,11,12While many non-Aboriginal clinicians are individually committed to practising in a culturally responsive way, improving cultural responsiveness needs to be a whole-of-service activity that involves multiple strategies across all levels of the workforce and organisational policy, management and practices to be effective ,16,17,18The core components, or themes, of the guideline were then operationalised into flexible activities that could be tailored to suit each service ,28,29, aThe project was co-designed and implemented using a community-based participatory research approach ,31 that n = 3), day programmes (n = 2), centre-based counselling and support (n = 3), outreach counselling and support (n = 4), groupwork and phone support (n = 1) and group or individual youth services (n = 2). Twelve services completed all project activities  were identified by the PHNs as being potentially willing to participate, with fifteen providing formal consent to participate (88%) (hereafter referred to as participating services). Participating services included a variety of AoD service types, including residential rehabilitation  engage stakeholders, develop co-design structures and secure approvals from ethics and participating sites; (ii) co-design the implementation process and best-evidence guideline; (iii) implement the guideline and monitor uptake. Phase 1 and the process evaluation outcomes are described in detail elsewhere  and the https://www.nada.org.au/resources/alcohol-and-other-drugs-treatment-guidelines-for-working-with-aboriginal-and-torres-strait-islander-people-in-a-non-aboriginal-setting/ (accessed on 1 June 2022)). Briefly, the guideline co-design process was facilitated by an Aboriginal project team member (RW) and overseen by the Aboriginal Project Advisory Group (27). The guideline identifies six themes: (1) Creating a welcoming environment, (2) Service delivery, (3) Engagement with Aboriginal organisations and workers, (4) Voice of the community, (5) Capable staff, and (6) Organisation’s responsibilities.A best-evidence guideline that describes key elements of culturally responsive service delivery in non-Aboriginal AoD treatment services was co-designed at the beginning of the project and this process is described fully in the guideline document (20) (See n = 6). Each cluster of services was randomised to an implementation starting date between June and October 2019, with approximately one month between clusters, as shown in Services were clustered based on PHN district/geographical region  in the setting where the service is delivered and took between 90 min to two hours to complete. Auditors were independent of the service being audited and at least one auditor at each audit was Aboriginal. Individualised written feedback from the audit findings was provided to each participating service, listing all guideline action areas with a descriptive assessment for each area reflecting the level of evidence observed during the audit  and recommendations for areas where potential improvements could be made. Implementation workshops were held with key staff from services (CEOs/managers and direct service delivery staff) to explain the guideline, review the audit feedback, set goals for improvement and develop a detailed action plan tailored to their service . Workshops were facilitated by JA and RW. Staff identified and prioritised specific activities that they would implement from the 21 action areas and were encouraged to select three key action areas for their service to progress over the next three months. For example, activities that operationalise guideline Theme 1: Creating a welcoming environment, might include processes to ensure that all clients are welcomed respectfully at first contact with the service, providing tea/coffee/water in the waiting room, accommodating children or other family members in the service, or displaying local Aboriginal artwork. These self-designed activities provide flexibility in how individual services operationalised and implemented the core components, enabling the practice change activities to be tailored to the needs and resources of individual services and the communities they serve ,4,5. Follow-up audits of services were conducted after three months to assess change in culturally responsive practices in the 21 action areas, following the same procedure as for the baseline audits. Where possible, the same service staff attended the follow-up audit. Services were provided with a second individualised feedback report, including discussion of any changes that had occurred.Change in audit score from baseline to follow-up audit on the three key action areas identified by staff at the implementation workshops (possible score 0–9).Change in audit score from baseline to follow-up audit in all other action areas from the guideline (other than the three key action areas selected by each service (possible score 0–54).To privilege Aboriginal values and views throughout analysis and reporting, we used the guideline themes that were developed by the Aboriginal Advisory Group to assess culturally responsive practices. The study aimed to identify the impact of the project on the cultural responsiveness of services using the following outcomes:The audit responses provided by staff were recorded into the audit tool. After each audit was completed, ratings of 0–3 were allocated to each of the 21 audit criteria, according to pre-specified rating rules, by one of the researchers conducting the audit (RW). A second researcher (SF) then independently reviewed the audit tool and rated the 21 criteria. The two sets of ratings were compared and any disagreement around ratings were resolved by discussion, until a consensus was reached. A two-sample Wilcoxon rank-sum (Mann–Whitney) test was used to analyse the difference in audit scores between baseline and follow-up audits, on the three key action areas (outcome 1) and all other action areas (outcome 2). All analyses were conducted using Stata 16 .The extent of change across the six guideline themes was identified by summing item ratings within each theme and calculating the rates of change for each theme. The frequency with which each individual action area was selected by service staff , and whether improvements were subsequently observed in those action areas, were descriptively explored.We used a program logic structure developed in previous work ,7 to buiTwelve of the fifteen participating services completed all service-specific project components. Some delays in completing the three-month follow-up audits occurred, with an average time between audits of 18 weeks (range 14–28 weeks) See . The lonn = 12). Outcomes are reported for services that completed baseline and follow-up audits (p < 0.005)  .p < 0.05) . The median follow-up scores were statistically significantly higher than the median baseline scores  . Overall, there were improvements in scores across all six themes of the guideline and all showed similar rates of improvement; Theme 5: Capable staff (+22%), Theme 3: Voice of the community (+18%), Theme 6: Organisation’s responsibilities (+18%), Theme 1: Creating a welcoming environment (+17%), Theme 2: Service delivery (+16%) and Theme 4: Engagement with Aboriginal organisations and workers (+16%). n = 6 services); 3Ai: Aboriginal community engagement to develop relationships (n = 4); 3Aiii: Local history and protocols are reflected in practice and/or policy (n = 5); and 4A: Developing connections with Aboriginal organisations and workers (n = 5) (see the guidelines in n = 8 services) and 2C: Staff are culturally responsive in therapeutic practice (n = 7)), Theme 3 ) and Theme 6 , 6Aiii: Service induction includes materials about working with Aboriginal people and materials are developed/reviewed by a local Aboriginal person (n = 8)).Service staff chose a wide variety of action areas from the guideline to prioritise; 16 of the 21 areas were selected at least once. Those most frequently selected as key action areas were: 1B: The physical environment is welcoming to Aboriginal people  developed a program logic that is directly tied to guidelines, shown in The current study used a community-based, participatory research approach to develop a best-evidence, service-level practice change process, supported by a program-logic framework previously developed by the authors ,29. The An important strength of the project is that the co-design and implementation was led by an Aboriginal researcher and AoD worker, with extensive consultation with senior Aboriginal AoD clinicians , funders, researchers, as well as links with workers (via the peak organisation for the NGO AoD sector) ,21,24. FIn addition to measuring change in audit scores , future studies should also aim to examine the impact of these changes on service delivery or utilisation outcomes, potentially through using routinely collected administrative data. Previous reviews of cultural responsiveness programs have highlighted the need for valid indicators of change and objective outcome measures ,12, and The project used a methodologically strong assessment process involving a standardised audit tool that reflected the best-evidence guidelines and a double-scoring system to enhance inter-rater reliability . The posParticipating services were self-selected, and it is possible that they may have had a pre-existing active interest in and/or resources to dedicate to improving their cultural responsiveness. The significant improvements in audit scores achieved by these services may not occur so quickly in other services. However, the participating services do represent a broad geographic and demographic area of NSW , as well as a variety of service delivery types. Service frontline and managerial staff rated the project as highly acceptable . A key nThe co-designed best-evidence guideline and pragmatic implementation process represents a feasible and acceptable method (27) for implementing service-wide improvements in cultural responsiveness and may be applicable to improving the cultural responsiveness of a wide variety of health and human services. The randomised stepped-wedge evaluation design, double-rated audit scoring, and standardised core intervention increased methodological rigour, while the flexibility with which individual services can operationalise and implement the guidelines allowed tailoring to available resources and needs.