We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC).We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group.Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents , non-Latino White  and non-Latino Other residents . In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents.This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations. In 2021 overdose deaths in New York City (NYC) were at their highest rate since reporting began in 2000, with fentanyl present in approximately 80% of those deaths .Naloxone, a highly effective opioid reverse agent, is available through pharmacies and community-based distribution by opioid overdose prevention programs (OOPPs). Inadequately stocked pharmacies and pharmacy deserts in racial minority and low-income communities, especially in metropolitan areas, have led to substantial racial/ethnic inequalities in pharmacy-based naloxone access –10. The In NYC, OOPPs are any program registered with New York State as a source of naloxone distribution and training, which include a range of community-based organizations, healthcare facilities, syringe service programs, and other organizations. Compared to OOPPs, pharmacies play a smaller role in naloxone distribution in NYC . In 2018n = 14), correctional health services (n = 8), shelters (n = 7), drug treatment programs (n = 50), healthcare facilities (n = 48), substance use-related community-based organizations (n = 7), drug treatment programs (n = 50), DOHMH (n = 5), multi-component priority programs (n = 14) and others (n = 17). Data were collected between April 1, 2018, and March 31, 2019. The quarterly counts of naloxone kits received by NYC residents from OOPPs were stratified by the naloxone recipients’ neighborhood of residence designated by United Hospital Fund (UHF) neighborhoods, racial/ethnic group  of the NYC Department of Health and Mental Hygiene (DOHMH). Individual-level naloxone recipient data was collected from 170 OOPPs using a standardized naloxone recipient form. The 170 OOPPs comprised syringe service programs , including the number of residents who identify as either non-Latino Black, non-Latino White, Latino or non-Latino Other, and the percentages of residents in poverty and residents with a Bachelor’s degree or higher in 2018 .Neighborhood-level characteristics were created by aggregating characteristics from ZIP codes to UHF neighborhoods. Incarceration rates for different neighborhoods, defined as the rate of current imprisonment among people who identified a specific neighborhood as their resident neighborhood at intake, were calculated using methodology from the Prison Policy Initiative .We conducted a multilevel negative binomial regression model nested by UHF neighborhoods to assess the difference in naloxone receipt rates across racial/ethnic categories. The outcome variable, quarterly naloxone receipt rate in a neighborhood, was defined as the number of naloxone kits received by individuals in each racial/ethnic group according to neighborhood and quarter, with racial/ethnic stratified population sizes defined as the offset. The independent variable of interest was categorical, representing the four mutually exclusive racial/ethnic groups noted above. Other covariates included in the multivariate models were neighborhood-level annual opioid-related overdose death rate, incarceration rate, percentage of residents in poverty, and the percentage of residents over 25 years old with a Bachelor’s degree or higher. We also conducted a sensitivity analysis where we replaced the opioid-related overdose death rate with the all-type overdose death rate in the model. Given the similarity in results, the latter results are not shown.Lastly, we used the Getis-Ord Gi* statistic for neighborhood-level geospatial analysis. Using the Gi* statistic and z-scores, we identified geospatial clustering of racial/ethnic-specific naloxone receipt rates. Hot spots were clusters of ≥ 2 adjacent UHF neighborhoods with significantly higher naloxone receipt rates than the expected rate. Cold spots were clusters of ≥ 2 adjacent UHF neighborhoods with statistically significantly lower naloxone receipt rates than the expected. We performed separate geospatial analyses for each racial/ethnic group to evaluate within-group variation in the distribution of naloxone receipt rate across neighborhoods in NYC. This analysis used R version 1.0.143, SAS version 9.4, and ArcGIS version 10. The Brown University School of Public Health and NYC DOHMH Institutional Review Boards approved and considered this study exempt.Across the 42 neighborhoods, 79,555 naloxone kits were distributed between April 2018 and March 2019. Of those kits, 28,034 were distributed to non-Latino Black residents, 27,343 to Latino residents, 15,898 to non-Latino White residents, and 8,280 to non-Latino Other residents. The median quarterly naloxone receipt rate for Black residents was 41.8 per 100,000, and for Latino residents was 22.0 per 100,000. White and Other residents had comparatively lower naloxone receipt rates across quarters of 13.6 and 13.3 per 100,000, respectively.In the bivariate multilevel regression models , we founIn the geospatial analysis , hot spoOur study found differences in naloxone receipt between and within racial/ethnic groups in NYC neighborhoods. Non-Latino Black and Latino residents had higher rates of naloxone receipt than non-Latino White residents. In the geospatial analysis, we identified neighborhoods where naloxone was distributed at higher and lower than expected rates within each racial/ethnic group. We found hot spots in each of the racial/ethnic group analyses; however, cold spots were found in some neighborhoods in the southern and southeastern areas of NYC for non-Latino Black and Latino residents only.Previous studies conducted in Philadelphia, Rhode Island, and Massachusetts have found similar results in which community-based naloxone was distributed at higher rates to neighborhoods with over 50% of residents identifying as Black , 19. HowWhen we conducted the race/ethnicity-specific geospatial analysis, we only found cold spots in the non-Latino Black and Latino analyses. Most cold spots were found in neighborhoods in Queens, which, compared to other NYC boroughs, has the highest concentration of foreign-born residents (47%) . Prior studies have found foreign-born Queens residents have low healthcare utilization compared to non-immigrant residents due to language barriers and inability to afford healthcare, limited to no access to public transportation and fears about documentation status –25. The To increase access, naloxone distribution by OOPPs should be expanded in these neighborhoods to the extent feasible and/or resources provided to expand naloxone access by other means that address distance and structural barriers. These activities should be implemented alongside additional efforts to educate foreign-born residents about the resources available when seeking social and healthcare services, reduce language and cultural barriers, and eliminate US Immigration and Customs Enforcement (ICE) enforcement in spaces where residents receive naloxone to minimize documentation status fears .Our study is not without limitations. Small event counts by neighborhood meant that we: a) were only able to include overall fatal overdose rates (as opposed to race/ethnicity-specific rates) at the neighborhood level as a covariate in our study, which may have led to under- or over-estimation of the neighborhood-level overdose burden within each of the racial/ethnic groups; b) implemented larger time periods (quarters) within a one year study period which may have masked temporal trends in naloxone receipt over time; and c) collapsed multiple racial/ethnic groups into one non-Latino Other category. The results indicating that those in the non-Latino Other group received less naloxone from OOPPs than other racial/ethnic groups suggest the importance of future work to better understand naloxone receipt barriers and facilitators for the different members of this group.Our study identified racial/ethnic differences in naloxone receipt in NYC. We found that non-Latino Black residents had a higher rate of naloxone receipt from OOPPs than non-Latino White residents. However, we also identified neighborhoods with within-group differences in naloxone receipt from OOPPs among non-Latino Black and Latino residents. The next steps in this line of inquiry are to identify opportunities for naloxone distribution approaches that could assess and then address reasons for geographic and population variation in naloxone receipt and the geographic and structural barriers contributing to this.


Mechanisms that explain behavior change within web-based lifestyle interventions are not well-studied. This secondary analysis explores whether the effects of the DUET web-based lifestyle intervention on diet, physical activity, and/or adiposity are mediated through changes in self-efficacy, social support, and perceived barriers . Data on mediators, diet quality, caloric intake, moderate-to-vigorous physical activity (MVPA), weight, and waist circumference (WC) were analyzed from 112 cancer survivors and their partners enrolled in the DUET intervention. Mediation analyses were performed using Mplus to execute regression analyses and determine associations. Mediation analyses supported an effect of the intervention on caloric intake , weight , and WC , interpreting these negative associations as intervention induced reductions in dietary barriers. Higher social support was significantly and positively associated with, but not a mediator for, improvements in self-reported and accelerometry-measured MVPA  and , respectively. Self-efficacy did not appear to mediate the intervention’s effects. Findings suggest that the effects of the DUET intervention on diet and adiposity stem from reducing perceived barriers to a healthful, low-calorie diet. More people are surviving cancer due to improvements in early cancer screening and advancements in reliable and effective treatments ,2. Hence2 is a significant predictor of cancer recurrence among breast and prostate cancer survivors [As with the prevalence of cancer survivorship, obesity rates in the U.S., as well as among cancer survivors, are also growing ,11. In 2urvivors ,13. Moreurvivors . Thus, turvivors ,16. Thesurvivors ,18. Over the past decade, many multi-behavioral interventions have been implemented among cancer survivors to improve diet and PA behaviors and target weight loss ,20,21,22For instance, the FRESH START trial, a personally-tailored mailed print diet and PA intervention conducted among 543 cancer survivors, was informed by the SCT and reported improvements in self-efficacy for diet as a key mediator for long-term increases in vegetable and fruit (V&F) consumption and decreases in fat intake at 2-year follow-up . AdditioThe interest of cancer survivors is shifting towards online programs to gain health information . This trTo date, very few studies have identified the SCT-mediating processes through which multi-behavior web-based interventions change health behavior among cancer survivors. Therefore, evaluating constructs that have been shown to be effective in improving diet and PA behaviors in previous, more traditionally delivered interventions is key to understanding behavior change using this newer technology. To address this gap, the current study explores whether the effects of the DUET web-based lifestyle intervention on diet, MVPA, and/or adiposity are mediated through SCT constructs . We hypothesize that the previously reported  improvemA secondary analysis was performed using baseline and 6-month follow-up data from the DUET intervention, a 2-arm, single-blinded, randomized controlled trial (RCT) in which 112 cancer survivors and their partners (56 dyads) were assigned to either a 6-month web-based diet and exercise, weight loss intervention or a wait-list control. The study was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board (IRB# 300003882) and registered with ClinicalTrials.gov (NCT04132219). All participants in the study provided written informed consent. Data collection started in October 2020 and ended in December 2021. The methods and primary outcomes of the DUET trial are published in detail elsewhere ,37. 2; (2) V&F intake < 2.5 cups/day; (3) MVPA < 150 min/week; and (4) regular Internet use and mobile phone ownership. Eligible cancer survivors were asked to identify a local partner who lived within a 10-minute driving distance and with whom they interacted at least biweekly; similar eligibility criteria were used to screen partners (exception: cancer diagnosis). Cancer survivors were ascertained through a combination of cancer registries, self-referral networks, and previously established lists of interested cancer survivors who were diagnosed and completed treatment for obesity-related cancers that have a 5-year survival rate of ≥70% . These individuals were telephoned and screened by the study staff. The eligibility criteria for the DUET study were as follows: (1) BMI > 25 kg/mhttps://duet4health.org, accessed on 4 September 2023) that offered a serialized program of 24 interactive educational e-learning sessions that were prompted by SMS text messages, as supported by the provision of the fitness tracker and digital scale. A key feature of the DUET website was the weekly self-guided e-learning sessions, which focused on providing instructions on making healthful dietary and PA choices, incremental goal setting, guidance for overcoming common barriers to a healthful diet and regular exercise, and practical strategies to guide long-term healthy behaviors. The website provided personalized progress reports to track diet and exercise behaviors and weight status. The website was tailored to both the survivor  and the partner and also encouraged helpful strategies on how to request and provide instrumental, informational, appraisal, and emotional support [® fitness tracker and Aria 2 digital scale provided guidance on tracking exercise activities and weight to enhance self-monitoring and internal motivation. Details on how the DUET intervention targeted self-efficacy, social support, and perceived barriers to diet and exercise and specified BCTs using the CALO-RE taxonomy [The DUET intervention utilized newer and personalized technologies, i.e., interactive website, Inspire Fitbit® fitness trackers, and Aria 2 digital scales  to improve diet and PA behaviors among cancer survivors and their partners. Details on the intervention content are described in a separate publication . In brie support . Additiotaxonomy  are deschttps://epi.grants.cancer.gov/asa24, accessed on 4 September 2023). Diet quality and average caloric intake were measured using the HEI-2015 [Two-day dietary recalls were conducted at baseline and 6-months via telephone by a registered dietitian on one weekday and one weekend day using the National Cancer Institute (NCI)-developed Automated Self-Administered 24-h (ASA24) dietary recall assessment web-based tool , using procedures supplied by the manufacturer and methods similar to those reported previously to obtain MVPA . For sub®  with both dyad members together. Remote assessment materials, instructions, and a video  were provided to participants in advance of the assessment. To measure weight, participants were asked to use a bathroom scale. A digital scale was provided with the assessment materials for participants who did not own a scale. During the Zoom call, a trained staff member advised participants to wear light clothing and remove their shoes during weighing. The scale was “zeroed-out” prior to weighing, and weight was measured twice and averaged for analysis. WC was measured twice on each dyad member using two sets of unmarked ribbons, as per the methodology proposed by Freudenheim and Darrow [Adiposity was assessed remotely by capturing data on both body weight and WC at baseline and 6 months. The study staff scheduled a remote assessment via Zoomd Darrow . The twod Darrow . Self-efficacy for diet was measured using a 20-item instrument  on 5 subscales  for high-calorie foods by Clark et al. . ConfideSocial support for diet was measured using a validated  4-item instrument on 3 subscales  by Sallis et al.  and asseThe frequency of encountering barriers to following a low-calorie, healthful diet was assessed using a 10-item questionnaire with anchors ranging from 1 = Never to 5 = Every day ,50. The To examine whether the hypothesized mediators had a mediation effect, the following three conditions, as depicted in All statistical analyses were performed using structural equation modeling software, Mplus  . Simple Sample characteristics and main outcomes of the DUET study were published previously . In brieStatistically significant differences from baseline to 6 months in diet and exercise perceived barriers were observed among dyads in the intervention arm. However, no statistically significant differences were observed between arms. While improvements in diet and exercise, social support, and self-efficacy were reported in the intervention compared to the wait-list control during the 6-month period, it did not achieve statistical significance. Lastly, 2 for each model, are shown in Overall, significant indirect effects support the effect of the DUET intervention on caloric intake, weight, and WC through reductions in perceived dietary barriers. However, significant mediating effects were not detected for diet quality or MVPA. Details on direct and total effects, as well as unstandardized parameter estimates, SE, 95% CI, and rLikewise, Scalable and effective diet and PA interventions that promote weight management among cancer survivors, as well as their family and friends, are needed . DUET isSurprisingly, self-efficacy—one of the more robust constructs of SCT—was not found to mediate DUET’s effect on diet, MVPA, and adiposity. These results differ remarkably from larger, traditionally delivered interventions among cancer survivors ,57. In tSocial support also was not found to mediate DUET’s effects on diet, MVPA, and adiposity. Our findings are similar to other website-based lifestyle interventions conducted among U.S. adults, such as the Guide-to-Health  and e-coAlthough self-efficacy and social support were not found to mediate DUET’s effect on diet, PA, and adiposity, our results found a significant mediating effect on caloric intake, weight, and WC through reductions in dietary barriers. These findings concur with the results of mediation analyses from many traditionally delivered lifestyle interventions . A systeIn contrast, our study results did not show that exercise barriers were a significant mediator of DUET’s effect on MVPA. Similar to dietary barriers, the DUET intervention focused on overcoming exercise-related barriers through weekly, self-paced website e-learning sessions that provided strategies to overcome common barriers , as well as barriers that are more specific and treatment-related . However, our study did not show evidence of mediation through a reduction in perceived barriers to exercise and, therefore, is similar to an app-based physical activity program conducted among adults, as well as other studies utilizing web-based platforms ,73,74. IThere are several strengths of this current study. DUET included a heterogeneous sample of cancer survivors and their partners in age (23–81 years) and broad reach across the U.S. . Additionally, DUET enrolled dyads with diverse family relationships and social networks  as compared to other dyadic interventions delivered among cancer survivors and their spouses or children ,75. To oThe use of web-based interventions is increasing in all populations, including cancer survivors. Online programs increase scalability and can maximize standardization and fidelity to health behavior theory to promote lifestyle change. However, there is a need to understand theoretical constructs that lead to behavior change. The present findings suggest that the effect of the DUET web-based intervention on diet and adiposity stems from reducing perceived barriers to a healthy, low-calorie diet. However, the intervention effects on self-efficacy and social support, along with our small sample size, likely contributed to null findings related to the lack of mediation by these constructs. Therefore, in applying these findings to the field of health education, particularly the growing field of eHealth, the ungirding of behavioral theory  and the systematic application of BCTs appears key in understanding and promoting behavior change. Health educators who deliver these interventions or those who procure eHealth programs for patient populations and other end-users need to familiarize themselves with the “active ingredients” that lead to desired outcomes, such as weight loss or improved health. In the case of DUET, we found that by reducing perceived barriers to a low-calorie diet, we may have been able to achieve the reductions in calorie intake and subsequent weight loss that were sought. Findings from this study should be replicated in future website-based interventions, implemented on a larger scale, to understand the “active ingredients” behind successful web-based lifestyle interventions.


Global evidence indicates that early onset of illicit substance use among adolescents and emerging adults is associated with negative mental-health related-outcomes that can persist into adulthood. However, the lack of quality regional data on adolescent illicit substance use and its determinants remains a common barrier to evidence-based policy-making and the development of school-based interventions in Africa. The purpose of our study was to estimate the prevalence and describe the correlates of cannabis and amphetamine use among school-going adolescents in eight sub-Saharan African countries (SSA) – Benin, Ghana, Liberia, Mauritius, Mozambique, Namibia, Seychelles, and Tanzania.We analysed 15,553 school-going adolescents that participated in the Global School-based Student Health Survey. A two-stage sampling approach was used to generate a nationally representative sample of school children (grades 7–12) in each of these countries. Students responded to a self-administered structured questionnaire that contained information on sociodemographic factors, family involvement factors, mental health factors, school environment factors and past-month cannabis and life-time amphetamine use.The overall prevalence estimates of past-month cannabis use and lifetime amphetamine use among school-going adolescents in the eight SSA countries was 4.39%  and 3.05%  respectively. In the multivariable logistic regression analysis, demographic characteristics , mental health factors (suicide ideation and attempt), lifestyle factors  and school level factors (truancy and bullying victimisation) showed strong associations with increased odds of both past-month cannabis use and lifetime amphetamine use. Social support at school was associated with increased odds for lifetime amphetamine, while parental monitoring decreases the odds for lifetime amphetamine use. It was also observed that parental tobacco use was associated with increased odds of both past-month cannabis use and lifetime amphetamine use.The relatively low overall prevalence estimates of past-month cannabis use and lifetime amphetamine use among school-going adolescents in not surprising. However, the identified risk and protective factors associated with cannabis and amphetamine use underscores the need for these eight countries in SSA to develop contextual and multi-sectoral intervention and school-based prevention programmes that could target school-going adolescents who may be at risk of misusing these illicit drugs.The online version contains supplementary material available at 10.1186/s12888-023-05283-w. The United Nations Office on Drugs and Crime (UNODC) has indicated that there is an increase of global prevalence of illicit drug use (including cannabis and amphetamine) for the past decade 2010–2022)  , 25; andSeychelles is categorised as a high-income country, with a high human development index [HDI rank of 72] , 25; andSD = 1.52).Participants in this study were school-going adolescents from eight sub-Saharan African countries. These countries included Benin 2016), Ghana (2012), Liberia (2017), Mauritius (2017), Mozambique (2015), Namibia (2013), Seychelles (2015), and Tanzania (2014). Data was obtained from a nationally representative sample of secondary school students who completed a computer-scannable questionnaire during their class period. A two-stage cluster sample design was used to produce data representative of all students in grades 7–12 within these participating countries. At the first stage, schools were selected with probability proportional to enrollment size. At the second stage, classes were randomly selected and all students in selected classes were eligible to participate. As stipulated by WHO-GSHS, participation in the study was voluntary, anonymous, and confidential as no identifying information was obtained . To get 6, Ghana This study had two outcome variables . Cannabis use was measured using a single item . Similarly, amphetamine use was measured using a single item . Further details  about all variables included in this study can be found in the Supplementary e-Table mental health factors ; lifestyle factors ; school-level factors ; interpersonal-level factors ; and family-level factors . The inclusion of these variables were based on previous publications based on the WHO-GSHS data , followed by Mauritius [5.74% ] and Liberia [5.65% ]. School going adolescents in Namibia reported the highest prevalence of amphetamine use [4.96% ], followed by Liberia [4.16% ] and Seychelles  and amphetamine  compared to males. The odds of past-month cannabis use were higher among adolescents aged 15 years , 16 years , and 17 years .The results from the multivariate logistic regression analysis of determinants of cannabis and amphetamine use among school-going adolescents are shown in Table mental health factors, participants who reported they have had suicidal ideation where less likely to report past-month cannabis use. However, adolescents who had attempted suicide had higher odds of both past-month cannabis use  and amphetamine use . For lifestyle factors, we found that school-going adolescents who reported they smoked cigarette were more likely to report cannabis use in the past month  and amphetamine . Additionally, adolescents who reported alcohol use in the past month had higher odds of using both cannabis  and amphetamine . We also found that participants who reported lifetime drunkenness had higher odds of using cannabis  and amphetamine . Leisure-time sedentary behaviour among school-going adolescents was only associated with higher odds of past-month cannabis use .With reference to school-level factors, the odds of cannabis use  and amphetamine use  was higher among school-going adolescents who were truant. Adolescents who reported they were bullied were more likely to use cannabis  and amphetamine . However, receiving social support in school was a protective factor against the use of amphetamine use . Family-level factors such as parental tobacco use was associated with increasing odds of both past-month cannabis use  and lifetime amphetamine use . However, being monitored by parents was a protective factor against the use of amphetamine .For School going adolescents from Ghana , Liberia , Mauritius , Namibia , Seychelles , and Tanzania  had higher odds of cannabis use. The odds of amphetamine use were higher among adolescents from Ghana  but lesser among adolescents from Mauritius  and Seychelles .In this study, we examine the prevalence estimate and describe the correlates of cannabis and amphetamine use among school-going adolescents in eight sub-Saharan African countries (SSA). The overall prevalence estimates of past-month cannabis use and lifetime amphetamine use among school-going adolescents in the eight SSA countries was 4.39% and 3.05% respectively. These prevalence estimates for both past-month cannabis use and lifetime amphetamine were higher among males than females. In the multivariable logistic regression analysis, demographic characteristics , mental health factors (suicide ideation and attempt), lifestyle factors  and school level factors  were associated with increased odds of both past-month cannabis and lifetime amphetamine use. Global and regional systematic review , 36, 39 In our study, school-level factors such as truancy and bullying victimisation were found to increase the odds of both cannabis and amphetamine use. However, receiving social support in school was a protective factor against the use of amphetamine. The relationship between illicit drug use and truancy among school-going students have been reported by previous studies , 12, 13.As reported in previous studies , 12, 18,The findings of this study has some limitations that should be noted when interpreting them. Firstly, as the WHO-GSHS data were collected using a one-off cross-sectional design, all the examined variables were measured at one point in time. Thus, assessment of causation and temporal relationship among the outcomes and exposure variables becomes a challenge. Secondly, the assessment of the variables in the study was based on a self-report, which are prone to recall bias and social desirability effects since the use of both cannabis and amphetamine use among underage persons maybe prohibited in the various SSA countries. Thirdly, it should also be noted that the study included only students who were present at school on the day of the survey; besides plausible variations in attendance rates, and that out-of-school going adolescents were not included. Finally, some possible behavioural and psychological factors that have been shown to be associated with both cannabis and amphetamine use were not considered since they were not available in the GSHS datasets. Taken together, these factors might have presented as potential sources of bias to this analysis, including possible underestimation of the prevalence of illicit drug use. Notwithstanding these limitations, this is one of the first studies to have a nationally representative data from eight countries in SSA to advance our knowledge of the prevalence estimates and factor associated with both cannabis and amphetamine use among in-school adolescents. Additionally, the use of a large sample obtained using a multi-sage systematic random sampling allows for generazability of our findings to other similar populations.This study examined prevalence estimates and described the correlates of cannabis and amphetamine use among school-going adolescents in eight sub-Saharan African countries (SSA) – Benin, Ghana, and Liberia, Mauritius, Mozambique, Namibia, Seychelles, and Tanzania. Our results found a relatively low overall prevalence estimates of past-month cannabis use and lifetime amphetamine use among school-going adolescents. We also found that both past-month cannabis use and lifetime amphetamine were associated with various multi-level factors including sociodemographic, family involvement, mental health, and school environment factors. These findings of this study support existing evidence and underscore the need for these eight countries in SSA to develop contextual and multi-sectoral intervention and school-based prevention programmes that could target school-going adolescents who may be at risk of misusing these illicit drugs.Below is the link to the electronic supplementary material.Supplementary Material 1 e-Table 1. Coding of demographic variables and exposure factors included study, and missing data


The availability of low-cost computing and digital telecommunication in the 1980s made telehealth practicable. Telehealth has the capacity to improve healthcare access and outcomes for patients while reducing healthcare costs across a wide range of health conditions and situations.This study compares the adoption, advantages, and challenges of telehealth services between high-income (HICs) and low-and-middle-income countries (LMICs) before and during the COVID-19 pandemic.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The key search terms were: “Telehealth”, “Telehealth in HICs”, “Telehealth in LMICs”, “The adoption of telehealth before COVID-19 was generally low in both HICs and LMICs. The impact of COVID-19 accelerated the adoption of telehealth at the facility level but not nationwide in both high-income countries and LMICs. The rapid adoption of telehealth at the facility level in both high-income and LMICs introduced several challenges that are unique to each country and need to be addressed.The lack of national policies and regulations is making the adoption of telehealth at the national level challenging in both high and low-middle-income countries. Governments and Stakeholders of healthcare must consider telehealth as a healthcare procedure that should be deployed in clinical working procedures. Primary quantitative and qualitative studies must be conducted to address challenges encountered during the pilot implementation of telehealth services in both high-income countries and LMICs before and during pandemics. The availability of low-cost computing and digital telecommunication in the 1980s made telehealth practicable . TeleheaIt is to this effect that this study compares the adoption of telehealth between high-income countries and LMICs before and during the COVID-19 pandemic. This study also assesses the advantages and challenges of telehealth before and during the COVID-19 pandemic in the context of high-income countries and LMICs.Studies were downloaded from six databases, namely: ProQuest, Scopus, Web of Science, Google Scholar, CINAHL , and EMBASE. In selecting the included studies for this paper, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The key search terms were: “Telehealth”, “Telehealth in High-Income Countries”, “Telehealth in LMICs”, “The eligibility criterion were the study must be published in the English language. Studies published before 2012 were excluded from this study. Grey literature, dissertations, and unpublished studies were excluded from this study. Only peer-reviewed published studies with high indexing were included. Studies that addressed the title, key search terms, and objectives of the study were included.Included studies were first classified into high-income countries and LMICs. The classification of these studies into high-income countries and LMICs was to determine if financial disparity played a role in the penetration of telehealth before COVID-19. If yes, did the COVID-19 pandemic accelerate the use of telehealth and how was it possible in financial constraint countries? Studies conducted in high income countries were categorized under “high-income countries” while studies conducted in lower-and-middle-income countries were categorized under LMICs. The World Bank classification of countries was used for this study.A total of 1688 studies were downloaded from the databases mentioned under section 2.1. A total of 441 duplicates were removed using Mendeley referencing software. A total of 191 studies not written in English language were removed. 371 studies were not peer-reviewed publications, hence, removed. A total of 322 studies were removed for not being full-text articles. A total of 363 studies remained for full-text review. Post-full-text review, a total of 317 studies were removed for not relating to the study title or objectives, or key search terms. A total of 46 studies remained and were included in this study. Figure The classified studies were further grouped into “before COVID-19 pandemic” and “during COVID-19 pandemic”. The grouped studies were placed under the subject matter they addressed. Table 10Included studies were from 19 countries. Figure In the context of both HICs and LMICs, almost no telehealth application had reached large-scale and enterprise-wide adoption as of 2012  see Tab. In PortIn context to the application of telehealth in specialised healthcare service delivery and the advantages of telehealth, telehealth was an equally effective way of treating paediatric palliative care in a high-come country like Australia even before the COVID-19 pandemic  see Fig. A studyThere were some challenges pre and post-implementation of telehealth in both HICs and LMICs before the COVID-19 pandemic  as has occurred in other developed countries  see Fig. As citeDuring the COVID-19 pandemic era, 78% of clinicians who took part in a study organised in the city of Makassar in Indonesia (LMIC) indicated their satisfaction with telehealth systems. 69% of participants indicated that telehealth allowed for quicker diagnosis and treatment  see Tab.Table 6Ap<0.01) were: lack of organisational effectiveness, health staff motivation, patient satisfaction, and trustworthiness. In this same study, lack of Information Communication and Technology (ICT) infrastructures and allocation of resources were identified as indirect barriers [Barriers to using telehealth interventions in older adults were identified in some developed countries include knowledge gaps, lack of willingness to adopt new skills, and reluctance to technology use . A scopibarriers . In LMICbarriers . Existinbarriers . Lack ofbarriers  (see TabBefore the COVID-19 pandemic, the use of telehealth was not common in both HICs and LMICs, and there were difficulties in its deployment. However, there were also effective applications of telehealth in specialized healthcare services, including telepsychiatric interventions and pediatric palliative care, as well as advantages for patients and healthcare workers in terms of cost savings. The impact of COVID-19 accelerated the adoption of telehealth at the facility level but not nationwide in both HICs and LMICs (see Table Primary quantitative and qualitative studies must be conducted to address challenges encountered during the pilot implementation of telehealth in both HICs and LMICs before and during the COVID-19 pandemic. Addressing these challenges will help countries adopt telehealth at a national level. LMICs must find innovative solutions to address peculiar challenges such as inadequate financial resources for mass-scale telehealth implementation, especially in sub-Saharan Africa.


Tremor affects up to 45% of patients with Multiple Sclerosis (PwMS). Current understanding is based on insights from other neurological disorders, thus, not fully addressing the distinctive aspects of MS pathology.To characterize the brain white matter (WM) correlates of MS-related tremor using diffusion tensor imaging (DTI).In a prospective case-control study, PwMS with tremor were assessed for tremor severity and underwent MRI scans including DTI. PwMS without tremor served as matched controls. After tract selection and segmentation, the resulting diffusivity measures were used to calculate group differences and correlations with tremor severity.d = 1.53, q < 0.001) and left corticospinal tract , compared to controls (n = 36). Furthermore, specific tracts showed a significant correlation with tremor severity, notably in the left medial lemniscus , and forceps minor of corpus callosum .This study included 72 PwMS. The tremor group (n = 36) exhibited significant changes in several pathways, notably in the right inferior longitudinal fasciculus (Cohen's MS-related tremor is associated with widespread diffusivity changes in WM pathways and its severity correlates with commissural and sensory projection pathways, which suggests a role for proprioception or involvement of the dentato-rubro-olivary circuit. Tremor is among the strongest predictors of impaired quality of life in patients with multiple sclerosis (PwMS), and can impact activities of daily living (ADLs). Current treatment modalities for MS-related tremor are lacking in their justification, measured efficacy, or outcomes. Deep brain stimulation is one of the few available options for severe medication-resistant tremor, though, it shows limited efficacy in treating MS-related tremor compared to essential tremor or Parkinson's disease-related tremor while causing permanent adverse effects in up to 25% of the cases. One reason may be that MS differs fundamentally from other causes of tremor with variable topography of pathology in the brain and spinal cord. Many studies on MS-related tremor are conducted with prior assumptions of involved neurocircuitry drawn from other causes of tremor, often scrutinizing cerebello-thalamocortical networks.8Tremor has been historically recognized as one of the clinical manifestations of MS, In a medium without an oriented microstructure, diffusivity is similar in three axial directions. Mean diffusivity (MD) is the average diffusivity in the three directions and can be used to describe the structural integrity of the tissue. The directional diffusivities, radial diffusivity (RD), and axial diffusivity (AD) describe water movement in compact white matter tracts. It has been previously shown that increased RD is associated with myelin injury, while AD correlates with axonal injury. Fractional anisotropy (FA) is a scalar value calculated from the directional diffusivities and reflects the directionality of diffusion. FA has been validated as a measure of myelination status. Damage to white matter (WM) causes an increase in mean diffusivity and a decrease in FA due to a loss of directional diffusion.Diffusion tensor imaging (DTI) is a reliable, validated technique that quantitatively assesses random water mobility, providing information about the tissue microstructure integrity measured in terms of diffusivity.In this study, we aimed to characterize the WM microstructural changes associated with MS-related tremor as well as describe how these changes correlate with tremor severity using diffusion tensor imaging (DTI), to offer a better understanding of MS-related tremor taking into consideration the distinct nature of the disease. having limb-predominant MS-related tremor not attributable to another etiology and British Medical Research Council Rating Scale motor strength in all extremities ≥ 4 were recruited, between 2019 and 2021, from the comprehensive MS care clinic at UT Physicians, McGovern Medical School, UTHealth. Subjects were sequentially enrolled, and subsequent adjustments to recruitment were made based on gender, age, and tremor severity to form the tremor group (MS-T). This method allowed us to minimize imbalance in our sample based on demographic and clinical characteristics. An additional group of PwMS matched by age and gender, without a clinically evident tremor, provided a comparison control group (MS-C) with a ratio between cases and controls of 1:1. The study was approved by the Institutional Review Board for the University of Texas Health Science Center at Houston – UTHealth (IRB HSC-MS-19-0305). All subjects participated in the study after giving written informed consent following approved procedures by the Committee for the Protection of Human Subjects of McGovern Medical School, UTHealth.In this prospective case-control study, PwMS diagnosed using 2017 McDonald's criteria,16 TETRAS quantifies tremor severity and its impact on ADLs with a focus on upper extremity action tremor while also assessing head, face, voice, and lower limbs. Evidence indicates that TETRAS offers improved characterization of tremor, especially in instances of severe tremor. As an additional method of evaluating tremor, Archimedean spiral drawings were obtained and scored according to the Tremor Research Group instructions. Upper limb ataxia, which has a possible confounding effect due to overlap in etiology and neuroanatomical correlates with tremor, was scored using the Scale for Assessment and Rating of Ataxia (SARA). Lastly, limb spasticity and extremity motor strength were assessed using the Modified Ashworth Scale and the British Medical Research Council Rating Scale, respectively. Disability data as quantified by the expanded disability severity scale (EDSS) was assessed as previously described. All clinical assessments were performed by raters not involved in image analysis.Symptomatic medications to lessen tremor severity, if present, were held for at least 24 h prior to clinical assessments only if medically cleared by the treating physician and with additional informed consent from the patient. Currently, there is no consensus as to rating scales to evaluate MS-related tremor severity. We used The Essential Tremor Rating Assessment Scale (TETRAS), a previously validated measure used in essential tremor that correlates strongly with other measures previously usurped to assess MS-related tremor. DTI quality control throughout data acquisition was assured and post-processed as detailed previously. Technical details on acquisition hardware and sequences can be found in the supplementary.MRI was performed using a 3T Philips Ingenia research scanner . High-resolution 3D T1-weighted, used for anatomical registration, were acquired at the start of each scanning session, as well as T2-weighted fluid-attenuated inversion recovery (FLAIR) images. Diffusion-tensor images (DTI) were obtained using a single-shot spin-echo diffusion-sensitized echo-planar imaging sequence with a balanced Icosa21 tensor encoding scheme. and validated by two trained raters. Voxel-wise lesion probability maps were created as previously described. A two-step approach was employed to identify and examine the potentially associated WM fiber pathways in an agnostic manner, summarized in White matter lesions were segmented on the T2-FLAIR and T1-weighted images using BIANCA,Atlas-based DTI segmentation: in this step, regional diffusivity values were obtained for various brain regions using an atlas-based method. By comparing the two groups, we identified WM regions potentially associated with MS-T. was used to create a mean FA image and skeleton for each group by averaging their FA images in a standard space and voxelwise comparisons were made to identify any significant differences. Using atlasquery, the identified voxels were localized on the ICBM-DTI-81 white-matter labels atlas.Tract-Based Spatial Statistics (TBSS): in FMRIB Software Library, TBSS to statistically infer the association with the study variable within WM pathways by analyzing the local voxel-wise connectomes. In MS-T, diffusion data were reconstructed in standard space. This analysis was conducted using quantitative anisotropy (QA) and FA separately as a tracking index and TETRAS as the study variable while controlling for the effects of age and gender.Correlational tractography: this technique uses connectometry, a more sensitive method compared to region-of-interest approaches, For each subject, 53 pathways were tracked using DSI Studio and a supervised automated method with a deterministic tractography algorithm with augmented strategies to improve reproducibility. The diffusion data were reconstructed using generalized q-sampling imaging (GQI) with a diffusion sampling length ratio of 2. GQI-based reconstruction has been validated on a similar acquisition protocol and has been shown to more consistently and accurately resolve crossing fibers compared to DTI-based reconstruction. The mean tract FA, MD, RD, and AD were obtained from the segmented pathways for MS-T and MS-C.Tractography offers a method for WM segmentation that can effectively accommodate individual anatomical variations in tract dimensions and shapes. A recent study highlighted its feasibility in MS, as it does not introduce systematic differences when tracking in normal appearing WM, T2 lesions or T1 lesions.jamovi (version 2.3), with a significance level set at p < 0.05. Demographic data's standard deviation was estimated using student's t-test, while the EDSS scores were compared using the Mann-Whitney U-test after testing for normality. Categorical variables were analyzed using contingency tables and chi-squared tests. To compare the variance in mean diffusivity measures of the pathways between MS-T and MS-C, ANCOVA was employed while controlling for the effects of age and gender, following residual plotting and inspection. Mean difference and effect size, quantified by Cohen's d (d), are reported. The p-values were adjusted for false discovery rate (q) using the Benjamini-Hochberg procedure.Statistical analyses for group differences were conducted using  The tremor severity measures  were considered as dependent variables. LPR regression was performed using the HDCI package with 1000 paired bootstraps. The lambda value was selected using 10-fold cross-validation to achieve the most regularized model within one standard error of the minimum (lambda.1se), minimizing the mean squared error. This analysis also included age, gender, and ataxia severity (SARA) as non-penalized explanatory variables. The partial correlation coefficients (spr) were calculated using Spearman's rank correlation for the selected pathways and their corresponding tremor measures while controlling for the effects of age, gender, and ataxia severity.In R (version 4.1.1), we studied the correlation between tract diffusivity measures and tremor severity in MS-T. Mean tract FA, MD, RD, and AD served as independent variables in the LASSO-partial ridge (LPR) regression.Raw data was generated at UTHealth. Anonymized derived data may be shared upon reasonable request to the corresponding or senior authors with researchers who provide a methodologically sound non-commercial proposal, subject to restrictions according to participant consent and data protection legislation.A total of 72 PwMS were included in this study, Tables S1 and S2.In MS-T, 89% of the subjects were right-handed (n = 32), 10 subjects were on tremor medications of which 9 held their medications 24 h prior to assessment, none of the control group subjects were on tremor medications. Data on clinical scores and tremor medications in MS-T are represented in the supplementary, q < 0.05) group differences in mean diffusivity of which 18 regions correlated with tremor severity, most prominently in the genu of the corpus callosum (left: spr = 0.53 and right: spr = 0.54), as well as the anterior corona radiata (left: spr = 0.53 and right: spr = 0.54). TBSS revealed significant widespread group differences in FA, while correlational tractography highlighted specific pathways that correlated with tremor severity, notably the CC-FMN , TR-A-L , CC-FMJ  and the ML-L . The results are summarized in Fig S1).The atlas-based DTI segmentation highlighted 57 WM regions exhibiting significant  followed by the left corticospinal tract (CST-L)  and the body of the corpus callosum (CC-B) . Other pathways with significant decreases were the left and right inferior fronto-occipital fasciculus , and the left inferior longitudinal fasciculus (ILF-L).A comparison was conducted between the two groups, for the segmented tracts using the mean pathway values of FA, MD, RD, and AD. Group differences in FA are depicted in d = -1.6, 95% CI: −2.15 – −1.06, q < 0.001), followed by the CST-L  and the IFOF-R . Other pathways with significant increases included the right anterior thalamic radiation (TR-A-R), followed by the parietal section of the left superior longitudinal fasciculus, and the IFOF-L as depicted in Table S3.In terms of MD, the most prominent increase in MS-T compared to MS-C was again seen in the ILF-R , followed by the CST-L , and the IFOF-R . The greatest increases in AD were observed in the TR-A-R , followed by the CST-L  and the ILF-R . Interestingly, the left dentatorubrothalamic tract was the only pathway that did not exhibit significant group differences for any of the diffusivity measures .A similar pattern was observed for RD, with the ILF-R , and the forceps minor of corpus callosum (CC-FMN) , followed by the forceps major of corpus callosum (CC-FMJ)  as shown in All 53 segmented tracts were evaluated. The correlations between tremor severity measurements and the diffusivity measures of the pathways were calculated while controlling for the effect of ataxia, age, and gender. A significant negative correlation between FA and TETRAS was noted in the left medial lemniscus (ML-L) . Meanwhile, the right component of TETRAS correlated negatively with the FA of the right anterior cortico-striatal tract (CS-A-R)  and the CC-FMN . The scores of the left Archimedean spiral correlated negatively with the FA of the left cingulum  and the right frontal cortico-pontine tract (CPT-F-R) , while the scores of the right Archimedean spiral correlated negatively with the left superior cortico-striatal tract (CS-S-L) , the CPT-F-R  and the CC-FMN .The left component of TETRAS correlated negatively with the FA of the ML-L .To explore the influence of laterality and handedness we interchanged the left and right medial lemniscus FA measures for left-handed participants (n = 4). Interestingly, this modification revealed a slightly stronger correlation with TETRAS , the right anterior corticostriatal tract , as well as the forceps minor . Significant correlations are listed in Looking at the diffusivities, positive correlations with TETRAS were found in the ML-L (MD:  degeneration, while it's severity may be modulated by dysfunction of specific WM pathways.Our results showed significant differences in diffusion metrics within several pathways in MS-T compared to MS-C. The greatest reduction in FA was seen in the right inferior longitudinal fasciculus, followed by the left corticospinal tract, and body of corpus callosum. In terms of MD and RD, the greatest increase was again seen in the right inferior longitudinal fasciculus, followed by the left corticospinal tract and right inferior fronto-occipital fasciculus, suggesting that demyelination largely drives dysfunction within several brain pathways. Interestingly, correlations between tremor severity and diffusivity measures for FA, MD, RD, and AD were seen in the left medial lemniscus, the forceps major of corpus callosum, and the forceps minor of corpus callosum, which all showed significant group differences, as well. Indeed, correlations between TETRAS and FA were stronger for the medial lemniscus when transposing the right-left brain orientation of left-handed participants. We hypothesize, in light of our findings, that MS-related tremor associates with widespread structural disconnectivity secondary to lesion-driven inflammation, especially in regions traversed by projection pathways and consequent axonal and possibly transsynaptic Heenan et al. suggested that, mechanistically, MS-related tremor is secondary to sensory feedback maladaptation and defects in internal estimates of limb dynamics. Indeed, peripheral limb cooling was shown in one study to reduce tremor in PwMS, though the mechanisms remain unexplored. Feys et al. reported correlations between tremor amplitude and lesion load in the contralateral pons, suggesting the possible involvement of the descending rubro-olivary pathway. Lesions in the midbrain can cause dystonia frequently associated with tremor, while thalamic or striatopallidal lesions can cause pure focal dystonia. A study showed that the resting and postural components of dystonia-related tremor occurred exclusively with lesions disrupting the dentato-rubro-olivary loop as well as the medial lemniscus.The medial lemniscus is part of the dorsal column-medial lemniscus system, which is responsible for relaying the peripheral mechanoreceptive sensations. in MS-related tremor due to its intimate anatomical proximity. The second explanation could be a reduction in sensory afferents modulating movement,40 as the medial lemniscus is the main pathway for proprioception and conveys sensory information to various circuits to regulate smooth motor action by providing positional and gravitational information.Therefore, two potential explanations exist for the strong correlation between tremor severity and the medial lemniscus diffusivity measures in our sample. One explanation could be the involvement of the dentato-rubro-olivary circuit16 EDSS differences between groups were primarily driven by higher cerebellar and ambulation subscores, due to the need for assistance devices secondary to ataxia, though all correlations were adjusted for SARA. Diffusion MRI fiber tracking is a user-defined process, which might affect reproducibility of results. We mitigated this issue methodologically by using a semi-automated approach to standardize the procedure.28 Another limitation is that our DTI sequence is not optimized fully for GQI-based reconstruction, although it has been validated on a similar acquisition protocol. Additionally, in this initial work, we did not explore in-depth the impact of MS-related lesions, either in the brain or spinal cord, on the described tracts. Lastly, inferences from our findings are restricted by the limited sample size and the exploratory nature of the study.Our study has some limitations, most notably the absence of a validated MS-related tremor scale to precisely characterize and measure tremor severity. TETRAS offers improved characterization of severe tremor and correlates well with other scoring systems previously usurped to quantify MS-related tremor, such as the Fahn-Tolosa-Marin scale.The results showed significant widespread changes in diffusivity measures along several association, projection, and commissural pathways associated with MS-related tremor. The greatest dysfunction between groups was seen in the inferior longitudinal fasciculus followed by the corticospinal tract. In the tremor group, we found a correlation between tremor severity and diffusivity measures of certain projection and commissural pathways. The correlations between tremor severity and diffusivity measures in the medial lemniscus might suggest a potential involvement of the dentato-rubro-olivary circuit in MS-related tremor or a reduction in sensory afferents affecting movement due to the medial lemniscus being the main pathway for proprioception. Further confirmatory studies with larger sample sizes are needed to validate the findings, studying both causality and temporality between tract-specific dysfunction and tremor incidence as well as severity.Click here for additional data file.Supplemental material, sj-pdf-1-mso-10.1177_20552173231208271 for Identifying the white matter pathways involved in multiple sclerosis-related tremor using diffusion tensor imaging by Ahmed Bayoumi, Khader M. Hasan, Jorge Patino, Zafer Keser, Joseph A. Thomas, Refaat E. Gabr, Claudia Pedroza, Arash Kamali, Mya C. Schiess, Jerry S. Wolinsky and John A. Lincoln in Multiple Sclerosis Journal – Experimental, Translational and ClinicalClick here for additional data file.Supplemental material, sj-pdf-2-mso-10.1177_20552173231208271 for Identifying the white matter pathways involved in multiple sclerosis-related tremor using diffusion tensor imaging by Ahmed Bayoumi, Khader M. Hasan, Jorge Patino, Zafer Keser, Joseph A. Thomas, Refaat E. Gabr, Claudia Pedroza, Arash Kamali, Mya C. Schiess, Jerry S. Wolinsky and John A. Lincoln in Multiple Sclerosis Journal – Experimental, Translational and Clinical


Co-delivery of SF and other active agents  for targeted SF nanosystems and synergistic drug combinations are also highlighted. All these studies showed promising results for targeted treatment of HCC and other cancers by SF-based nanomedicines. The outlook, challenges and future opportunities for the development of SF-based drug delivery are presented.As a Food and Drug Administration (FDA)-approved molecular-targeted chemotherapeutic drug, sorafenib (SF) can inhibit angiogenesis and tumor cell proliferation, leading to improved patient overall survival of hepatocellular carcinoma (HCC). In addition, SF is an oral multikinase inhibitor as a single-agent therapy in renal cell carcinoma. However, the poor aqueous solubility, low bioavailability, unfavorable pharmacokinetic properties and undesirable side effects  seriously limit its clinical application. To overcome these drawbacks, the entrapment of SF into nanocarriers by nanoformulations is an effective strategy, which delivers SF in a target tumor with decreased adverse effects and improved treatment efficacy. In this review, significant advances and design strategies of SF nanodelivery systems from 2012 to 2023 are summarized. The review is organized by type of carriers including natural biomacromolecule ; synthetic polymer (poly(lactic- Th. Th32]. efficacy .Nonionic α-cyclodextrins (α-CD) are ideal carriers to deliver drugs . MazzaglAs a natural anionic polysaccharide, hyaluronic acid (HA) directly binds to CD44, and RHAMM receptors overexpressed on various tumor cell surfaces. Mo et al. reported PEGylated HA-coated liposome for enhanced SF delivery and anti-tumor outcome via active tumor cell targeting and prolonged systemic exposure . For MDAcis-Pt) are two chemotherapeutic drugs with different antitumor mechanisms. Zhang et al. developed pH-sensitive hyaluronic acid NPs encapsulating with SF and cis-Pt, where interactions between cisplatin and HA was involved . Tw. Tw45]. 2 and SF were fabricated by non-covalent interactions. Then, LA was chemically linked to the surface of the NPs. Finally, siVEGF were loaded into the nanocarrier by electrostatic interaction. The improvement in the targeting property resulted in enhanced anti-cancer efficacy of SF. Recently, SF was loaded into manganese-doped MSNs by physical adsorption . Th. Th73]. Zhang et al. prepared SF and gadolinium (Gd) co-loaded liposomes (SF/Gd-liposomes) using Lipoid E80 and cholesterol as carriers for MRI-guided visualization of the delivery and HCC treatment . The sol2) nanosystems can react with H+ and glutathione (GSH) in the tumor microenvironment (TME) [2+ significantly increases the contrast of T1 in MRI, which is useful for tumor-specific imaging and multifunctional drug carrier systems [2 for targeting the delivery of SF, where aptamer could specifically bound to glypican-3 (GPC3) receptors on the surface of HCC [Manganese dioxide (MnOnt (TME) . The res systems . Wang ete of HCC .A dicarboxylic acid-containing ICG was selected as a NIR photosensitizer and fluorescent dye, which was co-loaded with SF by Pluronic F127 to produce self-assembled and self-monitored nanodrug . Throughγβ3 is regarded as the targeted site for HCC, arginine–glycine–aspartic acid (RGD) functionalized carriers are promising. The multifunctional SF theranostic nanosystems were prepared based on cyclic RGDfK and S-Cy5.5 fluorescent dyes-functionated PEG-PCL for fluorescence imaging-guided HCC treatment [Liu et al. designed a new nanocarrier platform for SF delivery, where the tumor chemotherapy process was guided and evaluated by NIR-II dual-modal optical coherence tomography and photoacoustic imaging . Becausereatment .Feng et al. designed a lipid-coated nanocarrier functionalized with peptides specific for glypican-3, which showed targeted drug delivery to human HCC xenograft tumors . PLGA anSLN appended with PEGylated galactose  was deveZhong et al. reported a redox-responsive SF delivery system based on apolipoprotein E peptide-decorated disulfide-cross-linked polymer and SF by self-assembly and self-crosslinked process . The restumor/Cblood value (0.66) than those of the former two (0.56 and 0.41) in a nude mice liver cancer model were found.Folate (FA) can enter cells through a receptor-mediated endocytosis pathway. It is highly expressed in tumor tissue at a level 100–300 times higher than that in normal tissues. The FA receptor is a good target for targeting delivery systems for many solid tumors. Zhang et al. prepared FA-functionalized polymeric micelles loaded with SPIONs and SF, which can increase the concentration of SF in HepG2 cells . Li et aFA-modified PEG-nitroimidazole grafts exhibited a targeting SF delivery ability in the treatment of hypoxic HCC . Since aThe presentative SF-based drug delivery systems are summarized in Ferroptosis is an alternative to the traditional apoptotic pathways for cancer therapy, which is regarded as an iron-based Fenton-type reaction. Since SF can induce the occurrence of ferroptosis, some combinational therapy methods have been proposed . Zhou et50 of SF NPs based on the drug–mate strategy was close to that of free SF (3.44 vs. 4.44 μg/mL). However, the pharmacokinetics of the former were largely improved, where the plasma concentrations of SF was 2 and 20 times than that of the SF solution and SF suspension, respectively. In vivo antitumor efficacy study further revealed the increased bioavailability and enhanced therapeutic efficacy of SF.The novel drug–mate strategy has been developed in the nanomedicine field. Namely, amphiphilic small molecule and hydrophobic drugs with poor solubility are selected as a mate and drug, respectively . Taking With the development of nanotechnology, nanocarrier-based SF delivery systems have been widely studied. Its poor pharmacokinetic properties have been improved to some extent. The synergistic drug combinations also exhibit potential for cancer treatment due to their superior therapeutic benefits to the classical monotherapeutics. The innovative optimization of nanocarriers structures  improves the bioavailability and therapeutic efficiency of anti-tumor drugs. The chemical and physiological properties of nanocarriers largely affect the synergistic actions combined drugs. However, some challenges still exist such as low drug loading, uncontrollable drug release, insufficient tissue penetration, loss of targeting ability, biosafety, etc. In particular, ligand- or surface-modified nanocarriers are utilized to enhance the SF anti-tumor effect. According to the receptors over-expressed on the surface of tumor cells, specific ligands, such as antibodies, proteins, peptides, aptamers or folic acid, were introduced for the surface modification of nanocarriers to achieve active targeting via biological substrate/receptor (antibody/antigen) recognition. However, the “overexpression” of relevant receptors on the surface of tumors is not sufficient to impart high selectivity due to tumor heterogeneity. Moreover, the development of nanoformulation often requires complex nanocarrier synthesis/modification, purification and fabrication. Some shortcomings such as stability, handling inconvenience, blood stability, reproducibility from batch-to-batch and scale-up issues are encountered. The reproducibility from batch to batch is also a problem. Most SF-based nanodrugs are studied at the cellular and animal level. There are various physiological barriers in terms of clinical translation.The selection of nanocarriers for SF delivery is essential to improve its biopharmaceutical properties. Various types of representative materials such as lipid- and polymer-coated nanomatrix, natural and synthetic polymeric, MSNs, pH- or GSH- responsive NPs, gold NPs, injectable sodium selenite NPs and in situ gel with lipid coating are utilized to promoting SF nanoformulations. The bioavailability, solubility, drug targeting and cytotoxicity of SF are improved, which is facile for circumventing some of the unfavorable outcomes of traditional SF regimens. SF-based nanodrugs cannot stay in the tumor site for a longer period when they enter the blood circulation by diffusion and via the ERP effect. Moreover, some nanocarriers are difficult to be removed from the blood stream due to high physicochemical stability and unsuitable particle size, which may increase systemic toxicity and organ damage. Appropriate surface modifications could enhance the localization and specific accumulation of nanocarriers in tumor cells by ligand–receptor interactions. Studies have shown that precise targeting of receptors on tumor cells or tumor vessels by ligand-modified nanocarriers can improve the efficacy of drugs. The application of biodegradable nanocarriers would be a promising strategy to control toxicity and improve biological compatibility. In the future, more attention should be paid to the surface characteristics, biosafety, targetability by connecting tumor-targeting ligands, controlled release with stimuli-responsive linkers, and so on. Moreover, it is important to combine SF with other treatments for synergistic therapy . Scientists should make more efforts to investigate the biodistribution, pharmacokinetic response and in vivo efficacy of various SF nanoformulations. All in all, SF nanoformulations hold great potential and prospects in cancer therapeutics in the future. It is urgent to study the mechanisms underlying how SF interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.


Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory CNS demyelinating disease. Two groups of monoclonal antibodies (mAbs) are used to prevent disease relapse, i.e., Food and Drug Administration (FDA)-approved mAbs , and off-label mAb drugs . The FDA-approved mAbs have high efficacy but more expensive compared to the off-labels, and thus are less accessible. This systematic review and network meta-analysis (NMA) was to assess the efficacy and safety of both classes of mAbs compared to the current standard treatments.Systematically searches were conducted in MEDLINE and SCOPUS from inception until July 2021. Randomized-controlled trials (RCTs) were eligible if they compared any pair of treatments  in adult patients with NMOSD. Studies with AQP4-IgG positive or negative were used in the analysis. Probability of relapse and time to event were extracted from the Kaplan-Meier curves using Digitizer. These data were then converted into individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate the median time to relapse and relative treatment effects using hazard ratios (HR). Two-stage NMA was used to determine post-treatment annualized relapse rate (ARR), expanded disability status score (EDSS) change, and serious adverse events (SAE). Risk of bias was assessed using the revised cochrane risk of bias tool.A total of 7 RCTs with 776 patients were eligible in the NMA. Five of the seven studies were rated low risk of bias. Both FDA-approved and off-label mAbs showed significantly lower risk of relapse than standard treatments, with HR (95% CI) of 0.13  and 0.16  respectively. In addition, the FDA-approved mAbs had 20% lower risk of relapse than the off-label mAbs, but this did not reach statistical significance. The ARRs were also lower in FDA-approved and off-label mAbs than the standard treatments with the mean-difference of−0.27  and−0.31, respectively.The off-label mAbs may be used as the first-line treatment for improving clinical outcomes including disease relapse, ARR, and SAEs for NMOSD in countries where resources and accessibility of the FDA-approved mAbs are limited.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=283424, identifier: CRD42021283424. Neuromyelitis optica spectrum disorder (NMOSD) is a devastating central nervous system (CNS) inflammatory demyelinating disease that approximately seventy-five percent is caused by autoantibodies targeting aquaporin-4 immunoglobulin G (AQP4-IgG) . PatientStandard immunosuppressive medication considered initial treatments for relapse prevention especially poor resource countries include prednisolone, azathioprine, and mycophenolate mofetil. However, many patients still relapse because of low efficacy and low adherence related to severe side effects . MonocloFifteen systematic reviews (SRs) have evaluated treatment effects of mAbs on relapse prevention in NMOSD –25. HoweA review protocol of this SR-NMA was developed and registered with PROSPERO (CRD42021283424). The study was conducted following the Preferred Reporting Item for Systematic reviews and Meta-Analysis (PRISMA) guidelines . RelevanRCTs were selected if they met all of the following inclusion criteria: (i) RCTs included adults with NMOSD; (ii) compared any pair of mAbs , immunosuppressive drugs , or placebo; (iii) had at least one of the following outcomes: time to relapse, annualized relapse rate (ARR), expanded status disability scale (EDSS) change after treatment, and SAE. Studies were excluded if published in a foreign language that could not be translated, compared dosages of the same drug, or had insufficient data for pooling after three contact attempts with authors.Interventions of interest were any off-label mAbs  and approved mAbs , whereas the control treatments could be any of the recognized standard treatments , placebo, or no treatment. For those RCTs with a placebo arm plus standard treatments, their comparator was categorized as the standard treatment.The primary outcome of interest was time to relapse, defined as the time since randomization to disease relapse. Relapse was defined according to the individual studies, such as worsening or appearance of new neurological symptoms 24 h or more post intervention, without evidence of fever or infection . The adjTwo independent reviewers performed the data extraction and quality assessment (SA and JK). The following data were extracted: general characteristics , patient characteristics , treatment regimens, and outcomes .Data for time to relapse were extracted from the Kaplan-Meier (KM) curve using the Digitizer program  includinA one-stage mixed-effect parametric survival model  was applp-value < 0.05 was considered statistically significant for all tests, except for heterogeneity where 0.10 was used.For secondary outcomes , the relative treatment effects were estimated for continuous and dichotomous outcomes by unstandardized mean difference (USMD) and risk ratio (RR), respectively. A two-stage NMA with a consistency model was applied to pool these relative treatment effects across treatment regimens and studies. The probability of being the best treatment was assessed using the rankogram and the Surface Under the Cumulative Ranking curve (SUCRA). Transitivity was explored by comparing the distribution of co-variables  among treatment arms and studies. The inconsistency was checked by the design-by-treatment interaction model. A comparison-adjusted funnel plot was used to assess publication bias. All analyses were performed using STATA version 17.0. A two-sided A total of 2,937 studies were identified but only 7 RCTs –10 with The risk of bias for each study is shown in the Six –7, 9, 10The comparison-adjusted funnel plot for time to relapse is shown in the n = 427)  . The USMn = 427) . Likewisn = 427) .n = 427)  and 0.03  higher EDSS change than these corresponding comparators. However, none of these comparisons reached statistical significance. A comparison-adjusted funnel plot suggested no evidence of publication bias  . The USMn = 427) . In contion bias .Seven RCTs –10 were We conducted the first NMA of efficacy and safety of current treatments in NMOSD using evidence based solely from RCTs. Our findings suggested that the FDA-approved and off-label mAbs represent an 87% and 84% significantly lower risk of relapse than standard treatments. In addition, both corresponding mAbs had between 0.27 and 0.31 significantly lower ARRs than standard treatments, while outcomes for EDSS and SAEs did not significantly differ.mAbs are classified into two categories in accordance with FDA approved data: off-label and FDA-approved mAbs. The former group previously demonstrated higher efficacy compared to classic immunosuppression and were considered more accessible than the FDA-approved mAb –10. HoweSurprisingly, a non-statistically significant difference was observed in increasing the risk of relapse when standard immunosuppressive drugs was compared to the placebo . The explanation might possibly cause by heterogeneity of each study design. Some of the study include placebo as immunosuppressive resistance patients, which allow patients to continue use previous immunosuppressive drug .mAbs can also be classified according to their mechanism of action such as C5 complement inhibitor , anti-B cell or anti-CD19 , and anti-IL-6 . For off-label mAbs, rituximab is classified as anti-B cell or anti- CD20, while tocilizumab is anti-IL-6. Most FDA approved and off-label mAbs have similar mechanisms (except for eculizumab) and it was therefore unsurprising that their outcomes did not significantly differ.Our findings were similar to those from a previous NMA , which cOur findings will inform neurologists and opthalmologists in treatment decision making, perhaps highlighting the possibility for off-label mAb use in preference to FDA-approved mAbs, especially in resource limited settings such as low and low-middle-income countries where accessibility may be limited. FDA-approved mAbs may represent a suitable alternative for patients that suffer from disease relapse following treatment with off-label mAbs.Our study had several strengths. First, we applied both one- and two-stage NMA approaches to compare FDA-approved mAbs and off-label mAbs indirectly. A total of seven RCTs were included considering all relevant clinical outcomes, including relapse time, ARRs, EDSS, and severe SAEs. New agents  were also included in the analysis of both FDA-approved and off-label mAbs. Individual patient (time to event) data were generated from the KM curves , leadingIn conclusion, off-label of the mAbs rituximab and tocilizumab may be used as the first-line treatments for improving clinical outcomes, such as disease relapse, ARR, and SAEs in countries where resources and accessibility to the FDA-approved mAb are limited. The FDA-approved mAbs may be considered as the next line treatments in patients who are failed from off-label mAbs or uncontrolled disease activity. A large-scale RCT of individual mAbs should be further conducted to evaluate optimal-dose, long-term treatment efficacy, and safety with immune suppressants. Furthermore, an economic evaluation should also be conducted to evaluate their clinical and cost-utility for informing treatment decision-making.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SA, SY, CD, UC, and ATh conceived and designed the work. SA and KT did the analysis. SA wrote the first draft of the manuscript with input from other authors. All authors interpreted the data, provided critical revision for important intellectual content, and approved the final version to be published.


Iran is amongst the first three countries in Middle East and North Africa (MENA) region where two-thirds of region’s new HIV infections are reported. HIV testing at the population level is key to interrupting the HIV transmission chain. The current study aimed to evaluate the history of HIV rapid diagnostic testing (HIV-RDT) and its correlates in northeast Iran.In this cross-sectional study, de-identified records of HIV-RDTs were extracted by the census method from the electronic health information system of 122 testing facilities between 2017 and 2021. Descriptive, bivariate, and multiple logistic regression analyses were performed to identify the factors associated with HIV-RDT uptake and risks and drivers of HIV-RDT positivity, separately among men and women.Conducting 66,548 HIV-RDTs among clients with a mean age of 30.31 years, 63% female, 75.2% married, and 78.5% with high school education or below, yielded 312 (0.47%) positive results. Test uptake was comparatively low among men and the unmarried sub-population. Prenatal care and high-risk heterosexual intercourse were the most frequent reasons for taking HIV-RDT among women and men, respectively (76% and 61.2%). High-risk heterosexual contact, tattooing, mother-to-child transmission (MTCT), having a partner at risk of HIV infection, and injecting drugs were test seekers’ most reported transmission routes. One-third of the newly-infected female clients were identified through prenatal testing. Multivariate analysis revealed older age at the time of testing (Adjusted Odd Ratio (AOR) = 1.03), divorce (AOR = 2.10), widowhood (AOR = 4.33), education level of secondary school (AOR = 4.67), and unemployment (AOR = 3.20) as significant demographic predictors of positive HIV-RDT . However, clients’ nationality, testing history, duration of HIV exposure, and reported reasons for taking HIV-RDT were not associated with the test result .Innovative strategies are required to scale up test uptake and positive yields among the key population in the region. The current evidence strongly suggests implementing gender-targeted strategies, according to the differences in demographic and behavioral risk between men and women. With a global estimation of 38.4 million people living with Human Immunodeficiency Virus (HIV), 1.5 million new infections, and 650,000 related death in 2021, HIV infection remains a significant public health concern in the world  times among men . Moreover, male clients were significantly less likely to be detected as positive when seeking tests voluntarily .Multiple regression revealed that widowed and divorced female clients had approximately three- and seven-time higher likelihood of a positive result of HIV-RDT, respectively . Regarding occupation, unemployment was accompanied by a 2.69 times higher HIV-RDT positivity rate . Moreover, non-pregnant women were more likely to be diagnosed as positive compared to pregnant clients . However, unlike men, age was not significantly associated with test positivity. .We evaluated the factors associated with HIV-RDT uptake and determinants of positive results among male and female test takers, aged 3–97 years, seeking HIV-RDT to check their status or being referred for testing, in 122 testing sites located in 15 cities in northeast Iran.We found a sharp decrease in the number of HIV tests performed in 2020 compared to 2019. Similar findings with an overall reduction of 50% in HIV testing were reported in the WHO Eastern Mediterranean region, where Iran is located , 26.19% According to the current findings, HIV-RDTs uptake among women was almost twice as high as among men. This seems to be a consistent finding across various studies –22. It cLow male testing uptake can increase HIV transmission to their female partners, as well . AccordiDespite taking fewer HIV-RDTs, men were approximately two times more likely to be identified as positive than women in bivariate analysis. Since most women in our study took HIV-RDT as prenatal care (70.6%), with probably low underlying risks, there were less likely than men to be identified as positive. Female clients might have also received more HIV-related education in prenatal visits, resulting in less inclination to have hazardous behaviors . The assIn the present study, older age was positively associated with higher HIV-RDT positivity, particularly among men. Young adults and adolescents are often less presented for HIV testing or using related services in Iran and MENA region , 26 or AOur findings showed non-married population’s engagement in HIV-RDT was relatively low. Married women in other studies had higher odds of being ever tested for HIV, attributed to testing for pre-marriage or prenatal care , 32. MorLevels of education were of great significance in tests seeking behavior and positive test results. In line with our findings, the odds of being ever tested for HIV rose along with an increase in the levels of education from illiteracy to school education in some African countries , 38, 39.Our finding supports less test-seeking behavior and a higher likelihood of HIV transmission among unemployed clients. Consistent with this, the state of being employed has been suggested as a significant factor in reducing HIV transmission and better HIV prevention outcomes , 41. In Despite the measures taken to reduce vertical transmission of HIV in Iran, leading to a decrease in the absolute number of vertically infected, MTCT is still a concern in the HIV care continuum . PreviouFirst-time test takers did not show a significantly higher chance of being identified as positive compared to re-testers in the current study. In contrast, Martelli et al., in Tanzania, Africa reported significantly higher positive yield in first-time testers, which was attributed to a lack of risk perception in first-time testers . HoweverIn our study, the population with hazardous behavior was less likely to seek HIV-RDT in PHC/VCTs. According to previous studies in Iran and other countries, those at the highest risk such as FSW and MSM are reluctant to be tested for HIV or even report their testing results in surveys due to some cultural constraints, fear of criminalization, and social rejection , 49. AnoOne limitation of our study is missing information in HIS due to the result being incompletely submitted in HIS or presented in a different dataset in the case of ACF. Another limitation was the study duration, which included the COVID-19 pandemic, which might affect the number of clients. Moreover, this study was a cross-sectional study with a sampling procedure based on the Census (gathering information about every member of the population). This caused an imbalance in population size between the compared groups, making us unable to fully measure confounding factors. Thus, the results are not supposed to show the causation or predict the main outcome (positive HIV-RDT) based on demographic or behavioral variables.This study is unique as no other study has analyzed the database of the HIS affiliated with other medical universities in Iran. Furthermore, we analyzed data from five years to be able to depict a reliable trend. Additionally, we used data from all centers including urban and rural areas with a large population size, hence we can claim that the method and results of this study can be extrapolated to Iran to expand the coverage.This study provides evidence on HIV-RDT uptake, drivers of HIV transmission, and demographic and behavioral risk determinates of positive HIV-RDT outcomes. These findings highlighted the need for target-specific interventions in the area which can have implications for policymakers to expand the testing coverage. Despite a downward trend in the number of testing over five years, we found an upward trend in positive yield. The study showed a relatively low HIV-RDT uptake among men and unmarried populations and promoting community-based testing outside conventional facilities with flexible hours, such as home, mobile or self-testing can lift the testing barriers among men. Moreover, higher HIV-RDT positivity rates among men, divorced, widowed, unemployed, and those with a high-school education or below ask for specific innovative preventive strategies to focus on these populations. Since married women consider a bridge population in HIV transmission, addressing HIV-related knowledge insufficiency, empowering them through life skill school-based education, and scaling up prenatal testing might help better combat the epidemic in the area.