HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.The online version contains supplementary material available at 10.1186/s12863-023-01128-3. Following exposure to SARS-CoV-2 (the virus that causes COVID-19), some individuals remain disease- or symptom-free while others develop a spectrum of symptoms from mild to severe with the potential for fatal outcomes –7, incluhttps://www.covidhge.com/). Most importantly, we have established the research project infrastructure necessary for future pan-Canadian genome sequencing studies. In this resource paper introducing the HostSeq Databank, we present its design characteristics, high-level analytic considerations pertaining to it, and the research opportunities this rich resource provides.In 2020, several countries launched efforts to identify the genetic factors affecting COVID-19 outcomes to support diagnostics, therapy and vaccine development. However, Canada was not poised to do so because, although population-based cohorts exist , 17, a nHostSeq Fig.  is a proWithin these studies, eligible participants include individuals of any age with a positive SARS-CoV-2 test performed by any Health Canada approved method. In some studies, suspected cases with clinically assessed COVID-19-related symptoms but without a positive test diagnosis were also included. Within the primary studies, each participant consented to use of their whole genome sequence for future research . ParticiAvailability of Data and Materials section.The HostSeq Databank shares data with the global research community following review and approval by the HostSeq-independent Data Access Compliance Office (DACO), as described below in the All HostSeq samples undergo whole genome sequencing in a standardized fashion at one of the three CGEn nodes: Toronto , Montréal (McGill Genome Centre at McGill University), and Vancouver (Canada’s Michael Smith Genome Sciences Centre) on the Illumina NovaSeq6000 platform at 30X depth. Prior to sequencing, quality assurance is performed at multiple stages throughout the process . Concordhttps://svn.bcgsc.ca/bitbucket/users/jmgarant). Software packages used to process and analyze the WGS data are listed in Table SSequenced samples are analyzed jointly using an in-house pipeline encoded in Nextflow  and SnakThe in-house pipeline is as follows. Sequences are aligned to the reference genome using DRAGEN mapper DRAGMAP v1.3.0; ), sorted.3.0; , sAs of December 20, 2022, 13 participating studies contributed data and biospecimens to HostSeq Table S. AlthougHostSeq Phenotype Portal described below in HostSeq Data Portals). For example, all laboratory test variables are converted into predefined units; text entries in French are translated into English; and medications and complications variables are coded by timeline (prior to illness vs. during illness vs. post-discharge follow-up). Any potential data errors detected in the harmonization process are communicated to the participating study teams and resolved through follow-up.Clinical data from the participating studies is systematically harmonized by the HostSeq team in an ongoing process. In the first stage, we verify the raw data by checking for missingness, consistency, inadmissible values, and aberrant values across the variables. In the second stage, we harmonize the data guided by a set of common definitions and rules, including application of uniform classification, coding, and measurement units specified in the HostSeq Codebook , most studies are province-specific: six studies in Ontario , one in Quebec , two in Alberta  and two in British Columbia . Table Shttps://www.cgen.ca/hostseq-studies-2).Study-specific sample sizes currently range from 11 to 4,602. To date, in the HostSeq databank the 13 studies have contributed 9,913 clinical records and submitted 10,978 samples , with an overall mean age (at recruitment) of 47.9 years. Distributions of sex and age vary across the studies , participants presented predominantly with mild or moderate symptoms and did not require admission to intensive care units or invasive ventilation support. Of the hospitalized patients, 54.0% were discharged home, 15.0% were transferred to other hospitals or healthcare settings  and 11.9% were reported deceased Table .Table 2HPhenotype Portal shows summaries for the major variables of the HostSeq harmonized clinical data; and (2) the Variant Search Portal enables queries in a genomic region to see all variants and their alleles identified in the HostSeq genomes. Both portals are static platforms that are updated periodically when a new release version of their respective data is available.HostSeq provides public access to two data portals: (1) The HostSeq Phenotype Portal (https://hostseq.ca/phenotypes.html) provides information for clinical variables at aggregate and study-specific levels. Users can access variables by category  and view their distributions . Displays are limited to variables with ≥ 70% completeness. Researchers can also find links to the HostSeq study protocol and up-to-date data dictionaries on this portal.The HostSeq Variant Search Portal (https://hostseq.ca/dashboard/variants-search) allows for queries of the HostSeq genetic data. The primary querying functionality is supported by the CanDIG-server [The G-server , a platfG-server  from theMethods). Our predicted population structure covers five major ancestry groups  with bi-allelic typing at 4-digit resolution . The numbers of unique alleles for HLA-A, HLA-B and HLA-C in 4436 genomes are 73, 145 and 49, respectively .Currently HostSeq provides 174.5 million short variants consisting of single nucleotide variants and indels. We report HLA Class I haplotypes for three loci  also depends on whether the studies measure those same features. Although the combination of study-level estimates or tests can be as efficient as joint analysis in large samples , meta-anGiven the dynamic nature of the COVID-19 pandemic, temporal and spatial variation within- and between-studies is another source of heterogeneity that is challenging and deserves consideration. Studies with prolonged recruitment and wide variation in dates of infection may allow such factors to be examined. When looking across the participating HostSeq studies, it may be of interest to examine changes in the profiles of recruited patients as the seropositivity rates and vaccination rates changed with time across Canada and as treatments changed and improved .Most of the participating studies are designed to include individuals who tested positive for SARS-CoV-2 at a participating institution or individuals who volunteered to donate blood and previously had a positive test. For such participants, it can be difficult to specify exactly what population they represent. To reduce bias and improve interpretation of results, the processes by which individuals join a given study needs to be considered . Here, wMethods to account explicitly for selection conditions are similar to methods used for the analysis of secondary traits in case–control studies , 50. FroFinally, as HostSeq includes various ancestries, care must be taken to avoid confounding through population stratification . This issue, alongside issues related to the heterogeneity of participating studies, are not unique to HostSeq, and arise in most collaborative multi-center or consortium-based research.Sex difference and X Chromosome Analyses below). We must also consider whether to adjust for factors such as comorbidities, which may be related both to the outcome and to the variant. This is of particular importance for severe COVID-19: in the ICU, 1-year mortality outcomes increase with each additional week spent in ICU, each decade in age, and each additional comorbid illness in the Charlson score [The choice of adjustment covariates in tests for association of outcome with a genetic variant is context dependent and open to discussion in many settings , 52. In on score . From a on score . If therFor the discovery stage in genetic association studies, power considerations are important. There have been suggestions that adjusting for too many covariates decreases power , 55, andACE2, Xp22.2), has been reported to be important in SARS-Cov-2 infection and genetic analysis has demonstrated association evidence with ACE2 variants [COVID-19 displays sexual dimorphism with greater severity in males –58. In aHowever, all published GWAS of SARS-CoV-2 susceptibility or COVID-19 severity, to the best of our knowledge, uses the traditional genotype coding  that assumes X-inactivation through a dosage compensation model . Yet, iPeople living in Canada are insured under single-payer health care systems administered at the provincial or territorial level. These systems broadly cover physician and hospital services, as well as procedures. This provides a unique opportunity to conduct passive follow-up to understand the short-term and long-term outcomes related to SARS-CoV-2 infection. Administrative health data are generated through patient contact with the health care systems and maintained in multiple databases that, with the appropriate approvals, can be linked using a unique encoded identifier to study specific, patient-level data (including genetic data). These data are administrative or procedural , clinical , laboratory , social , and environmental . The participant informed consent used by HostSeq allows for linkage to these data, transforming the HostSeq dataset into a longitudinal study. Specifically, linkage to administrative provincial data will provide: 1) a retrospective, longitudinal account of medical histories, health system utilization and diagnoses; and 2) prospective, longitudinal follow-up tracking the natural history of SARS-CoV-2 infection including multisystem inflammatory syndrome in children (MIS-C) and Long COVID, identifying new diagnoses , long-term health outcomes , and health resource utilization. Linkage of the HostSeq study samples to provincial administrative data offers opportunities to collect additional data on risk factors and longitudinal outcomes, and opportunities to extend genetic association analyses. Administrative data can also facilitate evaluation of the representativeness of study samples and inform future study design.The limitations of HostSeq data for investigation of specific scientific questions depend on limitations of the relevant participant studies. In addition, investigations that involve combining data or results from separate participant studies may require assumptions about comparability or heterogeneity; such assumptions should be scrutinized.Through the HostSeq initiative, Canada has built research infrastructure to investigate health effects of SARS-CoV-2 infection and COVID-19, and their association with genetic variants. This infrastructure can also be used for future epidemics. The unique features of the HostSeq project highlighted here present novel opportunities to develop, evaluate, and apply statistical methods that contribute to the understanding of genetic associations with COVID-19-related morbidity and mortality, as well as other phenotypes. The augmentation and linkage of the HostSeq questionnaire and genetic databank with other data resources is made possible by broad and flexible consent and will generate a dynamic population-based resource. This will allow for study of a broad range of research questions and sustained productivity over the years to come.Additional file 1: Table S1. HostSeq Core Consent Elements. In order to deposit datasets in HostSeq COVID-19 controlled-access Databank, all the elements in this table must be obtained in the research consent. Table S2. HostSeq Case Report Form. Table S3. Software used for processing WGS data. Table S4. List of HostSeq participating studies as described in respective protocols. Table S5. Distribution of sex and age across HostSeq studies . SD: Standard deviation; IQR: interquartile range. Figure S1. Quality of HostSeq genomes. (A) Missing rate < 5%, (B) Contamination rate < 3%, (C) Mean coverage >10. Figure S2. Predicted population admixture and ancestry classification in HostSeq genomes. Each bar represents a genome. Proportion of African, East Asian and European ancestries is determined, and genomes classified into 8 ancestry groups using GRAF-pop. They are further categorized into 5 superpopulations: AFR - African and African-American, AMR - Latin American Asian and Latin American African, EAS - Asian-Pacific Islander and East Asian, SAS - South Asian, and EUR - European. 3% of genomes remain uncategorized. Figure S3. Genetic distances score of HostSeq genomes. The four genetic distances (GD1-4) scores from GRAF-pop represent the distance of each genome from several reference populations and are used to predict ancestry. Barycentric coordinates of GD1 and GD2 are used to predict admixture proportion of African, East Asian and European ancestries.


Ecological momentary assessment (EMA)-based smoking cessation intervention may help personalize intervention for smokers who prefer to quit smoking unaided. This study aims to evaluate the effectiveness of EMA-based phone counseling and instant messaging for smoking cessation.n = 220) will receive a nurse-led brief phone counseling immediately after the 1-week EMAs and 10-week EMA-based advice via instant messaging applications . The 10-week EMA-based advice covers a summary of the 1-week EMAs, and tailored cessation support focused on personalized smoking triggers. The control group (n = 220) will not receive any intervention during the same period. The primary outcomes are participants' progression toward smoking cessation assessed by the Incremental Behavior Change toward Smoking Cessation (IBC-S) and biochemically validated abstinence at the 3-month follow-up. Secondary outcomes include self-reported and biochemically validated tobacco abstinence at the 6-month follow-up.This is a two-arm, accessor-blinded, simple individual randomized controlled trial . Participants will be recruited from community sites and online platforms in Hong Kong. Interventions will be delivered via a phone call and instant messaging. Current adult smokers who (1) self-report no intention to use smoking cessation services and medication in the coming month and (2) have not used smoking cessation services or nicotine replacement therapy in the past 7 days will be recruited. Recruited participants will be randomized to intervention or control groups via an online randomizer. All participants will be required to complete EMAs (five times per day for 7 consecutive days). The intervention group (The findings will provide evidence that the EMA-based tailored smoking cessation intervention can be adapted as a new health promotion strategy for current smokers who are unwilling to use smoking cessation aids.https://classic.clinicaltrials.gov/ct2/show/NCT05212220, identifier: NCT05212220. Smoking is the leading modifiable risk factor for premature death . Health Ecological momentary assessment (EMA) is the self-administered documentation of real-time data on real-world behaviors, cognitions, or events . EMA aimEMA-based smoking cessation intervention has been defined as tailored treatments provided to smokers based on individual smoking behaviors and smoking triggers obtained from EMAs over a certain period in the real-world environment. The interventions are delivered after the completion of all EMAs. Ecological momentary intervention (EMI), which is an intervention delivered immediately after each episode of EMA, has been used in smoking cessation in previous studies , 21. TheIn Hong Kong, where the smoking prevalence was low (10.3% in 2021), only 3.8% of current smokers have ever used a smoking cessation service . Thus, eClinicalTrials.gov (NCT05212220).This is a two-arm RCT  nested within an EMA-based observational study. During the 1-week EMA, all participants will be prompted to complete EMAs five times per day for 7 consecutive days to document their smoking triggers, smoking behaviors, and daily cigarette consumption. Subsequently, the intervention group will receive an EMA-based intervention, including 15-min nurse-led brief phone counseling and 10-week tailored messages via instant messaging applications. The control group will not receive any intervention after the 1-week EMA. Both groups will be followed up at 3 and 6 months see . The ConThis study has obtained ethical approval from the Institutional Review Board of the University of Hong Kong, Hospital Authority Hong Kong West Cluster (UW 20-524). Online consent to participate in this study will be obtained from study participants.Smokers with the following inclusion criteria will be invited to participate in the trial: (1) daily smokers using traditional cigarettes, electronic cigarettes, or heated tobacco products in the past week; (2) age ≥18 years; (3) owning a smartphone with internet access; (4) those who will be staying in Hong Kong during the 1-week EMA study because the EMA application's prompting capability can only be used in Hong Kong due to technical restrictions; (5) those who are able to read and write Chinese; (6) those who have no plan to use smoking cessation services or medications in the coming month; and (7) those who have not used smoking cessation services or nicotine replacement therapy (NRT) in the past 7 days. Participants' smoking status will be confirmed by measuring exhaled carbon monoxide (≥4 ppm) using a Smokerlyzer or salivary cotinine (≥30 ng/ml) using an iScreen OFD Cotinine Saliva Test Device , 26. SmoThe recruitment process will be conducted both offline and online. We will use a “foot-in-the-door” approach for offline recruitment, which has been shown to be a feasible and efficacious way to reach smokers at outdoor smoking hotspots (public outdoor areas where smokers gather to smoke) in the community in our previous study . Our recWe will also send mass emails or post advertisements online . Potential participants interested in this project can complete the online application form  by scanning the Quick Response code or clicking the URL on the advertisement. Our recruitment staff will then make appointments with the potential participants to complete recruitment procedures via face-to-face or virtual meetings on Zoom. During the face-to-face recruitment meeting, our recruitment staff will instruct them to do the saliva test to confirm their smoking status, complete the online consent form and the baseline questionnaire, and install and set up the EMA application. If participants prefer a virtual meeting, we will first mail them the saliva test kit. They will probably receive the kit in 2–3 days. During the virtual recruitment meeting, the recruitment staff will instruct the potential participant to verify their smoking status using the saliva test kit. Only those who pass the saliva test will be invited for the subsequent recruitment procedure.An EMA application has been developed for smokers to document all smoking triggers and smoking-related behaviors. After installing the EMA application on participants' smartphones, participants need to input the last five digits of their telephone number as an identifier and select the study start date (participants can start the next day at the earliest). Participants need to complete five signal-contingent EMAs per day for 7 consecutive days during their awake time, with a 3-h interval between two prompts. For example, if a participant sets the first prompt time at 9:00 a.m., he/she will be asked to complete an EMA at 9:00 a.m., 12:00 p.m., 3:00 p.m., 6:00 p.m., and 9:00 p.m., respectively.In each signal-contingent EMA time window, the application will first prompt the user to answer questions on smoking triggers and smoking-related behaviors, which takes ~1 min. If the user does not respond to the EMA prompt within 5 min, two subsequent prompts will be generated within 10 min. The corresponding EMA will be regarded as non-response if these additional prompts are not answered. All data will be uploaded to the server located at The University of Hong Kong immediately after each EMA completion.none) to 4 (very severe))? (2) How satisfied were you with your last night sleep pattern [score ranges from 0 (very satisfied) to 4 (very dissatisfied)]? The time for the first cigarette after waking up will be asked at the second EMA daily. Exposure to tobacco control policy, including health warnings on their tobacco pack, point-of-sale tobacco displays, smoking hotspots, and daily tobacco consumption, will be asked in the fifth EMA daily  and six negative affects . Social triggers include social gatherings, going to entertainment venues, seeing others smoking, and being recommended tobacco products by others. Habitual triggers include during breaks, upon waking, after meals, and at work. Withdrawal triggers include exposure to secondhand smoke, depression, irritability, tension, anxiety, restlessness, fatigue, and poor concentration . SmokingMA daily . A reminOverly frequent EMAs may increase participant burden and decrease the completion rate, but too few EMAs and longer measurement intervals may disengage the participant from EMA and make them forget to follow the EMA protocol . A meta-An incremental incentive strategy will be used. All participants will be given a HK$50 (US$6.37) shopping voucher for the completion of the baseline survey and a HK$15 (US$1.91) shopping voucher for completing three time-based EMA surveys within each day. They will be further rewarded with a HK$10 (US$1.27) shopping voucher for completing five surveys each day. In addition, participants will be further rewarded with HK$25 (US$3.19) shopping vouchers for completing more than 80% of the 1-week EMA surveys. Self-reported quitters who complete biochemical validation at 3- or 6-month follow-up will obtain an additional HK$50 (US$6.37) shopping voucher. Therefore, each participant can get up to HK$300 (US$38.22) for completing all requirements.After the 1-week EMA, participants in the intervention group will receive an EMA-based intervention package, which includes a 15-min nurse-led brief phone counseling and 10-week tailored messages via instant messaging applications. The intervention content is based on the US clinical practice guidelines for smoking cessation  and the Brief phone counseling will be provided by trained research nurses with 2 years of experience in smoking cessation counseling. These nurses have received a training session on an overview of the research project and the nurse report template. The research assistant will first summarize the 1-week EMA record in the nurse report for each participant and then send participants' nurse reports to the nurse. Afterward, the nurse will provide a brief phone counseling session that includes: (1) a summary of the 1-week EMA observation, including type and frequency of craving, nicotine dependence level, and pro-smoking triggers; (2) self-help techniques to manage craving and pro-smoking triggers; (3) increasing motivation to quit by raising awareness of the harms of smoking, providing tips for coping with triggers, and improving outcome expectancies. If the participants are interested in quitting, the nurse can refer them to current smoking cessation services .After the counseling, participants in the intervention group will receive personalized cessation messages through instant messaging applications  for 10 weeks. Participants can choose to respond or not to our messages . The 10-Simple individual randomization  will be applied. Qualtrics' randomizer will be used for random allocation. This will be implemented by research staff not involved in the recruitment to achieve allocation concealment. After a participant consent to the trial, the non-recruiting research staff will access the randomizer and enter the individual participant's 5-digit identifier. With the randomizer feature in place, Qualtrics will display a page indicating to which group the participant was allocated.Participants and the staff of intervention delivery cannot be blinded because of the behavioral nature of the intervention. However, outcome assessors and data analysts will not be involved in the recruitment and intervention delivery and are thus blinded to the group allocation .never) to 5 , and level of urge during the past 7 days [score range from 0  to 5 (extremely). IBC-S is a scale that can detect the effect of interventions on moving participants toward quitting attempts and preparation  self-reported 7-day point-prevalence abstinence at 3- and 6-month follow-ups; (2) biochemically validated abstinence at 6-month follow-up; and (3) self-reported use of smoking cessation services or medication from baseline at 3- and 6-month follow-ups. Ancillary outcomes include quit attempts at 3 and 6 months, satisfaction with the EMA and the study procedures, perceived importance , confideFor the process evaluation of the intervention, information on the type of intervention received, perceived usefulness of the intervention, and satisfaction toward the intervention will be measured at the 3-month follow-up. Brief phone counseling time will be collected from nurses. The EMA compliance rate and percentage of participants receiving both brief phone counseling and instant messages will also be calculated.*Power software (version 3), a total of 452 participants  is needed. However, due to the limited budget for this project, we plan to recruit 440 participants in total.To date, there has been no similar RCT to provide an estimate of the effect size of the EMA-based intervention. An updated Cochrane network meta-analysis indicated that the odds ratio of biochemical validation abstinence between tailored short messaging service (SMS) focused on how to quit and minimal smoking cessation intervention was 1.92 . One of The primary analysis will examine the effect of the EMA-based intervention on biochemically validated abstinence at 3 months and the difference in the IBC-S score between the two groups. The ITT approach will be used to include all randomized participants in the denominators and assume non-respondents at the 3-month follow-up as smokers with no change in the IBC-S score. We will conduct logistic regression models to compare abstinence between the intervention and control groups. We will use multivariable linear and logistic regression models adjusted for imbalanced sociodemographics assessed at baseline to summarize the intervention effect on IBC-S and biochemically validated abstinence at 3-month follow-up. Multiple imputations will be used to impute missing data for the observed data as a sensitivity analysis. Another sensitivity analysis for the primary outcomes will be performed through a complete case analysis. Subgroup analysis of comparing the primary outcomes between intervention group participants who receive both nurse-led counseling plus instant messaging and instant messaging only will be conducted to assess the utility of the counseling. All statistical analyses will be conducted using Stata/SE (version 16) or R (version 1.3.1073).In total, 459 participants were recruited from 21 March 2022 to 3 January 2023. All follow-up and data collection are expected to be completed in July 2023.It is the first RCT to examine the effectiveness of an EMA-based smoking cessation intervention on smoking cessation for current smokers. If the effectiveness of an EMA-based smoking cessation intervention is found, the intervention model can be adopted as a new health promotion strategy for engaging current smokers who do not want to use smoking cessation aids in quitting. Unlike most conventional smoking cessation studies, in which the target smokers are those who are motivated to quit with smoking cessation aids, our target smokers include those who have no intention to use smoking cessation aids within the following month and have not used smoking cessation aids in the past 7 days . TherefoThis study has obtained ethical approval from the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 20-524). Online written consent to participate in this study will be obtained from study participants.YTDC contributed to the conceptualization of the project. YTDC and MJZ contributed to the methods and investigation and wrote the original draft of the manuscript. MJZ served as the project administrator. All authors provided critical feedback and reviewed, edited, and approved the final manuscript.


Introduction: With the diminishing use of whole-brain radiotherapy (WBRT), there is increasing debate regarding the maximum number of brain metastases that should be treated with stereotactic radiosurgery (SRS). In patients with >10-15 lesions, some groups are proposing a new approach - selected-lesion SRS (SL-SRS) - where only a subset of intracranial lesions are chosen for irradiation. This study is an initial look into this practice.Methods: This is a cross-sectional exploratory survey study. A survey of 19 questions was created by the International Radiosurgery Research Foundation (IRRF) using open-ended and multiple-choice style questions on SL-SRS practices and indications with the goal of qualitatively understanding how SL-SRS is being implemented worldwide. The survey was distributed to physicians in the United States (US) and internationally who are members of the IRRF and who perform SRS frequently. Ten out of 50 IRRF institutions provided responses reflecting the practices of 16 physicians.Results: SL-SRS is being performed at 8/10 institutions. The most common reasons for using SL-SRS included patients with prior WBRT, patients with progressing systemic disease with central nervous system (CNS)-penetrating or immunotherapies available, specific requests from medical oncology, and cooperative studies using this approach. Lesion size was cited as the most important factor when choosing to irradiate any single lesion. The majority of respondents reported 30 mm and 40 mm as size cutoffs (by largest dimension) for treatment of a lesion in eloquent and non-eloquent locations, respectively. Eloquence of lesion location and attributable symptoms were also considered important. Progression of untreated lesions was the most common reason reported for bringing patients back for additional treatment.Conclusion: The responses to this survey show that SL-SRS is being used, allowing for small/asymptomatic brain metastases to be left safely unirradiated. It is currently used in patients who have >10-15 lesions with prior WBRT, those with progression of extracranial disease but with acceptable systemic treatment options, and those with poor functional status. The incorporation of this new approach into clinical trials should be considered for the safe study of the efficacy of new CNS-penetrating systemic therapies. Intracranial stereotactic radiosurgery (SRS) has become the mainstay initial and salvage treatment for most patients with brain metastases, both singular and multiple -2. SRS oGiven the trend away from using WBRT , there hTraditionally, this approach was considered in patients who had prior WBRT and who presented with >10-15 metastases. In order to avoid repeat WBRT and its risk of neurotoxicity ,11-14, SMore recently, SL-SRS has been proposed in patients without prior WBRT treatment in the context of newer and more available systemic therapy options with some degree of central nervous system (CNS) penetration. With this treatment philosophy, asymptomatic brain metastasis can, therefore, be left unirradiated and instead monitored radiographically as a patient continues systemic therapy. As it currently stands, this approach is in direct contradiction to the standard approach to treatment of CNS metastatic disease. As such, there is no prospective literature to guide SL-SRS practices, including indications for SL-SRS and which lesions should be chosen for treatment. Therefore, we surveyed clinicians skilled in SRS at high-volume centers on their experience and approach to SL-SRS, including factors they used to decide how many and which lesions to treat.This was a cross-sectional exploratory survey study developed by members of the International Radiosurgery Research Foundation (IRRF) with the goal of understanding current opinions on SL-SRS. The IRRF is a non-profit scientific and educational entity consisting of neurosurgeons, radiation oncologists, and medical physicists at academic and clinical centers that perform SRS, track outcomes, and develop research proposals and clinical trials surrounding SRS. Membership to the IRRF is reviewed by a Board of Directors. The 19-question survey was generated by IRRF members and distributed via e-mail to all IRRF-participating centers (Table Types of questions included in the survey included open-ended (Question (Q)2, Q3, Q5, Q6, Q8, Q9), yes/no , multiple choice with single response only , multiple choice with unlimited responses , and one ranking question (Q15). For Question 14, respondents were presented with a hypothetical case of a patient with a biopsy-proven carcinoma with >15 previously radiosurgically-treated brain metastases and asked to designate factors that would encourage them to consider SL-SRS with no limit on the number of factors they could choose. For Question 15, respondents were asked to rank five factors influencing their decision to treat a specific lesion with radiosurgery. Rankings of 1-2 were classified as “most important,” 3-4 as “moderately important,” and 5 as “not important.” Descriptive statistics  were calculated for questions that solicited numerical responses where appropriate. However, no inferential statistics were performed.Ten out of 50 institutions responded to the survey, reflecting a total of 16 clinicians across the 10 institutions. Six centers were located in the United States (US), and an additional four were located in Canada, India, Taiwan, and Turkey. There were five institutions whose responses reflected the practices of >1 clinician.SRS practicesThe number of radiosurgery cases performed at each institution in 2021 ranged from 168 to 741 cases (mean 406) (Table The majority of programs (six out of 10) had no formal or informal upper limit for the number of brain metastases that could be treated by single or fractionated SRS. The range for programs that did report an upper limit was 15-25 brain metastases. Table SL-SRS practicesSL-SRS was performed at eight of 10 institutions  Table . HoweverRespondents were asked to rank the importance of five factors that may influence their decision to treat any single lesion in SL-SRS Figure . Ninety Respondents were asked to comment on size cutoffs for treating lesions in eloquent or non-eloquent areas. Responses are depicted in Table Respondents designated several factors that would encourage them to consider SL-SRS in a hypothetical case of a patient with biopsy-proven carcinoma and >15 previously treated brain metastases Figure . “Prior Finally, when asked which factors would drive clinicians to bring back patients for treatment of the remaining lesions, “progression of other lesions” was the most cited factor  with SL-SRS may help clarify and consolidate the indications for this strategy.More intriguingly, with several institutions now reportedly using SL-SRS, this practice may additionally provide the basis for a unique opportunity. As new targeted immunotherapies are being designed and approved at an increasingly rapid pace, there is an increased need for understanding the CNS efficacy of each of these drugs -26,28. IIn our opinion, the use of CNS-penetrating treatments is revolutionizing how we view the treatment of CNS metastasis. Focal therapy carries unique complications that could be deferred if only select lesions are treated. This survey shows that patients with >10-15 brain metastases who have had prior WBRT, those with progression of extracranial disease still with acceptable systemic treatment options available, and those with poor functional status are currently being considered for SL-SRS in institutions worldwide. Larger lesion size, functionally eloquent location, and presence of symptomatology are the most common reasons to choose any given lesion for SRS. Future studies evaluating outcomes after SL-SRS are needed to form a consensus on how to best implement SL-SRS into standard practice. In addition, consideration of this technique for incorporation into new drug clinical trials may allow brain metastases more access to new agents and provide data for each drug’s CNS efficacy.


The Cogan’s sign is indicative of myasthenia gravis. This is the first report of neurological signs in a patient with post-COVID-19 vaccine-associated myasthenia gravis in Brazil. In this case, a previously healthy 68-year-old woman presented with proximal limb weakness, left ptosis, and diplopia 1 month after receiving her fourth dose of the COVID-19 vaccine. Neurological examination revealed the presence of Cogan’s sign, and she recovered rapidly after treatment. To our knowledge, this is the first reported case of myasthenia gravis associated with the COVID-19 vaccine in Brazil.  The Cogan’s sign is characterized by a transient overshoot twitch of lid retraction after a sudden return of the eyes to their normal position following a period of downward gaze. It is caused by a neuromuscular junction disorder known as myasthenia gravis,Myasthenia gravis is an autoimmune disease characterized by proximal weakness of the limbs and ocular muscles, with an annual incidence of 30 cases per million adults-Autoimmune diseases can occur after vaccinationA search strategy was developed to conduct endless searches in MEDLINE via PubMed. The following descriptors (bold), synonyms, natural language, and Boolean operators were used to cross-check the databases: MEDLINE  and (COVID-19 vaccine) and (Oxford AstraZeneca). The search was conducted on January 12, 2023.VIDEO 1 and VIDEO 2). The patient was administered pyridostigmine 60 mg four times daily. However, her condition continued to deteriorate, necessitating admission to the intensive care unit 2 months after the initial diagnosis due to dysphagia, dysarthria, and dyspnea. She was intubated and underwent five sessions of plasmapheresis. Rapid improvement was observed with prednisone (1 mg/kg) and azathioprine/pyridostigmine combination. The patient also underwent thoracic computed tomography, which showed no thymoma, and an anti-acetylcholine receptor antibody test, which showed a positive result. No analysis of the cerebrospinal fluid was performed. She is currently stable neurologically and receives azathioprine 50 mg and prednisone 10 mg daily with pyridostigmine 60 mg six times daily. The patient provided informed consent for the publication of this report.A previously healthy 68-year-old female patient presented with proximal limb weakness, left ptosis, and diplopia 1 month after receiving her fourth dose of the COVID-19 vaccine, (Oxford-Astra Zeneca®). She consulted a neurologist who requested electroneuromyography with repetitive stimulation of the four limbs, which revealed a decrement pattern, consistent with myasthenia gravis. The absence of clinical symptoms suggestive of infection (such as fever and dyspnea) and laboratory and imaging tests  ruled out infections as possible triggers. Neurological examination revealed the Cogan’s sign (Supplementary material - This case report demonstrated neurological signs in a patient with post-COVID-19 vaccine-associated myasthenia gravis. To our knowledge, this is the first report of post-COVID-19 vaccine-associated myasthenia gravis in Brazil.The Cogan’s sign, a characteristic of myasthenia gravis, was first described in 1965. It is elicited by instructing a patient to maintain a downward gaze for 15 s, followed by an upward gaze. When positive, the upper lid produces an overshoot,Other authors have previously described post-COVID-19 vaccine-associated myasthenia gravis, and we found 14 cases in the literature,,Myasthenia gravis cases after COVID-19 infection and COVID-19 vaccination may be caused by immune dysregulationThe limitations of our study include the fact that it involved a single case, and the period between vaccination and the onset of symptoms was longer than that described in previously reported cases. It is important to note that there are several types of COVID-19 vaccines, and this case demonstrates a rare adverse reaction to only one type. To the best of our knowledge, this study is the first case of post-COVID-19 vaccine-associated myasthenia gravis in Brazil, and the neurological signs were documented on video. This case showed neurological signs in a patient in an atypical context, which will assist medical students and doctors in considering myasthenia gravis after COVID-19 vaccination.


Loss to follow-up (LTFU) among adolescents and young adults living with HIV (AYALWH) is a barrier to optimal health and HIV services. We developed and validated a clinical prediction tool to identify AYALWH at risk of LTFU.We used electronic medical records (EMR) of AYALWH ages 10 to 24 in HIV care at 6 facilities in Kenya and surveys from a subset of participants. Early LTFU was defined as >30 days late for a scheduled visit in the last 6 months, which accounts for clients with multi-month refills. We developed a tool combining surveys with EMR (‘survey-plus-EMR tool’), and an ‘EMR-alone’ tool to predict high, medium, and low risk of LTFU. The survey-plus-EMR tool included candidate sociodemographics, partnership status, mental health, peer support, any unmet clinic needs, WHO stage, and time in care variables for tool development, while the EMR-alone included clinical and time in care variables only. Tools were developed in a 50% random sample of the data and internally validated using 10-fold cross-validation of the full sample. Tool performance was evaluated using Hazard Ratios (HR), 95% Confidence Intervals (CI), and area under the curve (AUC) ≥ 0.7 for good performance and ≥0.60 for modest performance.Data from 865 AYALWH were included in the survey-plus-EMR tool and early LTFU was . The survey-plus-EMR tool ranged from 0 to 4, including PHQ-9 ≥5, lack of peer support group attendance, and any unmet clinical need. High (3 or 4) and medium (2) prediction scores were associated with greater risk of LTFU  in the validation dataset. The 10-fold cross validation AUC was 0.66 (95%CI: 0.63–0.72). Data from 2,696 AYALWH were included in the EMR-alone tool and early LTFU was 28.6% . In the validation dataset, high  and medium scores  predicted significantly higher LTFU than low-risk scores . Ten-fold cross-validation AUC was 0.61 (95%CI: 0.59–0.64).Clinical prediction of LTFU was modest using the surveys-plus-EMR tool and the EMR-alone tool, suggesting limited use in routine care. However, findings may inform future prediction tools and intervention targets to reduce LTFU among AYALWH. Adolescents and young adults living with HIV (AYALWH) in sub-Saharan Africa continue to experience lower retention in care and poorer outcomes than adults, despite the availability of antiretroviral therapy (ART) to improve individual health and reduce transmission risk . Once trSeveral factors can increase risk of LTFU from care among AYALWH . These iMany countries in sub-Saharan Africa have adopted differentiated service delivery models, a form of client-centered care intended to improve system efficiencies, quality, and outcomes . ClientsClinical prediction tools are an effective, data-driven strategy to improve care and treatment decisions for a range of health conditions –31 incluA clinical prediction tool to identify AYALWH at risk of LTFU could support clinicians to better allocate intensified care to at-risk AYALWH before they are lost and to identify stable AYALWH for differentiated services. To address this gap, we developed and validated a clinical prediction tool to identify AYALWH at risk of LTFU using surveys and routine data.We conducted a prospective cohort study among AYALWH enrolled in care at six facilities in Kisumu and Homa Bay counties in Kenya. Selection criteria for the facilities were having an active electronic medical records (EMR) system, at least 100 AYALWH enrolled in care, and permission from facility managers. Data sources for this clinical prediction tool included AYALWH EMR and surveys. EMR data included all AYALWH ages 10 to 24 years enrolled in HIV care from October 1, 2018, until administrative censoring on February 29, 2020, due to COVID-19. Starting in April 2019, all eligible AYALWH ages 10 to 24 enrolled in care at the time were invited to participate in a cohort study that included behavioral surveys at enrollment and every 6 months. Study staff obtained written informed consent from AYALWH ages 18 to 24 or caregiver consent and adolescent assent for adolescents ages 10 to 17 years. Study staff administered face-to-face surveys during routine clinic visits in the participants’ preferred language .The primary outcome of the prediction tool was loss to follow-up, defined as >30 days late for a scheduled visit in the EMR during a 6-month period. We chose this definition to measure early risk of LTFU among AYALWH when interventions to support clinic attendance may be most effective . CountinCandidate predictors of LTFU were selected from AYALWH surveys and EMR data based on plausibly and prior studies among AYALWH , 13, 14.unmet clinical needs was computed as indicating at least one need was not met after reading aloud a list of standard services that should be offered at the clinic visit, including contraception and pregnancy information, screening for STIs, depression, gender-based violence (GBV), and substance use, nutrition assessment, and referral to peer support groups. Asking clients whether their clinical needs were met at the visit is often used to evaluate quality of care  0.1–7.6). Overall, 6-month LTFU in the EMR cohort was 28.6% (n = 770), with no significant difference between training and validation cohorts  . The traThe final predictive model using AIC included age group and newly enrolled status . Individual scores ranged from 0 (low risk) to 2 (high risk) . The preWe developed two clinical prediction tools, one using EMR data combined with survey data and one using only EMR data, to predict LTFU among AYALWH and found similarly poor predictive performance. Overall, both tools showed poor performance by standard measures. The survey-plus-EMR tool, which included PHQ-9 score, peer support group enrollment, and any unmet care needs had slightly better performance (AUC) than the EMR-alone tool in the training dataset. The EMR-alone tool, which only included age and time in care, predicted LTFU in the validation cohort. The tools had similar generalizability when cross-validated in the full samples. While both tools demonstrated moderate predictive ability, results may guide future clinical prediction tools and decision-support interventions with AYALWH.We chose the outcome of early LTFU to support early intervention before AYALWH are lost. The survey-plus-EMR analysis evaluated several additional variables that are likely associated with adolescent LTFU  to deterWe found that older age group (20–24 years) and longer time in care (six months or more) were predictors of LTFU, and older age has been shown to be associated with LTFU in prior studies [Compared to other clinical prediction tools developed for HIV prevention and care in sub-Saharan Africa, our tool included fewer variables and demonstrated lower performance by AUC. The ability of our tool to discriminate between AYALWH who were lost and not lost in both the training and validation cohorts ranged from 0.61 to 0.66, which is lower than the commonly used threshold of 0.7 . Other tet al. [et al., highlights, prediction tools with modest performance can offer useful information about challenges of implementing prediction tools into practice as well as other HIV service and client factors that need to be addressed for decision-support interventions in HIV care. Given the modest performance of both tools in our study, we do not recommend adapting these tools for routine care given the potential of mis-identifying AYALWH at risk of LTFU. Instead, the predictors evaluated in survey-plus-EMR and EMR-alone tools could be used as the basis for development of new prediction tools in similar populations and inform potential targets of future decision-support interventions with AYALWH.Other HIV-related prediction tools with performance of <0.7 by AUC have been evaluated in different research cohorts , 38 withet al.  developeet al. . The intOur study had strengths and limitations. To our knowledge, this is the first study to develop and validate a clinical prediction tool to identify AYALWH at risk of LTFU. We assessed psychosocial and service-related variables that have not been tested in prior prediction models for LTFU, and we considered both survey-plus-EMR and EMR-alone versions. The EMR-alone tool was limited to variables in that dataset, which were primarily clinical and demographic variables. LTFU using EMR data is subject to misclassification due to variable data quality and completeness . We trieIn summary, our clinical prediction tools using surveys-plus-EMR or EMR-alone showed modest predictive ability to identify AYALWH at risk of loss to follow-up and would have limited use to improve clinical decision making in this population. Accurately predicting LTFU among AYALWH remains challenging, especially as national guidelines change about visit timing for AYALWH change. Regardless, these results offer insights for future provider decision-support interventions to reduce LTFU among AYALWH clients, specifically the importance of including standard mental health screening and peer support services with this population.


Self-efficacy is a vital personal characteristic for student success. However, the challenge of cross-cultural comparisons remains as scalar invariance is hard to be satisfied. Also, it is unclear how to contextually understand student self-efficacy in light of cultural values in different countries. This study implements a novel alignment optimization method to rank the latent means of student self-efficacy of 308,849 students in 11,574 schools across 42 countries and economies that participated in the 2018 Program in International Student Assessment. We then used classification and regression trees to classified countries with differential latent means of student self-efficacy into groups according to Hofstede’s six cultural dimensions theory. The results of the alignment method recovered that Albania, Colombia, and Peru had students with the highest mean self-efficacy, while Slovak Republic, Moscow Region (RUS), and Lebanon had the lowest. Moreover, the CART analysis indicated a low student self-efficacy for countries presenting three features: (1) extremely high power distance; (2) restraint; and (3) collectivism. These findings theoretically highlighted the significance of cultural values in shaping student self-efficacy across countries and practically provided concrete suggestions to educators on which countries to emulate such that student self-efficacy could be promoted and informed educators in secondary education institutes on the international expansion of academic exchanges. PreviouRecognizing the importance of self-efficacy, large-scale international assessments, such as the Program for International Student Assessment (PISA), have measured it in their investigations ,b. PISA As a meaningful cross-country comparison requires scalar invariance that is difficult to establish , researcUnderstanding the factors that determine student self-efficacy is an important topic in the education field. These constitute a set of student, family, teacher, and school-level factors, such as student cognitive activation , family 2.2.1.Whenever one construct is compared in a large-scale assessment, there is always a risk of measurement bias being introduced, reducing the validity of scientific conclusions . Three tThe elimination of measurement bias is a precondition for achieving cross-cultural measurement invariance; hence, these two constructs  may be seen as opposite sides of the same coin . Scholar2.2.As scalar invariance is rarely achieved in large cross-national comparisons , researcIn 2014, Alignment method has been applied effectively in testing measurement invariance across groups e.g., , creatin2.3.The global population of students who attend study-abroad programs has increased enormously . The extCultural values refer to “trans-situational goals… that serve as guiding principles in the life of a person or other social entity” , p. 21. Previous studies have documented that a society’s cultural values could impact an individual’s psychological processes, such as self-efficacy, judgment, emotion, etc. . HoweverIn addition, there are scant cross-country comparisons in the previous studies that have the benefit of comprehensively considering the influence of cultural values. Six cultural values do not exist in isolation, but rather interact with each other to shape students’ beliefs, attitudes, and behaviors. For example, a student from a culture that values restraint may also value long-term planning, which could potentially increase their self-efficacy. However, if that same student also comes from a culture that values high power distance, they may struggle with expressing their opinions and taking control of their own learning, which could potentially limit their self-efficacy. Therefore, the second purpose of this study was to analyze all of six cultural dimensions using classification and regression tree analysis in order to identify the most influential cultural values, the interactive patterns of cultural values, and the distinct groups of countries at varying levels of student self-efficacy.2.4.In sum, student self-efficacy is an important factor that significantly contributes to academic achievement and serves as a defining characteristic of successful students. Scholars have made great efforts to make cross-country comparisons of student self-efficacy in order to better understand how to promote it and to decide which nations should be studied in more depth . HoweverAlso, as it is still difficult to disentangle the respective contribution of multiple cultural values to student self-efficacy when these values are dynamic and interactive in nature, we use classification and regression tree analysis to segment countries into small groups that share similar Hofstede’s six cultural dimensions, and decompose complicated interactions among these cultural values . These aWhich countries have the highest (and lowest) student perceptions of self-efficacy?Which cultural values proposed by How many distinct groups of countries existed in terms of student self-efficacy?The significance of our study is multifaceted. First, we employs a novel alignment optimization method to rank the countries and economies considering student self-efficacy which is a research gap has not been addressed. By conducting the analysis, we attempted to offer scientific information based on what the PISA 2018 data says, which could help guide policymakers and education stakeholders toward the right countries or economies to promote student self-efficacy. Second, by using observable cultural dimensions as explanatory variables to identify the distinct groups of countries in terms of student self-efficacy, this study helps educators facilitate student self-efficacy by focusing on those groups of exchange students that may experience cultural shock. Lastly, our study contributes to the broader understanding of the complex relationship between cultural values and student achievement, and may inspire further research in this area to better inform educational policies and practices across diverse cultural contexts.3.3.1.The current study used information of a sample of 15-year-old students in the PISA 2018 database.As participation in the PISA 2018 was optional for countries and schools (OECD), the initial data presented a non-ignorable number of missing values. Thus, we deleted the observations where >20% of the values were missing ; one cou3.2.https://www.hofstede-insights.com/country-comparison/). The cultural values for our final analytical sample can be found at Student self-efficacy was measured by five items in the PISA 2018 questionnaire. All items share the same question stem: “How strongly do you agree or disagree with the following statements.” Each item has four categories: 1 = Strongly disagree, 2 = Disagree, 3 = Agree, 4 = Strongly Agree, with a higher value indicating a better rate of self-efficacy. 3.3.3.3.1.h) calculated based on factor loadings and unique variance , CFI/TLI ≥ 0.95 , and RMSEA/SRMR ≤0.08 .h) and validity (CFA) assessments across these countries.The information of the rest of the 42 countries was kept for further analysis as they meet all of the criteria. The descriptive statistics of each item in the student self-efficacy scale were provided in 2 = 13181.33, df = 215, CFI = 0.966, TLI = 0.972, RMSEA = 0.078, SRMR = 0.031).Consequently, we evaluated the configural invariance of multi-group analyses based on the data from 42 countries. The results of the GOF indices showed that the configural invariance model fits the data well , B-S-J-Z (China) (9), Dominican Republic (12), Montenegro (25), Moscow Region (RUS) (27), Peru (29), and Portugal (32). That is, the equality of the factor loading condition holds for item ST188Q01HA across 35 other countries. The results of other items’ interceptions and loadings presented at 4.3.After testing the reliability and validity of the student self-efficacy scale and the assumptions of the alignment method, we were able to rank 42 countries and economies by comparing the factor mean values of student self-efficacy .As shown at the table, the rank order of factor means demonstrated that Albania showed the highest factor mean in student self-efficacy, followed by Colombia and Peru. The lowest three countries/economies in student self-efficacy were Slovak Republic, Moscow Region (RUS), and Lebanon.4.4.The root node was first split according to the power-distance dimension (this dimension had the largest reduction in impurity from the root to its child nodes). The left child node became a terminal node (G1); it contained seven countries (17%) that scored at least 91 and whose average factor mean score was 0.31. The right child node contained 35 countries (83%) whose power-distance scores were less than 91 and whose average factor mean score was 0.61. Among those countries, 14 (33%) with indulgence scores less than 29 became a terminal node with an average factor mean score of 0.53 (G2). The other 21 countries (50%), which had an average factor mean score of 0.66, were split further according to the individualism dimension. Fourteen countries (33%) with individualism scores less than 64 had an average factor mean score of 0.63 (G3), and seven (17%) with individualism scores equal or greater than 64 showed an average factor mean score at 0.71 (G4).4.5.Descriptive statistics showed that, for the terminal node with the lower factor mean scores (G1), average power-distance scores were extremely high (94.01) and both the individualism (32.14) and indulgence (28.83) scores were the second-to-last across all groups. Conversely, countries in the terminal node with the highest average value of factor mean scores (G4) were dominated by a low power distance (35.71), extremely individualist (81.57), and moderately indulgent culture (59.57). The countries in terminal nodes G2 and G3 shared similar high power distance  and collectivistic  cultures, but showed very different attitudes regarding an indulgent lifestyle (19.50 vs. 48.69).5.By applying the alignment method in CFA to a large-scale international assessment , this study answered our research questions regarding the comparisons of student self-efficacy across 42 countries and economies and the impact of cultural values on shaping student self-efficacy. We found that: (1) based on their factor mean scores, Albania, Colombia, and Peru comprised among the top league of the student self-efficacy assessment and Slovak Republic, Moscow Region (RUS), and Lebanon comprised the bottom; (2) Using Hofstede’s six cultural dimensions as predictors, CART analysis identified that three of the six cultural dimensions engaged one another in a complex interactive manner to impact student self-efficacy in a way that is far more complicated than that which many traditional statistical methods such as ANOVA can usually recover . Moreove5.1.h ≥ 0.70) across most of the countries and economies that participated in PISA 2018, which is consistent with previous research  have below-average scores in student self-efficacy, which is documented by previous studies. One international study found that Filipino students usually experience higher anxiety and lower math self-efficacy than American and Korean counterparts . This co5.2.2.Distinct patterns were detected after the most substantial partition at the first level of prediction. The indulgence dimension behaves uniquely, appearing only for countries reporting a lower score on the power-distance dimension. In the literature, indulgent culture has mixed effects on student self-efficacy. On one side, an indulgent culture can negatively impact student self-efficacy through low expectations and a lack of challenge . StudentOur study supported the second case. This discrepancy might be explained by the interaction between power distance and indulgence. Compared to G3-4, G2 scored higher in the power-distance dimension , which c5.2.3.Lastly, at the third level of the regression tree, the individualism dimension was very relevant for the groups of countries with moderate (G3) and high (G4) levels of student self-efficacy. Specifically, students in countries that scored <64 in the individualism dimension (G3) held weaker beliefs in their ability to fulfill their academic tasks than their counterparts in countries with scores of ≥64 (G4). Two reasons may explain this phenomenon: (1) the high self-efficacy scores may reflect cultural demands for personal responsibility. In individualistic societies, students are often expected to take responsibility for their own lives and academic success . This caMoreover, G4 also scored very low on the power-distance dimension 35.71; , reflect5.2.4.Although the rest three cultural dimensions of femininity, uncertainty avoidance, and long-term orientation have been potentially related to student self-efficacy e.g., , the CARIn sum, the current research recovered a discernible pattern in the way three cultural dimensions are able to significantly shape student self-efficacy. The CART analysis underlines that these dimensions are not conceptually well orderly, linear, or closely related; rather, they offered distinct contributions to predict student self-efficacy. These findings have important implications for educators and policymakers, as they suggest that cultural factors can have a significant impact on student motivation and achievement. Educators should be aware of these cultural differences and strive to create learning environments that are inclusive and empowering for all students, regardless of their cultural backgrounds .5.3.This study is subject to several limitations, which also provide avenues for further research. First, Albania ranks first among the participating countries and economies in PISA 2018. However, we did not provide empirical evidence that would justify Albania being placed in that position, which requires further field research. Investigating the specific factors that contribute to Albania’s high ranking in student self-efficacy would help provide a more nuanced understanding of the underlying causes and potentially inform policy recommendations for other countries.Second, a large sample size is crucial for CART analysis, but our study had a relatively small sample, which might affect the findings’ robustness. Subsequent research should consider incorporating more countries and economies to expand the sample size and improve result generalizability. Furthermore, conducting replication studies using alternative datasets like the Trends in International Mathematics and Science Study (TIMSS) or the Progress in International Reading Literacy Study (PIRLS) would support the validation and verification of our findings.Countries with low student self-efficacy may also benefit from more studies into the function of educational policies and initiatives that foster self-efficacy. This would aid in providing actionable suggestions on how to create a learning environment that is supportive of students’ self-efficacy in multiple cultural settings. Lastly, extending the study’s scope to include additional psychological categories like motivation, resilience, or well-being might help create a more complete picture of the link between cultural values and other elements of student achievement.5.4.The findings in the current study highlighted the importance of cultural values in shaping student self-efficacy across countries. Thus, the present study carries several theoretical and practical implications. Theoretically, our findings contribute to the literature by demonstrating that not all cultural values are related to student self-efficacy. The identification of three cultural values  allows for a broader understanding of the complicated process and mechanisms that buffer the impact of cultural values on student self-efficacy. These findings also demonstrated that research on self-efficacy should take cultural differences into account . Cross-cPractically, this study employed the alignment method to rank 42 countries and economies using the PISA 2018 dataset, offering valuable insights for policymakers and education stakeholders. By identifying countries or economies with lower student self-efficacy levels, our findings can inform targeted interventions and policies aimed at enhancing self-efficacy within these regions. This approach allows for a more focused allocation of resources and the development of tailored strategies that address the unique cultural factors influencing self-efficacy in each country. In addition, the ranking can facilitate international collaboration and knowledge sharing between countries with varying self-efficacy levels, leading to the development of best practices and innovative solutions to improve student self-efficacy across diverse cultural contexts. This study also informs educators in secondary education institutes on the internationalization of academic exchanges such that host institutions can better support exchange students’ academic success . We usedFinally, as teacher-student interaction is the basic social relationship in schools, our study underlined the need to increase teachers’ awareness of the roles that cultural values play in student cognitive behaviors . Schoolshttps://www.oecd.org/pisa/data/2018database/.Publicly available datasets were analyzed in this study. This data can be found at: RJ developed the ideas. RJ, RW, YX, and MZ jointly wrote the manuscript. All authors contributed to the article and approved the submitted version.This article was supported by the National Social Science Fund of China under the project “A longitudinal study of teacher identity and professional development of non-teacher-oriented graduates from high-level comprehensive universities” (Project No. BHA210136).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cancer-related fatigue (CRF) is a common side-effect of cancer and its treatments, but few studies have investigated CRF in head and neck cancer. Using data from 2847 patients included in the Head and Neck 5000 prospective clinical cohort, we investigated CRF over 12 months from cancer diagnosis. At baseline, shortly after diagnosis, 27.8% of patients had CRF. This rose to 44.7% at 4 months and fell to 29.6% at 12 months. In adjusted models, the likelihood of having CRF over 12 months was significantly higher in patients who were female, current smokers, and had comorbid conditions or depression at baseline. It was also higher in patients with stage 3 or 4 disease and who had multimodal treatment. The high prevalence of CRF indicates that there is a need for additional interventions and supports for affected HNC patients; these could be targeted towards patients in the higher risk groups.Cancer-related fatigue (CRF) is a common side-effect of cancer and its treatments. For head and neck cancer (HNC), CRF may exacerbate the symptom burden and poor quality-of-life. Using data from the Head and Neck 5000 prospective clinical cohort, we investigated clinically important CRF over a year post-diagnosis, assessing temporal trends, CRF by HNC site and treatment received, and subgroups at higher risk of CRF. Recruitment was undertaken in 2011–2014. Socio-demographic and clinical data, and patient-reported CRF  were collected at baseline (pre-treatment) and 4- and 12- months post-baseline. Mixed-effects logistic multivariable regression was used to investigate time trends, compare cancer sites and treatment groups, and identify associations between clinical, socio-demographic and lifestyle variables and CRF. At baseline, 27.8% of 2847 patients scored in the range for clinically important CRF. This was 44.7% at 4 months and 29.6% at 12 months. In the multivariable model, after adjusting for time-point, the odds of having CRF over 12 months were significantly increased in females and current smokers; those with stage 3/4 disease, comorbidities and multimodal treatment; and those who had depression at baseline. The high prevalence of clinically important CRF indicates the need for additional interventions and supports for affected HNC patients. These findings also identified patient subgroups towards whom such interventions could be targeted. Head and neck cancer (HNC) is an umbrella term for tumours that arise in the oral cavity, pharynx, larynx, nasal cavity and sinuses. The complexity of the disease means that patients often undergo aggressive multi-modal treatment . This trCancer-related fatigue (CRF) is one of the most common side-effects of cancer, affecting up to 90% of patients at some point . It has One of the research challenges in CRF is that some instruments used to measure it generate a “score”, but how those scores should be interpreted for individual patients or groups of patients at a single point in time is unclear. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)—a well-validated measure of functioning and QoL in cancer—includes a subscale which can be used to generate a fatigue score . In 2016Using data from the Head and Neck 5000 (HN5000) prospective, longitudinal, clinical cohort study ,19, we aThe protocol and HN5000 population have been reported elsewhere ,19. In bn = 3779)  included 5404 individuals who consented to participate over April 2011–December 2014. For this analysis, we defined the study population as comprising people who had been diagnosed with oral cavity, oropharynx, larynx, hypopharynx, thyroid or salivary gland cancer, identified using ICD10 codes. We further limited consideration to individuals who had received treatment (curative or non-curative) and did not have recurrent disease during follow-up ( = 3779) . Due to Participants completed a health and lifestyle survey at baseline (before treatment started) and a series of standard questionnaires at 4- and 12-months post-baseline. The baseline survey collected data on socio-demographic variables  and lifestyle . The questionnaires included the EORTC QLQ-C30  and the Information abstracted from participants’ medical records at baseline included patient characteristics ; ICD10 tumour site ; TNM staFor this study, we focussed on the fatigue subscale (“FA”) of the EORTC QLQ-C30, which includes three questions on fatigue experienced over the past week. Question responses were combined and linearly transformed into a score in the range 0–100, treating missing data as recommended ; higher n = 2847) and those who were in the study population but did not complete the subscale (n = 932), were compared using chi-square tests.To be included in the analysis of CRF, individuals in the study population had to have completed the FA subscale questions at baseline . To assep ≤ 0.05 (two-sided) was considered statistically significant throughout.The proportions of participants with clinically important CRF at each time-point—baseline, 4 and 12 months—were computed overall, by cancer site and by treatment received; the analysis of treatment was limited to the 4- and 12-month time-points. Mixed-effects multivariable logistic regression was used to examine time trends and identify factors associated with presence of clinically important CRF over time . These models are particularly appropriate for longitudinal data as they allow for inclusion of all surveys completed by each individual, taking within-subject correlations into account and producing robust error estimates . First, There were no differences in age-group, sex, ethnicity and stage between the 2487 participants included in the analysis and the 932 HN5000 recruits in the study population who did not complete the CRF questions at baseline. There were statistically significant differences in deprivation, cancer site and comorbidities. The analysis dataset included fewer deprived patients with fewer comorbidities and more patients with thyroid and salivary gland cancers..Of the 2847 patients in the analysis dataset, 704 (24.7%) had cancer of the oral cavity, 1119 (39.3%) oropharyngeal cancer, 786 (24.8%) laryngeal or hypopharynx cancer, 186 (6.5%) thyroid cancer and 132 (4.6%) cancer of the salivary glands . More thAt baseline, 27.8% of participants scored in the range for clinically important CRF. This rose to 44.7% at 4 months and declined  to 29.6% at 12 months . When exWhen considered by treatment received, at 4 months more than half of those who had multi-modal treatment had CRF . The prevalence was much lower among those who had a single treatment modality . The prevalence of CRF declined at 12 months, but was still 30% or higher in all treatment groups with the exception of those who had surgery alone (25.0%).The prevalence of clinically important CRF by socio-demographic, lifestyle and other clinical factors at each time-point is shown in In the multivariable mixed logistic regression model, the odds of clinically important CRF were four times higher at the 4-month time-point  than at baseline; at 12 months the OR was 1.67 (95% CI 1.37–2.03) . DepressThis is the first large-scale longitudinal study to investigate CRF in HNC patients, and the predictors of this over time. We found that a more advanced tumour stage, multimodal treatment, female sex and being a smoker were all associated with a higher odds of CRF over 12 months. Additionally, those who had depression and more co-morbidities at baseline (before treatment commenced) were more likely to have CRF over 12 months.One of the most striking findings was the high prevalence of CRF in this cohort. Forty-five percent of patients overall, and more than half of those with oropharyngeal cancer, scored in the range for CRF at 4-month follow-up, while the prevalence fell afterwards, with 30% having CRF at 12-month follow-up. The higher prevalence at 4 months could perhaps be explained by the fact that some patients would have still been undergoing systemic treatments, during which patients often experience severe fatigue . This isSeveral predictors of CRF have been identified in the current study. The strongest relationship—a 14-fold increase in odds—was found among those who had depression at baseline. Depression was assessed using self-completion of the HADS, which has high sensitivity and specificity compared to semi-structured interviews with patients . The preA previous study of 70 HNC patients reported a correlation between CRF and depression before, during and shortly after chemoradiation ; anotherThe higher odds of CRF among female patients observed here is consistent with findings from a meta-analysis of 24 studies of CRF measured at various time-points in a range of cancer sites ; that anIn terms of clinical variables, a previous study of 140 HNC patients on average 3–4 months after the completion of treatment, reported that fatigue was more likely to be identified as a concern by those with advanced disease and who had had radiotherapy and/or chemotherapy . This haOne question raised by our findings is the extent to which the fatigue is a result of the cancer, the treatment or some other factor (and would therefore have been present in the absence of cancer). The lack of pre-diagnosis data and a non-cancer comparator population means that it is impossible to know to what extent cancer and/or its treatment presents an “excess risk” of fatigue. Some studies in other cancers have shown slightly higher mean levels of CRF (as measured using the EORTC QLQ-C30) in survivors than population controls ,42, but Across cancer as a whole, there is a growing evidence-base around interventions for CRF ,47,48 anhttps://www.wcrf.org/researchwefund/fitness-patients-chemo-radiotherapy-head-neck-cancer/, accessed on 17 June 2023; https://www.isrctn.com/editorial/retrieveFile/d9ef52ed-595e-4d35-aca6-446b4bedd973/42265, accessed on 17 June 2023). Should the findings from such studies be positive, it is possible that routine implementation of physical activity interventions before, during or after treatment could have benefits in terms of CRF for some patients.In terms of specific interventions for CRF in HNC, ongoing research is starting to explore the feasibility and acceptability of exercise and/or physical activity interventions (Our results highlight the importance of identifying, at the pre-treatment stage, patients’ smoking status to improve timely access to smoking cessation services. It could be helpful to explain to patients who smoke that, if they were willing to engage with behaviour change, this could potentially reduce their chances of CRF. Similarly, the observed association between comorbidities and CRF indicates that HNC management should include ensuring that patients’ other conditions are optimised.In terms of strengths, the HN5000 cohort provided a large sample, recruited from multiple UK centres. This enabled a comprehensive analysis of the trajectory of CRF in the first year following diagnosis; most past studies have been limited to single centres, with relatively small sample sizes and/or cross-sectional designs. The EORTC QLQ-C30 is a widely used and well-validated cancer-specific health-related QoL questionnaire, but the FA subscale includes only three questions and does not distinguish between emotional, physical and cognitive CRF. In addition, HN5000 participants were disproportionality at an earlier cancer stage, compared to the entire HNC population. Thus, the observed association between more advanced stage cancer and CRF, and the differences between those included in the analysis and those who did not complete the CRF questions at baseline means we have likely under-estimated the true prevalence of CRF in HNC patients. However, there is no reason to believe internal comparisons within the cohort are biased. Finally, the lack of an external age- and sex-matched non-cancer comparator population is a limitation.Almost one-third of HNC patients report clinically important CRF at 12-months post-diagnosis. The odds of CRF over 12-months are increased in those with significant depression pre-treatment and in women, smokers and those with more advanced disease who have multi-model treatment and other comorbidities. These findings indicate the need for additional focus during HNC follow-up on this debilitating symptom and for the implementation of interventions to alleviate CRF.


Despite the promising efficacy and tolerability of alectinib in treating advanced anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), the role of alectinib in neoadjuvant setting remains understudied in ALK-rearranged resectable lung cancer.Our report concerns two cases of early-stage NSCLC with complete pathologic responses to off-label use of long-course neoadjuvant alectinib. PubMed, Web of Science, and Cochrane Library were searched comprehensively for ALK-positive resectable cases with neoadjuvant alectinib. The papers were chosen following PRISMA recommendations. Seven cases from the literature and two present cases were evaluated.Two cases with stage IIB (cT3N0M0) EML4-ALK lung adenocarcinoma received long-course (more than 30 weeks) of neoadjuvant alectinib followed by R0 lobectomy with the complete pathological response. In our systematic review, 74 studies were included in the original search. Application of the screening criteria resulted in 18 articles deemed eligible for full-text reading. Following the application of the exclusion criteria, out of six papers, seven cases were selected for inclusion in the final analysis and were included in the systematic review. None of the studies were included in the quantitative analysis.We report two cases of lung adenocarcinoma with resectable ALK-positive that achieved pCR with long-course neoadjuvant alectinib. Our cases and a systematic review of the literature support the feasibility of neoadjuvant alectinib treatment for NSCLC. However, large clinical trials must be conducted in the future to determine the treatment course and efficacy of the neoadjuvant alectinib modality.https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022376804. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement, also known as the ALK-positive variant, is one of the significant driver mutations in non-small-cell lung cancer (NSCLC) and accounts for about 5% of NSCLC –3. This We are fortunate that there have been advances in ALK tyrosine kinase inhibitor (ALK-TKI) targeted therapies for ALK-positive lung cancer over the last decade. Now, various drugs can be used for first-line treatment options in advanced lung cancer with ALK rearrangement, from the initial generation of crizotinib to the second generation of ceritinib, alectinib, and brigatinib, to the third generation of lorlatinib –10.Previous studies suggest that in resectable non-small cell lung cancer, neoadjuvant chemotherapy, radiotherapy, immunotherapy, and combination therapy play an important role. Early meta-analysis suggests that neoadjuvant chemotherapy can lead to an absolute survival improvement of 5% at five years, from 40% to 45% in stage I-III resectable cases . In addiFor resectable NSCLC with a specific oncogenic driver positive, the published neoadjuvant study focused mainly on the epidermal growth factor receptor (EGFR) pathway. The early randomized phase 2 study of CTONG1103 showed that neoadjuvant erlotinib is more effective than neoadjuvant chemotherapy in EGFR-positive patients with stage IIIA-N2 NSCLC . AccordiAlectinib is a highly selective ALK inhibitor currently used as the front-line or second-line treatment for advanced ALK-positive NSCLC , 21. HowAlthough several previous studies have reported cases receiving neoadjuvant treatment with alectinib , 22, givA 51-year-old male heavy-smoker patient presented to our hospital in July 2021 with chest pain for two months. In contrast-enhanced computerized tomography (CT) of the chest, a mass of approximately 53 mm in length was found in the left lower lobe, along with an isolated nodule of 6 mm in the same lung lobe Figure 1The patient was recommended to receive neoadjuvant alectinib therapy followed by surgical resection after a multidisciplinary discussion. Alectinib was given at 600 mg twice daily for three cycles (12 weeks) from July 15, 2021. Imaging evaluation of the efficacy showed a partial response, the patient was advised to consider receiving surgical treatment, but the patient refused surgery, continued with oral alectinib treatment, and the patient's mass continued to shrink. After 30 weeks of therapy, A CT scan was performed to assess the efficacy of neoadjuvant therapy. A partial response was achieved after neoadjuvant therapy, with 66% shrinkage of the mass (18 mm×15 mm), and the solitary nodule in the left lower lobe disappeared Figure 1A 48-year-old man with no smoking history was referred to the hospital with an asymptomatic mass in the middle lobe of the right lung. An enhanced computed tomography scan revealed a large mass with a diameter of 58 mm and an additional nodule (5 mm) on the right interlobar pleural in the same lobe Figure 3After multi-disciplinary team consultation and acquiring informed consent from the patient, the patient began to receive treatment with neoadjuvant alectinib at 600 mg twice daily. After eight weeks of treatment with alectinib, this patient was evaluated as having a partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.After 32 weeks of alectinib treatment, a re-evaluation showed a 70% reduction of the tumor in the right middle lobe, with no pleural nodules detected Figure 3This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard . In addiWe established our search strategy in PubMed by leveraging Medical Subject Headings (MeSH) terms for case reports and case series study types involving neoadjuvant alectinib in lung adenocarcinoma with EML4-ALK rearrangement. The generated search strategy was then transferred to the Web of Science and Cochrane Library using a Polyglot translator . The lasWe included case reports, case series, or letters that met all of the following criteria (1): cases with NSCLC, (2) with confirmed presence of EML4-ALK rearrangement, (3) with neoadjuvant alectinib treatment, (4) with pathological response outcome. There were no patient demographics or language restrictions, and no publication date restrictions were placed on the included studies.Titles and abstracts were screened for the records obtained during the literature search. Two reviewers (LS and SH-G) separately screened titles and abstracts, and consensus settled discrepancies. After that, the full texts of eligible papers were retrieved and independently double-screened, with any discrepancies being forwarded to a third reviewer (ZL).The following information was extracted from the included articles: age of the reported case, gender, smoking status, symptoms, baseline cTNM stage, EML4-ALK variant status, neoadjuvant treatment course, radiologic response, pathologic response, and adverse effects. All of the identified studies were listed by the authors, as well as the year of publication. Data extracted from each study was conducted by two reviewers independently (LS and SH-G), with any inconsistencies referred to a third reviewer (ZL). The data was summarized and compiled into an online Excel spreadsheet for the authors to access.Case reports are biased by their nature. However, standardized techniques have been developed to evaluate the methodological quality of case reports. We utilized the Newcastle-Ottawa Scale (NOS), as modified by Murad et al., to rate the quality of the case series and reports included in the study . This toEach article's data included in our systematic review was retrieved, compiled, and shown in a table. The cases were then described narratively in the text to combine and highlight the similarities and differences between them and to draw conclusions finally. We used descriptive statistics to summarize demographics and clinical characteristics due to the descriptive nature of this systematic review and the small number of cases. Continuous variables were reported using means, while dichotomous variables were reported using frequencies and percentages.We used descriptive statistics to summarize demographics and clinical features due to the descriptive nature of this systematic review and the small number of cases. Continuous variables were reported using means or median, while dichotomous variables were reported using frequencies and percentages.A PRISMA flow diagram that depicts the study selection procedure is shown in A summary of the characteristics is presented in All patients underwent lobectomy combined with mediastinal lymph node dissection and had R0 resection. Postoperative pathological results suggested pCR in 2 cases (28.6%), major pathological response (MPR) in 3 cases (42.9%), and non-MPR in 2 cases (28.6%).We could not do a quantitative meta-analysis due to the case report or case series nature of the studies on this subject.The quality of case reports and case series were assessed using Murad et al.’s standardized tool. According to the risk of bias score and classification rules mentioned above, five cases were scored 5, two cases were scored 4, and all cases were evaluated as low-risk of bias. A detailed quality assessment for each case is available in Our case report is the first to document a long-course of neoadjuvant alectinib treatment. Two patients with ALK-positive stage IIB NSCLC received more than six months of induction alectinib treatment and then had surgery for R0 resection after imaging evaluation showed the best shrinkage. Pathological evaluation after surgery showed that the treatment achieved pCR. In addition, there were no severe treatment-related adverse reactions (TRAEs) or severe perioperative adverse events. The patient had oral alectinib as postoperative adjuvant therapy, and follow-up showed no recurrence or metastasis.Based on the case reports we have presented, we have conducted a systematic review of seven cases from six studies, including cases with neoadjuvant alectinib. In our systematic review, all patients with stage IIIA-IIIB NSCLC treated with a short-course of preoperative alectinib (6-12 weeks) had a postoperative pathological evaluation. Two patients had pCR, three had MPR, and two had non-MPR. There were no reported severe TRAEs. Compared with previous cases, our reported cases of long-course neoadjuvant alectinib had similar therapeutic safety and surgical feasibility. In addition, the pathological response evaluation of our reported cases reached pCR after surgery, which may bring long-term survival benefits to patients.One of the most critical questions is what kind of patient should receive neoadjuvant targeted therapy for ALK-positive NSCLC. In addition, the choice of therapeutic drugs and treatment cycles is another critical question.The first neoadjuvant treatment exploration of ALK-TKI was a small sample of retrospective studies of crizotinib. In the study, all 11 patients were cases with N2 (stage IIIA or IIIB) who received crizotinib for 28-120 days before surgery. The study found that 10 out of 11 patients (91.0%) had a partial response, while one had a stable disease. Additionally, two patients (18.2%) achieved pCR .With the iterations of ALK-TKI, from first-generation to third-generation drugs, we also have more available TKIs for neoadjuvant strategy against the ALK pathway. More stringent requirements are necessary for choosing drugs with higher objective response rates (ORR), remission depth, and better safety for neoadjuvant therapy, with the purpose of the neoadjuvant therapy per se. The SAKULA study showed the clinical benefit of ceritinib for neoadjuvant therapy. The study included seven patients with ALK-positive stage II-III NSCLC who received two cycles (28 days per cycle) of ceritinib induction therapy followed by surgery, with a 57% MPR and 2 cases achieving pCR (29%). However, it was worrying that all seven patients had treatment interruptions due to adverse events, and five cases experienced dose downregulation .A series of studies on the front-line alectinib in advanced NSCLC showed that alectinib has a higher ORR and a greater tumor remission depth than crizotinib and may be more valuable for neoadjuvant therapy , 32, 33.Most reported cases in our review were locally advanced patients with initial clinical stage III. However, the two cases we reported were stage IIB patients with suspicious intrapulmonary metastatic nodules (T3) at initial evaluation and recommended to receive induction therapy after multidisciplinary discussion. Notably, our patients had a smaller tumor load and earlier clinical stage than previously reported cases, which may have contributed to the eventual postoperative pathological evaluation to achieve pCR.Additionally, studies included in our review had administered targeted therapy for 2-3 months, while few cases had received long cycles of alectinib preoperatively. Our reported cases, however, received more than six months of alectinib each, and both patients underwent surgery after achieving the best objective response when the tumor reached maximum remission. The earlier initial clinical stage is another critical factor contributing to our cases' postoperative pCR. However, this hypothesis requires further confirmation through strictly designed clinical trials.The current NAUTIKA1 trial involving the neoadjuvant treatment of alectinib is enrolling patients with resectable stage II, IIIA, or selective IIIB (T3N2 only) ALK-positive NSCLC. These patients will receive alectinib induction therapy for eight weeks, followed by surgery . The othOur study is the first to focus on long-course neoadjuvant alectinib in lung adenocarcinoma with the EML4-ALK variant. It aims to integrate all available cases from the literature in a systematic review with a standardized quality appraisal. While our review is a crucial starting point for understanding the preoperative ALK-TKI therapy strategy, its findings need to be expanded upon by more rigorous studies in prospective clinical trials. However, our narrative synthesis of case reports has several weaknesses, including subjectivity and a lack of detailed patient information and long-term follow-up data to judge overall survival accurately. Additionally, the small sample size of seven cases prevented a thorough quantitative synthesis, and generalizability is limited due to missing cases and publication bias. Furthermore, our analysis of neoadjuvant therapy findings was restricted by the lack of control over reported pathological response results.We present two cases of resectable ALK-positive lung adenocarcinoma that had a pCR following long-course neoadjuvant alectinib treatment. Our cases, along with a systematic review, show that neoadjuvant alectinib treatment is a feasible option for NSCLC. However, large clinical trials are necessary in order to determine the treatment course and efficacy of neoadjuvant alectinib.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was approved by the institutional review board (IRB)/ethics committee of Beijing Chest Hospital, Capital Medical University.ZL, LS, and SG contributed to the study's conception, data interpretation, and manuscript writing. LS, SG, LT, QM, SZ, DY, YD, and ZL analyzed the patient data. All authors contributed to the article and approved the submitted version.