Does a home-based intervention that is individually tailored and goal oriented improve health-related quality of life (HRQOL) and participation and ameliorate symptoms in the chronic phase of traumatic brain injury (TBI)?In this randomized clinical trial including 120 adult participants in the chronic phase of TBI, no significant results were seen in disease-specific HRQOL or social participation. However, generic HRQOL and TBI- and anxiety-related symptom levels improved significantly in the intervention group compared with the control group.These findings suggest that an individually tailored and goal-oriented rehabilitation program might be effective in improving generic HRQOL and symptom burden in the chronic phase of TBI. Traumatic brain injury (TBI) can cause long-lasting and heterogeneous difficulties that require an individually tailored approach to rehabilitation. However, high-quality studies of treatment options in the chronic phase of TBI are lacking.To evaluate the effect of a home-based, individualized, and goal-oriented rehabilitation intervention in the chronic phase of TBI.This study was an intention-to-treat parallel-group assessor-blinded randomized clinical trial with 1:1 randomization to an intervention or control group. Participants included adults in southeastern Norway who had sustained a TBI more than 2 years earlier, lived at home, and had ongoing TBI-related difficulties. A population-based sample of 555 individuals were invited, and 120 were included. Participants were assessed at baseline, 4 months, and 12 months after inclusion. Specialized rehabilitation therapists provided the intervention in patients’ homes or via video conference and telephone. Data collection was conducted between June 5, 2018, and December 14, 2021.The intervention group received an 8-session individually tailored and goal-oriented rehabilitation program over 4 months. The control group received usual care in their municipality.Preestablished primary outcomes were disease-specific health-related quality of life  and social participation . Preestablished secondary outcomes included generic HRQOL (measured by the EuroQol 5-dimension 5-level [EQ-5D-5L] questionnaire), difficulty with TBI-related problem management , TBI symptoms (measured by the Rivermead Post Concussion Symptoms Questionnaire [RPQ]), psychological distress , and functional competency .P = .30) or social participation . At 12 months, the intervention group (n = 57) had significantly higher generic HRQOL  and fewer symptoms of TBI  and anxiety  compared with the control group (n = 55). At 4 months only, the intervention group (n = 59) had significantly less difficulty managing TBI-related problems  compared with the control group (n = 59). No adverse events were reported.Among 120 participants in the chronic phase of TBI, the median (IQR) age was 47.5 (31.0-55.8) years, and the median (IQR) time since injury was 4 (3-6) years; 85 (70.8%) were male. A total of 60 participants were randomized to the intervention group, and 60 were randomized to the control group. Between baseline and 12 months, no significant between-group effects were found for the primary outcomes of disease-specific HRQOL  that were maintained at 12-month follow-up. These findings suggest that rehabilitation interventions could help patients even in the chronic phase of TBI.NCT03545594ClinicalTrials.gov Identifier:  This randomized clinical trial assesses the effect of a home-based, individualized, and goal-oriented rehabilitation intervention among adult patients with chronic traumatic brain injury. However, some studies11 have found that rehabilitation can improve QOL and community integration among patients in the chronic phase of TBI. The Cognitive Rehabilitation Task Force of the American Congress of Rehabilitation Medicine12 recommends as a practice standard the provision of holistic neuropsychological rehabilitation targeting cognitive, emotional, and interpersonal difficulties in patients with chronic consequences of acquired brain injury. Furthermore, bringing interventions to the patient’s home environment might be especially important.13 However, a systematic review14 found that studies of community-based rehabilitation in the chronic phase of acquired brain injury are characterized by small samples, unclear description of intervention content, and lack of common outcome measures.There are few methodologically rigorous studies that document treatment options in the chronic phase of TBI. The World Health Organization Rehabilitation 2030 Initiative15 Goal-oriented rehabilitation is an approach that has been found to increase the patient-centeredness of interventions as well as patient self-efficacy and motivation.16 Overall, individually tailored and goal-oriented interventions might address unmet rehabilitation needs in patients living with the chronic consequences of TBI, but these interventions need more investigation.A challenge when investigating interventions among patients with TBI is the highly heterogeneous consequences of the injury. Interventions should further be aimed not only at symptom reduction, but also at improving HRQOL and participation. To better meet the challenges of individual patients, TBI interventions should be tailored to the specific problem profiles reported by the patient rather than being prespecified by researchers.13 Their study included 81 veterans and their family members; at the end of intervention, the intervention group had less difficulty managing self-identified TBI-related problems  and higher levels of community integration than the control group. However, this trial13 did not include long-term follow-up, and the intervention needs to be replicated in a civilian population with more severe injuries. In the current study, the intervention manual used by Winter et al13 was adapted to investigate the effect of the intervention among civilian patients with TBI of all severities in the context of a health care system with universal access. The objective of this RCT was to establish whether a home-based, goal-oriented, and individualized rehabilitation program would be effective in improving HRQOL, social participation, and target outcomes and in reducing TBI-related and psychiatric symptoms.A randomized clinical trial (RCT) of a home-based goal-oriented intervention has been conducted in the US by Winter et al.CONSORT) guideline for RCTs.17 The trial was approved by the Data Protection Office at Oslo University Hospital. All participants provided written informed consent.This study followed the Consolidated Standards of Reporting Trials  and again at 12 months after inclusion. Full details are provided in the trial protocol in International Classification of Diseases, Tenth Revision, Clinical Modification codes S06.01-S06.09) with radiologically verified intracranial abnormalities; age 18 to 72 years; time since injury of more than 2 years; living at home, and presence of ongoing TBI-related difficulties. Exclusion criteria included inability to provide informed consent or collaborate in the goal-setting process, presence of a severe ongoing neurological or psychiatric condition, and/or active misuse of substances. Due to the COVID-19 pandemic, the intervention was delivered mainly by video conference for participants recruited after March 12, 2020. Ability to use a computer was therefore added as an inclusion criterion. Participants were encouraged to include a family member or close friend as a coparticipant if available. Effort was made to include a sample representative of patients seen in our outpatient clinic . The full eligibility criteria are provided in the The principal investigator (C.R.) identified potentially eligible participants by screening patients in southeastern Norway who were included in previous studies and outpatient registries, who then were invited by letter. Patients were thereafter contacted by telephone and screened for eligibility. Inclusion criteria included a diagnosis of TBI (based on Box. ICD-10-CM codes S06.01-S06.09); radiologically verified intracranial abnormalitiesTBI diagnosis Unable to provide informed consentSevere progressive neurological condition or severe ongoing psychiatric disorder that may confound outcomesUnable to collaborate in goal-setting processInsufficient command of Norwegian language (cannot communicate with rehabilitation therapists or respond to questionnaires)Active substance misuse and/or violent tendencies that may put rehabilitation therapists at riskICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; TBI, traumatic brain injury.Abbreviations: 18 If eligibility was confirmed at baseline and written consent provided, participants were randomized to the intervention or control group. The intervention was delivered in the participant’s home or by video conference or telephone. Assessments at 4 months and 12 months after inclusion were conducted either at the hospital or through telephone interviews and mailed questionnaires. All participants were asked about the services they were receiving at all time points using the Needs and Provisions Complexity Scale–Gets subscale, which measures levels of service provided .19 Data were collected between June 5, 2018, and December 14, 2021.Demographic and injury-related data were collected; data on race and ethnicity were not collected because it is not conventional in Norwegian research practice. All participants were evaluated using the Glasgow Outcome Scale–Extended version .The intervention group received an 8-session rehabilitation program over 4 months. In-home and video conference sessions typically lasted 2 hours, while telephone sessions typically lasted 1 hour. Four experienced rehabilitation therapists  delivered the intervention, and 1 rehabilitation therapist  followed up with each participant throughout the intervention. If available and relevant, family members or local health care personnel participated in sessions.20 was performed to quantify baseline levels, the expected level, and actual goal attainment. Rehabilitation strategies for goal attainment were then established in an action plan. Strategies were based on suggestions made by participants, family members, and rehabilitation therapists and mainly involved environmental support and compensatory strategies. Suggestions from rehabilitation therapists were informed by knowledge about evidence-based treatment approaches related to the functional domain in question. The rehabilitation therapists kept up to date through literature searches and had clinical discussions in cases of new issues. In addition, 3 psychoeducational topics  were discussed with all participants. Treatment fidelity was ensured both by calibration during a feasibility study21 as well as frequent meetings among rehabilitation therapists and evaluation of the rehabilitation therapists’ adherence to the intervention manual  by senior researchers  in 10% of sessions.An overview of intervention content is available in the eFigure in All control group participants received feedback on their baseline assessment, and a brief report was sent to their general practitioner. Because an active control group was not feasible, the control group continued to receive any concomitant care (registered at each time point) they were already receiving, with no additional treatment. In Norway, municipal health care services are mainly responsible for treatment in the chronic phase of TBI. There are no specialized TBI services in the communities, but specialized health care services at hospitals are provided when needed .21 Disease-specific HRQOL was measured using the Quality of Life After Brain Injury (QOLIBRI) overall scale .22 Participation was measured using the Participation Assessment With Recombined Tools–Objective (PART-O) social subscale .24 Because the COVID-19 pandemic influenced participation options, the PART-O may not have been the ideal outcome measure. The social subscale was believed to be the least influenced by COVID-19 restrictions and was selected as the index of participation before statistical analyses.Two primary outcomes, disease-specific HRQOL and participation, were defined based on experiences from the feasibility study.13 At baseline, participants were asked to identify 3 main ongoing problems related to their TBI and the current degree of difficulty in managing each of the problems on a Likert scale from 0 to 4 . Rehabilitation therapists would prompt participants to identify problem areas related to activities in their everyday lives to ensure they would be amenable to intervention. A mean severity score across the 3 target outcomes was calculated. For the other secondary outcomes, 5 questionnaires were used: the EuroQol 5-dimension 5-level questionnaire 25 to measure generic HRQOL, the Rivermead Post Concussion Symptoms Questionnaire 26 to measure TBI symptoms, the Patient Health Questionnaire 9-item scale 27 and the Generalized Anxiety Disorder 7-item scale 28 to measure depression- and anxiety-related symptoms, and the patient version of the Patient Competency Rating Scale 29 to assess functional competency.Secondary outcomes included target outcomes, generic HRQOL, TBI symptoms, depression- and anxiety-related symptoms, and functional competency. Outcome measures consisted of 1 interview-based assessment and 5 questionnaires. For the target outcomes, an interview-based measure was adapted from the study by Winter et al.30).Sample size calculations were conducted before the trial and were based on between-group differences in the change in primary outcomes. The significance level was Bonferroni corrected for a clinically meaningful between-group mean difference of 12% on the QOLIBRI overall scale (with an estimated SD of 20%) and a between-group mean difference of 1.8 on the PART-O (with an estimated SD of 3.0). Thus, with equal randomization to treatment groups, power of 80%, and a significance level of α = .025 (correcting for 2 primary outcomes), the sample size was calculated as 55 patients in each group for both primary outcomes. Allowing for an attrition rate of 10%, 60 participants were included in each treatment group. Sample size calculations were performed using G*Power software, version 3  generated in Stata software, version 15 (StataCorp LLC), by an independent statistician, and the randomization list was provided in a fixed sequential order. The allocation sequence could only be accessed by the principal investigator (C.R.), who was not involved in inclusion procedures. Rehabilitation therapists were responsible for the inclusion of participants and sent a sham number to the principal investigator via email to receive information on group allocation.Outcome assessors were blinded. Statistical analyses were conducted by an independent statistician. The first author (I.M.H.B.) wrote the Results section of this article while blinded to group allocation.P < .025 was applied. For secondary outcomes, mean values with 95% CIs were estimated, and a significance level of 2-tailed P < .05 was applied. Statistical analyses were performed using Stata software, version 17.Linear mixed-effects models were fitted to primary and secondary outcome variables with time and time-by-treatment interaction as categorical fixed effects. The main effect of treatment was removed from the model to adjust for potential baseline differences in the outcome. The models included a random intercept and a random effect for time. Three variables  could not be modeled with the random effect for time; thus, only a random intercept was used. Based on the linear mixed-effects models, mean values for primary outcomes were estimated with 97.5% CIs for all time points  for each group. We also estimated mean within-group and between-group differences in change from baseline to 4 months and from baseline to 12 months. Analyses were performed using the intention-to-treat approach. To accommodate for having 2 independent primary outcomes, a conservative significance level of 2-tailed Among 120 participants included in the intention-to-treat analysis, the median (IQR) age was 47.5 (31.0-55.8) years, and the median (IQR) time since injury was 4 (3-6) years; 85 participants (70.8%) were male and 35 (29.2%) were female. A total of 60 participants were randomized to the intervention group  and 60 to the control group . Overall, 4 participants withdrew from the study or could not be reached at 12 months. The study flowchart is shown in Baseline demographic and clinical characteristics were generally similar between groups . A totalP = .30) or social participation . For the secondary outcomes, a statistically significant difference at 12 months was observed in favor of the intervention group (n = 57) vs the control group (n = 55) for generic HRQOL , TBI symptoms , and anxiety symptoms . At 4 months only, participants in the intervention group (n = 59) had significantly less difficulty managing main TBI-related problems  compared with participants in the control group (n = 59). Full results of the linear mixed model are shown in From baseline to 12 months, no statistically significant between-group differences were found for the primary outcome measures of HRQOL . The control group showed statistically significant improvements only in difficulty managing main TBI-related problems  and TBI symptoms  and a slight but statistically significant decrease in social participation   .This RCT aimed to evaluate the effect of a home-based, individually tailored, and goal-oriented intervention in improving HRQOL and participation, TBI-related difficulties, and symptoms. Although the 2 primary outcomes, disease-specific HRQOL  and social participation , did not reveal between-group differences, we did see group effects in favor of the intervention group for the secondary outcomes of generic HRQOL, target outcomes severity, TBI-related symptoms, and anxiety.31 The decision to use the QOLIBRI overall scale to measure the primary outcome of HRQOL was based on the prevailing thought that disease-specific HRQOL measures might be more sensitive in revealing small but clinically meaningful differences.32 The QOLIBRI overall scale and the PART-O social subscale may both have been affected by COVID-19–related social restrictions. In addition, while the EQ-5D-5L has been widely used in research, the QOLIBRI overall scale was more recently developed, and its responsiveness in RCTs is unknown. The PART-O was chosen to measure the second primary outcome of participation because the scale is validated to measure participation after TBI. Due to the COVID-19 pandemic, only the social subscale of the PART-O was analyzed because it was thought to be less affected by the pandemic due its inclusion of digital types of socialization. However, a small decline in social participation was seen in both groups, but this decrease was statistically significant in the control group only. The reduced participation is likely a result of social distancing during the COVID-19 pandemic and might even have camouflaged a positive change in the intervention group because their social participation did not decline. In summary, although the lack of effect on primary outcomes may signify a lack of effect in targeted areas, it may also signify low sensitivity to change in the primary outcome measures.The lack of significant between-group differences in the 2 primary outcomes warrants discussion. It is, however, noteworthy that a significant effect on HRQOL was found in the generic HRQOL measure. Some researchers argue that studies should include both generic and disease-specific measures of QOL.13 which resulted in less difficulty with managing target outcomes and higher levels of community integration. Target outcomes are not well established in the field of rehabilitation, but they allow for an individualization of outcomes that might be particularly well suited to populations with heterogeneous difficulties, such as those with TBI.15 In this RCT, the severity of target outcomes differed between groups at 4 months only, which is comparable with findings from the study by Winter et al,13 which included only 1 outcome assessment. These effects were not maintained at 12 months. We can only speculate about the reasons for these temporal patterns. Decreases in intervention effects over time are well known to occur, as are study effects in control groups due to study procedures and follow-up.33 The findings highlight the need for development of plans to maintain rehabilitation intervention effects, such as prolonged follow-up and booster sessions.This RCT was modeled after a study by Winter et al,34 indicating positive intervention effects at an individual level. In a future trial, it would be of interest to include measures of self-efficacy because increased self-efficacy has been proposed to be a primary factor in transfer effects of rehabilitation interventions.35 The fact that intervention participants did not experience worsening in most of the outcomes during the follow-up period from 4 months to 12 months indicates sustainable effects over time.Reductions in TBI- and anxiety-related symptoms were seen. Reduced anxiety may signify less worry and stress as participants experienced less difficulty managing TBI-related problems. The fact that the intervention group showed within-group improvements over time on all outcome measures except the PART-O social subscale supports this interpretation. High goal attainment has been previously documented in this trial,12 This may partly explain the small differences between groups.This intervention aimed to address common health care needs among patients in the chronic phase of TBI. Although efforts were made to standardize intervention design and intensity, treatment content was individualized. There is an inherent challenge in measuring mean group effects of an intervention addressing individual needs, despite the fact that symptom heterogeneity requires individual tailoring of rehabilitation.12 Furthermore, the individually tailored nature of this intervention renders it a potential proof of principle study with relevance for patients with other chronic conditions, such as those with other neurological and brain injury etiologies. A similar approach to caregiver support has been shown to be effective in patients with dementia.36 The applicability of this approach in other populations should be evaluated in future studies.The fact that this intervention resulted in positive changes many years after injury confirms that rehabilitation in the chronic phase of TBI may be effective.This study has several limitations. It is important to emphasize that only participants with a radiologically verified intracranial injury were included. The eligibility criteria only allowed inclusion of patients with the capacity to contribute to goal setting and with self-reported TBI-related symptoms. Hence, results might not be applicable to patients with mild TBI without intracranial damage or patients with severe difficulties in awareness and cooperation in goal-setting procedures. Both primary outcomes may have been affected by the COVID-19 pandemic, but other findings nonetheless indicate effectiveness. Although this is one of the larger trials of individualized home-based rehabilitation in chronic TBI sequelae to date, the sample size is nonetheless limited. Both the sample size and the multiple outcomes applied in this trial entail a risk of both type 1 and type 2 errors. Lack of an active control group and exposure to follow-up in the control group  could potentially bias results.In this RCT of a home-based, individually tailored, and goal-oriented intervention in the chronic phase of TBI, participants in the intervention group reported significantly improved generic HRQOL and fewer TBI- and anxiety-related symptoms, which were maintained at 12-month follow-up. These findings suggest that rehabilitation interventions could help patients in the chronic phase of TBI improve their HRQOL and symptom burden.


Given the limited availability of research on the association between COVID-19 infection and breastfeeding success, the primary objective of this study is to conduct a comprehensive evaluation of this relationship.This prospective cohort study included 260 women who were on the postnatal ward of an academic hospital affiliated with Tehran University of Medical Sciences during the COVID-19 pandemic (between March and August 2021). Among these women, 130 had tested positive for COVID-19 in pregnancy, while the remaining 130 were considered healthy. The study aimed to assess various factors, including sociodemographic characteristics and the results of four validated questionnaires: The Bristol Breastfeeding Questionnaire, The Multidimensional of Perceived Social Support (MPSS), The Breastfeeding Self-Efficacy Scale (BSES), and The Postpartum Partner Support Scale (PPSS). These questionnaires were administered to each participant to gather relevant data. After eight weeks, a telephone follow-up was carried out to assess the success of breastfeeding. The evaluation focused on determining if exclusive breastfeeding was maintained or not. Data was collected by questioning mothers about their infants’ feeding habits in the past 24 h. Exclusive breastfeeding refers to the exclusive use of breast milk without the introduction of other liquids or solid foods.P < 0.001) and a higher prevalence of cesarean section (P = 0.001) compared to the control group. The proportion of women who exclusively breastfed was higher in the control group (98.5%) than in women with a history of COVID-19 infection (89.2%) (P = 0.011). Furthermore, the case group reported lower scores in perceived social support and the Breastfeeding Self-Efficacy Scale, in contrast to the control group. Notably, there was a significant correlation between breastfeeding success and women’s breastfeeding self-efficacy score.Women with a previous COVID-19 infection (case group) had a lower mean infant gestational age (The findings of this study offer valuable insights for healthcare professionals, enabling them to promote early initiation of breastfeeding in mothers with a history of COVID-19 infection, while ensuring necessary precautions are taken. Breastfeeding rates during the COVID-19 lockdown have been the subject of several studies comparing them to the pre-pandemic period . A CanadTo date, research on the association between COVID-19 infection and breastfeeding success remains limited. Recent studies have sought to investigate the impact of COVID-19 infection on various aspects of breastfeeding, such as initiation, duration, and exclusivity. A systematic review study suggested a potential predominantly negative influence of COVID-19 infection on breastfeeding success, although there were a few instances where certain mothers viewed the lockdown positively as it provided protection for the bond between mother and infant . UnderstOne of the primary concerns during the COVID-19 pandemic is the possibility of transmitting the virus through breast milk . InitialThe stress and anxiety brought about by the pandemic, along with the disruptions to healthcare services, have the potential to adversely affect breastfeeding outcomes . A publiFurthermore, the utilization of personal protective equipment while breastfeeding can present difficulties for both mothers and healthcare providers, potentially affecting the overall breastfeeding experience. Concerns about transmitting the virus to their infants may also lead some mothers to feel hesitant about breastfeeding, while others may face separation from their infants due to hospital policies related to COVID-19 .Understanding the potential risks and benefits of breastfeeding during the pandemic is crucial for healthcare providers and mothers to make informed decisions about infant feeding practices. The objective of this study was to investigate the association between COVID-19 infection and breastfeeding success.This prospective cohort study was conducted between March and August 2021, during the COVID-19 pandemic. It involved 260 women recruited on the postnatal ward of an academic center affiliated with Tehran University of Medical Sciences. Among them, 130 women had tested positive for SARS-CoV-2 in pregnancy based on a positive nasopharyngeal swab, and gave birth at 34 to 41 weeks. Additionally, 130 healthy women were randomly selected to serve as the control group.The inclusion criteria for this study encompassed breastfeeding women aged between 20 and 40 years-old who received breastfeeding education, tested positive for COVID-19 but did not require ICU admission, had no history of severe postpartum depression or other psychological problems. Exclusions from the study involved women with preterm neonates requiring neonatal intensive care unit (NICU) admission, contraindications to breastfeeding, previous unsuccessful breastfeeding attempts, underlying maternal disorders that could impact breastfeeding, and the current use of illicit drugs.This study was approved by the ethics committee of Tehran University of medical sciences (IR.TUMS.MEDICINE.REC.1400.530). Eligible women provided written informed consent before they were enrolled in this study. The participants’ information was collected securely and solely used for the purpose of this study.Sociodemographic and obstetrics information including maternal age, gravidity, parity, baby’s gestational age (based on week), mode of delivery and the number of live children were collected. For this study, we utilized four validated questionnaires included The Bristol Breastfeeding questionnaire, The Multidimensional of Perceived Social Support (MPSS), The Breastfeeding Self-Efficacy Scale (BSES) and The Postpartum Partner Support Scale (PPSS). In addition, telephone follow-up was conducted eight weeks later to evaluate the success of breastfeeding, assessing whether it remained exclusive or not. In this study, our objective was to assess exclusive breastfeeding based on the World Health Organization (WHO) recommendation , 12. We The PPSS designed by Dennis et al. consists of 20 items that were rated on a 4-point Likert scale, ranging from “strongly disagree” to “strongly agree” . This inThe MPSS is a 12-item checklist, rated on a 7-point Likert scale, that evaluates perceived social support from friends, family and significant other . Salimi The Bristol Breastfeeding questionnaire, developed by Ingram et al., is an assessment tool for evaluating different aspects of efficient breastfeeding, including infant positioning, attachment, sucking, swallowing, and comfort. The Cronbach’s alpha coefficient for the Bristol Breastfeeding Scale was reported as 0.96, indicating high internal consistency .The Breastfeeding Self-Efficacy Scale (BSES) is a checklist consisting of 14 items that measure maternal confidence in her ability to breastfeed her infant, using a 5-point Likert-type scale . The valP < 0.05.Data analysis was performed using SPSS software . A comparison of the total scores for each questionnaire was conducted between two groups: lactating women with a history of COVID-19 infection and healthy lactating women. For this comparison, an independent t-test or Mann-Whitney U test was employed, as appropriate. The Pearson Correlation Coefficient was used to assess the relationship between breastfeeding wellbeing and questionnaire scores. Maternal factors were compared between the two groups using either a chi-square test or Fisher’s exact test. The significance level was set at P < 0.001) in the case group, and the rate of cesarean section was significantly higher (P = 0.001) compared to the control group.A total of 260 women participated in the study, including 130 lactating women with a history of COVID-19 infection and 130 healthy women as a control group. Table P = 0.011).Regarding breastfeeding practices, there was a notable difference observed between the two groups. The percentage of women practicing exclusive breastfeeding was significantly higher among the healthy women (98.46%) compared to the lactating women with a history of COVID-19 infection (89.23%) (P = 0.001)  Table .P = 0.001)  recommends that breastfeeding should be initiated or continued by women with COVID-19 infection, with necessary precautions such as wearing a mask and practicing proper hand hygiene before and after breastfeeding .Previous studies have shown that the transmission of COVID-19 disease through breastmilk is rare or non-existent , 23. HowThe lower rate of exclusive breastfeeding among mothers with COVID 19 infection can be attributed to various factors. One significant factor is the increased postpartum maternal anxiety levels due to the stress and uncertainty surrounding the infection. Healthcare providers also contribute to this issue as they express concerns about the potential contamination of breastmilk in women who have had COVID-19 . During Additionally, this study revealed that lactating women who had previously experienced a COVID-19 infection reported significantly lower levels of perceived social support and breastfeeding self-efficacy when compared to healthy lactating women. This finding aligns with the results of a cross-sectional study conducted by Piankusol et al., which demonstrated that reduced family support during the COVID-19 lockdown was associated with a decrease in exclusive breastfeeding rates among lactating women .A recent review conducted by Pacheco et al. highlighted the negative effects of separating mothers from their infants to prevent the transmission of COVID-19. This separation has been found to have detrimental effects on the initiation and duration of breastfeeding, ultimately impacting maternal mental health and overall well-being .Therefore, it is crucial for healthcare providers to consistently support and encourage breastfeeding among mothers who have contracted COVID-19. However, it is equally important for these providers to implement appropriate precautions to minimize the risk of transmitting the virus.This study has limitations that should be acknowledged. Firstly, the number of participants was small, which may restrict the generalizability of the findings. Secondly, in the case group, the rate of cesarean section was significantly higher, and infected women had a notably lower mean infant’s gestational age compared to the control group. These factors have the potential to influence the rate of exclusive breastfeeding. However, despite these limitations, we employed various validated questionnaires to assess breastfeeding success and maternal mental health. This approach enabled us to gather valuable information that can be utilized by healthcare providers in assisting pregnant women to achieve successful exclusive breastfeeding.Lactating women with a history of COVID-19 infection, who sought care at our academic center, exhibited lower rates of exclusive breastfeeding, as well as lower levels of perceived social support and breastfeeding self-efficacy, when compared to healthy lactating women. These findings emphasize the importance of healthcare providers offering tailored support and counseling to mothers who have experienced COVID-19 infection, in order to facilitate positive breastfeeding outcomes. It is crucial to conduct further research to investigate the effects of COVID-19 on breastfeeding during the first six months of an infant’s life, including the potential long-term consequences associated with reduced rates of exclusive breastfeeding.


D mapping technique was then demonstratedthrough reproducible hyperspectral mapping of oxidized sites and bubbleareas.Tip-enhanced photoluminescence (TRPL) is a powerful techniqueforspatially and spectrally probing local optical properties of 2-dimensional(2D) materials that are modulated by the local heterogeneities, revealinginaccessible dark states due to bright state overlap in conventionalfar-field microscopy at room temperature. While scattering-type near-fieldprobes have shown the potential to selectively enhance and revealdark exciton emission, their technical complexity and sensitivitycan pose challenges under certain experimental conditions. Here, wepresent a highly reproducible and easy-to-fabricate near-field probebased on nanoimprint lithography and fiber-optic excitation and collection.The novel near-field measurement configuration provides an ∼3orders of magnitude out-of-plane Purcell enhancement, diffraction-limitedexcitation spot, and subdiffraction hyperspectral imaging resolution(below 50 nm) of dark exciton emission. The effectiveness of thishigh spatial X Among them,two types of near-field probes, including the “Campanile”probe3 with in-plane near-field enhancementand probe–substrate-based gap mode plasmonic4 with sensitivity in the out-of-plane direction have beensuccessfully employed to optically map the subdiffraction limit localizedexcitonic states in two-dimensional (2D) transition-metal dichalcogenides(TMDs)6 across local heterogeneities such as pointdefects,8 twin boundaries,4 and localized strain.11Tip-enhanced photoluminescence(TEPL) nanospectroscopy and -imaging is a demanding technique thatenables spectrally and spatially resolved emission of materials atlength scales beyond the diffraction limit.D)14 in 2D TMDs have long radiative lifetimes16 and are the excitonic ground state in tungsten-based TMDs, makingthem attractive for quantum information applications.19 The XD exciton dipole is oriented out of plane and orthogonalto the bright exciton (XB),20 making it accessible at room temperature through out-of-plane near-fieldcoupling.22 Gap-mode plasmonic cavity enhancement has been suggested to selectivelyisolate XD emission at room temperature.22 However, to the best of our knowledge, reproducible and robust directspectral and spatially resolved TEPL of dark excitonic propertiesover micrometer-scale dimensions has yet to be fully demonstrated.Consequently, the impacts of the nanoscale heterogeneities on theXD have much information to be unveiled.Recently discovered spin-forbidden dark excitons(XD nanoimaging in monolayer (ML)WSe2. This gap-mode plasmonic cavity couples out-of-planeXD emission into the near-field probe and attached opticalfiber, allowing for direct observation at resolutions on the orderof the probe radius (tens of nanometers).22 The in-plane bright state, on the other hand, is not enhanced dueto polarization mismatch, while the out-of-plane Purcell cavity selectivityenhances the dark state emission by ∼3 orders of magnitude,enabling high spatial resolution hyperspectral mapping of local heterogeneitiessuch as nonemissive oxidized sites and nanobubble areas. This efficientnanoimaging configuration provides direct insights into the impactof chemical modifications and localized strain on the dark states.Here, wedemonstrate a unique TEPL configuration using a nanoimprintedfiber probe with a thin plasmonic coating that, when coupled to agold surface, enables X23 With tuning-fork feedback,the pyramid probe provides excellent topographic sensitivity and aconfined light intensity profile.24 To enhanceout-of-plane dark excitonic emission, a gap mode plasmonic cavitywas fabricated by coating the probe with a ∼20 nm gold thinfilm and the substrate with a 100 nm gold film to support the ML WSe2. The sample was separated from the substrate gold by ∼2nm of atomic layer deposition (ALD) grown SiO2 to reduceOhmic contact and photoluminescence quenching .25 The spontaneous decay rate of a quantum emittercan be significantly modified by a photonic cavity through the Purcelleffect, where the Purcell factor FP isinversely proportional to V is the effectivemode volume. In the probe-based gap mode configuration the mode volumescales with the gap spacing.26 The enhancedemission signal in the lateral direction is determined by the radiusof the probe apex, while the signal in the out-of-plane directioncan be dynamically controlled by changing the probe–sampledistance.21 The strong polarity of thegap mode results in several orders of magnitude stronger near-fieldenhancement for the out-of-plane dipole emission than for that ofthe in-plane emission.22As shown in 27 A low-power (<20 μW) 632.8 nm He–Ne laserwas coupled into the fiber , as shown in The measurements were conducted using a AIST-NTTRIOS scanningprobe microscope, where the probe–sample distance was regulatedby the tuning fork operating in shear-force mode.Section S2 in the SupportingInformation for more details). For the detection profile, a singledipole was scanned across the sample surface, and the collected intensitywas monitored in the probe. 28 This high NA property of the probe is primarily determinedby the optical cavity and tapered angle of the nanoimprinted pyramidalprobe.23 This confined excitation spotis critical for probing the dark state emission, as it minimizes theamount of bright excitons that are excited, which can act as backgroundnoise and obscure the signal from the dark states in the room-temperaturespectra. In contrast, the scattering-type near-field technique typicallyhas a far-field spot size coupled from the side objective lens typicallyon the order of micrometers,10 leadingto a larger amount of bright excitons being excited. Moreover, theaddition of a gold coating to the pyramid probe not only forms thegap mode with the gold substrate but also helps to reduce the relativeintensity of the sidebands beyond the apex of the probe. This is attributedto the more efficient coupling of evanescent energy toward the apexof the probe through the gold coating, which improves the spatialresolution and sensitivity of the TEPL technique.The resolutionof a TEPL system is determined by both the collectionand excitation spot sizes, which were first simulated using LumericalFDTD ,34 generally known forcausing less probe wear compared to the illumination mode. Furthermore,it is operated in reflection mode by delivering light through theprobe, allowing for great flexibility and ease of use.The strongpolarization collection anisotropy is the key featureof this TEPL technique, which enables nanoscopic imaging of dark states.By utilizing the out-of-plane probe–sample coupling, the techniquesignificantly enhances the out-of-plane polarized dark state emission,while the in-plane polarized bright state emission is not enhanced.The plasmonic coupling also limits the collection volume of the darkstate emission, resulting in extremely high imaging resolution. Incontrast to scattering-type near-field techniques,2 sample was initially measuredusing the pyramidal probe with and without gold coating to evaluatethe effect of the gap mode. The results in 29 The integrated PL intensity of these twopeaks shows linearly increases with the excitation power , whichrules out the possibility of biexciton emission that would exhibita nonlinear power response.35 Thus, thenewly observed feature can be attributed to dark excitons. Furthercharacterizations below similarly confirm this assignment. The appearanceof the dark exciton emission band confirms a significant enhancementfactor specifically of XD over XB. As shownin 14 However, our measurements in 3, which is consistent with the simulated results.The PLemission of the WSeD emissionand the near-field enhancement, a retraction curve wasobtained to observe the PL intensity evolution as a function of probe–sampledistance.36 As shown in B increased linearly asthe probe–sample distance decreased. This increase in signalintensity was induced by stronger far-field excitation and collection,which was also observed in retraction curves using a bare pyramidprobe without the plasmonic coating . In the second regime, below 15 nm, the XD intensityincreased sharply as the probe entered the plasmonic near-field regime,with a dimension on the order of the curvature radius of the probe,approximately 20 nm.36 Correspondingly,the XB intensity has a relatively smaller change. ThisPL evolution with the probe–sample distance reveals selectivenear-field enhancement of the dark state emission over the brightstate emission, which was also confirmed by the increase of XD/XB intensity ratio with the decrease of ALD spacerlayer as shown in Figure S3c in the SupportingInformation.Tofurther investigate the correlation between the XB emission started to quench, while the increaserate of the XD slowed down, which can be attributed tononradiative damping by the nanocavity.4 Based on this observation, the probe–sample distance at theset point (95% of free amplitude) of tuning fork vibration was estimatedto be around 12 nm .It is worth noting that before the probe was incontact with thesample, the X2 sample at a constant probe–sampledistance. The feedback signal for height sensing was set as the amplitudechange, while the emission spectrum was integrated for 200 ms at eachpixel with an 8 nm step size. The total time to perform the near-fieldscan at a dimension of 800 nm × 800 nm was approximately 55 min.To deconvolve the XD and XB signals, two Lorentzianpeaks centered at the respective wavelength were used to fit the spectrumrecorded at each pixel (see Section S4 inthe Supporting Information for details). The integrated PL intensityof each peak at every pixel was calculated to generate the XD and XB maps.In the near-fieldimaging experiment, the gold-coated pyramid probesscanned over the ML WSe2 sample containingnanoscale oxidation featureswas imaged to demonstrate the imaging capabilities of the novel near-fieldtechnique that combined a correlated shear-force image and opticalmappings. The shear-force image in Figure S5), thetextured features were identified as oxidized regions with high surfacepotential. These features are not present in the freshly preparedsample  and are a result ofaround 1 month oxidation under ambient conditions.An ML WSeB andXD emissions was demonstrated by comparing the recordedPL emission at oxidized and nonoxidized sites. B and XD emission, whileposition 1 only shows XB emission. Although the oxidizedsites have little to no emission, the diffraction-limited excitationand collection around the probe result in nonprobe-enhanced XB emission being collected from outside of the near-field spot.For this reason, XB maps cannot resolve smaller oxidizedregions, unlike the XD maps. D and XB, respectively. The nonemissive oxidized featuresand the flake edge can be clearly identified in the XD mapat the corresponding position in the height image, whereas these featuresare less clear in the XB map. D and XB maps were determined by using the standard90–10 method,37 which were ∼50and ∼200 nm, respectively. This confirms that this gap-mode-basedconfiguration provides a spatial resolution approximately equal tothe apex radius of the probe on the out-of-plane XD mapwhich was ∼4 times higher than that of the XB map.The spatial resolution difference between the X2 samples. These nanobubbles are generatedduring sample preparation under ambient conditions where water molecules,air, or nanoparticles can be trapped between the ML and substrate.39 Such bubbles have emerged as an important means of engineering theexcitonic states, through potential modulations of localized strain11 or alterations in doping concentration.39The near-field technique was also applied to mapregions of nanobubblesin the ML WSe2 was in contact with the substrate, two bubble sites(areas 2 and 4), and the adjacent region (area 3) which appeared tobe suspended, as indicated by its disappearance after the near-fieldexperiments, which was confirmed in the AFM image in Figure S7.2a. Notably, the height change in area 3 was notcaptured in the shear-force image  in the rapid raster scan conducted prior to the experiments, likelydue to the reduced height sensitivity of the high-speed scan. Consequently,the suspended region with reduced support cannot be captured accuratelyin the shear-force image.The height maps in B emission compared to the flat area. This enhanced emissionwas also observed in far-field imaging using an objective lens, aswell as the results by the as-imprinted pyramid probe without thegold coating . However,when the coated probe was used, it was found that enhanced XD emission was also present in these sites, which is not accessiblethrough the far-field approach. This enhanced XD was furtherconfirmed by repeated near-field mapping in area 4 using a differentprobe .As shown in B and XD exciton peaks. This suggests that the straineffect in these areas is relatively small, consistent with the estimatedstrain of less than 0.1% associated with the geometric structure ofthe bubble in area 4 . The enhancedXB and XD emission observed at the bubble sitescan be attributed to the lifting of contact with the substrate, whichreduces the potential substrate dopant effect,40 and the other dielectric screening effects.41 This is further supported by the reduced emissionobserved in area 3 in the optical maps obtained during the high-speedscan  and the scan usingthe bare pyramid probe scan , where no significant height changes in area 3 were observed.Figure S10, revealing an energy shift in thebright states and a larger energy difference between the XB and XD emissions (see Section S10 in the Supporting Information). This observation aligns with recentstudies highlighting the sensitivity of XD emission tostrain. For instance, Kim et al.9 havereported a correlation between strain-induced excitonic emission andXD, with lifetimes reaching tens of nanoseconds. Gellyet al.19 have shown that dynamic controlof strain can facilitate the funneling of XD and increasethe emission. Moreover, Hasz et al.10 reportedan increase in the XD emission with increasing strain usinga scattering-type near-field probe at the nanobubble sites. Thesefindings further underscore the significance of our technique in investigatingdark excitons.Additionally, a scan on smaller bubbles is shown in 2. The near-field configuration, whichconsists of a pyramidal probe coated with a thin gold film and goldsubstrate, offers distinct advantages over the traditional scattering-typeprobes. Such a reduced interaction with the excitation laser promotesa stable TEPL scan and provides an excitation profile that minimizesthe far-field background. Both experimental and theoretical resultsconfirm the capacity of the near-field configuration to selectivelyenhance XD emission within an optical volume consistentwith the gap spacing. The high contrast in the spatial resolutionsbetween the dark and bright states provides independent optical accessto XD and consequently a direct analysis of the local oxidizedfeatures and bubble sites. Our study provides experimental proof thatthe formation of nanobubbles can enhance the XD emissionefficiently, which was previously inaccessible with far-field opticalmapping. These findings align with recent research efforts19 on the impact of localized strain on dark state emission, whichaims to better understand the photophysics of the strain localizedquantum emitter. Overall, our approach offers an alternative methodfor TEPL on 2D materials and has broad implications for probing thelocal excitonic emission in these materials.In conclusion, we have successfully used a novelnear-field configurationto perform hyperspectral near-field mapping of spin-dark excitonicemission in ML WSe


In shallow subduction zones, fluid behavior impacts various geodynamic processes capable of regulating slip behaviors and forming mud volcanoes. However, evidence of structures that control the fluid transfer within an overriding plate is limited and the physical properties at the source faults of slow earthquakes are poorly understood. Here we present high-resolution seismic velocity models and reflection images of the Hyuga-nada area, Japan, where the Kyushu-Palau ridge subducts. We image distinct kilometer-wide columns in the upper plate with reduced velocities that extend vertically from the seafloor down to 10–13 km depth. We interpret the low-velocity columns as damaged zones caused by seamount subduction and suggest that they serve as conduits, facilitating vertical fluid migration from the plate boundary. The lateral variation in upper-plate velocity and seismic reflectivity along the plate boundary correlates with the distribution of slow earthquakes, indicating that the upper-plate drainage system controls the complex pattern of seismic slip at subduction faults. Vertical fluid pathways in the upper plate of the Hyuga-nada subduction zone, Japan, facilitate upward fluid migration from the plate boundary that host slow earthquakes and produce seafloor mud volcanoes. High fluid pressure is a prerequisite condition for slow earthquakes to nucleate at subduction faults4. At shallow parts of subduction zones (depth < 15 km), the pore fluid pressure is primarily controlled by the compaction/dehydration reactions of sediments entering the subduction zone3. Once released from the source, the fluid migrates upward via permeable zones into the forearc wedge owing to its buoyancy6, forming mud volcanoes and cold seeps on the forearc basins and trench slopes7. Subducting seamounts (topographic highs at the plate boundary) impact the hydrological system in subduction zones by causing a heterogeneous distribution of permeability in the upper plate and forming a subduction channel filled with fluid-rich sediments10. However, the evidence on fluid distribution directly linked to subducting seamounts is limited. In particular, the along-strike extent of the impact of the subducting seamount is poorly constrained. In addition, our understanding of how the complex structure formed by subducting seamounts modulates the slip pattern at subduction faults remains unclear11.Plate boundaries in subduction zones portray a wide spectrum of slip behavior, from day-to-year-long slow slip events to instantaneous faulting, governed by diverse physical factors. Pore fluid is one of the most influential parameters of seismic slips, and pore fluid behavior has been intensively studied in recent years13, the source areas of which are delineated by long-term slow slip events on the downdip side14 16 implies that these events occur at the plate interface, driven by the spatiotemporal variation in the fluid pressure therein19. Another fluid-related phenomenon in the Hyuga-nada area is abundant mud volcanoes on the seafloor22. Although geochemical analyses of core samples suggested that these mud volcanoes are fed by the dehydration of clay minerals at shallow crustal depths21, the origin of the fluid is poorly understood. Moreover, the hydrological system responsible for the transfer of deep fluids is unknown.The Hyuga-nada subduction zone in southwest Japan is an excellent area to study the relationship between subduction earthquakes and forearc hydrology. Adjacent to the Nankai Trough, where megathrust earthquakes of magnitudes greater than 8 occur frequently, the Hyuga-nada area historically hosted several interplate earthquakes of magnitudes ~7e14 Fig. . On its 25. We compare the Vp model with the reflection image on the coincident line for structural interpretations. Based on the seismic results, we suggest the origin of deep fluids and their pathways up to the seafloor mud volcanoes. We also compare them with the spatial distribution of slow and regular earthquakes to discuss the structural controls on their occurrence. The structural characterization on the subduction megathrust faults using our study method can provide important information to evaluate the spatial extent of future megathrust earthquakes in the region.To better understand the geodynamic system in the Hyuga-nada subduction zone, we performed a dense seismic refraction experiment using ocean bottom seismographs (OBSs) and a multichannel seismic (MCS) reflection survey in the summer of 2020. For the refraction study, we laid out 50 OBSs at 2-km intervals on the seismic line HYU01) Fig. . The sei Fig. . T26, suggesting that the subduction of the Kyushu-Palau Ridge increases the porosity of the forearc wedge over a broad region (about four times broader than the ridge itself). Interestingly, some of the low-velocity columns dip slightly toward the summit of the ridge located in the middle of the study area. Based on their fan-shaped geometry radiating from the seamount, we interpret that the low-velocity features represent an intensive fracture network; previous studies utilizing sandbox experiments explain that such networks consisting of subvertical faults can develop above subducting seamounts27. The dense distribution of fracture zones in the vicinity of the Kyushu-Palau Ridge may reflect the stress concentration in the region caused by seamount subduction, and their lower seismic velocities in the western part  close to the seismic profile, indicating another typical feature of mud volcanoes  in the region. For example, while tremors and VLFEs actively occur around the subducting Kyushu-Palau Ridge, where the plate boundary is reflective and exhibits low seismic velocities (Vp of 3.5–4.5 km/s), their activities disappear in the western part of the profile , it may also be true for shallow subduction zones .Several episodes of tremors and VLFEs are observed within a localized area of an ~30-km rangeThe seismic data were acquired through two research cruises conducted in August 2020. During the KM20-05 cruise by the R/V Kaimei of Japan Agency for Marine-Earth Science and Technology (JAMSTEC), we deployed 50 OBSs along the HYU01 profile at 2-km intervals. Each OBS contained three‐component geophone and hydrophone sensors . The OBSs recorded the acoustic signals from 596 airgun shots triggered every 200 m along the 120-km-long seismic line. All the OBSs were recovered by the R/V Kairei during the KR20-10 cruise, providing the seismic records of the airgun signals. We also collected the MCS reflection data on the same line as the OBS refraction survey, using a 5.6-km-long 444-channel streamer cable onboard the Kaimei; the shooting interval for the reflection survey was 50 m. For both the surveys, the Kaimei’s tuned airgun arrays  were used as the source.41. Then, we determined the first breaks in the refraction waves manually, using the vertical component of the geophone data. The picking error ranging from 30 ms to 60 ms were assigned to each pick, depending on the offset and the noise level of the data. A total of 27,902 first arrivals were used for a traveltime tomography analysis42 to derive a preferable Vp model. The initial Vp model for the first-arrival traveltime tomography (FAT) was created by referring to the seismic refraction studies close to the survey line considered in this study25 . The data were processed following a standard prestack flow that included trace editing, tidal static correction, and low-cut filtering (of 1–3 Hz). The processing also included swell-noise attenuation, deghosting, source signature deconvolution, 2D surface-related multiple elimination, least-squares adaptive subtraction, and high-resolution radon demultiple for noise reduction. Velocity analyses and prestack Kirchhoff depth migration were performed to produce the final seismic reflection image Fig. .https://www.ngdc.noaa.gov/mgg/gdas/). The data were gridded at 1arc-min (bin size), and then were transformed to the vertical component of the magnetic field produced by the same source magnetized in the vertical direction [reduced-to-pole (RTP) anomaly]. The paleo latitude of the study area was assumed to be 26° N, while considering the northward convergence direction of the Philippine Sea Plate.The magnetic anomaly data were downloaded from the Marine Trackline Geophysical Database of the National Centers for Environmental Information (Supplementary Information FilePeer Review File


All-optical switches control the amplitude, phase, and polarization of light using optical control pulses. They can operate at ultrafast timescales – essential for technology-driven applications like optical computing, and fundamental studies like time-reflection. Conventional all-optical switches have a fixed switching time, but this work demonstrates that the response-time can be controlled by selectively controlling the light-matter-interaction in so-called fast and slow materials. The bi-material switch has a nanosecond response when the probe interacts strongly with titanium nitride near its epsilon-near-zero (ENZ) wavelength. The response-time speeds up over two orders of magnitude with increasing probe-wavelength, as light’s interaction with the faster Aluminum-doped zinc oxide (AZO) increases, eventually reaching the picosecond-scale near AZO’s ENZ-regime. This scheme provides several additional degrees of freedom for switching time control, such as probe-polarization and incident angle, and the pump-wavelength. This approach could lead to new functionalities within key applications in multiband transmission, optical computing, and nonlinear optics. Here the authors demonstrate the active control of an all-optical switch harnessing the interaction of light with the constituent materials. The response speeds up by two orders of magnitude and scales accordingly with the strength of the light matter interaction. In all-optical switching, a light pulse interacts with the device’s constituent material, changing its optical response. For example, an intraband pump can energize free electrons in a transparent conducting oxide (TCO), increasing their effective mass, making the materials less absorptive12 and thus increasing overall transmission. Conversely, an interband pump can generate photocarriers that increase the metallicity and absorption of TCOs14. This mechanism is often suggested for dynamic photonic devices capable of modulating the amplitude or phase of light passing through them. Importantly, all-optical switches can operate without the resistive-capacitive delays of electronic circuits. Instead, the speed of optically-induced permittivity modulation is limited by the relaxation mechanisms of the switching material, which can range from a few femtoseconds16 to several nanoseconds18. The fast permittivity change enables several interesting phenomena and applications that are not achievable by other means of switching. Large and rapid modulation of the dielectric permittivity in TCOs has led to nonreciprocal optical devices19, photon acceleration20, and ultrafast optical switching22, to name a few examples.Switchable optical devices enable real-time control over the polarization, amplitude, or phase of light24. The wavelength range where the real part of the material dielectric permittivity changes its sign is known as the Epsilon-Near-Zero regime. Strong light-matter interaction due to the large field enhancement and the slow group velocity of light near the ENZ point enables a plethora of interesting optical phenomena without the need for complex composite structures. Examples of such phenomena include dramatic reflectance and transmittance modulation25, remarkably strong nonlinearity enhancement28, time refraction29, broadband30 and narrowband31 absorption, optical time reversal32, and high-harmonic generation33, in addition to on-chip modulators35. When an ENZ medium is fabricated on a reflective metal, free-space light can couple into radiative bulk plasmon-polaritons, called Ferrell-Berreman (FB) modes37. Strong light-matter interaction in such multilayer cavities has been employed to demonstrate broadband absorbers30 and polarization switches9.Recently, field-enhanced slow-light effects in epsilon-near-zero materials, including TCOs, have further enhanced these nonlinear optical phenomena by several orders of magnitude41, thermal45, and optical methods54. These studies have focused on the scaling of modulation with power55, enhancement with engineered structures14, and modulation limits57.Any optical switching device relies on two major functionalities: the magnitude of the dielectric permittivity change, which governs the modulation depth, and the overall material response time that governs the switching speed. There have been numerous studies on modulating the permittivity of materials in various ways, including electrical58, which is generally fixed and/or defined by the response times of the material constituents. The challenge in controlling the speed of all-optical switches is that the relaxation time of the switching material is an intrinsic property. As a rule, this property can be changed or adjusted at the film growth/fabrication step but not dynamically during device operation. Thus, the overall switching response is assumed to be fixed after the device is fabricated. In one such study, the relaxation time of cadmium oxide-based switches was decreased by increasing the doping concentration11. Epsilon-near-zero switches utilizing aluminum-doped zinc oxide have a picosecond response13 when controlled by an interband pump, but a femtosecond response15 when controlled by an intraband pump. All-optical switches with higher quality factors generally have a longer response time than those with a lower quality factor59. The carrier dynamics of gold nanorods can be somewhat modified by pumping them at varying wavelengths or angles, varying the switching time to a limited degree60. Overall, the range of switching times obtained in these prior studies are within the same timescale order, determined by the carrier dynamics in the single switching material.Thus far, few studies have focused on engineering the switching speed of tunable and tailorable devices61. In black phosphorus, for the same pump wavelength, the decay time of sub-bandgap probes decreases at shorter wavelengths62. In titanium nitride, a sub-picosecond electron-phonon response is only observed when the probe wavelength is close to the epsilon-near-zero (ENZ) wavelength18. These experiments highlight that the device operational wavelength has an important role in the observed dynamics of a structure. Extending this idea, we demonstrate a device-level approach to controlling all-optical switching speed in a dual-active-material structure employing the Epsilon Near Zero properties of the materials.Interestingly, several works studying the carrier dynamics of different materials report wavelength-dependent response times. For example, in pump-probe studies of gold, longer wavelength probes exhibit faster relaxation times as they interact with states that relax faster than those probed by shorter wavelengths17, while that of AZO shows a much faster relaxation time spanning picoseconds15. Our approach for engineering the temporal dynamics involves combining these materials, resulting in a double-resonant device that supports a radiative ENZ mode in the TiN layer and a Ferrell Berreman mode in the AZO layer63. Upon using a 325-nm-wavelength optical pump, electrons in both TiN and AZO are simultaneously excited, leading to transient reflectance modulation due to changes in permittivity. Notably, the reflectance modulation is most pronounced near the epsilon-near-zero regions of the corresponding materials. The device switching time is nanosecond-speed in proximity to the ENZ wavelength of TiN, following its carrier dynamics, and picoseconds, close to the ENZ of AZO, consistent with AZO dynamics. This highlights the significant influence of light-matter interaction with distinct materials in an optically modulated device. Moreover, we establish a model for the temporal dynamics of devices employing multiple functional materials. We further demonstrate that the device switching time can be controlled utilizing a multitude of parameters, including the angle of incidence and the polarization of probe beam, and the pump-wavelength configurations. Ultimately, we discuss the experimental findings and their implications for designing more complex all-optical switches.Here, we show the utilization of two technologically relevant, robust materials with extensively studied relaxation dynamics: plasmonic titanium nitride (TiN) and aluminum-doped zinc oxide (AZO), in a single multi-resonant device. Individual transient characterization of TiN demonstrates an overall relaxation time spanning nanosecondsp-polarized light near the ENZ points of TiN and AZO, evident in Fig. We developed a TiN-AZO FB resonator by depositing a 130-nm-thick layer of TiN on a silicon substrate, followed by the growth of a 250-nm-thick AZO layer Fig.. Supplem18, and blue-shifting the resonance in the near-infrared (NIR) range13 . We performed the pump-probe spectroscopy on the AZO using the setup shown in Fig. 13. The reflectance spectrum blueshifts, decreasing the reflectance to the left of the minima and increasing to the right  simulations (COMSOL Multiphysics) with our material’s measured optical properties show that at 325 nm , 48% of the pump light is absorbed in the TiN layer and 39% in the AZO layer. Thus, upon excitation by the pump, electrons in both AZO and TiN are excited, modulating the permittivity of both materials. Carriers in AZO relax at ultrafast timescales while the permittivity of TiN takes longer to settle to steady-state due to its slower lattice cooling relaxation process.FEM simulations (COMSOL) using the extracted optical properties of TiN and AZO show that 80% of p-polarized light is absorbed in the TiN near its ENZ point in the visible. Similarly, 90% of p-polarized is absorbed by the AZO near its ENZ point in the NIR Fig. . Thus, tp-polarized light in the AZO. As a result, the speed of the modulation at 1180 nm (solid blue line) mirrors that of AZO on silicon (blue dots).To further illustrate the phenomenon, in Fig. At wavelength regimes where the probe interacts comparably with TiN and AZO, the response has attributes of both materials. Figure α is the weighted contribution of TiN (with the 2-time constants τ1 & τ2) and β is the weighted contribution of the AZO (single time constant τ). Γ is an offset attributed to slower thermal effects and noise due to probe fluctuations. Supplementary Table Plotting the temporal response of the device at different probe wavelengths shows a gradual decrease in the overall relaxation time with increasing wavelength Fig. . The effSupplementary Information Section While extensive strides have been conducted in the dynamic control of the phase, amplitude, and polarization of light with optical devices, there exists a gap in engineering the temporal dynamics of tunable systems. In this work, by employing an all-optical double-layer switch comprising both fast and slow-responding materials, we demonstrated advanced control over the temporal dynamics of such a hybrid all-optical switch. The device supports two p-polarized light resonances – a radiative visible ENZ mode in the TiN layer and an infrared Ferrell-Berreman mode in the AZO layer. When excited by the same 325 nm wavelength pump, close to these resonances, the device has a switching speed under 10 ps when probed at 1180 nm and over 2 ns when probed at 508 nm. The probe follows the relaxation dynamics of the constituent material near its epsilon near zero point, where the light-matter interaction is the strongest. By sweeping the probe between these ENZ-related resonances, one can operate the same device at switching speeds spanning two orders of magnitude, enabling a great degree of control over the switching speed.The proposed approach utilizes slower materials that are very robust and allow to enhance the field intensities while faster materials ensure an ultrafast dynamic response. We show that fast permittivity modulation can be obtained even when materials with relatively slow dynamics are used as a back reflector, to enhance the modulation at the desired operational wavelength. Our findings underline the importance of conducting broadband pump-probe characterization of the full device stack, including spacers, back reflectors, and substrates in addition to the active layer when designing all-optical switches. Furthermore, when designing complex time-varying devices utilizing multiple materials, a good understanding of the dynamic response of each constituent material is required to achieve the desired performance.We show that the overall temporal response of a dual-material all-optical switch can be represented by a weighted sum of the relaxation behaviors of each of the constituent materials. The zero-to-zero response of an all-optical switch at a particular wavelength is dictated by the material with the stronger light-matter interaction, in other words, by the material that confines the most incident light within it. By changing the probe-light wavelength to interact with different materials in the device, the range of operating speeds and thus bandwidth can be varied by two orders of magnitude. We experimentally demonstrated that controlling the probe-light interaction with the individual TiN or AZO layers enables the large variation of the observed speed. Moreover, we mapped the light-matter interaction of the probe with the materials and correlate their relative absorbances with particular relaxation times. Finally, we demonstrated that further control over the switching speed can be attained by controlling the probe polarization, angle of incidence, as well as the pump wavelength.48. However, in most practical applications, such switches would still need to communicate with electrical components, whose speed is limited to gigahertz scales. To mitigate the modulation strength versus bandwidth compromise, it is desirable to have the response speed of the modulating effect be only a couple of times faster than the operating speed of the device one is trying to get67. Thus, the option of tunable switching speeds that match slowly increasing electronic switching speeds offers a way to bridge the gap between electronic and optical communications.Our approach can be used to mix and match materials with significantly different temporal dynamics to achieve multiple switching speeds and bandwidths within the same platform for multiband data transmission. In the field of all-optical switching beyond Moore’s Law, optical switches have been demonstrated to operate at femtosecond speeds, offering terahertz or higher switching rates68, negative refraction64, time refraction29, and photonic time crystals69 that require ultrafast changes in the material permittivity at fast, femtosecond timescales, while operating at large laser powers.Robust, laser-tolerant materials can be also employed as back reflectors in optical switching schemes and nonlinear optical experiments. Their slower speeds do not affect the ultrafast response of the active medium. Examples of such systems include nonlinear optical phenomena such as frequency shiftsFinally, our method can be used to extract the temporal dynamics of individual materials in complex, multilayer structures by controlling where the probe light is strongly confined.Harnessing control over the all-optical switching speeds by developing a holistic approach to studying the temporal dynamics of time-varying devices and incorporating the contribution of each material will be crucial in developing time-varying devices for telecommunications optics and other nonlinear optical applications.Supplementary informationPeer Review File


Herpes zoster (HZ) is the clinical syndrome associated with reactivation of latent varicella-zoster virus (VZV). Several factors have been implicated to promote VZV reactivation; these include immunosuppression, older age, mechanical trauma, physiologic stress, lymphopenia, and more recently, infection with severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2). Recent reports suggest an increase in the number of HZ cases in the general population during the global COVID-19 pandemic. However, it is unknown what proportion of HZ during the pandemic is due to reactivation of wild-type or vaccine-strain VZV.Here we report the first known case of HZ concomitant with SARS-CoV2 infection in a 20-month-old female who was treated with a single dose of dexamethasone, due to reactivation of the vaccine-type strain of VZV after presenting with a worsening vesicular rash.In this case, we were able to show vaccine-strain VZV reactivation in the context of a mild acute symptomatic COVID-19 infection in a toddler. Being able to recognize HZ quickly and effectively in a pediatric patient can help stave off the significant morbidity and mortality associated with disease process. VZV, a neurotropic human alpha herpesvirus, is responsible for Varicella (Chickenpox) during primary infection and HZ (Shingles) during reactivated infection . After iSARS-CoV-2 elicits a variety of immunologic disturbances . LymphopHere we describe a toddler who developed severe progressive Herpes Zoster due to reactivation of vaccine strain (vOka) a few days after an acute COVID-19 infection. This case should help pediatricians to understand the pathogenesis of Shingles in young children without a history of previous chickenpox or exposure to chickenpox.th she received a single dose of dexamethasone (0.6 mg/kg) for reactive airway disease likely triggered by acute COVID.A 20-month old female with a past history of gastroesophageal reflux, laryngomalacia, bronchiolitis, reactive airway disease, and perinatal intraventricular hemorrhage presented to clinic with the chief complaint of a recurrent rash. She tested positive for SARS-CoV-2 in January 2021, then again 1 year later on January 11th, 2022. She was seen in the Pediatric Emergency Department on January 12 and 13 2022 due to wheezing; on the 12Four days after the patient tested positive for SARS CoV-2 January 15th), she developed an erythematous, pruritic patch in her antecubital fossa; the rash subsequently developed vesicles that appeared fluid-filled , due to continued spreading of the rash and lack of improvement on oral acyclovir, the patient presented to the Pediatric Emergency Department. At this time, providers noted a vesicular rash on her right upper extremity and posterior neck, in various stages of healing that proceeded along a dermatomal distribution Fig. c. The paThe following day, the patient was seen in our Pediatric Infectious Disease clinic. At that time she was noted to have a vesicular and papular rash on her right arm, armpit, and upper back along the C5/6 dermatome that looked consistent with HZ. During this visit, the lesions no longer appeared to be exhibiting signs of a secondary infection, so cephalexin was stopped. Acyclovir was continued for an additional 5-days.The patient returned to the ED 10 days after she was seen in our clinic, and 6 days after stopping oral acyclovir, due to erythematous rash on her right cheek  was sent to the Viral Diagnostic Laboratory at Yale-New Haven Hospital, was also positive for VZV DNA by PCR (probe sequence: (FAM)TCT CGA CTG GCT GGG ACT TGC G(TAMRA), forward sequence: 5′-TCT TGT CGA GGA GGC TTC TG-3′, reverse sequence: 5′-TGT GTG TCC ACC GGA TGA T-3’, [th was sent to Merck for identification of the origin of the VZV strain as part of the US Varicella Zoster Identification Program (VZVIP). This test was carried out in Dr. Anne Gershon’s laboratory at Columbia University. The isolate was studied for five single nucleotide polymorphisms (SNPs), four of which are in ORF 62, which has mutations in positions 105705, 106262, 107252, and 108111 that distinguish wild-type Oka VZV from the Oka/Merck vaccine-strain, as well as a SNP marker at ORF38, a characteristic of clade 2 subtypes of VZV, from which the vaccine strain was derived. DNA from patient’s VZV was amplified by PCR and identified as the Oka/Merck vaccine strain by DNA sequencing.The swab obtained in the pediatrician’s office was reported as positive for VZV by PCR, while HSV PCR was negative (Quest). A second specimen . This pTo the best of our knowledge, this is the first known report of VZV vaccine-induced herpes zoster following recent symptomatic COVID-19 infection. Due to the temporal association of the HZ eruption and her COVID-19 infection, we questioned whether there may be an association.This patient had been previously vaccinated with the VARIVAX vaccine, and reportedly had no known positive contacts with either Varicella or HZ, which raised our suspicion for vaccine reactivation. Importantly, during our investigation into the etiology of her VZV reactivation, we were able to sequence the strain and prove that it was indeed the Oka/Merck vaccine strain.There have been previous reports linking COVID-19 infection to VZV reactivation –9, 11–17Another recent study from a team in Brazil  found thIn terms of the pathophysiology, there has been speculation that lymphopenia and T-cell dysfunction resulting from COVID-19 infection may weaken the immune system in a way to allow for VZV to be reactivated , 11, 12.Although our patient did not have a complete blood count in any of her encounters for this illness, it is also possible that lymphopenia from the dexamethasone she initially received in the Emergency Department contributed to her development of VZV. There is evidence that even a single dose of dexamethasone can yield marked suppression of circulating lymphocytes . Use of In this case, we were able to show vaccine-strain VZV reactivation in the context of a mild acute symptomatic COVID-19 infection in a toddler. Being able to recognize the possibility of Varicella vaccine reactivation in the context of a recent COVID-19 infection is important to prevent delay in the subsequent diagnosis and treatment. VZV and its reactivation form, HZ, carry the potential of significant morbidity and mortality, especially within the young pediatric population. Prompt identification and treatment can stave avert worse disease sequelae. Reactivation of VZV is a rare occurrence within the pediatric population therefore we offer the above case to increase awareness.


Despite being a major obstacle for eradication efforts, the genetic variation and timing of formation of this latent reservoir remains poorly understood. Previous studies on when virus is deposited in the latent reservoir have come to contradictory conclusions. To reexamine the genetic variation of HIV in CD4+ T cells during ART, we determined the divergence in envelope sequences collected from 10 SIV infected rhesus macaques. We found that the macaques displayed a biphasic decline of the viral divergence over time, where the first phase lasted for an average of 11.6 weeks (range 4–28 weeks). Motivated by recent observations that the HIV-infected CD4+ T cell population is composed of short- and long-lived subsets, we developed a model to study the divergence dynamics. We found that SIV in short-lived cells was on average more diverged, while long-lived cells harbored less diverged virus. This suggests that the long-lived cells harbor virus deposited starting earlier in infection and continuing throughout infection, while short-lived cells predominantly harbor more recent virus. As these cell populations decayed, the overall proviral divergence decline matched that observed in the empirical data. This model explains previous seemingly contradictory results on the timing of virus deposition into the latent reservoir, and should provide guidance for future eradication efforts.HIV can persist in a latent form as integrated DNA (provirus) in resting CD4 Antiretthe host –7. This et al. , viral rebound occurs upon treatment interruption – 12, suget al.  tested wet al.  of non-defective env sequences in the proviruses in CD4+ T cells of SIV-infected rhesus macaques on ART, and found that the divergence undergoes a biphasic decline over time. We estimated from data the distributions of proviral divergence in the short- and long-lived subsets of CD4+ T cells at the start of ART, and found that the short-lived cells harbor more diverged provirus from later in infection, while long-lived cells harbor less diverged provirus from earlier in infection. Furthermore, we developed a mathematical model to predict divergence kinetics during ART given these initial distributions and decay rates, and found that the model captures the observed biphasic decline of the divergence.We postulate that the seemingly contradictory observations regarding the reservoir in the literature may be confounded by the presence of dynamically heterogeneous infected CD4251 stock) and initiated ART at ≈ 48 weeks post-infection. Intact proviruses in CD4+ T cells were quantified using the intact proviral DNA assay (IPDA) (env) sequences in SIV DNA in circulating CD4+ T cells were then obtained using single genome sequencing, and filtered to remove any sequences with defects  resulting in non-defective proviral env sequences; see Methods and Fray et al.  , 34 periy et al.  for detay et al. ; see Metenv sequences from the consensus sequence of the infecting virus stock. Based on the prior knowledge that at least two T cell subsets with different half-lives exist (≈ 11.6 weeks (range 4–28 weeks). Macaque T624 is an exception, and was found to have spontaneously controlled viral replication to low levels before ART  in the short-lived cells, and shifted left (dominated by sequences with fewer mutations) in the long-lived cells. This lends further support to the finding that the CD4+ T cell subsets with different decay rates and divergence distributions at the start of ART (see Methods). The simulations start with populations of cells with the estimated distributions of mutations in the short- and long-lived cell populations based on the individual experimental sequence data from each macaque. These cells then decay stochastically over time at the estimated decay rate  by estimating half-lives using pooled data for all 10 macaques and then adjusting for individual variations (referred to here as mixed-effects parameters) (blue lines in 3 simulations), and (ii) by estimating half-lives separately for each macaque using only its own data (green lines in 3 simulations). We found that either the mixed-effects parameters  or the individually estimated half-lives  captured the empirically observed heterogeneity across macaques. The variability of the empirical data was based on about 20 sequences per time point . Similar agreement is seen between the experimental observations and model simulations when the proviral DNA sequences are replaced with plasma viral RNA sequences at the start of ART, retaining non-defective proviral DNA sequences for subsequent time points; We found that the overall divergence decline predicted by the model matched the empirical decline trends; me point . EncouraWe investigated the relative contribution of the model parameters to the divergence over time. Here the model parameters are: the initial frequency of short-lived cells To investigate whether the shape of the mutation distributions of diverged provirus in short- and long-lived cell subsets has any impact on the biphasic decline, we simulated different combinations of mutation profiles  to S5. O+ T cells, even during suppressive antiretroviral therapy  are harbored in short-lived CD4+ T cells, while proviruses from earlier in infection are harbored in long-lived cells. We further found that in the SIV-infected macaques studied here, the mutational profile in the short-lived cells was shifted right, being dominated by viruses circulating near the start of therapy. Conversely, the mutational profile in long-lived cells was shifted left, being dominated by viruses from earlier in infection. The forces driving this shift in the mutational profiles in short- and long-lived cells are as of yet unclear, and require further investigation.HIV persists as latent provirus in a reservoir of resting CD4 therapy –5. This  therapy , 7. Seve therapy , 19–22. ay rates , 33, we ogresses –39. ThusUsing the estimated distribution of mutations and half-lives as inputs, we developed a mathematical model to predict the divergence dynamics during suppressive ART . Our model predicts that when these cell populations decay during ART, the overall virus divergence declines in a biphasic manner, similar to that observed in our experiments. By exploring different combinations of mutational profiles at the start of ART using simulations, we found that biphasic decline occurred whenever the short-lived population had on average more diverged virus than the long-lived population.≈1 to ≈7 months) in this cohort of SIV-infected macaques, well before the impact of clonal expansion becomes prominent (≈5 to 10 years or shorter in SIV-infected macaques on ART (≈3 years (146 weeks). This helped reduce the impact of a third stable CD4+ T cell subset with no decay observed in this cohort s cohort , possibl+ T cells with integrated non-defective provirus env sequences, which may include both productively infected and latently infected cells. Thus, the predictions made here are not directly comparable to studies that focus exclusively on the latent reservoir.Our experimental data, and therefore our model, investigated CD4+ T cell population before ART  can lead to very different conclusions of how diverged the proviruses in an individual are with respect to a founder virus.Interestingly, since short-lived cells form a greater fraction of the total CD4fore ART , 33, thefore ART –22. As tet al. , where et al. . This du+ T cell subsets, with variations arising from differences in sampling times, inherent stochasticity of the sampling, and individual heterogeneity.Thus, our results present a unifying model, suggesting that the seemingly conflicting observations in previous studies, as well as the heterogeneity observed in recent studies, may not be in conflict. Rather, they may be a result of different snapshots of the CD4last in first out - the viruses replicating later in infection, which tend to be highly diverged, will be predominantly harbored in short-lived CD4+ T cells, and will be lost earlier than the long-lived cells harboring less diverged proviruses. This suggests that recent clinical trials that focus almost exclusively on viruses circulating near the start of ART (The model proposed here has the characteristic of t of ART  may missth Edition (NIH). The regulatory standards of the indicated committees have also been followed in all the experiments which involved laboratory animals.Animals were housed at Bioqual Inc., Rockville, MD. Approval for all animal work was granted by the Institutional Care and Use Committees of Bioqual and the National Institutes of Health, and has been determined to be in accordance with the guidelines outlined by the Animal Welfare Act and Regulation (USDA) and The Guide for the Care & Use of Laboratory Animals, 8Macaca mulatta) were infected intrarectally via repetitive challenge with the SIVmac251 swarm  , as well as single genome sequencing of the envelope gene  , 44. Perope gene , 34, 42.≈ 4 years) on ART, with longitudinal sampling of peripheral blood at weeks 0, 4, 8, 12, 28, 48, 92 104, 120, 146 and 208 or 216 post initiation of ART. When the decay kinetics of CD4+ T cells with intact proviruses were studied in this cohort  using M51 swarm ). Divergfunction  was usedfunction ), using function ) and ipsfunction ).et al.  the sequences at the start of ART come from a mixture of short- and long-lived cells, and (ii) the sequences at the last time point come only from long-lived cells, i.e., when all the short-lived cells have died out. Thus, to obtain the distribution of mutations in the long-lived cells at the start of ART To estimate the distribution of mutations in non-defective provirus of infected cells at the beginning of ART in the short- and long-lived CD4We obtained a histogram of mutations by defining each bin to represent 1 mutation. The same procedure was followed whether the data for the start of ART comprises non-defective proviral DNA or plasma viral RNA.3 runs for each pair of initial distributions.We developed a model of the dynamics of sequence divergence based on different initial distributions of mutations in short- and long-lived cells, and the corresponding dynamics of these cells once treatment was started, assuming no new cell infections and no cell proliferation; Divergence was computed analytically as follows. All decay simulations were carried out in Python 3.8.12 using packages pandas (v1.3.5) , 51 and Supplement 1


Approximately 20–50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need.RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs.We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC –PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation.Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study.The online version contains supplementary material available at 10.1186/s13046-023-02754-6. Colorectal cancer (CRC) is the third most commonly malignancy worldwide . SurgicaPatient-derived tumor organoids (PDOs) are three-dimensional, self-assembling structures of cancer cells isolated from surgical specimens. PDOs were shown to recapitulate the cyto-architecture and, to a significant degree, the heterogeneity of the originating tumor . PDOs caInterleukin 6 (IL-6) acts on cancer cells by inducing the expression of STAT3-dependent genes, thereby promoting cancer cell proliferation and survival , 13. STARNA-seq analysis was performed on 9 primary colon tumor samples, 25 samples derived from primary liver metastasis and 10 samples from the second or third wave of liver metastasis. All the primary tumor had at least one matched liver metastatic sample and for six of them RNA-sequencing was performed also on adjacent normal liver tissue  were dissolved in DMSO. For all the experiments, the maximal concentration of DMSO used as a control was ≤ 0.05%. Recombinant IL-6 was from Peprotech .https://www.ebi.ac.uk) under the accession number PRJNA288518 and PRJNA603221 , a xanthine family molecule, is a phosphodiesterase inhibitor, inflammatory cytokine regulator, immunomodulator, antioxidant and antifibrotic agent , 59. It With regard to the other compounds, we note that dexketoprofen has potential anticancer actions, mainly through inhibition of cyclooxygenase 1 (COX-1) . NotablyA limit of this study is that we did not test combinatorial treatments among the four selected drugs. On one side, this may be relevant in light of the partial convergence in the mechanism of action of at least two of the compounds tested (e.g.: anti-inflammation), which may have led to potentiation mechanisms. Another limit of the present study is that we did not test the PDO response to the drug in the presence of tumor-microenvironment-associated components. We have provided evidence here that CAFs concurrently isolated and cocultured with the PDOs, exhibited a prominent ability to secrete IL-6 after 5-FU treatment, thus suggesting that CAFs may initiate a paracrine stimulation of the epithelial cancer cells, mediated by the expression of gp130, limited in our system to the EpCAm positive cells. On the other hand, the persistence of IL-6 secretion even in late passage PDOs  may indicate that the CAF-mediated paracrine stimulation may be followed by autocrine production of IL-6 by the epithelial components. This strengthen the possibility of using pentoxifylline as an adjuvant in in vivo settings, were CAFs and many other TME components are not artefactually separated or reduced by PDO passaging. It also raises the suggestion of using early passage PDOs for assessing the contribution of TME remnants to the drug response, when coculturing is not feasible. A systematic coculturing approach is ongoing and will be addressed in future studies on a larger cohort of CRC-PDOs.This proof of concept study shows that PDOs represent a suitable platform to validate molecular data, to test clinically viable compounds and, ultimately, obtain key insights on the mechanism of action of the identified drug candidates. Pentoxifylline may represent an interesting candidate for combinatorial therapy. A larger cohort of samples will be needed to further validate those observations.Additional file 1.Additional file 2.