This study analyzes the victimization trajectories of partner violence against women surrounding divorce, depending on whether the couple has children together.Prior studies have found that partner violence is associated with an increased risk of divorce. No study has assessed the victimization trajectories surrounding divorce for women with and without children, although women with children may remain at higher risk of violence following divorce.Using Finnish record‐linkage data of 22,468 divorced and 333,542 continuously married women and their husbands, we used repeated‐measures logistic regression analyses to assess changes in victimization for partner violence before and after divorce. The outcomes considered were police‐reported crimes committed by husbands against their wives and hospital‐treated assault injuries recorded for wives.The risk of crime victimization for partner assault was already elevated from 2 to 3 years before divorce, peaked in the year prior to divorce, and then mainly leveled off 1–2 years after divorce. Hospital data show that the time of the greatest risk was from 6 to 12 months before divorce, when divorce is usually filed for. Women with younger children experienced elevated risks of physical violence shortly before divorce and remained at higher risk of menace than women without children for a year after divorce.Divorcing women committed assaults against their husbands, but these were mostly accompanied by victimization, suggesting that resistant violence was common for women as perpetrators. Women with a history of victimization need support, especially at the starts of their divorce processes. Individuals who have experienced the dissolution of a marriage have poorer health outcomes compared with continuously married individuals  on female patients and police‐reported data (2011–2017) on victims of intimate partner violence and their perpetrators—the present study assessed how the risk of victimization changes before and after divorce for divorcing women, as compared with continuously married women. We also assessed whether the victimization trajectories are different for women with and without children, given that women with children are more likely than childless women to stay in contact with their estranged husbands  and Statistics Finland provided information on police‐reported crimes (other outcomes). The register‐based study profiles describing how we constructed the population datasets for the analyses of hospitalizations and crimes are shown in Figure We first focus on 41,766 married women who divorced between 2011 and 2014 and follow their outpatient and inpatient hospitalizations for assault injuries for 4 years before and 3 years after their divorce (2007–2017). If a study person experiences several divorces between January 1, 2011 and December 31, 2014, we use information on the most recent divorce. We complement these data for divorcing women with a comparison group of women who stay continuously married for the observation period. The comparison group includes 304,026 continuously married women who were married to and lived with their husbands for at least 2 years between December 31, 2012 and December 31, 2014, and who did not experience any divorce, separation, or widowhood between January 1, 2005 and December 31, 2017.We use the National Hospital Discharge Records from 2006 to 2017 to form the outcome of outpatient or inpatient hospitalizations for assault injuries, using the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD‐10). The study comprises the external causes of the injuries, including both physical and sexual causes (ICD‐10 codes: X85–Y09). A few women who were killed without being hospitalized are included as cases in our outcome measure on the day of their death, based on their death records. The outcome is coded as one if a woman is hospitalized at least once during a 6‐month observation period and zero otherwise.N = 22,468) is smaller than that for hospitalizations  because of the different timelines to collect divorces (2 vs. 4 years).We then focus on 22,468 married women who divorced in 2014–2015 and follow their crime victimization for and perpetration of partner violence for 3 years before and 2 years after their year of divorce (2011–2017). We complement the data for divorcing women with a comparison group of women who stay continuously married for the observation period. The reason for limiting the timelines differently for crimes and hospitalizations is that medical records have been available for a long period of time but police records for petty assaults improved in 2011 following a legal reform. Since 2011, petty assaults could be prosecuted and investigated by the police without the victim's active request, resulting in the better coverage of partner assaults  is included in our analyses  and stalking (25:7a§). Illegal menace is punishable when “A person who raises a weapon at another or otherwise threatens another with an offence under such circumstances that the person so threatened has justified reason to believe that his or her personal safety or property or that of someone else is in serious danger shall be sentenced for menace…. We study the same crimes for women as perpetrators as for women as victims: partner assaults and menace. To qualify for the perpetrator–victim linkage, the perpetrator needs to be the wife and the victim the husband. Given that we had constructed two crime datasets for partner assaults for women—the first dataset for women as victims of their husband's violence and the second for women as perpetrators of the violence—we merged these datasets for divorcing women to study the extent to which the occurrence of police‐reported partner assault in a given year was mutual. In these analyses, we excluded the comparison group of continuously married women because of their extremely low crime rates against their husbands.We use the same dataset of the divorced for perpetration as for crime victimization , intermediate education , and tertiary education . Age is a variable with 1‐year increments, based on the year and month of birth. It is a time‐varying variable. Calendar year is used as a time‐varying variable in the analysis of hospitalization, but it is time‐invariant in the analysis of crimes due to its multicollinearity with years surrounding divorce year.We assess the trajectories of hospitalizations for assault injuries for 4 years before and 3 years after the date of divorce. We divide the time to and since divorce into 14 six‐month (183‐day) observation periods surrounding the date of divorce for divorcing women and surrounding a random date—randomized between January 1, 2013 and December 31, 2014—for the continuously married. We use repeated‐measures logistic regression analysis with an outcome of one if a woman received inpatient or outpatient hospital care for assault injuries at least once during a 6‐month observation period and zero otherwise. The analysis controls for correlations within individuals by using generalized estimation equations with an unstructured correlation matrix . The outcomes are defined as one if women are victimized at least once during the observation window and zero otherwise. The results are presented as unadjusted predictions (left panel) and as adjusted predictions, estimated at the mean value of other covariates (right panel). The adjusted predictions are controlled for time‐varying covariates of age, and for time‐invariant covariates of year, education, the duration and order of marriage, and having children. Table P‐values for these differences are based on the standard errors calculated using the delta method. Table We assess the victimization trajectories of partner assault (left panel) and menace (right panel), according to whether women have children. These results are presented as the unadjusted trajectories for divorcing and continuously married women Figure . We thenTo study the trajectories of crime perpetration by women against their husbands, we use the same longitudinal approach. These findings are presented as the unadjusted trajectories for divorcing women alongside the corresponding figures for victimization, to illustrate the level differences observed for women surrounding divorce. We also describe the number of women who are only victims, both victims and perpetrators, and only perpetrators in a given year surrounding divorce.To study whether having children modified the trajectories of crime victimization, we first categorize having biological children into two groups: no children and one child or more. Having children aged under 18 years is defined by using the pseudonymized identifiers of both the mother and the father and using information on their children's vital statuses and ages. Children who died or reached the age of 18 before the month of divorce are excluded from the total sum of children, as well as those who were not fathered by the husband their mother divorced. Secondly, we further categorize women according to the age of their youngest child as follows: no children, youngest child aged under 12 years, and youngest child aged 12 years and over.Table For divorcing women, the risk of assault injuries was already elevated at baseline 4 years before divorce, as compared with continuously married women  and hospital‐treated assault injuries . These outcome indicators provided partly similar and partly different results. Both indicators suggested that there is an increasing pattern of partner assault for women prior to divorce. However, the results for police‐reported assaults indicated that partner violence decreased rapidly from 1 to 2 years after divorce, indicating that most aggressive ex‐husbands adjusted to life post‐divorce Figure . In victIn our hospitalization analyses, we used the 3‐digit ICD‐10 codes for assaults (ICD‐10: X85–Y09), given that the perpetrator identifiers were not widely used for medical data at the time of our study  and continuously married women  and in the crime datasets of divorced  and continuously married women Figure S2. Trajectories of hospitalization for assault injuries (6‐month probability) before and after the date of divorce for divorcing women, and before and after a random date for continuously married women. The outcome is “corrected” to zero for those whose husband is never registered as a perpetrator against this wife by the police from 2009 to 2017.Figure S3. Trajectories of hospitalization for assault injuries (6‐month probability) before and after the date of separation (the end of cohabitation) for divorcing women, and before and after a random date for continuously married women.Click here for additional data file.


Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa‐cel), an autologous haematopoietic stem cell gene therapy (HSC‐GT) product, has demonstrated sustained clinical benefits in MLD. Arsa‐cel was approved for NHS treatment in February 2022 for asymptomatic late infantile or early juvenile disease, or early symptomatic early juvenile MLD. We evaluate the impact of this approval in the largest real‐world dataset of MLD HSC‐GT. Hospital records were reviewed for all patients referred for NHS treatment following arsa‐cel approval. Information was gathered about disease phenotype, presentation, eligibility, and affected siblings. In the year following NHS approval, 17 UK MLD patients were referred for treatment. Four patients met eligibility criteria and have been treated, including 1 infant who weighed 5 kg at leukapheresis. Eleven patients failed screening: 10 symptomatic patients with late infantile disease and 1 with early juvenile disease and cognitive decline. Two further patients with later onset subtypes did not meet the approval criteria. Three out of four treated patients were diagnosed by screening after MLD was diagnosed in a symptomatic older sibling. The success of HSC‐GT for MLD has heralded a new era of hope for families affected by this devastating disease, yet currently, most patients are ineligible for treatment at diagnosis. The feasibility of apheresis in infants and the availability of a licenced, effective HSC‐GT product highlights the urgent need for newborn screening to ensure that patients can be diagnosed and treated before symptom onset. There is a relationship between enzyme dose delivered, and biochemical and clinical outcomes, and allogeneic HSC better prevents disease progression than reverses established disease.Timely HSC‐GT using gene‐modified autologous HSC that delivers normal or supraphysiological enzyme levels has the potential to alter the natural history of such diseases. Early diagnosis and prompt access to gene therapy are imperative, especially in rapidly progressive diseases that involve the nervous system, since there is an obligate delay in enzyme‐competent cells engrafting this compartment. Pre‐symptomatic diagnosis is possible through newborn screening (NBS) and allows earlier treatment by harvesting HSC from young infants which can then be sent for gene therapy manufacture.MLD is a rare, autosomal recessive, lysosomal storage disease with an estimated incidence of 1 case in 40  000 live births.The condition is classified according to age of symptom onset. Children developing symptoms before the age of 2.5 years have late infantile disease, the juvenile form is characterised by symptom onset between the age of 2.6 and 16 years (early juvenile <7 years and late juvenile from 7 to 16 years), and adult‐onset disease occurs from age 16 onwards.Allogeneic HSC transplant has shown limited efficacy in attenuating the neurological deterioration that characterises MLD, particularly in those patients with early‐onset disease,+ stem cells transduced ex‐vivo with a lentiviral vector encoding the human ARSA gene, has demonstrated sustained clinically relevant benefits in children with early onset MLD, by preserving cognitive and motor function, and slowing demyelination and brain atrophy.Atidarsagene autotemcel (registered as Libmeldy®—hereafter referred to as ‘arsa‐cel’), an autologous HSC‐GT product based on autologous CD34We evaluate the impact NHS arsa‐cel approval has had on UK patients with early onset MLD in the largest real‐world dataset of a gene‐therapy‐treated MLD cohort outside of clinical trials. Multi‐centre natural history studies have provided a convincing picture of the different types of MLD2n = 17) to RMCH for consideration of HSC‐GT since Libmeldy was approved for NHS treatment in February 2022. Information was gathered about disease phenotype and clinical presentation along with eligibility for HSC‐GT and whether any siblings were affected. Patients were screened against the licencing criteria, and where appropriate , were reviewed by a multi‐disciplinary expert panel including metabolic, neurology, and neuropsychology representatives to confirm their eligibility status.Hospital records were reviewed for all UK patients referred , including 1 patient who was screened at birth due to a previously affected sibling and weighed approximately 5 kg at the time of leukapheresis, met eligibility criteria  70), 1 with late juvenile disease and cognitive decline (FSIQ 51), and a further symptomatic patient with adult‐onset disease. Table In summary, we have treated 4 eligible early‐onset MLD patients out of the 17 NHS patient referrals received. In addition, we have demonstrated the feasibility of mobilisation, leukapheresis, product manufacture, and infusion in patients with weights as low as 5.5 kg. Despite this, the vast majority (79%) of children referred for HSC‐GT were deemed ineligible due to advanced disease.4Despite the hope afforded by HSC‐GT for patients with MLD, the substantial number of ineligible patients referred to RMCH, is a powerful reminder of the of urgent need to implement a national NBS program for the condition. A recent qualitative MLD caregiver survey conducted in the UK strongly supports the need for such NBS programs.We acknowledge that the number of patients referred for consideration of Arsa‐cel treatment on the NHS in this first year exceeds the known incidenceStudies have demonstrated the presence of elevated sulfatides associated with MLD can be detected from dried blood spots.A condition is suitable for a screening program if it strongly fulfils the Wilson and Junger principles.A formal application to add MLD to the UK newborn blood spot program was made in December 2021 to the national screening committee marking an important milestone for the MLD community.The rarity and complexity of MLD, whose typical presentation can overlap with other neuromuscular disorders, causes diagnostic delays frequently described by families affected by the disorder.NBS will prevent delays in diagnosis and the associated burden faced by families, allowing families time to process this diagnosis and prepare for HSC‐GT.In conclusion, our largest real‐world dataset of patients treated with arsa‐cel autologous HSC‐GT for early onset MLD highlights the importance of a prompt diagnosis and referral to maximise the potential treatment benefit. NBS has the potential to reduce the current high proportion of ineligible patients by ensuring rapid diagnosis at birth and timely HSC‐GT before symptom onset while being aware of the stark reality patients who are ineligible for treatment will succumb to their disease due to a late diagnosis. We must lobby together to fast‐track an MLD UK NBS program to transform the therapeutic landscape of the condition, allowing this new era of stem cell gene therapy to achieve its full potential.Rob Wynn, Simon Jones, and Claire Horgan conceived and designed the study. Claire Horgan, Kelly Watts, Dipak Ram, Stewart Rust, Rebekah Hutton, Simon Jones, and Rob Wynn collected and supplied all institutional data. CH wrote the manuscript. All authors reviewed, edited, and approved the submitted manuscript.The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.Claire Horgan declares that she has no conflicts of interest. Kelly Watts declares that she has no conflicts of interest. Dipak Ram declares that he has no conflicts of interest. Stewart Rust declares that he has no conflicts of interest. Rebekah Hutton declares that she has no conflicts of interest. Simon Jones has received grant funding and licencing revenue from Orchard Therapeutics. Rob Wynn has received grant funding and licencing revenue from Orchard Therapeutics.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients. All patients are consented to data collection and sharing. This is a service outcome paper and not a research study so specific ethics approval not required.


Findings evidenced improvements in quality of life amongst distressed PEER participants, mediated by increases in psychological flexibility and self‐compassion, and reductions in distress. Peer support and mindfulness were not significant mediators. Together, this suggests that the psychosocial benefits of PEER observed for highly distressed adolescents are linked to the specific therapeutic approaches used in the program, rather than being non‐specific effects of peer connection or recreation. Findings from this evaluation provide further evidence for the efficacy and mechanisms of the effect of PEER for supporting distressed adolescents impacted by cancer. The study also demonstrates the viability and utility of the therapeutic approaches  used, showing that they have psychosocial benefits for this population.PEER is a four‐day residential program for adolescents impacted by their own or a relative's cancer, with both psychosocial  and recreational components. This study aimed to determine whether previously observed improvements in quality of life amongst highly distressed participants were mediated by improvements in processes targeted by psychotherapeutic elements of the program . Adolescents attending PEER completed surveys assessing the quality of life and proposed mediator variables at pre‐program, post‐program and two‐month follow‐up. Adolescents experiencing high/very high levels of baseline distress ( Acceptance and Commitment Therapy (ACT) and self‐compassion show promise in facilitating adolescents' adjustment to their own or their parent/sibling's cancer.PEER is an ACT‐ and self‐compassion‐based program developed for adolescents impacted by cancer.Highly distressed participants have been shown to experience greater improvements in quality of life after participating in PEER.Highly distressed PEER participants experienced improved quality of life from baseline to two‐month follow‐up, mediated by changes in therapeutic processes .The benefits of the PEER program are linked to the specific therapeutic approaches used, rather than peer connection or recreation.ACT and self‐compassion have demonstrated psychosocial benefits for distressed adolescents impacted by cancer.1For adolescents, a personal or familial cancer diagnosis can cause significant psychosocial disruption at an already dynamic developmental life stage. Just over 40% of young people diagnosed with cancer experience clinical levels of distress  programs have been identified as a promising format of psychosocial intervention for adolescents impacted by cancer, as they combine the chance to ‘escape’ the immediate cancer situation with opportunities for peer connection, support and learning coping strategies  delivered to groups of 3–10 adolescents by two facilitators trained in ACT and experienced in providing support to this population. These sessions were interspersed with group recreational activities  impacted by their own or a relative's cancer, which draws from ACT and self‐compassion in its therapeutic approach. The program involves seven psychosocial sessions  observed amongst PEER attendees who presented with high or very high levels of distress at the beginning of the program, as this group was previously noted to derive the greatest benefit from program participation , the person with cancer was more likely to still be in active treatment (p = 0.033), and on average that person had been diagnosed more recently (p = 0.018). There was no difference in participant age, cancer experience category , ethnic background, employment status or length of engagement with CanteenAs previously reported, the 2017 evaluation of PEER involved 148 adolescent participants who attended the program and completed the evaluation at two or more time points , the end of the program (T1) and 2 months following program completion (T2). This survey included demographic questions2.32.3.1very sad/unsatisfied to very happy/satisfied), with scores ranging from 0 to 10). This item is derived from the Personal Well‐being Index‐School Children , with scores summed to produce an overall distress score (range 10–50). Following Australian Bureau of Statistics guidelines, scores are categorised as indicating low (10–15), moderate (16–21), high (22–29) or very high (30–50) distress  using a 5‐point Likert scale  to rate how often they have felt supported by peers; total scores range from 11 to 55. Preliminary work with this measure has established its validity and reliability with young people attending therapeutic/recreational programs  using a 5‐point Likert scale . Total scores range from 0 to 32. The AFQ‐Y8 has been demonstrated to be more psychometrically robust and more accurate at classifying clinical depression and anxiety than the original 17‐item measure . Total scores ranged from 5 to 25. The full scale has demonstrated reliability, validity and theoretical coherence, including in adolescents  was for them, using a 5‐point Likert scale . Total scores range from 0 to 40, with higher scores indicating lower mindfulness. The CAMM has demonstrated reliability and confirmed single‐factor structure with adolescents  and satisfaction, as previously reported . As missing data was minimal (maximum 3% for each item), values were not imputed for incomplete items.2.4.1A mixed linear model was used to examine whether distressed participants' QOL improved across the three time points , with regression coefficients treated as random variables. Three models were tested: (1) a linear effect of time on QOL with no additional covariates or factors; (2) a quadratic effect of time on QOL with no additional covariates or factors; and (3) a quadratic effect of time on QOL, with demographics  included as additional covariates or factors.2.4.2The mediation analyses were conducted using the MEMORE (MEdiation and MOderation for REpeated measures) macro for SPSS, which allows testing of mediation effects in repeated measures designs with two occasions of testing , psychological flexibility  and self‐kindness . Participating in PEER is associated with reduced distress and increased psychological flexibility and self‐kindness (significant path As); changes in these mediating variables are linked to improved QOL (significant path Bs). The overall change in QOL over time (path C) was significantly altered after accounting for the indirect effect of each mediator (path C′), indicating significant mediation effects for these variables. The results show that peer support and mindfulness did not significantly mediate the effects of program participation on QOL. Together, these results suggest that the observed improvement in distressed participants' QOL after participating in PEER was specifically linked to improvements in distress, psychological flexibility and self‐kindness.Figure 4This study explores the mechanisms underlying benefits of PEER for distressed participants, with results indicating that increases in the therapeutic processes underpinning the program—particularly psychological flexibility and self‐kindness—are linked to improvements in QOL following participation. Reduction in distress also mediated this change, whilst mindfulness and peer support were not statistically significant mediators. This builds on findings from the previous process evaluation of PEER which identified that the program resulted in clinically significant improvements in QOL and distress for some participants, with those who reported high and very high levels of baseline distress appearing to benefit more from the program (Patterson, McDonald, Kelly‐Dalgety, Luo, & Allison, The evidenced mechanisms of the effect of the PEER program provide further evidence to support the use of ACT and self‐compassion as therapeutic approaches when working with adolescents impacted by their own or a family member's cancer, particularly those experiencing higher levels of distress. Whilst previous literature evidences the benefits of these approaches for young people (Bluth et al., Interestingly, neither mindfulness nor peer support was significant mediators of the improvement in QOL in this study. That mindfulness did not mediate this change suggests that the observed impacts of ACT for adolescents impacted by cancer are not solely attributable to this therapeutic component; that is, the six elements of ACT in combination appear to offer greater psychosocial benefit than mindfulness in isolation. Likewise, that peer support did not mediate improvements in QOL suggests that program benefits for distressed participants are not purely due to opportunities for peer support and connection. However, qualitative testimonials from participants evidenced the clear value adolescents found in connecting, sharing experiences and exchanging support with peers (reported in the previous PEER evaluation paper (Patterson, McDonald, Kelly‐Dalgety, Luo, & Allison, Finally, improvements in QOL were also mediated by reductions in distress—perhaps unsurprisingly, as these participants were experiencing high to very high levels of distress at the beginning of the program. The effect sizes for this mediation were the largest of all mediators, although caution is required when interpreting this comparison, as the relatively small sample precluded entering multiple mediators in a single analysis.4.1It is important to note that the results of this study are only true of a subset of participants: those adolescents with clinically elevated levels of distress at baseline (Australian Bureau of Statistics, 4.2The findings of this study not only confirm the benefits and underlying therapeutic processes of the PEER program; they also demonstrate the viability and impact of ACT and self‐compassion for adolescents who are experiencing high levels of distress as a result of their own or a family member's cancer. Improvements in QOL amongst distressed adolescents were specifically mediated by increases in psychological flexibility and self‐kindness, suggesting that therapeutic interventions can improve these processes in this population, with resulting psychosocial benefits. The finding that mindfulness and peer support did not mediate improvements in quality of life suggests that incorporating ACT and self‐compassion as part of therapeutic intervention may be more effective than programs based solely on peer support and/or mindfulness. Whilst further research comparing different interventions would be needed to confirm this, healthcare providers and community organisations may want to prioritise programs and services that incorporate ACT and self‐compassion when considering the most appropriate referrals to make, or support services to offer, distressed young people impacted by cancer.Canteen is a registered charity supported by government funding and donations from individuals, corporations, trusts and foundations. The evaluation of the PEER program received no specific funding.The authors would like to acknowledge Dr Richard Tindle for his contribution to the statistical analysis, the Canteen staff who conducted the PEER program, and all the young people who participated in the evaluation. Open access publishing facilitated by The University of Sydney, as part of the Wiley ‐ The University of Sydney agreement via the Council of Australian University Librarians.All authors on this paper are affiliated with Canteen, which owns the intellectual property rights to the PEER program; there are no other conflicting interests associated with this project.


Radiation recall is an unpredictable, poorly understood inflammatory reaction within the confines of previously irradiated tissue that occurs following exposure to a systemic agent. In this article, we will focus on a subcategory of radiation recall, called radiation recall pneumonitis (RRP), precipitated by immune checkpoint inhibitors (ICI). Historically, RRP can develop weeks to years after radiation treatment to the lung, most commonly after receiving certain chemotherapeutic agents, but more recently has been recognized in association with immunotherapy agents (ICIs). Up until now, RRP following exposure to ICIs has been described in patients who have received radiation to the lung itself. Here we present three cases of RRP in patients who received radiation to areas adjacent to the lung parenchyma, and developed pulmonary infiltrates in an area adjacent to the radiation field while on ICI therapy. Since ICI induced RRP is treatable and steroid sensitive, early recognition and treatment are important. Radiation recall is an unpredictable, poorly understood inflammatory reaction within the confines of previously irradiated tissue that occurs following exposure to a systemic agent. In this article, we will focus on a subcategory of radiation recall, called radiation recall pneumonitis (RRP) precipitated by immune checkpoint inhibitors (ICI). Up until now, RRP following exposure to ICIs has been described in patients who have received radiation to the lung itself. Here we present three cases of RRP in patients who received radiation to areas adjacent to the lung parenchyma, and developed pulmonary infiltrates in an area adjacent to the radiation field while on ICI therapy. Since ICI induced RRP is treatable and steroid sensitive, early recognition and treatment are important. Radiation recall is an unpredictable, poorly understood inflammatory reaction within the confines of previously irradiated tissue that occurs following exposure to a systemic agent anywhere from weeks to months and even years after irradiation. In this article, we will focus on radiation recall pneumonitis (RRP) precipitated by immune checkpoint inhibitors (ICI).Radiation recall injury was first described in 1959 by D'Angio et al.RRP is a subcategory of radiation recall that involves previously irradiated lung fields that has been historically attributed to chemotherapies as mentioned above.ICIs, first FDA approved in 2011, have become standard treatment for a myriad of locally advanced and metastatic cancers by harnessing the intrinsic immune response of T‐cells against tumour antigens with the sometimes‐unintended consequence of T‐cell attack on self‐antigens. This can cause a spectrum of adverse events independent of other (neo‐) adjuvant therapies, including immune checkpoint inhibitor pneumonitis, the most frequently described ICI adverse event in the lung.Since the original reports in 2017, several case series have been published with regards to ICI‐induced RRP involving not only nivolumab, but other anti‐PD‐1 therapies, such as pembrolizumab.A 71‐year‐old man, a former 15‐pack‐year smoker, was diagnosed with local cutaneous squamous cell carcinoma of the mid‐upper anterior chest in April 2018. He received 30 fractions of radiation to the right axilla, right infra‐clavicular and supra‐clavicular regions in June to July 2018 for a total of 60 Gy. Metastatic disease to the bilateral lungs and right adrenal gland was found in November 2018 and the patient was subsequently started on systemic cemiplimab in December 2018. In January 2018 after his third cycle, the patient began to develop worsening dyspnea with exertion and mild rash on his palms and feet. Chest computer tomography (CT) scan showed new opacity with air bronchograms in the right upper lobe (RUL) in the area adjacent to previous right axillary radiation  vertebrae for moderate cord compression from paraspinal metastasis. Two weeks later, he was started on systemic avelumab (10 mg/kg infusion every 2 weeks). After his tenth avelumab infusion and 5 months after his last radiation therapy, the patient developed progressive shortness of breath. Evaluation did not reveal any infectious aetiology or worsening metastasis. CT chest and PET scan were significant for bilateral, dense consolidations in the regions adjacent to the previous RT (Figure The final patient is a 68‐year‐old man with renal clear cell carcinoma and epidural disease, treated with radiation to T6 and T9‐11 vertebrae, followed 3 months later by adjuvant nivolumab and ipilimumab. Three months after initial radiation therapy and after his fourth ICI cycle in September 2022, the patient developed subacute dyspnea. CT chest showed new bilateral paravertebral findings in the right upper lobe and left lower lobe adjacent to the patient's radiation field (Figure Here we report three patients who received radiation treatment to extrapulmonary sites and developed pneumonitis following ICI treatment. Imaging at symptom onset showed new consolidation restricted to the area of the lung adjacent to the area of the radiation.We hypothesize that the lung received radiation as an ‘innocent bystander’ and RRP was unmasked by the ICI treatment in a two‐step or ‘two‐hit’ process. At the time of the initial radiation, the lung parenchyma may have received a low‐dose of radiation which did not reach an inflammatory threshold for clinical detection. This caused a pre‐existing vulnerability, which was then potentiated and activated by the immune augmentation created by the ICI drugs leading to clinically detectable pneumonitis. Differing from the diffuse presentation of immune checkpoint pneumonitis, this ICI associated RRP was only radiographically detectable in a well‐demarcated anatomical region corresponding to the previous field of radiation—the only area of lung parenchyma that received both inflammatory hits. The well‐demarcated areas on the CT scans, especially in Case 1, demonstrate the geographical nature of RRP with the infiltrates localized to the area of the radiation rather than a diffuse, multi‐lobar pattern in ICI pneumonitis.In addition, the presentation in these cases seems distinct from radiation pneumonitis alone based on the temporal association with ICI treatment, and the fact that the lung was not radiated directly. While RT pneumonitis is sometimes seen without direct pulmonary radiation, most frequently when the spinal areas are radiated for paraspinal disease, our patients did not have clinically relevant symptoms or radiographic findings until after ICI initiation, making RRP more likely. Finally, while none of these cases were biopsy‐proven, their clinical symptoms, radiographic changes and subsequent improvement after systemic steroid treatment suggest an inflammatory pneumonitis rather than an infectious or malignant aetiology.The presentation of RRP with ICI therapy up until now has only been described in patients who received radiation directly to the lung parenchyma. The three patients that we describe here never received direct radiation to the lung—only radiation to areas adjacent to the lung parenchyma. Since ICI induced RRP is treatable and steroid sensitive, early and timely recognition and treatment are important. We give evidence here that extrapulmonary radiation in locations close to the lung but not directly to the lung parenchyma followed by ICI can cause RRP.All authors discussed the results and contributed to the final manuscript.This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.None declared.The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.


This paper outlines the evidence base for early intervention for eating disorders; provides a global overview of how early intervention for eating disorders is provided in different regions and settings; and proposes policy, service, clinician and research recommendations to progress early intervention for eating disorders.Currently, access to eating disorder treatment often takes many years or does not occur at all. This is despite neurobiological, clinical and socioeconomic evidence showing that early intervention may improve outcomes and facilitate full sustained recovery from an eating disorder. There is also considerable variation worldwide in how eating disorder care is provided, with marked inequalities in treatment provision. Despite these barriers, there are existing evidence‐based approaches to early intervention for eating disorders and progress is being made in scaling these.We propose action steps for the field that will transform eating disorder service provision and facilitate early detection, treatment and recovery for everyone affected by eating disorders, regardless of age, socioeconomic status and personal characteristics. Early intervention for eating disorders is in its infancy.We summarise existing early intervention approaches for eating disorders from around the globe.We propose key policy, service, clinician, and research recommendations to progress early intervention for eating disorders. CBT‐TCognitive Behaviour Therapy‐TenDUEDduration of an untreated eating disorderEDeating disordersFREEDFirst Episode Rapid Early Intervention for Eating DIsordersUKUnited KingdomUSUnited States1Eating disorders (EDs) are severe psychiatric disorders that affect up to 15% of cisgender women and 5% of cisgender men   is the time between first onset of a diagnosable ED and the start of evidence‐based ED treatment. A recent literature review  was developed to provide an early intervention service model and care package for emerging adults (16–25‐year‐olds) with an ED of <3 years duration   and waits of over 6 months from referral to treatment are common BEAT, . HoweverEarly intervention for adults over age 25 is lacking in the UK. Early intervention initiatives are also heavily focussed on England  and tied to specialist community‐based ED services. University outreach is available in some regions and the UK ED charity, Beat, is trialling a ‘Synergy Support Programme’ to offer individual and family support to under 18's with an emerging ED.3.2The UK and Australian health systems resemble each other in terms of a robust public health system closely linked with primary health care workers such as GPs. In Australia, however, there is a greater reliance on private health care alongside the government funded systems. In 2006, private psychological treatment services for people with mental health disorders were included under Australia's Medicare system for the first time, meaning these treatment options became subsidised by the Federal Government. In 2019, expanded Australian Medicare items were made available for EDs. These enable a rebate for up to 40 sessions of evidence‐based therapy and 20 dietetic sessions over a 12‐month period, for patients with anorexia nervosa and patients who meet criteria for a severe ED  in primary care settings and found the programme produced significant reductions in ED symptoms  was primarily women aged between 16 and 30 years. Results were strongest for symptoms of bulimia nervosa/binge eating compared to those of anorexia nervosa. As noted, StudentBodies and StudentBodies‐EDs have also been used with positive outcomes in Germany  for adult women awaiting outpatient psychological therapy for bulimia nervosa or binge eating disorder  and adult services despite convincing economic, physical and mental health arguments for youth mental health care that spans this age divide  and an often transient population . Creative solutions are needed to tackle such challenges. Online programs and virtual working are possible approaches and examples from the US and Europe offer evidence‐based solutions in this area. Another approach is using brief interventions that can be delivered by facilitators of variable expertise under expert supervision. The 8‐session Body Project Treatment is one such example  characterising first episode cohorts and following them into recovery are needed. These may help to identify biomarkers/predictors for early or delayed recovery and identify those who may be at risk of illness progression and a less favourable course.There are various encouraging research streams underway that will start to address these needs. Initial investment in Canada has allowed for a focus on early intervention via primary care settings and additional research is planned. In the UK, the 4‐year EDIFY project  launched in late 2021. This project brings together researchers, clinicians and young people with the goal of co‐creating an interdisciplinary, evidence‐based model of how EDs develop and are maintained. The FREED team are also piloting a FREED‐on‐Mobile (FREED‐M) app to encourage help‐seeking amongst young people with EDs. The app delivers youth‐friendly psychoeducation via animations and downloadable resources, with the goal of encouraging young people to seek help for their ED. In Australia, calls have been made for a youth‐focussed research agenda for EDs (Allison et al., 5Attending to these recommendations would transform ED service provision and allow early intervention to be a standard part of best practice care. Progress in other areas of psychiatry shows that this is possible. We invite those working in the ED field to mobilise change, so that we can move away from a landscape where up to 80% of those with an ED do not receive treatment (Kazdin et al.,


For efficient cancer theranostics, surface modification of nanomaterials plays an important role in improving targeting ability and reducing the non‐specific interactions with normal tissues. Recently, the biomimetic technology represented by coating of cancer cell membranes (CCMs) has been regarded as a promising method to strengthen the biocompatibility and targeting specificity of nanomaterials. Furthermore, the engineered CCMs (ECCMs) integrated with the natural biological properties of CCMs and specific functions from other cells or proteins have offered more possibilities in the field of cancer theranostics. Herein, the recent progresses in the design and preparation of ECCMs are summarized, and the applications of ECCMs in targeting delivery, activation of immunity, and detection of circulating tumor cells are reviewed. Finally, the current challenges and future perspectives with regard to the development of ECCMs are briefly discussed. Engineered cancer cell membranes (ECCMs) including hybrid CCMs and functionalized CCMs have offered increasing possibilities in the field of cancer theranostics. This review summarizes the recent advances in the development of ECCMs for different biomedical applications, in particular for targeted drug delivery, immunity induction, and circulating tumor cell capture and detection. However, these nanoplatforms face a series of common problems after intravenous administration such as poor tumor targeting ability, short circulation time, and non‐specific interactions with normal tissues and so on, thus hindering their clinical translation. One practical method to address these issues confronted by nanomaterials is to introduce functional or active targeting molecules onto their surfaces. Although various ligands, aptamers, or antibodies have been modified onto the surfaces of nanomaterials, their applications are still impeded by the insufficient targeting efficiency and the quick clearance by reticuloendothelial system (RES).Recently, various nanoplatforms have been developed for biomedical applications due to their good biocompatibility, high drug loading capacity, controlled drug release ability, as well as enhanced tumor penetration ability.1 Thes With the up‐to‐date advances in cell and molecular biology, diverse cell membranes (CMs) possessing the unique functionalities as the mostly used biomimetic materials, have exhibited significant advantages in precision cancer theranostics. Since the discovery in 2011 showing that the coating of red blood cell (RBC) membranes could effectively extend the half‐life of NPs in vivo, natural CMs with flexible membrane proteins have been extensively used to cover NPs, thus conferring them with diverse biological interfaces. Several recent reviews have summarized the applications of CM‐coated NPs in cancer theranostics, highlighting the advantages of different CMs. For example, leukocyte membranes can endow the NPs with immune escape ability, dendritic cell (DC) membranes render the NPs with homotypic targeting toward lymph nodes, and platelet membranes highly expressed with P‐selectin enable the NPs to actively target to cancer cells.Fortunately, biomimetic technology has become a promising strategy adopted to decorate nanomaterials to render them with excellent biocompatibility and low immunogenicity.13 Wit On the one hand, the rapid proliferative potential of cancer cells makes it much easier to obtain the CCMs than to acquire other types of CMs. On the other hand, the unique membrane proteins of CCMs enable the nanoplatforms with excellent homologous targeting to cancer cells and immune evasion from RES. Therefore, CCMs have been widely used to camouflage diverse NPs for different cancer nanomedicine applications such as imaging, drug delivery, and tumor vaccines. However, the applications of pure CCMs or pure CCMs‐derived NPs are limited because the CCMs lack the therapeutic capacity to directly treat tumors and the tumor antigens expressed on CCMs may be down‐regulated to escape from recognition of immune systems.Among the various types of CMs, cancer CMs (CCMs) with multiple tumor antigens have been widely explored for cancer theranostics.23 On  In particular, the beauty of ECCMs lies in the fact that they can not only be used to coat NPs for targeting delivery, but also be directly used for inducing anti‐tumor immunity utilizing the engineered membrane proteins. In this review, we introduce the recent progresses in the design and preparation of ECCMs and provide an overview of their applications in cancer theranostics, including targeting delivery, activation of immunity, and detection of circulating tumor cells (CTCs)  fabricated through fusing CCMs with other types of CMs or making CCMs express specific proteins provide a new direction to overcome the drawbacks and improve the biomedical performances of CCMs. Compared with pure CCMs, the ECCMs and ECCM‐based biomimetic nanosystems maintain the properties of CCMs and are able to undertake more complexed tasks in the tumor microenvironment.29 In ) Figure . The rep2The engineering of CCMs makes it possible to integrate the applicable membrane proteins of different CMs or insert the additional functional proteins into the CCMs. Based on the strategy to prepare ECCMs, the ECCMs can be divided into two types: Hybrid CCMs and functionalized CCMs.2.1 Since the CCMs are characterized by homologous targeting and immune escape ability, they can be fused with different types of CMs to strengthen their performance in cancer theranostics, for example, with erythrocyte membranes to decrease the clearance by RES or leukocyte membranes to reduce the interference of homologous leukocytes. Depending on the time of membrane fusion, the preparation of hybrid CCMs can be categorized into two approaches. The first approach is to fuse cancer cells with another type of cells to form fused cell lines before extracting the hybrid CCMs, and the second one is to extract CCMs and another type of CMs and fuse the two types of membranes to obtain the hybrid CCMs.The most convenient method to prepare ECCMs is to blend CCMs with membrane fragments from other types of cells to form hybrid CCMs, which can optimize the construction of membrane proteins and inherit the intrinsic properties of source cells.40 Sin2.1.1 Briefly, 4T1 cells were mixed with DCs at a ratio of 1:2 in the phosphate buffer saline (PBS) containing PEG and dimethyl sulfoxide to fuse the two cells. Then, the fused cells were incubated with interleukin (IL)‐4 for additional 6 h before harvesting the hybrid membranes to ensure that the co‐stimulatory molecules and peptides‐major histocompatibility complex (MHC) from DCs were expressed on the membranes of fused cells. Different from the pure cancer cells that down‐regulate related antigens to achieve immune escape, the complete tumor antigens as well as DC‐derived immune stimulatory molecules were present on the membranes of the fused cells. As shown in Figure In this way, cancer cells and another cell lines are required to be co‐cultured together to form fused cell lines that share and possess the characteristics of two source cells. The specific membrane proteins of the original cells can be presented on the membrane of the fused cells. Therefore, the hybrid CCMs extracted from the fused cells have at least two types of biological functions. For instance, Liu and coworkers fused the murine mammary carcinoma tumor (4T1) cells and DCs under the stimulation of polyethylene glycol (PEG) to obtain the fused cells and further extracted the hybrid CCMs Figure .30]30NP) exhibited the highest binding efficiency to both SIINFEKL peptide bound to H‐2Kb  antibody and CD80 antibody, demonstrating the successful fabrication of CD80/OVA‐functionalized CCMs  B16‐F10 cells to overexpress two additional genes Figure .39]39 NPs were first used to treat 4T1 cells in vitro to induce the highest percentage of cell apoptosis (58.15%) than free DOX and single CM‐coated NPs ‐loaded poly onto the liposome surface to strengthen their targeting ability. The hybrid CCM‐functionalized liposomes can significantly improve the water solubility, biocompatibility, and targeting ability of both CSME and Ce6, and display less uptake by macrophages and more uptake by 4T1 cells than those without membrane fusion. The half‐decay time of the hybrid CCM‐functionalized liposomes was 3.5 h, which was significantly longer than that of free Ce6 (1.3 h) and liposomes without membrane fusion (1.9 h). Both the in vivo fluorescence imaging and anti‐tumor assay data demonstrated that the fabricated liposomes could be significantly accumulated at the tumor site to realize improved synergistic therapeutic effect.In another work, Xie et al. developed a drug delivery system based on hybrid CCM‐functionalized liposomes that were loaded with the cytotoxic compound chikusetsusaponin IVa methyl ester (CSME) and photosensitizer chlorin e6 (Ce6) for combinational therapy.49 In 3.2 During the process of immunotherapy, the tumor‐associated antigens can be recognized and processed by APCs that can present the specific antigens to native T cells to activate cytotoxic T lymphocytes (CTLs) for cancer cell treatment. Therefore, the CCMs with multiple tumor antigens have a great potential in improving the response of immune system, and the ECCMs with more special proteins can be designed as tumor vaccines to promote the maturation of APCs or artificial immune cells to directly activate native T cells.Since the immune system plays an essential role in protecting body health and eliminating harmful cells, immunotherapy that can simulate the immune system has become one promising method for tumor therapy. To induce anti‐tumor immunity, it is important to utilize tumor antigens and stimulatory molecule to activate the immune cells and reverse the immunosuppression.50 Dur3.2.1 Owing to the fact that the CCMs only maintain part of tumor antigens, the effect of CCM‐derived tumor vaccines is limited without the participation of immune adjuvants. Therefore, tumor vaccines can be developed using CCM‐coated NPs, where the NPs act as adjuvants to facilitate the activation of immune cells. It seems to be a promising way to prepare tumor vaccines using natural immune adjuvants to engineer the CCMs.Tumor vaccines that use tumor antigens and immune adjuvants to stimulate the APCs and induce anti‐tumor immunity have aroused extensive attention in recent years.52 Owi Herein, the RBC membranes can be considered as a natural immune adjuvant, which utilizes their splenic APC targeting capacity to deliver the tumor antigens on the B16‐F10 CMs to APCs. The ratio of RBC membranes to B16‐F10 CMs was optimized to be 20: 1 to render the nano‐Ag@erythrosomes with the best targeting specificity to the spleen. The treatment of nano‐Ag@erythrosomes induced 62.2% maturity of DCs in vitro  than those only treated with the vaccine (7.33%), demonstrating that the combination of the vaccine and aPDL1 could efficiently activate the immune system for enhanced tumor inhibition.Encouraged by the ability of senescent RBCs to target splenic APCs, Han et al. fused B16‐F10 CMs with RBC membranes to develop tumor antigen‐loaded nanoerythrosomes (nano‐Ag@erythrosome) as a tumor vaccine Figure .35]35) NPs for photothermal therapy of tumors. The addition of OMVs significantly promoted the maturation of DCs as the percentage of CD80+ or CD86+ DCs after treated with the HPDA@[OMV‐CC] NPs significantly increased to 66.1% and 84.2%, respectively. The enhanced levels of IL‐12 and IFN‐γ in the tumor tissues further demonstrated that the HPDA@[OMV‐CC] could promote the secretion of cytokines and activate immune response. In summary, the hybrid CCM‐coated nanoplatform could act as a tumor vaccine to induce specific anti‐tumor immunity and realize the homologous targeting delivery of therapeutic agents in vivo.Bacterial outer membrane vehicles (OMVs) with many antigens can also be considered as a prospective natural adjuvant to induce immune response.55 Fur3.2.2Different from induction of anti‐tumor immunity via promoting the maturation of DCs, the other important approach to activate immune system is to directly stimulate native T cells, thus producing CTLs. The APCs always play the role of presenting the tumor antigens to native T cells through expressed p‐MHC or co‐stimulatory molecules on the cell surface. Inspired by the antigen presentation mechanism of APCs, various artificial APCs that can replace the functions of endogenous APCs have been designed for presenting antigens to native T cells. Cancer cells that overexpress MHC on the cell membranes have been used to prepare CCM‐based artificial APCs to directly stimulate the population of cancer‐targeting CTLs.57 Therefore, the membranes of the double knock‐in B16 CD80/OVA cells expressing CD80, OVA, as well as MHC have been used to construct artificial APCs. In this context, the functionalized CCMs were collected and coated onto PLGA NPs under sonication to construct the biomimetic artificial APCs ([CD80/OVA]NPs). The obtained [CD80/OVA]NPs with a size of 100 nm were able to successfully stimulate T cells. In vitro biological activity assay showed that only the double knock‐in [CD80/OVA]NPs could elicit the phenotypic changes of T cells and activate multiple CD8+ T cell phenotypes, including CD69+, CD25+, and memory T cells. The [CD80/OVA]NPs showed significant inhibitory effect in the treatment of either prophylactic B16 or therapeutic B16 tumor model and significantly improved the survival rate of tumor‐bearing mice. In summary, the [CD80/OVA]NPs can act as artificial APCs to directly stimulate T cells, thus inducing anti‐tumor immune response to inhibit tumor growth.As mentioned in Section 39 The The FMs with whole tumor antigens and immunological co‐stimulatory molecules enabled the MOF@FM to act as a tumor vaccine to be recognized by DCs or act as artificial APCs to directly stimulate T cells , pure 4T1 CMs (CM) group (50.1%), and pure DCs membranes (DM) group (42.3%). The percentage of CD80+ and CD86+ DCs after treated with CM was higher than that treated with DM, demonstrating that the CM carrying tumor antigens played a leading role in FMs‐induced maturation of DCs. The splenocytes of mice treated with MOF@FM exhibited higher population of CD3+ and CD8+ T cells (14.45%) than those treated with other groups of MOF@CM (9.69%) and MOF@DM (11.02%)  from the fused cells composed of 4T1 cells and DCs, and used the FMs to camouflage a fluorescent metal‐organic framework (MOF) to achieve the MOF‐supported FM (MOF@FM).31 Thes Figure . As show) Figure . These r3.3 Therefore, it is of great significance to develop new biological technology for efficient isolation and detection of CTCs in blood. Recently, NP‐based sensors with a large surface area to volume ratio have been widely researched to capture and detect CTCs. However, the number of CTCs in the whole blood is extremely low compared with billions of other types of cells, such as RBCs and white blood cells (WBCs). Therefore, the detection efficiency of CTCs is always limited by the interference from RBCs or WBCs. With the homologous targeting ability of CCMs, the CCM‐coated NPs were demonstrated to recognize CTCs in blood. In particular, the ECCM‐derived sensors may have improved targeting ability toward CTCs and reduced interference from other types of cells, thus enhancing the separation purity of CTCs.The CTCs in peripheral blood circulatory system originating from solid tumors are closely related to the development, metastasis, and recurrence of tumors.58 The2S nanodots (NDs) with hybrid CCM‐camouflaged magnetic NPs  and WBC membrane (from RAW 264.7 cells) were fused to obtain the hybrid CCMs (HM). The HM‐coated magnetic NPs were further modified with streptavidin (SA), then grafted with the aptamer‐functionalized Ag2S NDs through SA‐biotin interaction. Herein, the multivalent aptamers (Tetra‐DNA) were first prepared by DNA assembly and further mixed with the precursor solution of Ag2S NDs, then the mixture solution was heated to 60℃ to synthesize the multivalent aptamer‐functionalized Ag2S NDs via a one‐pot method. The multivalent aptamers could further increase the affinity between the prepared bioprobe and CTCs. As expected, the prepared HM‐coated magnetic NPs displayed enhanced separation performance of CTCs due to their homotypic binding to CTCs with reduced interference from WBCs. In mixed cell samples (500 MCF‐7 cells and 106 RAW264.7 cells), the capture efficiency of the prepared bioprobe for CTCs was 97.63%, which was higher than that of uncoated bioprobe (No‐M), pure CCM‐coated bioprobe (CM), or pure WBC membrane‐coated bioprobe (WB)  Figure . The HM‐) Figure . The HM‐4Remarkable advances have been made in the development of ECCMs and ECCM‐coated nanoplatforms to facilitate cancer theranostics. This review mainly summarized the preparation methods of ECCMs and the applications of ECCMs in cancer theranostics. Various methods have been investigated to prepare ECCMs, including fusion of cells, fusion of CMs, and functionalization of CCMs. Encouraged by the diverse functions of ECCMs, ECCMs and ECCM‐derived nanoplatforms have been developed for targeting delivery, activation of immunity, and detection of CTCs.Despite such desired advances made in the preparation and application of ECCMs, there are still several challenges remaining to be explored. First, it will make a lot of sense to let the ECCMs retain the required membrane proteins during the synthetic process, which is meaningful to guarantee the functions of ECCMs. Second, it is important to optimize the functionalization approach of ECCMs to prevent the damage of the original membrane structure and proteins. Third, considering that the ECCMs carry various membrane proteins and tumor antigens, the in vivo long‐term biosafety of ECCMs should be investigated and ways to improve their biosafety should be explored. To sum up, the inherent characteristics of ECCMs make them exhibit great potentials in precision cancer theranostics, and the opportunities and challenges confronted by the ECCMs will further promote the continuous exploration of ECCMs in the field of biomedicine.There are no conflicts of interest to declare.


To rule out underlying developmental brain defects such as schizencephaly, pediatric seizures necessitate a thorough examination. Adults who receive a diagnosis later in life may face severe management and prognosis difficulties. To avoid underdiagnosis of developing brain abnormalities, imaging should be a part of the workup for pediatric seizures. Imaging is critical to the diagnosis and therapy of such cases.Closed‐lip schizencephaly with the absence of the septum pellucidum is a rare congenital malformation of the brain that can be associated with a variety of neurological conditions. We report the case of a 25‐year‐old male with left hemiparesis who presented with recurrent seizures from childhood, poorly controlled with medications, and increased tremors. He has been taking anticonvulsant for the last 7 years and is under symptomatic management. Magnetic resonance imaging of the brain revealed closed‐lip schizencephaly with absent septum pellucidum. Normal MRI at the level of optic nerve. It is thought to affect 0.54–1.54 out of every 100,000 live births.2A 25‐year‐old male presented to the outpatient clinic with a chief complaint of increased tremors in both upper extremities, more on the right side, without any weakness. He had a history of recurrent seizures since childhood for which he was under antiepileptic medication  but was poorly controlled. Appropriate workup on the cause of seizure was not done in the past. There was no significant family history of neurological or psychiatric disorders. There was no history of any birth‐related trauma or maternal exposure to any medications. The patient was unemployed, a non‐smoker, a non‐drinker, and denied any history of recreational drug use.The patient was alert and oriented on physical examination, with no signs of distress. His vital signs were within normal limits. Neurological examination revealed high‐amplitude moderate frequency resting tremor of both upper extremities with left‐sided weakness (power 4/5 in both left upper and lower limb). Evaluation of tremor was done with recorded video analysis and during office examination. Babinski reflex was negative bilaterally. Considering the possibility of tremors due to valproate, the antiepileptic regimen was switched to levetiracetam.MRI brain showed subtle T2 hyperintense curvilinear cleft communicating the lateral ventricle and subarachnoid space of right frontoparietal convexity which is lined by closely opposed gray matter. Absence of the septum pellucidum resulting in direct communication between the lateral ventricles and squaring off of the frontal horns. Figures  and 2. MThe patient was started on anti‐seizure medication for seizure disorder and referred to a neurologist for further evaluation and management of his tremor. Physical therapy was also initiated to address his left hemiparesis and improve motor function.Examination on subsequent follow‐up visits showed improvement in tremor and hence the decision to continue levetiracetam was made. The patient has ongoing physical therapy sessions with only slight improvement in his motor function. The patient did not experience any seizure episodes after the medication was changed.3Type I (closed‐lip): Cleft is fused, preventing cerebrospinal fluid (CSF) passage.Type II (open‐lip): A cleft is present, which permits CSF to pass between the ventricular cavity and subarachnoid space.Schizencephaly is a rare congenital neuronal migration disorder characterized by a cleft lined by heterotopic gray matter, which connects the surface of the cerebral hemisphere to the lateral ventricle.Type 1 (trans‐mantle): No CSF‐containing cleft on MRI, but contains a trans‐mantle column of abnormal gray matter.Type 2 (closed‐lip): Presence of cleft containing CSF, but the lining lips of abnormal gray matter are abutting and opposed to each other.Type 3 (open‐lip): Presence of cleft containing CSF. The lining lips of abnormal gray matter are not abutting each other.Griffith PD has proposed a new method of classification of schizencephaly based on the appearance of schizencephaly in children and fetuses which led to reassessment of possible etiological and mechanistic causes of schizencephaly.EMX2 gene mutation. Maternal age, substance abuse, and lack of prenatal care are also potential risk factors.Developmental delays and a variety of neurological impairments can be linked to both kinds of schizencephaly. The etiopathogenesis of schizencephaly remains unclear, but it may result from external factors like middle cerebral artery stroke or genetic factors like Also, recent research has looked at the use of fiber tractography and diffusion tensor imaging (DTI) in the diagnosis and treatment of brain abnormalities such as schizencephaly.DTI and fiber tractography may provide valuable information for the diagnosis and management of these conditions, while genetic testing and molecular profiling may help to identify underlying genetic causes and potential treatment targets.COL4A1 mutations, EMX2‐germline mutations, SHH gene, and SIX3 gene.Some genetic mutations have been reported as possible etiological factors for schizencephaly. The main genes identified in this regard are The usage of valproic acid (VPA), which has been demonstrated to account for 14% of tremors in patients using VPA in a study conducted by Zhang et al., can be linked to the tremor reported in our case.As the precise source of the disorder is unclear, controlling its symptoms and deficiencies serve as the mainstay of treatment.4To sum up, rare congenital brain anomalies such as closed‐lip schizencephaly may appear in a range of neurological deficits and developmental delays. Like in our instance, such deficits may come to light during maturity as a variety of neurological symptoms. The cause of recurrent neurological symptoms should be identified to determine the best treatment option and prognosis. This should be done whenever feasible in an environment with plenty of resources.Chhabi Khadka: Conceptualization; formal analysis; project administration; supervision; visualization; writing – original draft; writing – review and editing. Umang Gupta: Conceptualization; data curation; methodology; software; validation; visualization; writing – review and editing. Prakriti Bhandari: Conceptualization; formal analysis; investigation; project administration; writing – original draft. Prabin Pandey: Conceptualization; methodology; supervision; visualization. Shailes Paudel: Conceptualization; formal analysis; investigation; methodology; validation; writing – review and editing.None.The authors have no conflict of interest to declare.Ethical approval was not required for the case report as per the country's guidelines.Written informed consent was obtained from the patient to publish the report.


Anthropogenic developments alter the environment and resources available to wildlife communities. In response to these real or perceived threats from this development, species may adjust their spatial occurrence. Additionally, wildlife species may adjust when in diel time (24‐h light–dark cycle) they occupy sites on the landscape to adapt to changing conditions. However, many wildlife studies only focus on where a species does and does not occur, ignoring how species may shift their diel activity at sites to mitigate threats. We used a multi‐state diel occupancy modeling framework to investigate how a community of mammals  respond to differing levels of anthropogenic development and forest cover across two climatic seasons. We collected camera trap data at 240 survey locations across the summer and winter of 2021–2022. We modeled multi‐state diel occupancy for 14 mammal species with extent of development/forest and season hypothesized to influence diel occupancy and season hypothesized to influence the probability of detection. We found that all species displayed heterogeneity in both diel occupancy and detection either by extent of development/forest and or season. Within the mesocarnivore species group, coyote and red fox were less sensitive to development and had higher occupancy probability at these sites in general but used them more during the night, while more sensitive mesocarnivores including fisher and bobcat occupied the day state only when there was increasing forest cover. Our results highlight the importance of incorporating diel activity in habitat modeling to better understand the relationship between a species and its landscape, particularly in a region that is vulnerable to increased anthropogenic pressure. Anthropogenic developments alter the environment and resources available to wildlife, and in response wildlife may alter both where and when they occur on the landscape. We used a multi‐state diel occupancy model to investigate how a community of mammals respond to differing levels of development and forest cover across seasons. We found that many mammals vary in both spatial and diel occupancy in response to anthropogenic development. Forests are an important landcover that provides cover and food sources for many species in our study area, as such we predicted that increasing amounts of forest cover would have a positive effect on occurrence in the daytime for mesocarnivores and herbivores/small mammals. Alternatively, anthropogenic factors including development and roads may be perceived as areas of high risk and thus avoided during the day when human interference is greatest and only used at times when disturbance is minimal , fisher (Pekania pennanti), coyote (Canis latrans), red fox (Vulpes vulpes), gray fox (Urocyon cinereoargenteus), and long‐tailed weasel (Mustela frenata); the urban‐adapted omnivore species consisted of species that commonly occur in suburban environments and included raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), and striped skunk (Mephitis mephitis); and the herbivore/small mammal group consisted of common prey species and included: white‐tailed deer (Odocoileus virginiana), eastern cottontail (Sylvilagus floridanus), gray squirrel (Sciurus carolinensis), red squirrel (Tamiasciurus hudsonicus) and eastern chipmunk (Tamias striatus). Note that the coyote could also be grouped as an urban‐adapted omnivore, however, we group them as a carnivore because they are still highly carnivorous in urban environments . Each camera in a survey site was placed in a different micro‐habitat and 50 cm–1 m off the ground to maximize detections of mammal species within the site  and winter . We placed two north‐facing camera traps  within 100 m of one another at selected survey sites  to calculate the proportion of each buffer area that contains forests (forest.cover) and residential development , and used the Rhode Island DOT data set  to calculate the road density within the buffer . We created a housing unit index for each buffer by using the 2020 U.S. Census Data . We standardized the housing units per census block into units per square kilometer and multiplied this by the area of each block that is within the buffer area to get a single housing unit density for each survey site buffer (housing). This index was used as an approximation of the number of people living within the buffer zone of each survey site. Separate inference from each of these variables was determined to not be possible given the high‐level of pair‐wise correlation among them (|r| > .68). As such, we applied a principal component analysis  where negative values indicate more anthropogenic features and positive values indicate more available forest , gray squirrel (Sciurus carolinensis), eastern cottontail (Sylvilagus floridanus), eastern chipmunk (Tamias striatus), red squirrel (Tamiasciurus hudsonicus), and other small rodents . We recognize this is a crude index that aims to capture spatial variation in potential prey availability and does not capture the range of all food components of each species' diet. However, it has the potential to capture an otherwise missed source of spatial variation. For each survey site we combined all prey species detections and calculated the average number of detections overall per trap during night and day, separately, for both the summer and winter seasons (prey). Lastly, by stacking the detection matrices for each survey period by species, we created a seasonal covariate (season) as a categorical variable where summer was the reference category.We quantified the amount of forest and anthropogenic disturbance by summarizing four landscape variables within a 1 km buffer zone of each survey site to capture the variation between each survey site as well as the broader spatial variation around a survey site that can influence a species' occurrence at that site. We used the Rhode Island Land Use and Land Cover 2020 dataset . Therefore, the full model allows 𝝍4 to be higher or lower than what we would expect given independent use of day‐only and night‐only sites. We linked site covariates to model parameters using the multi‐nominal logit link function where state 1 was the reference category  no use, (2) day use, (3) night use, and (4) night and day use, where we are interested in estimating the respective state occupancy probabilities 𝝍season or PCA), (3) additive covariate models (season + PCA), and (4) interaction covariates models (season ✕ PCA). For mesocarnivore species, we included four additional models within the model set that included the prey variable using the full and reduced parameterizations as a single covariate model and additive covariate with season. For all models, we considered detection probability to vary by state and season. Due to our study area occurring in a temperate landscape dominated by deciduous vegetation, we expect that changes in both the vegetation cover and availability of resources between winter and summer would have an effect on our ability to detect most species. Further, there are differences in seasonal behaviors for many species in our study due to life history traits such as breeding and young‐rearing, and we hypothesized that these seasonal behavioral shifts would add to variation in our ability to detect a species.Each species' data was separately fit to a small set of models. For the urban‐adapted omnivores and herbivore/small mammal species, we considered a total of 10 competing models that incorporated combinations of variables modeling state‐occupancy: full and reduced parameterizations as (1) no covariate models, (2) single covariate models  or Dirichlet). Otherwise, covariate models with parameter effects were given relatively diffuse prior distributions of Logistic  was the most supported model for four mesocarnivore species , three herbivore/small mammals , and one urban‐adapted omnivore , while the full model occupancy varying by PCA was the most supported model for one mesocarnivore (bobcat). The reduced multi‐state model was most supported for one mesocarnivore (long‐tailed weasel) and two urban‐adapted omnivores (Virginia opossum and striped skunk); as such, there is no evidence that these species use the day/night state more than or less than expected from how they use the day and night states. Models including a covariate for amount of prey availability at a site was not the most supported model for any of the mesocarnivore species.We found the full MSDOM with state occupancy varying by For the eight species that had a seasonal parameter for state occupancy in the most supported model, species with a higher probability of occurrence in the day‐use state during summer (𝜂 < 0.1) – relative to not occupying a site – included three mesocarnivores  and fisher (𝜂 = 0.99)), and long‐tailed weasel (𝜂 = 0.25) and white‐tailed deer (𝜂 = 1.00) had a higher probability of occupying a site at night. Two herbivore/small mammals (eastern cottontail (𝜂 = 0.98) and red squirrel (𝜂 = 0.99)) had a higher probability of occupying the day/night state as forest cover increased at a site . Recent studies have found that occupancy of some mesocarnivore species including bobcat and coyote is positively influenced by increasing distance from developed areas  are typically classified as nocturnal animals, and thus we did not expect to see high occurrence during the day state regardless of the landscape characteristic or season and hypothesized that they would occupy areas with increased development primarily at night. These species have been shown to benefit from occupying landscapes with a relatively large anthropogenic footprint , and eastern cottontails  of day and night between seasons, increases in night occupancy during the winter could be a result of increased availability or behavioral shifts. Additionally, many species exhibit variation in diel activity between summer and winter as a result of life history traits such as breeding and young‐rearing ; data curation ; formal analysis (supporting); investigation ; methodology ; visualization ; writing – original draft (lead). Laken S. Ganoe: Data curation ; investigation ; methodology ; writing – review and editing . Charles Brown: Funding acquisition (supporting); methodology ; supervision (supporting); writing – review and editing . Brian D. Gerber: Conceptualization (lead); formal analysis (lead); funding acquisition (lead); methodology ; supervision (lead); visualization ; writing – original draft (supporting); writing – review and editing .There are no conflicts of interest to declare.


To investigate trajectories of sustainable working life , disability pension (DP), or unemployment) in Swedish residential regions using a population‐based twin cohort, while assessing sociodemographics and twin pair similarity.Sample of 60 998 twins born in 1925–1958. SWL was assessed through main labor market status in each year in 1998–2016 based on > 180 days with SA/DP, > 180 days with unemployment, or >half of yearly income from old‐age pension for not in SWL, and employment  for SWL. Residential regions were classified into nine groups based on Swedish municipalities. Group‐based trajectory models and multinomial logistic regression were applied separately for all regions.In all regions, the largest trajectory group was sustainable working life. Three to four trajectory groups developed toward unsustainable working life with different exit points from sustainable working life. A small proportion were grouped with partial stable or increase in sustainable working life. Increased age, being a woman, <12 years of education, and history of unstable working life increased, and being married and twin pair similarity decreased the likelihood of belonging to trajectories toward unsustainable working life.In all regions, most of the individuals followed a sustainable working life trajectory. A reasonable proportion of individuals followed trajectories developing toward unsustainable working life. The influence of sociodemographic and familial factors on trajectory groups was similar in all regions. Based on results of unsustainable working life , being a woman has shown to be associated with an increased risk of sickness absence or disability pension.The aim was to investigate trajectories of sustainable working life in Swedish residential regions using a population‐based twin cohort with a follow‐up from 1999 to 2016. Based on the hypothesis that residential regions related to larger cities might have better opportunities for sustainable working life than the smaller ones, the aim was to investigate the regions separately. We further aimed to assess the role of various sociodemographic factors and twin pair similarity for belonging to the regional trajectory groups.2The data were derived from the Swedish Twin study of Disability pension and Sickness absence (STODS) and include 119 907 twins born in Sweden between 1925 and 1958 identified through the Swedish Twin Registry (STR).2.1The data on time of emigration (censoring), annual days of unemployment, employment, and old age pension for 1994–2016 were from Statistics Sweden database Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA).2.2Large cities—municipalities with a population of at least 200 000 inhabitants with at least 200 000 inhabitants in the largest urban area.Commuting municipalities near large cities—municipalities where more than 40% of the working population commute to work in a large city or municipality near a large city.Medium‐sized towns—municipalities with a population of at least 50 000 inhabitants with at least 40 000 inhabitants in the largest urban area.Commuting municipalities near medium‐sized towns—municipalities where more than 40% of the working population commute to work in a medium‐sized town.Commuting municipalities with a low commuting rate near medium‐sized towns—municipalities where <40% of the working population commute to work in a medium‐sized town.Small towns—municipalities with a population of at least 15 000 inhabitants in the largest urban area.Commuting municipalities near small towns—municipalities where more than 30% of the working population commute to work in a small town/urban area or more than 30% of the employed day population lives in another municipality.Rural municipalities – municipalities with a population of <15 000 inhabitants in the largest urban area, very low commuting rate (<30%).Rural municipalities with a visitor industry—municipalities in rural area that fulfill at least two criteria for visitor industry, that is, number of overnight stays, retail, restaurant, or hotel turnover per head of population.The type of living area, that is, regions, was from LISA.2.3Data on age, sex, education level, marital status, occupation sector at baseline in 1998 were from LISA.2.4Descriptive statistics (mean with standard deviation [SD]) and frequencies with percentage (%) were calculated for the final sample and across residential regions. Group‐based trajectory model (GBTM), an application of finite mixture modeling, was used to estimate change over time in a repeatedly measured outcome. GBTM is designed to identify groups with similar longitudinal response patterns over timeBased on the best fitted model for each region, multinomial logistic regression was applied to elucidate the association of sociodemographic factors and zygosity with the identified trajectories. For the assessment of twin pair similarity, zygosity was added to the regression models to study monozygotic twins' likelihood of belonging to trajectory groups compared to dizygotic twins. Twin pair similarity assumed that twins share genetic factors (100% for MZ and ≈50% for DZ) and family background that includes home and social family environment primarily during childhood.All analyses were performed using Stata version 14.3Descriptive statistics of the study population are presented in Table For the region 1 , five sustainable working life trajectories were identified with 64% of the individuals in the stable sustainable working life in trajectory group (TG) 5 , we observed similar TGs as region 1 except TG3 that showed stable increase in sustainable working life  had a less likelihood of belonging to these trajectory groups in nearly all regions.4.1The Swedish welfare system is guided by principles of universalism and solidarity with a superseding aim to promote social equity4.2Demographic composition, educational level, occupational sector etc., were assumed to affect the likelihood of belonging to the trajectories of sustainable working life. Our results indicated that increased age, being a woman, having low education, and history of sickness absence and unemployment played a role for the likelihood of individuals belonging to trajectories developing toward unsustainable working life. Our results are supported by earlier findings of associations between being woman, older ages and sickness absence and disability pension.4.3Furthermore, twin pair similarity (zygosity) played a role in the likelihood of belonging to trajectory groups. Hence, an assumption remains that familial confounding  might play a role for sustainable working life. Twins are known to be representative of the general population4.4Strengths of this study include the large sample size, long follow‐up, no dropout, and the availability of the high‐quality data from Swedish national registries. Having data from recent years is another strength since neither regional differences in sustainable working life nor sociodemographic characteristics of regions are stable over time.5In all regions, most of the individuals followed a sustainable working life trajectory. A reasonable proportion of individuals followed trajectories developing toward unsustainable working life, while a small proportion were grouped in trajectories following either stable or increase in sustainable working life. The influence of sociodemographic and familial factors on trajectory groups was similar in all residential regions.Approval of the research protocol: The study protocol was designed and performed according to the principles of the Helsinki Declaration. The ethical vetting was performed and approved by the Regional Ethical Review Board of Stockholm, Sweden . For this project, the Regional Ethical Review Board of Stockholm stated that the consent to participate was not applicable in these type of large register studies. None of the authors had access to any kind of identifying information. Informed consent: Not applicable. Registry and the Registration No. of study: Not applicable. Animal studies: Not applicable. Conflict of interest: None declared.Table S1–S2Figure S1–S6Click here for additional data file.


Paramyxoviridae, which include several highly contagious viruses with zoonotic potential. In this case report we describe the detection of FeMV in archived brain tissue of a 2‐month‐old Bengal cat with nonsuppurative encephalitis from the year 2011 in Switzerland by high‐throughput sequencing (HTS). Our metagenomics approach was able to obtain a full‐length sequence covering the entire FeMV genome. Phylogenetic analysis showed that our FeMV strain clustered within FeMV genotype 1. We were able to detect FeMV RNA by in situ hybridization (ISH) in brain sections with inflammatory lesions and demonstrated its potential neurotropism and association with encephalitis. Our results provide further insight into this recently discovered morbillivirus and encourage further investigations into the pathogenesis and epidemiology of associated diseases in cats and potentially other species.Feline morbillivirus (FeMV) is a recently discovered morbillivirus of the family  Ffusion glycoproteinFeMVfeline morbillivirusFFPEformalin‐fixed and paraffin embeddedHTShigh‐throughput sequencingISHin situ hybridizationNnucleoproteinPphosphoprotein1Morbillivirus of the family Paramyxoviridae includes various viruses responsible for highly contagious diseases in humans and animals, such as measles virus, rinderpest virus and canine distemper virus.The genus 2In 2011, a 2‐month‐old female Bengal cat was admitted to a veterinary practice in the Canton of Ticino, Switzerland. The kitten was underweight and received initial medical treatment including an antiparasitic, antibiotics and corticosteroids. In the following days however, the neurological condition of the kitten rapidly deteriorated with apathy, stupor, anisocoria and aggressive behavior. None of the siblings nor the queen was sick. Because of lack of improvement, the kitten was euthanized, and the brain was removed and submitted to the Division of Neurological Sciences of the Vetsuisse Faculty of Bern for further neuropathological investigations. Histopathology identified an unusually mild lymphocytic inflammation of the brain associated with neuronal degeneration and necrosis consistent with an acute viral infection. Lesions were most prominent in the thalamus, basal ganglia, hippocampus, and brainstem. We also observed inclusion bodies in the soma of neurons. We performed further etiologic investigations by immunohistochemistry  as well as reverse transcription PCR (rustrela virus and Borna disease virus 1 [in 2022]) and all were negative  using a probe targeting the nucleoprotein (N) gene of FeMV and detected an abundance of FeMV RNA in the soma of neurons and astrocytes Figure . Notably3Morbilliviruses are a major threat to human and animal health and some have a high potential for cross species transmission.Authors declare no conflict of interest.Authors declare no off‐label use of antimicrobials.Authors declare no IACUC approval was needed. Owners of the animals of which tissue samples were used retrospectively in this study provided informed consent for the use of these materials for research purposes.Authors declare human ethics approval was not needed for this study.Data S1: Supporting Information.Click here for additional data file.Figure S1: Phylogenetic analysis of FeMV strains based on a partial nucleotide segment of the large polymerase protein (L). Representative FeMV strains were obtained from NCBI GenBank with corresponding accession numbers shown in brackets. Colors indicate the genotypes  and clades  of FeMV strains.Click here for additional data file.Table S1: Primers and probes used for orthobornavirus and rustrela virus (RusV) RNA detection.Click here for additional data file.Table S2: Whole genome comparison between the discovered feline morbillivirus (FeMV) strain Locarno/CH2011 and the FeMV reference strain and FeMV strain “SS1.”Click here for additional data file.


Long‐acting and extended delivery (LAED) HIV treatment regimens are becoming increasingly accessible to consumers. After more than a decade of clinical research, long‐acting antiretroviral formulations have been approved for treatment and prevention , 2. LongLAED regimens have the potential to reshape the HIV treatment and prevention landscape through dosing schedules that are measured in months rather than days. To realize their maximum impact, it is important to recognize that product innovations in HIV and other areas of medicine face a variety of challenges when moving to wide‐scale implementation , 5. An iThere are questions about whether future LAED regimens could face similar challenges in their delivery, uptake and persistent use, as well as concerns about facilitating access in resource‐constrained environments and in key populations. LAED regimens have the potential to overcome many of these challenges, but questions remain about how best to offer HIV prevention and treatment choices, how to manage product switching and what constitutes optimal service delivery while using LAED products. For this supplement, we invited scholars to submit multidisciplinary articles designed to advance the development, future use and equitable delivery of LAED regimens for HIV prevention and treatment. We received several abstracts spanning original research, commentaries, reviews and viewpoints. After careful review and deliberation, the editorial team selected 16 contributions that illustrate current LAED advances and challenges to improve the development, retention and equitable delivery of LAED regimens across low‐, middle‐ and high‐income countries.Users’ desires and choices may also impact LAED uptake and persistent use. As illustrated by the studies included in the first section of our supplement, a deeper understanding of end‐users’ preferences can guide the development of new LAED and service delivery models and emphasize their significance in creating demand for LAED products.Graham et al.’s  study exBiello et al.’s  researchFinally, Lorenzetti et al.’s  review eTaken together, these studies underscore the importance of acknowledging choice as a key tenet of the increasing availability of HIV prevention and care products and ensuring that programmes help address users’ needs and concerns to maximize their appeal and behavioural congruence.For LAED to achieve its potential impact on the HIV epidemic, it needs to reach populations with the greatest need. These populations often face disparities in health access, either within countries or regions where health resources are limited. Mgodi and colleagues’ commentary  focuses Recognizing these constraints, four manuscripts focus on cost considerations as a critical barrier to access and discuss strategies that can be leveraged to overcome these challenges. Gaayeb and colleagues  discuss Meyer‐Rath et al.  extend tJenkins et al.  echo manWarren et al.  emphasizOngoing research and evaluation will help inform best practices as the menu of HIV prevention and care regimens is implemented and scaled. As the final section of our supplement highlights, these efforts will require multisectoral partnerships throughout the LAED development and dissemination pipeline and must ensure that all communities who could benefit from LAED regimens are included and represented.Kim et al.  argue thGrimsrud et al.'s  commentaCelum et al.’s  commentaThree manuscripts serve as a reminder to ensure that the benefits of LAED accrue to populations that are frequently left behind. Hosek et al.’s  viewpoinTaken together, the contributions to this supplement highlight the opportunities and synergize the rollout and scale‐up of LAED regimens across the globe. The manuscripts in this supplement note how structural, policy, community and healthcare contexts might facilitate or hinder the delivery of LAED regimens. Like other prevention and care efforts, the success of LAED regimens will require countries to allocate the appropriate resources required for a tailored strategy that maximizes LAED access and persistent use among its constituents. As illustrated by the manuscripts in this supplement, these tailored efforts will require an understanding of users’ needs across settings, collective buy‐in from stakeholders and communities, and comfort in creating evidence‐based implementation guidelines to support patients’ switches between HIV prevention and care regimens. Moreover, while the existing data indicate the potential of LAED regimens to help achieve global HIV prevention and care goals, continued investments are needed to ensure equity in access among key populations. LAED regimen research with understudied and/or excluded populations should remain a priority to ensure their inclusion in regulatory guidelines. We hope that the key considerations raised in this supplement will serve to advance the field as existing and emerging LAED regimens are approved and implemented.The authors declare no competing interests.JAB and SD‐M contributed to the initial draft of the manuscript. CF provided feedback, reviewed and edited the draft, and approved the final version prior to submission.Publication of this open‐access supplement was supported by funding from the National Institutes of Health.The authors alone are responsible for the views expressed in this issue. They do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated nor any of the funding agencies supporting their work.


A recent study by Johnson et al. , publishDespite the abundance of preclinical studies showing the regenerative potential of EVs, their therapeutic application in humans has been limited by the lack of a readily scalable method for clinical‐grade EV purification. LEAP‐purified EVs from activated platelets were shown to retain functionalities related to potential regenerative actions with regards to proliferation and migration of dermal fibroblasts and to angiogenesis, both of which are critical components of skin wound healing. Other frequently used methods to isolate EVs include ultracentrifugation and tangential flow filtration, both of which may need the support of additional methods to provide highly concentrated EVs for clinical treatments, making the process both lengthy and cumbersome. The evolution of efficient ways of purifying and concentrating EVs is crucial for their translation into clinical therapeutic use, and perhaps the LEAP technology is an important step forward.Several clinical trials have been registered by ClinicalTrial.gov using mesenchymal stem cell‐derived EVs to treat patients with different diseases, but only a few of them have reported the clinical results (reviewed in Klyachko et al., The present study (Johnson et al., The authors also observed no differences in the recovery times between placebo injection and allogeneic‐platelet EVs injection in healthy individuals. From the design of the present study, it is not possible to draw conclusions about wound healing in an individual where efficient tissue regeneration is absent. It is well known that the healing process is conditioned by many systemic and local factors and that in pathological conditions healing is characterized by impaired tissue regeneration. In such conditions the EVs could be beneficial by reactivating a regenerative process. Indeed, in a recent case‐control interventional study, repeated local administration of autologous serum‐derived EVs for the treatment of chronic venous ulcers, unresponsive to conventional treatments, did show a significant improvement in recovery (Gibello et al., The study by Johnson et al.  on allogThe authors declare no conflicts of interest.