Tumour Marker Expression in Head and Neck Malignancies to Identify Potential Targets for Intraoperative Molecular Near-Infrared Imaging.

BACKGROUND: Oral and laryngeal squamous cell carcinoma (OSCC and LSCC) and papillary thyroid carcinoma (PTC) are common head and neck cancers (HNCs) typically treated surgically. Challenges in tumour delineation often lead to inadequate resection margins in OSCC and LSCC, and missed multifocality in PTC. Fluorescence imaging (FLI) using near-infrared tumour-targeting tracers may improve intraoperative identification of malignancy, facilitating precise excision. This study evaluates six potential FLI targets in OSCC, LSCC and PTC. MATERIALS AND METHODS: Immunohistochemical staining was performed on OSCC (n = 20), LSCC (n = 10) and PTC (n = 10), assessing CEA, c-Met, EpCAM, EGFR, integrin αvß6 and VEGF-α. Expression was scored (0-12) using the total immunostaining score (TIS) system, and categorized into absent (TIS 0), low (TIS 1-5), moderate (TIS 6-8) or high (TIS 9-12). RESULTS: Integrin αvß6 showed significant overexpression in OSCC (TIS: 12; p < 0.001) and LSCC (TIS: 8; p = 0.002), with 80% of OSCC and 90% of LSCC exhibiting moderate-high expression. Similarly, EGFR expression was moderate-high in most OSCC (87.5%; TIS: 8) and universally high in LSCC (100%; TIS: 12). In PTC, EGFR and VEGF-α expressions were low-moderate, but significantly higher than in healthy tissue (TIS: 6; p < 0.006). CONCLUSION: This study highlights integrin αvß6 and EGFR as viable FLI targets in OSCC and LSCC, especially integrin αvß6 for tumour margin delineation. In PTC, despite lower expressions, the significant overexpression of VEGF-α, c-MET, and EGFR suggests their potential as FLI targets. Our findings support the development of tumour-targeted FLI tracers to improve surgical precision in HNC.

Food-Based Interventions as Therapy for Inflammatory Bowel Disease: Important Steps in Diet Trial Design and Reporting of Outcomes.

Diet therapy for inflammatory bowel disease (IBD) is an international research priority but guidance for IBD-specific diet trial design is lacking. This review critically evaluates key elements of prospective IBD food-based intervention trials and identifies gaps. Electronic databases were searched for interventional IBD diet studies. Prospective primary studies/trials were included if used food-based dietary strategies. Forty studies/trials evaluating 29 food-based strategies as therapy for IBD were identified. Considerable heterogeneity in diets, trial design, and methodology exists. Thirty-one trials (78%) intended the diet to modulate inflammation but 14/31 (46%) did not have a primary endpoint measuring an objective change in inflammatory activity and 20/31 (65%) controlled for medication stability prior to application of diet at baseline. Higher-quality IBD diet trials used symptom-based assessment tools coupled with an objective evaluation of inflammatory activity. Dietary advice trials are the most common. One-third of trials developed and administered diet education without a dietitian. Evaluation and reporting on adherence to diet therapy occurred in <60% of trials. Failure to include or report on key elements of trial design reduced the interpretability and validity of the results. This is a considerable limitation to advancing scientific knowledge in this area. Diet therapy trials should adhere to similar rigorous quality standards used to develop other IBD therapies. Therefore, a set of practical recommendations was generated to provide the authors' perspective to help inform the future design of high-quality IBD diet trials.

High-quality inflammatory bowel disease (IBD) diet trials are lacking and existing trials are fraught with methodological flaws. This review is intended to assist clinician-researchers in the design and conduct of future food-based intervention trials to raise the quality of IBD diet research.

Impact of Reclassification of Oncocytic and Follicular Thyroid Carcinoma by the 2022 WHO Classification.

BACKGROUND: The 2022 WHO Classification categorizes oncocytic (OTC) and follicular thyroid carcinoma (FTC) based on the degree of capsular and vascular invasion into minimally invasive (MI), encapsulated angioinvasive (EA) and widely invasive tumors (WI). While associations with clinical outcomes have been studied extensively in FTC, robust clinical data are lacking for OTC. We aimed to investigate the impact of the reclassification of OTC and FTC by the 2022 WHO Classification on clinical outcomes. METHODS: All adult OTC and FTC patients treated at the Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. All tumors were extensively revised by two independent pathologists, facilitated by Palga: Dutch Pathology Databank. Kaplan-Meier curves were used to study the association of the 2004 and 2022 WHO Classification with overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and radioactive iodine (RAI) refractory disease. RESULTS: Fifty-two OTC and 89 FTC patients were included, of which 15 (28.8%) OTC and 34 (38.2%) FTC tumors were reclassified as EAOTC or EAFTC. The 2022 WHO Classification substantially improved risk stratification in both subtypes for DSS, compared with the 2004 edition. Ten-year DSS rates were 100% for MIOTC, 92.9% for EAOTC and 56.5% for WIOTC, compared to 100% (MIOTC) and 64.2% (WIOTC) following the 2004 WHO Classification. For FTC and RAI-refractory disease, similar trends were observed. CONCLUSION: Classification of OTC and FTC into three subcategories as defined by the 2022 WHO Classification substantially improves discrimination between low, intermediate and high risk patients, especially for DSS and RAI-refractory disease.

Implementing group care in Dutch and Surinamese maternity and child care services: the vital importance of addressing outer context barriers.

BACKGROUND: By addressing physical and psychosocial needs, group care (GC) improves health-related behaviours, peer support, parent-provider interactions and may improve birth outcomes. Hence, global implementation of GC is encouraged. Context analyses prior to implementation are vital to elucidate which local factors may support or hinder implementation. METHODS: Contextual analyses conducted in the Netherlands and Suriname were compared to identify the factors relevant to the implementability of GC as perceived by healthcare professionals (HCPs). 32 semi-structured interviews were conducted with Dutch and Surinamese healthcare professionals. Audio recordings were transcribed verbatim and coded using the Framework approach. The Consolidated Framework for Implementation Research guided the development of the interview guide and of the coding tree. RESULTS: Outer setting: Concerns regarding funding surfaced in both countries. Due to limited health insurance coverage, additional fees would limit accessibility in Suriname. In the Netherlands, midwives dreaded lower revenue due to reimbursement policies that favour one-on-one care. Inner setting: Appropriate space for GC was absent in one Dutch and three Surinamese facilities. Role division regarding GC implementation was clearer in the Netherlands than in Suriname. INNOVATION: HCPs from both countries expected increased social support, health knowledge among women, and continuity of care(r). Individuals/innovation deliverers: Self-efficacy and motivation emerged as intertwined determinants to GC implementation in both countries. Individuals/innovation recipients: Competing demands can potentially lower acceptability of GC in both countries. While Dutch HCPs prioritised an open dialogue with mothers, Surinamese HCPs encouraged the inclusion of partners. PROCESS: Campaigns to raise awareness of GC were proposed. Language barriers were a concern for Dutch but not for Surinamese HCPs. CONCLUSIONS: While the most striking differences between both countries were found in the outer setting, they trickle down and affect all layers of context. Ultimately, at a later stage, the process evaluation will show if those outer setting barriers we identified prior to implementation actually hindered GC implementation. Changes to the health care systems would ensure sustained implementation in both countries, and this conclusion feeds into a more general discussion: how to proceed when contextual analyses reveal barriers that cannot be addressed with the time and resources available.

Transcutaneous sentinel lymph node detection in skin melanoma with near-infrared fluorescence imaging using indocyanine green.

The aim of the study is to assess whether indocyanine green (ICG) fluorescence can replace technetium in the preoperative detection of sentinel lymph nodes (SLN) from cutaneous melanoma. The current golden standard for SLN detection is the radioisotope technetium. A promising alternative is fluorescence imaging (FLI) using ICG. In this study, we enrolled patients undergoing sentinel lymph node biopsy (SLNB) for skin melanoma at the Erasmus Medical Center between November 2022 and July 2023. The SLNB procedure was performed as a standard of care. After general anesthesia, ICG was injected intradermally around the primary tumor site. Both the patient and the surgeon were not blinded for the location of the SLN. FLI was performed before incision, in vivo after incision, and ex vivo. Fluorescent SLNs were confirmed using the gamma probe in all cases. Thirty-two patients were included in this study, and a total of 39 SLNs were harvested. The transcutaneous detection rate of ICG was 21.9%. The combined ex vivo ICG fluorescence and technetium uptake was 94.9%. One SLN contained only ICG (2.6%) and one SLN contained only technetium-uptake (2.6%). FLI using ICG resulted in a relatively low transcutaneous detection, which means that exclusive use of this technique in its present form is not feasible. However, we did find a high accumulation of ICG in the SLN, indicating the potential of ICG in combination with other imaging techniques.

PRAP study-partial versus radical adrenalectomy in hereditary pheochromocytomas.

OBJECTIVE: Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC. METHODS: Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality. RESULTS: The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09). CONCLUSION: In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.

Supplementation with avian-derived polyclonal antibodies against Methanobrevibacter gottschalkii and M. ruminantium decreases ex vivo methane production and modifies ruminal fermentation in Angus crossbred steers.

The study aimed to investigate the effect of supplementing polyclonal antibodies (PAP) of avian origin against the ruminal methanogens Methanobrevibacter gottschalkii Ho (PAP-Ho) and M. ruminantium M1 (PAP-M1) on ruminal fermentation profile and methane production in Angus crossbred cattle (13 steers and 1 heifer). The experiment was conducted using a randomized block design with a 3 × 2 + 1 factorial arrangement, replicated in three periods. The factors included proportions of PAP against Ho and M1 in the mixture (100:0, 50:50, and 0:100 Ho:M1) and level of each mixture (3- or 6-mL per d). Cattle in control treatment did not receive PAP supplementation. Ruminal fluid was collected from the animals on d 0, 14 and 21 of treatment to determine of ruminal fermentation profile and ex vivo methane production. There was no effect of level of inclusion on ex vivo methane production. Supplementation with PAP-M1, either alone or in combination with PAP-Ho, decreased ex vivo methane output compared to the control group. Furthermore, in vivo molar proportion of propionate tended to be greater with PAP-M1, alone or combined with PAP-Ho, when compared with the control group. The study concluded that polyclonal antibodies against ruminal methanogens have the potential to decrease enteric methane emissions in cattle. The research provided important insights into the potential use of PAP as a strategy for reducing greenhouse gas emissions from cattle. Further research is needed to confirm these findings and to determine the practicality and feasibility of using PAP.

fMRI and gene therapy in adults with CNGB3 mutation.

Achromatopsia is an inherited retinal disease that affects 1 in 30,000-50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.

Exploring the role of motherhood in healthcare engagement for women living with HIV in the USA.

Mothers living with HIV are faced with managing their own complex healthcare and wellness needs while caring for their children. Understanding the lived experiences of mothers living with HIV, including grandmothers and mothers with older children - who are less explicitly represented in existing literature, may guide the development of interventions that best support them and their families. This study sought to explore the role of motherhood and related social/structural factors on engagement with HIV care, treatment-seeking behaviour, and overall HIV management among mothers living with HIV in the USA to inform such efforts. Semi-structured interviews were conducted between June and December 2015 with 52 mothers living with HIV, recruited from the Women's Interagency HIV Study (WIHS) sites in four US cities. Five broad themes were identified from the interviews: children as a motivation for optimal HIV management; children as providing logistical support for HIV care and treatment; the importance of social support for mothers; stressors tied to responsibilities of motherhood; and stigma about being a mother living with HIV. Findings underscore the importance of considering the demands of motherhood when developing more effective strategies to support mothers in managing HIV and promoting the overall health and well-being of their families.

Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.

ABSTRACT: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)-cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor-triggered NK-cell and T-cell receptor (TCR)-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell-based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

New insights into plasmodesmata: complex 'protoplasmic connecting threads'.

Intercellular communication in plants, as in other multicellular organisms, allows cells in tissues to coordinate their responses for development and in response to environmental stimuli. Much of this communication is facilitated by plasmodesmata (PD), consisting of membranes and cytoplasm, that connect adjacent cells to each other. PD have long been viewed as passive conduits for the movement of a variety of metabolites and molecular cargoes, but this perception has been changing over the last two decades or so. Research from the last few years has revealed the importance of PD as signaling hubs and as crucial players in hormone signaling. The adoption of advanced biochemical approaches, molecular tools and high-resolution imaging modalities have led to several recent breakthroughs in our understanding of the roles of PD, revealing the structural and regulatory complexity of these 'protoplasmic connecting threads'. We highlight several of these findings that we think well illustrate the current understanding of PD as functioning at the nexus of plant physiology, development, and acclimation to the environment.

Infectious Complications Following CD30 Chimeric Antigen Receptor T-Cell Therapy in Adults.

Infections are increasingly recognized as a common complication of chimeric antigen receptor (CAR) T-cell therapy. The incidence of clinically-defined infection after CD19.CAR T-cell therapy for relapsed/refractory lymphoma ranges from 60-90% in the first year after CAR T-cell therapy and is the most common cause for non-relapse mortality. However, infectious risk after CAR T-cell therapy targeting other malignancies is not well understood. Herein, we report for the first time, infectious complications after CD30.CAR T-cell treatment for patients with Hodgkin's lymphoma and peripheral T-cell lymphoma. Since CD30 is only expressed on a subset of activated T and B-cells, we hypothesized that CD30.CAR T-cell patients would have reduced incidence and severity of infections after infusion compared to CD19.CAR T-cell patients. We retrospectively evaluated all 64 patients who received CD30.CAR T-cells at a single institution between 2016-2021, and assessed infections within one year after cell infusion, comparing these data to a contemporary cohort of 50 patients who received CD19.CAR T-cells at the same institution between 2018-2021. 23 CD30.CAR T-cell patients (36%) and 18 CD19.CAR T-cell patients (36%) developed a microbiologically confirmed infection. Infection severity and bacterial infections were higher in the CD19.CAR T-cell group compared to CD30.CAR T-cell recipients who more commonly had grade 1 respiratory viral infections. Our data reflect expected outcomes for severity and infection type in CD19.CAR T-cell patients and provide a benchmark for comparison with the novel CD30.CAR T-cell product. Although our findings require replication in a larger cohort, they have implications for antimicrobial prophylaxis guidelines after CD30.CAR T-cell therapy. KEY POINTS: 1) The incidence of infections within the first year after CD30.CAR T-cell therapy was equivalent to that following CD19.CAR T-cell therapy2) Viral infections were more common after CD30.CAR T-cell therapy but bacterial infections predominated after CD19.CAR T-cell therapy.

Sex differences in asthma control, lung function and exacerbations: the ATLANTIS study.

BACKGROUND: Asthma is a heterogeneous disease with a prevalence and severity that differs between male and female patients. QUESTION: What are differences between male and female patients with asthma with regard to asthma control, lung function, inflammation and exacerbations? METHODS: We performed a post hoc analysis in the ATLANTIS (Assessment of Small Airways Involvement in Asthma) study, an observational cohort study including patients with asthma from nine countries with a follow-up of 1 year during which patients were characterised with measures of large and small airway function, questionnaires, inflammation and imaging. We compared differences in baseline characteristics and longitudinal outcomes between male and female patients with asthma. RESULTS: 773 patients were enrolled; 450 (58%) of these were female. At baseline, female patients with asthma were in higher Global Initiative for Asthma (GINA) steps (p=0.042), had higher Asthma Control Questionnaire 6 (F: 0.83; M: 0.66, p<0.001) and higher airway resistance as reflected by uncorrected impulse oscillometry outcomes (ie, R5-R20: F: 0.06; M: 0.04 kPa/L/s, p=0.002). Male patients with asthma had more severe airway obstruction (forced expiratory volume in 1 s/forced vital capacity % predicted: F: 91.95; M: 88.33%, p<0.01) and more frequently had persistent airflow limitation (F: 27%; M: 39%, p<0.001). Blood neutrophils were significantly higher in female patients (p=0.014). With Cox regression analysis, female sex was an independent predictor for exacerbations. INTERPRETATION: We demonstrate that female patients are in higher GINA steps, exhibit worse disease control, experience more exacerbations and demonstrate higher airway resistance compared with male patients. The higher exacerbation risk was independent of GINA step and blood eosinophil level. Male patients, in turn, have a higher prevalence of persistent airflow limitation and more severe airflow obstruction. These findings show sex can affect clinical phenotyping and outcomes in asthma. TRIAL REGISTRATION NUMBER: NCT02123667.

Extant and extinct bilby genomes combined with Indigenous knowledge improve conservation of a unique Australian marsupial.

Ninu (greater bilby, Macrotis lagotis) are desert-dwelling, culturally and ecologically important marsupials. In collaboration with Indigenous rangers and conservation managers, we generated the Ninu chromosome-level genome assembly (3.66 Gbp) and genome sequences for the extinct Yallara (lesser bilby, Macrotis leucura). We developed and tested a scat single-nucleotide polymorphism panel to inform current and future conservation actions, undertake ecological assessments and improve our understanding of Ninu genetic diversity in managed and wild populations. We also assessed the beneficial impact of translocations in the metapopulation (N = 363 Ninu). Resequenced genomes (temperate Ninu, 6; semi-arid Ninu, 6; and Yallara, 4) revealed two major population crashes during global cooling events for both species and differences in Ninu genes involved in anatomical and metabolic pathways. Despite their 45-year captive history, Ninu have fewer long runs of homozygosity than other larger mammals, which may be attributable to their boom-bust life history. Here we investigated the unique Ninu biology using 12 tissue transcriptomes revealing expression of all 115 conserved eutherian chorioallantoic placentation genes in the uterus, an XY1Y2 sex chromosome system and olfactory receptor gene expansions. Together, we demonstrate the holistic value of genomics in improving key conservation actions, understanding unique biological traits and developing tools for Indigenous rangers to monitor remote wild populations.

Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.

Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination of endogenous PrP halts prion disease progression. In this study, we describe Coupled Histone tail for Autoinhibition Release of Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates endogenous DNA methyltransferases, thereby reducing transgene size and cytotoxicity. When delivered to the mouse brain by systemic injection of adeno-associated virus (AAV), Prnp-targeted CHARM ablates PrP expression across the brain. Furthermore, we have temporally limited editor expression by implementing a kinetically tuned self-silencing approach. CHARM potentially represents a broadly applicable strategy to suppress pathogenic proteins, including those implicated in other neurodegenerative diseases.

Amodal completion across the brain: The impact of structure and knowledge.

This study investigates the phenomenon of amodal completion within the context of naturalistic objects, employing a repetition suppression paradigm to disentangle the influence of structure and knowledge cues on how objects are completed. The research focuses on early visual cortex (EVC) and lateral occipital complex (LOC), shedding light on how these brain regions respond to different completion scenarios. In LOC, we observed suppressed responses to structure and knowledge-compatible stimuli, providing evidence that both cues influence neural processing in higher-level visual areas. However, in EVC, we did not find evidence for differential responses to completions compatible or incompatible with either structural or knowledge-based expectations. Together, our findings suggest that the interplay between structure and knowledge cues in amodal completion predominantly impacts higher-level visual processing, with less pronounced effects on the early visual cortex. This study contributes to our understanding of the complex mechanisms underlying visual perception and highlights the distinct roles played by different brain regions in amodal completion.

Peer Bullying Victimization Trajectories for Sexually and Gender Diverse Youth from Early Childhood to Late Adolescence.

Sexually and gender diverse (SGD) youth experience more peer bullying victimization than heterosexual, cisgender youth during adolescence, yet the emergence and persistence of these disparities remain underexplored. Also, it is unclear which factors are associated with these disparities across development, and how these disparities are linked to late adolescent health discrepancies. This study utilized the sample from the Millennium Cohort Study in Britain (N = 10,080; 51.3% assigned female at birth; Mage = 2.28, SDage = 0.46 at Wave 2), in which 23.74% of youth reported non-heterosexual attraction, 21.59% reported non-heterosexual identity, and 1.08% reported gender identity not in line with the sex assigned at birth. Using latent class growth modeling, four peer bullying victimization trajectories were identified, with early peak (7.2%), late childhood peak (6.3%), adolescence onset (12.8%), and low (73.6%) rates of victimization. SGD youth, compared to heterosexual and cisgender youth, were found to have increased odds of being in the victimization-involved classes, especially the adolescence onset class. The study further revealed that SGD youth reported more mental health and relational difficulties in childhood, which were linked to their heightened risk of longer-lasting victimization. Further, long-term victimization was found to partially account for the disparities in health and well-being for SGD youth in late adolescence. In conclusion, SGD youth were more likely to experience longer-lasting bullying victimization during childhood and adolescence, its related mental and relational vulnerabilities were already established in childhood, and such victimization disparities were further linked to their detrimental health and well-being in late adolescence. The design, hypotheses, and target analyses of the current study were preregistered on 21st April 2023 at https://osf.io/f2zxy .