Adenovirus infections after allogeneic hematopoietic cell transplantation in children and adults: a study from the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation.

The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.

Transcriptomic signatures across a critical sedimentation threshold in a major reef-building coral.

Sedimentation is a major cause of global near-shore coral reef decline. Although the negative impacts of sedimentation on coral reef community composition have been well-documented, the effects of sedimentation on coral metabolism in situ have received comparatively little attention. Using transcriptomics, we identified gene expression patterns changing across a previously defined sedimentation threshold that was deemed critical due to changes in coral cover and community composition. We identified genes, pathways, and molecular processes associated with this transition that may allow corals, such as Porites lobata, to tolerate chronic, severe sedimentation and persist in turbid environments. Alternative energy generation pathways may help P. lobata maintain a persistent stress response to survive when the availability of light and oxygen is diminished. We found evidence for the expression of genes linked to increased environmental sensing and cellular communication that likely allow P. lobata to efficiently respond to sedimentation stress and associated pathogen challenges. Cell damage increases under stress; consequently, we found apoptosis pathways over-represented under severe sedimentation, a likely consequence of damaged cell removal to maintain colony integrity. The results presented here provide a framework for the response of P. lobata to sedimentation stress under field conditions. Testing this framework and its related hypotheses using multi-omics approaches can deepen our understanding of the metabolic plasticity and acclimation potential of corals to sedimentation and their resilience in turbid reef systems.

Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party.

Background: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. Methods: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. Findings: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). Interpretation: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. Funding: There was no external funding source for this study.

Late effects and treatment related morbidity associated with treatment of neuroblastoma patients in a tertiary paediatric centre.

BACKGROUND: Survival of neuroblastoma patients has improved over recent decades, but chronic health issues and treatment related late effects cause significant morbidity in survivors. AIMS: We aimed to describe late effects and long-term toxicity in neuroblastoma patients treated at a tertiary, paediatric institution in Australia. METHODS & RESULTS: Patients with neuroblastoma treated primarily at The Children's hospital at Westmead were eligible for inclusion. Retrospective analysis of 65 (45 with high-risk and 20 with non-high-risk disease) neuroblastoma patients were performed via medical record review. Approximately 60% of patients were >5 years from diagnosis and termed the "full effects cohort" who had a range of medical and psychosocial late effects analysed through descriptive means. The remaining 26 patients who had not yet reached 5 years post treatment had audiometry analysis only. Of the 65 patients, 72% were alive at last follow-up. The median length of follow-up was 7 years from diagnosis amongst survivors. Therapy was according to contemporary protocols for neuroblastoma and ranged from standard cytotoxic therapies to intensive multimodal regimens and/or experimental therapy depending on risk group/relapse status. Of the 39 full effects cohort, 85% suffered from at least one late effect. Late effects were common in the endocrine, dental and audiometry domains with 38%, 49% and 72% of patients affected in these areas, respectively. Neuro-cognitive domains were also notably affected with 46% of patients suffering a deficit. Two thirds of survivors were disease free at last follow-up. CONCLUSION: Survivors of high-risk neuroblastoma suffer from a range of chronic illnesses, which lead to morbidity and affect quality of life of survivors.

Surgical drainage procedures for paediatric chronic pancreatitis: a scoping review.

Paediatric chronic pancreatitis (CP) is a relatively rare entity, but it can be accompanied by debilitating complications such as pseudocysts, chronic pain and pancreatic duct obstruction. Surgical drainage procedures, such as pancreaticojejunostomy or cystogastrostomy/jejunostomy to address these complications may be required; however, there is a paucity of evidence as to the efficacy and long-term outcomes of these operations in the paediatric population. A scoping review of contemporary (post-2000) studies detailing surgical pancreatic drainage procedures performed in children (< 18 years) was undertaken. After screening, 24 case series detailing a total of 248 patients met the inclusion criteria. Longitudinal pancreaticojejunostomy and cystogastrostomy were the most common surgical procedures performed in children with CP and pseudocysts, respectively. Overall generally favourable outcomes were reported, but all studies were considered to have a high risk of bias. Operative management for paediatric CP is infrequently required; therefore, large prospective studies or trials focusing on this population are infeasible, limiting the best available evidence on the topic to case series, level IV. Recommendations to improve the quality of surgical care in the paediatric CP population could include centralisation and the formation of registries to allow accurate long-term follow-up.

Sepsis rates after template prostate biopsy with single-dose prophylactic antibiotic.

Introduction: Urosepsis is a significant risk associated with prostate biopsy. Resistance of microorganisms to antibiotics is a challenging issue for clinicians in everyday practice. In the current study, we investigated the rates of sepsis and hospital admissions following transperineal (TP) prostate biopsies using a single dose of gentamicin. Material and methods: Data for consecutive patients who underwent TP prostate biopsies (March 2019-March 2020) were included. Patients received a single-dose of prophylactic gentamicin 120 mg IV and had skin preparation with antiseptic povidone-iodine or chlorhexidine solution prior to the procedure. Patient's electronic records were reviewed for rates of sepsis and readmission to hospital within 7 days following TP prostate biopsy. Results: A total of 365 consecutive patients were included in the study. After exclusion of non-eligible patients, 280 patients were included in final analysis. The median age was 67 years (32-83), the median prostate-specific antigen (PSA) level was 8.5 ng/ml (0.2-58), and the median prostate size was 44 cc (10-188). Approximately 58% of patients had one or more comorbidities in the form of diabetes mellitus (DM), hypertension, asthma, chronic kidney disease, or ischemic heart disease. Adenocarcinoma was found in 71.7% of patients. None of the 280 patients developed sepsis. Urinary tract infection (UTI) occurred in 2.8% of patients with E.coli, none of them required hospital readmission. Conclusions: Our single centre experience showed a 0% sepsis rate after TP prostate biopsy with single prophylactic dose of gentamicin. Future randomized controlled trials (RCTs) should explore the possibility of performing these procedures without antibiotic prophylaxis in order to reduce the unnecessary use of antibiotics.

Late Effects After Haematopoietic Stem Cell Transplantation in ALL, Long-Term Follow-Up and Transition: A Step Into Adult Life.

Haematopoietic stem cell transplant (HSCT) can be a curative treatment for children and adolescents with very-high-risk acute lymphoblastic leukaemia (ALL). Improvements in supportive care and transplant techniques have led to increasing numbers of long-term survivors worldwide. However, conditioning regimens as well as transplant-related complications are associated with severe sequelae, impacting patients' quality of life. It is widely recognised that paediatric HSCT survivors must have timely access to life-long care and surveillance in order to prevent, ameliorate and manage all possible adverse late effects of HSCT. This is fundamentally important because it can both prevent ill health and optimise the quality and experience of survival following HSCT. Furthermore, it reduces the impact of preventable chronic illness on already under-resourced health services. In addition to late effects, survivors of paediatric ALL also have to deal with unique challenges associated with transition to adult services. In this review, we: (1) provide an overview of the potential late effects following HSCT for ALL in childhood and adolescence; (2) focus on the unique challenges of transition from paediatric care to adult services; and (3) provide a framework for long-term surveillance and medical care for survivors of paediatric ALL who have undergone HSCT.

Long-term health-related quality of life in young childhood cancer survivors and their parents.

PURPOSE: Few studies have investigated the health-related quality of life (HRQoL) of young childhood cancer survivors and their parents. This study describes parent and child cancer survivor HRQoL compared to population norms and identifies factors influencing child and parent HRQoL. METHODS: We recruited parents of survivors who were currently <16 years, and >5 years postdiagnosis. Parents reported on their child's HRQoL (Kidscreen-10), and their own HRQoL (EQ-5D-5L). Parents rated their resilience and fear of cancer recurrence and listed their child's cancer-related late effects. RESULTS: One hundred eighty-two parents of survivors (mean age = 12.4 years old and 9.7 years postdiagnosis) participated. Parent-reported child HRQoL was significantly lower than population norms (48.4 vs. 50.7, p < .009). Parents most commonly reported that their child experienced sadness and loneliness (18.1%). Experiencing more late effects and receiving treatments other than surgery were associated with worse child HRQoL. Parents' average HRQoL was high (0.90) and no different to population norms. However 38.5% of parents reported HRQoL that was clinically meaningfully different from perfect health, and parents experienced more problems with anxiety/depression (43.4%) than population norms (24.7%, p < .0001). Worse child HRQoL, lower parent resilience, and higher fear of recurrence was associated with worse parent HRQoL. CONCLUSIONS: Parents report that young survivors experience small but significant ongoing reductions in HRQoL. While overall mean levels of HRQoL were no different to population norms, a subset of parents reported HRQoL that was clinically meaningfully different from perfect health. Managing young survivors' late effects and improving parents' resilience through survivorship may improve HRQoL in long-term survivorship.

The lived experience of children and adolescents with cancer.

BACKGROUND: The lived experience of children and adolescents diagnosed with cancer differs greatly from that of the adult cancer patient. A diagnosis of cancer disrupts almost every developmental life stage and continues to affect the child, and potentially their whole family, throughout adulthood. OBJECTIVE: While it is important to recognise the potential for post-traumatic growth, a considerable proportion of children and adolescents will experience poorer psychological, social, educational and quality-of-life outcomes. Parents, particularly mothers, have been shown to experience levels of post-traumatic distress even greater than that of survivors. As such, there exists a critical need to provide family-centred support from diagnosis through to long-term survivorship or bereavement. DISCUSSION: Ongoing surveillance, proactive management of chronic health conditions, and health behaviour education are critical to survivors' lifelong wellbeing and can be facilitated locally by general practitioners with support from tertiary healthcare teams in a shared-care arrangement.

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.

The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of paediatric cancer patients.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

A Review of Acute and Long-Term Neurological Complications Following Haematopoietic Stem Cell Transplant for Paediatric Acute Lymphoblastic Leukaemia.

Despite advances in haematopoietic stem cell transplant (HSCT) techniques, the risk of serious side effects and complications still exists. Neurological complications, both acute and long term, are common following HSCT and contribute to significant morbidity and mortality. The aetiology of neurotoxicity includes infections and a wide variety of non-infectious causes such as drug toxicities, metabolic abnormalities, irradiation, vascular and immunologic events and the leukaemia itself. The majority of the literature on this subject is focussed on adults. The impact of the combination of neurotoxic drugs given before and during HSCT, radiotherapy and neurological complications on the developing and vulnerable paediatric and adolescent brain remains unclear. Moreover, the age-related sensitivity of the nervous system to toxic insults is still being investigated. In this article, we review current evidence regarding neurotoxicity following HSCT for acute lymphoblastic leukaemia in childhood. We focus on acute and long-term impacts. Understanding the aetiology and long-term sequelae of neurological complications in children is particularly important in the current era of immunotherapy for acute lymphoblastic leukaemia (such as chimeric antigen receptor T cells and bi-specific T-cell engager antibodies), which have well-known and common neurological side effects and may represent a future treatment modality for at least a fraction of HSCT-recipients.

Impact of Universal Newborn Hearing Screening on cochlear implanted children in Ireland.

OBJECTIVES: Cochlear Implant (CI) is an established treatment for severe to profound hearing loss (HL). Early diagnosis and intervention in HL are crucial in order to provide access to sound and increase the likelihood of spoken language development in pre-lingually deaf children. In April 2011, the Health Service Executive (HSE) implemented the Universal Newborn Hearing Screening (UNHS) in a phased regional basis in Ireland. This study aimed to investigate the general clinical pathway for UNHS referrals to the CI service and to evaluate the impact of earlier referrals via UNHS on functional outcomes in children. METHODS: The first part of this study constituted a retrospective review of 100 children referred to the National Hearing Implant and Research Centre (NHIRC) via UNHS from November 2011 to December 2016. Implanted children referred via UNHS were categorised into three groups according to their medical status. Their clinical pathway to cochlear implantation was evaluated. Functional outcomes were investigated based on medical and developmental status, respectively. In the second part of this study, developmentally healthy implanted children referred post-UNHS were compared with medically healthy children referred pre-UNHS under the age of four, from January 2005 to June 2011. Current implant status of children, age at referral and functional outcomes were investigated. RESULTS: Medically healthy children were referred to the NHIRC at an earlier age than the medically complex children (2.8 months vs 5.2 months, p < 0.01) and the children presenting with auditory neuropathy spectrum disorder (ANSD) (2.8 months vs 5.3 months, p < 0.01). On average they attended their first appointment and were implanted at a younger age than the ANSD group (6.1 months vs 10.1 months, p < 0.01; 16.3 months vs 29.4 months, p < 0.001, respectively). Developmentally healthy children had significantly better functional outcomes than children with developmental delays. Children referred via UNHS were referred and implanted at a younger age than those referred pre-UNHS. The former group achieved better Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores 2 years post-implantation. CONCLUSION: UNHS in Ireland is an important platform for earlier diagnosis and management of congenital HL and our results show that early intervention has a positive impact on functional outcomes in children.

Defining the clinical phenotype of Saul-Wilson syndrome.

PURPOSE: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. METHODS: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages. RESULTS: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. CONCLUSIONS: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

Salivary cortisol reveals overt and hidden anxiety in survivors of childhood cancer attending clinic.

BACKGROUND: Symptoms of anxiety may arise from fear of cancer recurrence and memories of traumatic experiences during treatment. This study aimed to identify changes in mental health and cortisol, a biological marker of stress, associated with oncology surveillance clinic attendance. METHODS: Adolescent and young adult (AYA) survivors of childhood cancer (aged 12-30 years, N = 46) attending a survivorship clinic were recruited. The State-Trait Anxiety Inventory, an anxiety self-rating and open answer question, and salivary cortisol collections were completed two weeks before and one day before clinic, on clinic day and two weeks after. RESULTS: Trait anxiety scores were consistent with the normal population. State anxiety scores two weeks after clinic were significantly lower than baseline (p = 0.02). Cortisol diurnal slopes were flatter than baseline after clinic (p = 0.02). Evening cortisol levels were significantly higher than baseline two weeks post clinic (p = 0.02). LIMITATIONS: Combined results from biological and psychometric assessments can be difficult to interpret. Larger cohorts will further delineate cortisol pathway activity and distress in AYA cancer survivors. CONCLUSIONS: Psychometric evidence indicates that AYA survivors of childhood cancer perceive themselves to be less anxious after a survivorship clinic visit. Biological evidence, however, indicates a dysregulation of the hypothalamic-pituitary-adrenal axis which may be linked to clinic attendance. Weak correlations suggest that cortisol may not be a reliable indicator of self-perceived anxiety. This may be due to confounding lifestyle factors influencing the stress response or potential 'coping strategies' developed during past treatment experience which may, hypothetically, have masked self-perceived anxiety.