Benefits Of Early Intervention Research Articles

Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation

ObjectivesGamete and embryo–foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. MethodsNω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. ResultsPE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. ConclusionThese findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.

Functionality, complications, and survivorship of total shoulder arthroplasty in patients under 60 years old

BackgroundAs total shoulder arthroplasty (TSA) expands to younger patients, it is crucial to weigh the benefits of early intervention against potential complications and implant longevity in patients under 60 years of age. This study examines mid-term outcomes in this patient subset. MethodsBetween 2009 and 2019, a retrospective analysis was conducted on 50 patients (25 male, 25 female) who underwent anatomic TSA (TSA) under the age of 60 with minimum 5 years follow-up. Demographic and baseline variables were extracted from medical records. Pre-operative and post-operative outcomes of range of motion (ROM) and strength were recorded. Patient-reported outcomes (PROs) were obtained. ResultsFifty patients were followed for an average of 8.7 ± 2.4 years, having a mean age of 54.1 ± 8.4 years. Comparison of pre-operative and post-operative measurements revealed significant improvements in active ROM, including external rotation (ER) (p < 0.0001), forward elevation (FE) (p < 0.0001), and internal rotation (IR) (p = 0.0001). There were significant improvements in functional strength scores, including ER (p = 0.0005) and FE (p = 0.0002). PROs included visual analog scale (VAS) (2.2 ± 2.6), Single Assessment Numeric Evaluation (SANE) (80.3 ± 17.6), American Shoulder and Elbow Surgeons (ASES) score (76.4 ± 22.8), and Simple Shoulder Test (SST) (8.9 ± 3.2). The 5-year and 10-year implant survival rates were found to be 98.0 % and 83.3 %, respectively. There were 7 postoperative complications in 5 patients (14.0 %), including glenoid loosening (n = 2), infection (n = 1), atraumatic instability (n = 1), lesser tuberosity avulsion (n = 1), painful arthroplasty (n = 1) and traumatic rotator cuff insufficiency (n = 1). Subsequently, all 5 patients underwent revision shoulder arthroplasty at an average of 6.5 years after the initial procedure. ConclusionPositive mid to long-term outcomes, including significant improvements in ROM and strength, along with high 5-year and 10-year implant survival rates support TSA as an effective treatment option for patients under the age of 60.

Supervised contrastive learning enhances graph convolutional networks for predicting neurodevelopmental deficits in very preterm infants using brain structural connectome

Very preterm (VPT) infants (born at less than 32 weeks gestational age) are at high risk for various adverse neurodevelopmental deficits. Unfortunately, most of these deficits cannot be accurately diagnosed until the age of 2-5 years old. Given the benefits of early interventions, accurate diagnosis and prediction soon after birth are urgently needed for VPT infants. Previous studies have applied deep learning models to learn the brain structural connectome (SC) to predict neurodevelopmental deficits in the preterm population. However, none of these models are specifically designed for graph-structured data, and thus may potentially miss certain topological information conveyed in the brain SC. In this study, we aim to develop deep learning models to learn the SC acquired at term-equivalent age for early prediction of neurodevelopmental deficits at 2 years corrected age in VPT infants. We directly treated the brain SC as a graph, and applied graph convolutional network (GCN) models to capture complex topological information of the SC. In addition, we applied the supervised contrastive learning (SCL) technique to mitigate the effects of the data scarcity problem, and enable robust training of GCN models. We hypothesize that SCL will enhance GCN models for early prediction of neurodevelopmental deficits in VPT infants using the SC. We used a regional prospective cohort of ∼280 VPT infants who underwent MRI examinations at term-equivalent age from the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS). These VPT infants completed neurodevelopmental assessment at 2 years corrected age to evaluate cognition, language, and motor skills. Using the SCL technique, the GCN model achieved mean areas under the receiver operating characteristic curve (AUCs) in the range of 0.72∼0.75 for predicting three neurodevelopmental deficits, outperforming several competing models. Our results support our hypothesis that the SCL technique is able to enhance the GCN model in our prediction tasks.

Prodromal multiple sclerosis: considerations and future utility

A multiple sclerosis (MS) prodrome has recently been described and is characterised by increased rates of healthcare utilisation and an excess frequency of fatigue, bladder problems, sensory symptoms and pain, in the years leading up to clinical onset of disease. This important observation may have several potential applications including in the identification of risk factors for disease, the potential to delay or prevent disease onset and early opportunities to alter disease course. It may also offer possibilities for the use of risk stratification algorithms and effective population screening. If standardised, clearly defined and disease specific, an MS prodrome is also likely to have a profound influence on research and clinical trials directed at the earliest stages of disease. In order to achieve these goals, it is essential to consider experience already gleaned from other disorders. More specifically, in some chronic neurological disorders the understanding of disease pro-drome is now well advanced and has been successfully applied. However, understanding of the MS prodrome remains at an early stage with key questions including the length of the prodrome, symptom specificity and potential benefits of early intervention as yet unanswered. In this review we will explore the evidence available to date and suggest future research strategies to address unanswered questions. In addition, whilst current understanding of the MS prodrome is not yet sufficient to justify changes in public health policy or MS management, we will consider the practical utility and future application of the MS prodrome in a wider health care setting.

ACCELERATED AGING IN MID LIFE: BEHAVIORAL, EMOTIONAL, AND PHYSIOLOGICAL MARKERS OF AGING

Abstract The aging process starts at midlife and is multifactorial, involving behavioral, emotional, and biological pathways. Most studies to date have focused on either older ages, when age-related diseases already are present, or a single mechanism, thus missing the full scope of the aging process. The proposed symposium aims to fill this gap by highlighting the many-sided nature of aging among midlife adults, especially the contributions of behavioral, emotional, and biological markers. We will discuss how physical capacity, sensory modulation, and exposure to violence are associated with biological age, reflecting the true state of the body and the diversity of aging. Understanding these relationships can both illuminate early markers of the aging process and support the design of tailored interventions to reduce the prevalence of accelerated aging. The symposium will present the latest research on the combined markers to gain insight into normal and accelerated aging. Professor Agmon will give an overview of newly developed behavioral markers that quantify the aging process, such as the photogrammetry-based analysis of posture and physical capacity battery. Roy Tzemah-Shahar will discuss the relationships between physical capacity metrics and rate of aging, Merav Asher will explicate the association between one’s sensory profile and the rate of aging, and Khalil Iktilat will share how exposure to violence explains the accelerated aging of midlife Muslims. Finally, we will discuss the need for more research on midlife adults and the potential benefits of early interventions.

Optimal treatment of asymptomatic patients with severe aortic stenosis: protocol of a prospective, multicentre, registry study

IntroductionDecisions regarding the optimal timing of intervention for asymptomatic aortic stenosis (AS) are controversial. The study aims to identify potential risk factors for asymptomatic patients with severe AS that are...

Understanding Patient Preferences for Intervention in Individuals with Precursor Multiple Myeloma: The Preference Study

Background: The standard of care for patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) consists of watchful waiting until progression to clinically manifest multiple myeloma. While an increasing number of clinical trials are exploring the premise that early intervention in this MGUS/SMM patient population will prevent progression to multiple myeloma, little is known about how patients might balance the risks against potential benefits of early intervention. Methods: To quantify preference for attributes of intervention in individuals with MGUS and SMM, we developed an online conjoint instrument with four attributes that we identified as being salient to clinical decision making: prevention of multiple myeloma, monthly cost, inconvenience, and risk of long-term side effects. We recruited individuals from two nationwide prospective cohorts to take the online instrument. To be eligible to participate, participants had to be age 18 or older, have a diagnosis of MGUS or SMM, and have no concurrent malignancy requiring active therapy. Logistic regression models were used to investigate the attributes that drive decisions of early treatment. In addition, we used a latent profile analysis to investigate latent classes defined by patient choices and assess patient characteristics that predict class membership. Results: Participants (n=272) were 43% male, with a mean age of 64.1 (SD: 9.7) years. Logistic regression models suggest a strong preference for choosing interventions based on a higher likelihood of multiple myeloma prevention (odds ratio [OR] per 10% change:1.86, 95% confidence interval [CI]: 1.72, 2.00) and avoidance of side effects (OR: 0.10, 95%CI: 0.08, 0.13). Latent profile analysis identified three latent profiles: the first profile defines individuals who predominantly value avoidance of side effects, the second profile characterizes individuals who value keeping costs low, and the third profile of individuals values multiple myeloma prevention above other attributes. Mean age was similar across latent profiles. A higher proportion of individuals in profile two (group prioritizing cost) did not complete college and had a household income of less than $100,000. A similar proportion of individuals with SMM prioritized avoiding side effects as they did multiple myeloma risk reduction. Conclusions: Overall, we found that low side effects and prevention of multiple myeloma are desirable intervention attributes in patients with MGUS and SMM. The prioritization of myeloma prevention vs low side effect profile was not perfectly coupled with an individual's disease burden. These findings reinforce the notion that a “one size fits all” approach to prevention and interception of multiple myeloma may not be suitable for all patients, and thus a diverse interventional portfolio may be needed to reach broad populations of patients with precursor conditions to multiple myeloma.

The Journey to Early Identification and Intervention for Children with Disabilities in Fiji.

Early identification of developmental delay or disability and access to early intervention improves outcomes for children with disabilities and their families. However, in many low- and middle-income countries, services and systems to enable timely, co-ordinated care and support are lacking. The aim of this research was to explore the experiences of families of children with developmental disabilities in Fiji in accessing services for intervention and support across sectors. This qualitative study involved conducting interviews with caregivers of children with disabilities (n = 12), and relevant key stakeholders from health, education, disability, and social support sectors (n = 17). We used journey maps to identify key stages of the families' journeys, identify key barriers and enablers at each stage, and provide multi-sectoral recommendations for each stage. Enablers include proactive help seeking behaviours, the use of informal support networks and an increasingly supportive policy environment. Barriers to identification include a lack of awareness of developmental disabilities and the benefits of early intervention among service providers and the community. A lack of service availability and capacity, workforce issues, family financial constraints and a lack of collaboration between sectors were barriers to intervention once needs were identified, resulting in significant unmet needs and impacting inclusion and participation for children with disabilities. Overcoming these challenges requires a multi-sectoral approach.

Epigenetic and neuroplasticity in neurodevelopmental disorders: possibilities of physical exercise

This article deals with the relationship between the mechanisms of neuroplasticity and epigenetics provided through the regular practice of physical exercise for the treatment of neurodevelopmental disorders. The aim of the study was to focus on the benefits of early interventions, especially physical exercise, in cases of neurodevelopmental disorders through epigenetic and neuroplasticity mechanisms. For this, a critical review of a narrative nature was carried out in the Scielo, PubMed and PsycInfo databases, as well as consultation in books on the subject. The results show us that exercise seems to promote epigenetic improvements, which can prevent the onset of neurodevelopmental disorders and also promote changes through neuroplasticity, which can mitigate the deficits caused by pathologies, especially if it occurs during early childhood. We can then understand that exercise tends to improve neurodevelopment, but a more robust base of empirical studies on this subject is needed.

"I thought it would just be, like, older men in white coats": A qualitative exploration of first encounters with mental health services.

Individuals whose mental health is becoming a concern may not receive the care they require. Although efforts have been made to reduce barriers to accessing services, including stigma reduction campaigns and healthcare practitioner training, there remains a lack of understanding of individual perspectives regarding help-seeking behaviour. The aim of this study was to explore people's first experiences accessing mental health services. A qualitative descriptive approach was adopted. Interviews were conducted with eight service users. Data were analysed using reflexive thematic analysis. The COREQ checklist guided this study (Tong et al., 2007, International Journal for Quality in Health Care, 19, 349). Three themes were identified: learning to navigate an unfamiliar system, making sense of mental health services, and promoting a positive image for those in need of care. Uncertainty about mental health services and stigmatizing images could be mitigated by developing positive media-based interventions. Systemic barriers need to be addressed and services need to be better resourced to ensure the benefits of early intervention are available to those experiencing mental health challenges. To encourage people to access services earlier, services need to be promoted in a positive way.

Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants

BackgroundChildhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence (“comorbidity”) of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood.MethodsWe carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types.ResultsChildhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types.ConclusionsThis meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288).

Reimagining eating disorder spaces: a qualitative study exploring Māori experiences of accessing treatment for eating disorders in Aotearoa New Zealand

BackgroundHealth, illness, and the body are conceptualized within the cultural context of a society. The values and belief systems of a society, including media portrayals, shape how health and illness present. Traditionally, Western portrayals of eating disorders have been prioritized over and above Indigenous realities. This paper explores the lived experiences of Māori with eating disorders and their whānau (family/support system) to identify the enablers and barriers to accessing specialist services for eating disorders in New Zealand.MethodKaupapa Māori research methodology was used to ensure the research supported Māori health advancement. Fifteen semi-structured interviews were completed with Māori participants including; those with an eating disorder diagnosis (anorexia nervosa, bulimia nervosa, and binge eating disorder), and/or their whānau. Structural, descriptive, and pattern coding was undertaken within the thematic analysis. Low’s spatializing culture framework was used to interpret the findings.ResultsTwo overarching themes identified systemic and social barriers to accessing treatment for Māori with eating disorders. The first theme, was space, that described the material culture within eating disorder settings. This theme critiqued eating disorder services, including idiosyncratic use of assessment methods, inaccessible service locations, and the limited number of beds available in specialist mental health services. The second theme, place, referred to the meaning given to social interactions created within space. Participants critiqued the privileging of non-Māori experiences, and how this makes a place and space of exclusion for Māori and their whānau in eating disorder services in New Zealand. Other barriers included shame and stigma, while enablers included family support and self-advocacy.ConclusionMore education is needed for those working in the space of primary health settings about the diversity of those with eating disorders to enable them to look beyond the stereotype of what an eating disorder looks like, and to take seriously the concerns of whaiora and whānau who present with disordered eating concerns. There is also a need for thorough assessment and early referral for eating disorder treatment to ensure the benefits of early intervention are enabled for Māori. Attention given to these findings will ensure a place for Māori in specialist eating disorder services in New Zealand.Graphical

Risk factors for development of cerebral edema following cardiac arrest

BackgroundCerebral edema following cardiac arrest is a well-known complication of resuscitation and portends a poor outcome. We identified predictors of post-cardiac arrest cerebral edema and tested the association of cerebral edema with discharge outcome. MethodsWe performed a retrospective chart review including patients admitted at a single center between January 2015–March 2020 following resuscitation from in-hospital and out-of-hospital cardiac arrest who had head computed tomography imaging. Our primary outcome was moderate-to-severe cerebral edema, which we defined as loss of grey-white differentiation with effacement of the basal and ambient cisterns and radiographic evidence of uncal herniation. We used logistic regression to test associations of demographic information, clinical predictors and comorbidities with moderate-severe cerebral edema. ResultsWe identified 727 patients who met the inclusion criteria, of whom 102 had moderate-to-severe cerebral edema. We identified six independent predictors of moderate-to-severe cerebral edema: younger age, prolonged arrest duration, pulseless electrical activity/asystole as initial rhythm, unwitnessed cardiac arrest, hyperglycemia on admission, and lower Glasgow coma score on presentation. Of patients with moderate-to-severe cerebral edema, 2% survived to discharge, 56% had withdrawal of life-sustaining therapies and 42% progressed to death by neurological criteria. ConclusionsOur study identified several risk factors associated with the development of cerebral edema following cardiac arrest. Further studies are needed to determine the benefits of early interventions in these high-risk patients.

"Then they prayed, they did nothing else, they just prayed for the boy and he was well": A qualitative investigation into the perceptions and behaviours surrounding snakebite and its management in rural communities of Kitui county, Kenya.

IntroductionHuman-snake interactions are common in tropical regions where subsistence-farming and livestock-herding activities predominate alongside proliferation of snakes. Local beliefs and perceptions about snakes and snakebites influence human behaviour. Understanding these beliefs and perceptions can inform the development of resources to drive behaviour change and to minimise the risk of injury to both humans and snakes. This qualitative study, conducted between May and July 2019, sought to explore the beliefs and perceptions regarding snakes and snakebites, and methods of prevention and management among members of the community in Kitui County, Kenya.MethodsSemi-structured interviews were used to collect qualitative data from 23 participants, recruited using a stratified purposeful sampling strategy in four selected sub-counties of Kitui county. Interview data was anonymised and coded and a thematic analysis was conducted using NVivo 12.ResultsPeople from Kitui county mostly had negative perceptions about snakes. There was a generalised awareness of the need to prevent snakebite, predominantly through keeping snakes away from homes/compounds. However, implementation was limited by financial constraints. Participants also identified logistic and financial obstacles to early hospital presentation following a snakebite, and they expressed a strong preference of having their snakebites treated in a hospital over consulting traditional healers. There was a universal recognition of the benefit of early intervention with a specific appreciation of the utility of the black stone. Furthermore, the removal of a snake’s “teeth” was an expected treatment outcome for some community members, with the failure to do so perceived as causing poor wound healing or persistence of symptoms. Some religious groups held views which differed from most participants.ConclusionThere is a need to explore and clarify common misconceptions about snakes and first aid treatment of snakebites, encourage learning about the true nature of snakes, and highlight beneficial uses of snakes. A change in the epistemological conception of community education material by enhancing the value and use of local forms of knowledge, and the employment of art techniques to transmit this knowledge, could improve community perception and methods of snakebite prevention. Patient expectations should be appropriately managed by discussing possible outcomes, incorporating follow-up visits and addressing long-term complications of snakebites.

Automated Decision Support For Community Mental Health Services Using National Electronic Health Records: Qualitative Implementation Case Study

BackgroundA high proportion of patients with severe mental illness relapse due to nonadherence to psychotropic medication. In this paper, we use the normalization process theory (NPT) to describe the implementation of a web-based clinical decision support system (CDSS) for Community Mental Health Services (CMHS) called Actionable Intime Insights or AI2. AI2 has two distinct functions: (1) it provides an overview of medication and treatment history to assist in reviewing patient adherence and (2) gives alerts indicating nonadherence to support early intervention.ObjectiveOur objective is to evaluate the pilot implementation of the AI2 application to better understand the challenges of implementing a web-based CDSS to support medication adherence and early intervention in CMHS.MethodsThe NPT and participatory action framework were used to both explore and support implementation. Qualitative data were collected over the course of the 14-month implementation, in which researchers were active participants. Data were analyzed and coded using the NPT framework. Qualitative data included discussions, meetings, and work products, including emails and documents.ResultsThis study explores the barriers and enablers of implementing a CDSS to support early intervention within CMHS using Medicare data from Australia’s national electronic record system, My Health Record (MyHR). The implementation was a series of ongoing negotiations, which resulted in a staged implementation with compromises on both sides. Clinicians were initially hesitant about using a CDSS based on MyHR data and expressed concerns about the changes to their work practice required to support early intervention. Substantial workarounds were required to move the implementation forward. This pilot implementation allowed us to better understand the challenges of implementation and the resources and support required to implement and sustain a model of care based on automated alerts to support early intervention.ConclusionsThe use of decision support based on electronic health records is growing, and while implementation is challenging, the potential benefits of early intervention to prevent relapse and hospitalization and ensure increased efficiency of the health care system are worth pursuing.

37-OR: Childhood Screening and Interception Strategies: An Economic Cohort Simulation Model

T1D screening and monitoring studies suggest opportunities for scaling up to public health population-based programs. Genetic Risk Scores (GRS) for T1D are also demonstrating the ability to identify those at higher risk of progressing to T1D as well as an increased opportunity for implementation into public health settings potential as a result of practical considerations, including falling gene sequencing costs.Previous studies have shown that screening and monitoring children for T1D progression significantly decreases DKA events at diagnosis, which has been shown to have both short- and long-term benefits. Furthermore, identification of those at higher risk of T1D provides an opportunity to intervene and delay T1D onset. A non-stochastic, state transition cohort simulation projected 20US births through adolescence. Data from previously collected natural history studies, including TEDDY, DIPP &amp; DAISY were used to model the patient journey. Children seroconverting to islet autoantibodies (IAB) each year and children with lower T1D risk were simulated as separate cohorts with distinct progressions. Interception strategies were layered over this natural history projection. Success of GRS screening followed by annual IAB and glucose monitoring to intercept T1D progression and reduce DKA events was explored. Therapeutic intervention to delay T1D onset was also simulated.Real-world benchmarks for newborn screening (85%) and patient follow-up (80%) as well as rapid T1D progression (&amp;lt;12 months) for some children limited maximum interception at dysglycemia to 52% of children progressing to T1D by age 15 using a GRS screening strategy. Short-term net incremental costs range reach $1.1B at current test costs or $225K per T1D case interception. Breakeven costs could be achieved with $40 IAB test cost and $5 GRS costs with a therapeutic to delay T1D onset by 3 years or possibly by including assessment potential long-term benefits of early intervention and improved glycemic control. Disclosure M.Trusheim: Other Relationship; CO BIO CONSULTING LLC. S.Kostense: Employee; Janssen Research &amp; Development, LLC. L.A.Ferrat: None. R.Mcqueen: Consultant; Merck &amp; Co., Inc., Monument Analytics, Research Support; Eli Lilly and Company. R.D.Neusner: Employee; Janssen Pharmaceuticals, Inc. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. M.Rewers: Consultant; Janssen Research &amp; Development, LLC, Medscape, Provention Bio, Inc., Research Support; Dexcom, Inc., JDRF, Roche Diagnostics USA. J.L.Dunne: Employee; Janssen Research &amp; Development, LLC, JDRF.

Ventriculomegaly thresholds for prediction of symptomatic post-hemorrhagic ventricular dilatation in preterm infants.

Benefits from early surgical intervention in preterm infants with intraventricular hemorrhage (IVH) prior to symptomatic ventriculomegaly must be weighed against risks of surgery. We calculated thresholds of common ventriculomegaly indices at a late-intervention institution to predict subsequent symptomatic ventriculomegaly requiring neurosurgery. We retrospectively reviewed neuroimaging and neurosurgical outcomes in preterm infants with grade III/IV IVH between 2007 and 2020. Frontal-occipital horn ratio (FOHR), frontal-temporal horn ratio (FTHR), anterior horn width (AHW), and ventricular index (VI) were measured. Area under the receiver operating curve (AUC) for predicting intervention (initiated after progressive symptomatic ventriculomegaly) was calculated for diagnostic scan, scans during weeks 1-4, and maximum measurement prior to intervention. Threshold values that optimized sensitivity and specificity were derived. A total of 1254 scans in 132 patients were measured. In all, 37 patients had a neurosurgical intervention. All indices differed between those with and without intervention from the first diagnostic scan (p < 0.001). AUC of maximum measurement was 97.1% (95% CI 94.6-99.7) for FOHR, 97.7% (95% CI 95.6-99.8) for FTHR, 96.6% (95% CI 93.9-99.4) for AHW, and 96.8% (95% CI 94.0-99.5) for VI. Calculated thresholds were FOHR 0.66, FTHR 0.62, AHW 15.5 mm, and VI 8.4 mm > p97 (sensitivities >86.8%, specificities >90.1%). Ventriculomegaly indices were greater for patients who developed progressive persistent ventriculomegaly from the first diagnostic scan and predicted neurosurgical intervention. We derived thresholds of common ventriculomegaly indices (ventricular index, anterior frontal horn width, fronto-occipital horn and fronto-temporal horn index) to best predict the development of progressive symptomatic post-hemorrhage hydrocephalus in preterm infants with intraventricular hemorrhage. While current thresholds were established by a priori expert consensus, we report the first data-driven derivation of ventriculomegaly thresholds across all indices for the prediction of symptomatic hydrocephalus. Data-derived thresholds will more precisely weigh the risks and benefits of early intervention.

Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

BackgroundVariable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the ‘PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease’ (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance.ResultsCurrent guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations.ConclusionsWider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.

The Role of Childhood Trauma in Psychosis and Schizophrenia: A Systematic Review.

Schizophrenia (SCZ) is a prevalent cause of disability worldwide. Distinguished mainly by psychosis, behavioral alterations could range from hallucinations to delusions. This systematic review examines evidence of a relationship between childhood trauma/adverse life events and psychosis, especially in SCZ. A methodical search provided reproducible results using these five databases: PubMed, ScienceDirect, Semantic Scholar, JSTOR, and Cochrane Library. The systematic search focused on articles published between July 2016 and July 2021. The search strategy utilized specific keywords relevant to SCZ, psychosis, and childhood trauma. The formulation of specified inclusion and exclusion criteria was necessary to ensure a comprehensive narrowed-down search, such as the inclusion of free full-text articles published or translated in English and exclusion of irrelevant subject areas. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a strategic search initially identified 741 articles; three additional articles were identified from citation searching. After relevance screening, duplicate removal, and quality appraisal, 12 studies from databases/registers and three from citation searching met the criteria proving relevance to our review with minimal evidence of bias. The final selected 15 studies included observational studies and reviews. A review of relevant data unveiled findings on childhood adversity, individual lived experiences, and their involvement in SCZ. Evidence suggests that certain neurobiological processes occur in brain after trauma. The inflammation and dysregulation from oxidative stress predispose patients to an at-risk-mental state, facilitating the progression to SCZ. This review encourages further evaluation of early trauma detection and the potential benefits of early intervention.

Pembrolizumab Added to First-Line Cyclophosphamide, Bortezomib and Dexamethasone in Newly Diagnosed Transplant Non-Eligible Myeloma Patients: A Phase 2A Open Label, Multi Centre Study

Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. The combination of the proteasome inhibitor (PI) Bortezomib, an alkylator (Cyclophosphamide or Melphalan) and Dexamethasone (Dex) /Prednisone is a widely used first-line therapy. Most patients achieve a rapid response within the first two cycles. The lack of a deep response to the bortezomib-based therapy predicts an inferior outcome, a poor response to newer PIs and limited therapeutic options. Different studies highlighted the role of the PD1/PDL1 pathway in myeloma immune escape and progression. The expression of PDL1 by myeloma cells is higher in relapsed or refractory disease and on minimal residual disease cells. At least one preclinical study showed that the binding of PD1 to PDL1 expressed by the myeloma cells leads to a reverse signal that induces resistance to bortezomib and melphalan. Also, Bortezomib is known to enhance anti-myeloma immune response by different mechanisms, including stimulating myeloma cell apoptosis, sensitizing myeloma cells to natural killer cell mediated killing and enhancing antigen presentation by dendritic cells. This suggests a mutual potentiation between Pembrolizumab and Cyclophosphamide, Bortezomib and Dex (CyBorD). An early immune-based intervention is likely more beneficial. With time and disease progression, the host is more immune-compromised and the disease is more refractory with redundant escape mechanisms. The benefits of early intervention are carefully weighed against the potential risks and other available therapeutic options. The adaptive design of this CMRG-006 trial is meant to select the population with the highest need for treatment improvement while still in the early phase of therapy. We expect the combination of Pembrolizumab and CyBorD to be more effective and well tolerated.Design and Methods: Phase 2A, pilot study. Non-transplant eligible newly diagnosed myeloma patients (NTE-NDMM) will start their standard nine cycles of CyBorD (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycle). Patients not having primary disease progression and achieving less than Very Good Partial Response (VGPR) after 2 cycles will be screened for this study during cycle 3. Eligible patients will receive Pembrolizumab 200 mg IV every 3 weeks starting with day 1 of cycle 4 (P-CyBorD). After completion of cycle nine of CyBorD, Pembrolizumab will be administered as a single agent for up to total of 35 doses. The objectives are to evaluate the efficacy and tolerability of P-CyBorD. The key inclusion criteria are having a NTE-NDMM with a measurable disease; no primary progressive disease and not achieving VGPR after two cycles of CyBorD; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-PD1 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and AL amyloidosis. S ample Size: A maximum of 20 patients will be enrolled to ensure 16 or more patients evaluable for response. Patients with less than VGPR after two cycles of CyBorD have ≤20% probability to achieve ≥VGPR after cycle 9. With the addition of Pembrolizumab, a minimal clinically important difference (MCID) of 10% would be meaningful, and a 50% response rate (≥VGPR) in 16 evaluable patients will be statistically significant.This study is currently recruiting. Clinicaltrials.gov #: NCT04258683. DisclosuresKotb: Amgen: Honoraria; BMS: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Othman: Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Reece: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; GSK: Honoraria.