A Review of JAK Inhibitors for Treatment of Alopecia Areata in the Military Health Care System.

INTRODUCTION: Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional impairment, and significant psychological distress. This condition is understood to be caused by autoimmunity to the hair follicle and subsequent arrest of hair growth. New medications, baricitinib and ritlecitinib, belong to the Janus kinase (JAK) inhibitor family and are among the first FDA-approved treatments for severe AA. In this manuscript, we aim to answer the question: What treatment options exist for AA in the military health care system (MHS)? In doing so, we review the pathogenesis, physical and psychosocial impact of AA, conventional treatment of AA, and the efficacy and safety of baricitinib and ritlecitinib. METHODS: A literature search was performed using PubMed, Embase, and Ovid for the history and pathogenesis of AA, psychosocial impact of disease, functional impairments, and current treatments. Keywords "alopecia areata," "current therapy for alopecia areata," "pathogenesis alopecia areata," "baricitinib," "ritlecitinib," "JAK inhibitor alopecia," "JAK inhibitor safety," "baricitinib efficacy," "alopecia eyelash," "alopecia nails," and "psychosocial impact of alopecia" were used for the search. The TRICARE manual was searched for guidelines applicable to the treatment of AA, DoD Instruction 6130.03 Volume 2 for medical standards for military service, and the U.S. Central Command Modification 15 for fitness of deployment to Central Command area of operations. RESULTS: Traditional treatments such as intralesional steroids may be effective for some patients, but difficulty lies in controlling extensive or refractory disease. Janus kinase inhibitors, baricitinib and ritlecitinib, are found effective at improving severe refractory disease; baricitinib induced hair regrowth in 32.6% more patients than placebo, and ritlecitinib was found to be superior to placebo by at least 24%. Currently, there is no coverage for therapeutic treatment of hair growth in the MHS. Additionally, military members are disqualified for continued service if they require immunomodulator medications such as baricitinib and ritlecitinib. Those on immunomodulators are unable to deploy worldwide. CONCLUSIONS: Baricitinib and ritlecitinib are effective treatments for widespread, progressive, and refractory AA. Although JAK inhibitors demonstrate improved effectiveness compared to non-immunomodulator treatments, their use in the MHS for this purpose is limited.

Development of the national injury resource database (NIRD).

INTRODUCTION: Lack of an accurate, publicly available database of burn/trauma resources creates challenges in providing burn care. In response to this gap, our group developed the National Injury Resource Database (NIRD), a comprehensive database of all US burn centers (BC) and trauma centers (TC) and their capabilities. METHODS: Lists of all national BC and TC were obtained from the American Burn Association (ABA), the American College of Surgeons, and every state department of health. Data was cross-checked and included BC/TC were linked with a 7-digit identification number using the American Hospital Association Quick Search guide. Each center's resources and verification status were validated with electronic or telephonic communications. RESULTS: The final database includes 135 BC and 617 TC, of which 18 are BC-only, 500 are TC-only, and 117 are combined BC/TC. ABA-verified BC (n = 76) are only found in Washington DC and 31 states, and 8 states have no BC. In the last 10 years, a net increase of 7 burn centers was found nationally. The ABA's online BC directory is outdated. CONCLUSIONS: NIRD represents the only up-to-date, comprehensive listing of BC and TC in existence. It categorizes all currently operating BC and TC across myriad classifications of designation and capabilities.

Direct Observation of Ni Nanoparticle Growth in Carbon-Supported Nickel under Carbon Dioxide Hydrogenation Atmosphere.

Understanding nanoparticle growth is crucial to increase the lifetime of supported metal catalysts. In this study, we employ in situ gas-phase transmission electron microscopy to visualize the movement and growth of ensembles of tens of nickel nanoparticles supported on carbon for CO2 hydrogenation at atmospheric pressure (H2:CO2 = 4:1) and relevant temperature (450 °C) in real time. We observe two modes of particle movement with an order of magnitude difference in velocity: fast, intermittent movement (vmax = 0.7 nm s-1) and slow, gradual movement (vaverage = 0.05 nm s-1). We visualize the two distinct particle growth mechanisms: diffusion and coalescence, and Ostwald ripening. The diffusion and coalescence mechanism dominates at small interparticle distances, whereas Ostwald ripening is driven by differences in particle size. Strikingly, we demonstrate an interplay between the two mechanisms, where first coalescence takes place, followed by fast Ostwald ripening due to the increased difference in particle size. Our direct visualization of the complex nanoparticle growth mechanisms highlights the relevance of studying nanoparticle growth in supported nanoparticle ensembles under reaction conditions and contributes to the fundamental understanding of the stability in supported metal catalysts.

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min-1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.

Metal-Support Interactions in Heterogeneous Catalysis: DFT Calculations on the Interaction of Copper Nanoparticles with Magnesium Oxide.

Oxide supports play an important role in enhancing the catalytic properties of transition metal nanoparticles in heterogeneous catalysis. How extensively interactions between the oxide support and the nanoparticles impact the electronic structure as well as the surface properties of the nanoparticles is hence of high interest. In this study, the influence of a magnesium oxide support on the properties of copper nanoparticles with different size, shape, and adsorption sites is investigated using density functional theory (DFT) calculations. By proposing simple models to reduce the cost of the calculations while maintaining the accuracy of the results, we show using the nonreducible oxide support MgO as an example that there is no significant influence of the MgO support on the electronic structure of the copper nanoparticles, with the exception of adsorption directly at the Cu-MgO interface. We also propose a simplified methodology that allows us to reduce the cost of the calculations, while the accuracy of the results is maintained. We demonstrate in addition that the Cu nanowire model corresponds well to the nanoparticle model, which reduces the computational cost even further.

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD.

SIGNIFICANCE STATEMENT: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. BACKGROUND: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. RESULTS: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. CONCLUSIONS: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD.

BACKGROUND: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope. METHODS: We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR <15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. RESULTS: There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [-0.05 to 0.03]; baseline UACR [-0.02 to 0.04]; CKD progression rate [-0.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [-0.11 to -0.02]; CKD progression rate [0.01 to 0.15]). CONCLUSIONS: These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.

Combined spectroscopic and computational study for optimising catalyst design in hydrocarbon transformations.

Molecular interactions of hydrocarbons within the confined pores of heterogeneous catalysts can influence reaction pathways, which play a crucial role in determining the overall efficacy of catalytic transformations. We probe the interactions of n-butane with a solid-acid zeolite, mordenite, combining inelastic neutron scattering with DFT calculations. This reveals that the solid-acid sites within mordenite induce a conformer change, which could be key in designing optimised catalysts, for hydrocarbon transformations.

Competition between reverse water gas shift reaction and methanol synthesis from CO2: influence of copper particle size.

Converting CO2 into value-added chemicals and fuels, such as methanol, is a promising approach to limit the environmental impact of human activities. Conventional methanol synthesis catalysts have shown limited efficiency and poor stability in a CO2/H2 mixture. To design improved catalysts, crucial for the effective utilization of CO2, an in-depth understanding of the active sites and reaction mechanism is desired. The catalytic performance of a series of carbon-supported Cu catalysts, with Cu particle sizes in the range of 5 to 20 nm, was evaluated under industrially relevant temperature and pressure, i.e. 260 °C and 40 bar(g). The CO2 hydrogenation reaction exhibited clear particle size effects up to 13 nm particles, with small nanoparticles having the lower activity, but higher methanol selectivity. MeOH and CO formation showed a different size-dependence. The TOFCO increased from 1.9 × 10-3 s-1 to 9.4 × 10-3 s-1 with Cu size increasing from 5 nm to 20 nm, while the TOFMeOH was size-independent (8.4 × 10-4 s-1 on average). The apparent activation energies for MeOH and CO formation were size-independent with values of 63 ± 7 kJ mol-1 and 118 ± 6 kJ mol-1, respectively. Hence the size dependence was ascribed to a decrease in the fraction of active sites suitable for CO formation with decreasing particle size. Theoretical models and DFT calculations showed that the origin of the particle size effect is most likely related to the differences in formate coverage for different Cu facets whose abundancy depends on particle size. Hence, the CO2 hydrogenation reaction is intrinsically sensitive to the Cu particle size.

An Insight into the Role of Reactant Structure Effect in Pd/C Catalysed Aldehyde Hydrogenation.

The different activity of a 1% Pd/carbon catalyst towards aromatic and aliphatic aldehydes hydrogenation has been explored by 13C NMR relaxation. The ratio between T1 relaxation times of adsorbed (ads) and free diffusing (bulk) molecules (T1ads/T1bulk) can be used as an indicator of the relative strength of interaction between the reactant and the catalytic surface, where the lower the T1ads/T1bulk, the higher the adsorption strength. It can be seen that 1% Pd/carbon showed a reverse catalytic behaviour towards benzaldehyde and octanal hydrogenation, which can be explained by analysing the T1 relaxation times related to each substrate in the presence of the catalyst. Comparing and correlating the different T1ads/T1bulk values, we were able to prove that the different catalytic results mainly depend on the contrasting adsorption behaviour of substrates on the catalyst. Moreover, the role of the solvent has been disclosed, as NMR results revealed that the adsorption of the reactants was strongly affected by the choice of solvent, which is revealed to be critical in modulating catalytic activity. As a consequence, T1ads/T1bulk measurements can provide a guide to the selection of appropriate reaction conditions for improving catalytic activity.

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.

BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Thiol Functionalised Supports for Controlled Metal Nanoparticle Formation for Improved C-C Coupling.

The myriad applications of metal nanoparticle systems have individual demands on their size, shape and electronic states, demanding novel synthetic methods to optimise these properties. Herein we report our method of exploiting strong thiol-Pd binding as a precursor for forming small, uniform Pd nanoparticles on activation. We validate our approach with a range of characterisation techniques and contrast our design strategy with an analogous wetness impregnation method, showing the drastic improvements for catalytic C-C coupling. The presence of the thiol groups offers greater control over nanoparticle formation, particularly temperature resolution on activation, potentially allowing more targeted nanoparticle formation procedures.

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Longitudinal investigation of the relationship between omega-3 polyunsaturated fatty acids and neuropsychological functioning in recent-onset psychosis: A randomized clinical trial.

Alterations in polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6, have been implicated in the pathophysiology of psychotic disorders, but little is known about their associations with neuropsychological functioning. The present study includes 46 recent-onset psychosis patients who participated in a larger (n = 50) double blind, placebo-controlled randomized clinical trial comparing 16 weeks of treatment with either risperidone + fish oil (FO) (EPA 740 mg and DHA 400 mg daily) or risperidone + placebo and completed neuropsychological assessments at the baseline timepoint. We investigated the relationship between baseline omega-3 (i.e., eicosapentaenoic acid, EPA; docosapentaenoic acid, DPA and docosahexaenoic acid, DHA) and omega-6 (i.e., arachidonic acid, AA) PUFA with baseline MATRICS Consensus Cognitive Battery (MCCB) and Brief Psychiatric Rating Scale (BPRS) scores. Twenty-five patients had neuropsychological data available at 16 weeks following participation in the clinical trial, which included 12 patients assigned to risperidone + FO and 13 patients assigned to risperidone + placebo. At baseline both higher DHA and EPA correlated significantly with better social cognition after controlling for functioning on other neuropsychological domains, total BPRS score, AA level and substance use. Also, at baseline higher AA correlated significantly with hostility/uncooperativeness after controlling for DHA + EPA + DPA, overall neuropsychological functioning and substance use. Patients treated with risperidone + FO demonstrated a significant longitudinal increase in social cognition that was significantly higher at 16 weeks compared to patients treated with risperidone + placebo. DHA also correlated significantly with social cognition at the 16-week timepoint. This study provides novel evidence for a differential role of omega-3 vs. omega-6 PUFA in neuropsychological deficits and symptoms in recent-onset psychosis and its treatment.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone.

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

Exploring the origins of crystallisation kinetics in hierarchical materials using in situ X-ray diffraction and pair distribution function analysis.

The discovery of novel catalytic materials is predicated on understanding contemporary synthetic processes. With this fundamental knowledge in place it becomes possible to modify the final material with subtle changes to the synthesis process. In this vein, hierarchical materials, formed by the addition of a mesoporogen within the hydrothermal synthesis, have attracted a significant amount of attention due to their catalytic benefits over analogous microporous species. In this work we monitor the hydrothermal synthesis in situ of a hierarchical and a microporous aluminophosphate, for the first time, combining total scattering and pairwise distribution function data. In doing so we observe the local formation of the species, and the longer range crystallisation processes concurrently.

Observational study on the incidence of nephrogenic systemic fibrosis in patients with renal impairment following gadoterate meglumine administration: the NSsaFe study.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a rare life-threatening condition strongly associated with the administration of gadolinium-based contrast agents in patients with severe or endstage renal impairment. PURPOSE: To prospectively determine the incidence of NSF in patients with renal impairment after administration of gadoterate meglumine. STUDY TYPE: Prospective. POPULATION: In all, 540 patients with moderate, severe, or endstage renal impairment, scheduled to undergo a routine contrast-enhanced MRI with gadoterate meglumine. Mean age was 69.7 ± 12.7 years (range: 21-95) with 58.4% of males. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T, sequence according to each site practice. ASSESSMENT: Medical history, indication(s) for current MRI and adverse events were recorded for each patient. Patients were followed up over 2 years after administration with three visits separated by at least 3 months to detect any signs/symptoms suggestive of NSF. STATISTICAL TESTS: Descriptive. RESULTS: Renal impairment was graded as moderate for 69.4% of patients, severe for 16.0% and endstage for 12.1%; 2.6% had undergone a kidney transplant. Estimated glomerular filtration rate ranged from 4 to 59 mL/min/1.73 m2 except one value of 74 mL/min/1.73 m2 in a patient with kidney transplant. Central nervous system exploration was the main MRI indication (34.7%) and mean dose injected was 0.22 ± 0.09 mL/kg. Overall, 446 patients (82.6%) attended at least one follow-up visit and completed the NSF questionnaire and 329 (60.9%) attended the 2-year visit. No suspicion of NSF was reported in all 446 patients, including 119 patients with severe or endstage renal impairment. No deaths and no adverse events were reported during the MRI examination and the usual period of follow-up after gadoterate meglumine administration. DATA CONCLUSION: No cases of NSF were observed in the 446 patients with moderate to endstage renal impairment followed up over a maximum of 2 years after injection of gadoterate meglumine. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:607-614.

Investigating patterns of neural response associated with childhood abuse v. childhood neglect.

BACKGROUND: Childhood maltreatment is robustly associated with increased risk of poor mental health outcome and changes in brain function. The authors investigated whether childhood experience of abuse (e.g. physical, emotional and sexual abuse) and neglect (physical and emotional deprivation) was differentially associated with neural reactivity to threat. METHODS: Participants were drawn from an existing study and allocated to one of four groups based on self-report of childhood maltreatment experience: individuals with childhood abuse experiences (n = 70); individuals with childhood neglect experiences (n = 87); individuals with combined experience of childhood abuse and neglect (n = 50); and non-maltreated individuals (n = 207) propensity score matched (PSM) on gender, age, IQ, psychopathology and SES. Neural reactivity to facial cues signalling threat was compared across groups, allowing the differential effects associated with particular forms of maltreatment experience to be isolated. RESULTS: Brain imaging analyses indicated that while childhood abuse was associated with heightened localised threat reactivity in ventral amygdala, experiences of neglect were associated with heightened reactivity in a distributed cortical fronto-parietal network supporting complex social and cognitive processing as well as in the dorsal amygdala. Unexpectedly, combined experiences of abuse and neglect were associated with hypo-activation in several higher-order cortical regions as well as the amygdala. CONCLUSIONS: Different forms of childhood maltreatment exert differential effects in neural threat reactivity: while the effects of abuse are more focal, the effects of neglect and combined experiences of abuse are more distributed. These findings are relevant for understanding the range of psychiatric outcomes following childhood maltreatment and have implications for intervention.