Salivary inflammatory biomarkers as a predictor of post-traumatic stress disorder and depressive symptom severity in trauma patients: A prospective study.

BACKGROUND: Although post-traumatic stress disorder (PTSD) and depression screening are recommended for traumatic injury patients, routine screening is still uncommon. Salivary inflammatory biomarkers have biological plausibility and potential feasibility and acceptability for screening. This study tested prospective associations between several salivary inflammatory biomarkers (proinflammatory cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α; and C-reactive protein), collected during hospitalization and PTSD and depressive symptoms at 5-month follow-up. METHODS: Adult traumatic injury patients (N = 696) at a major urban Level 1 trauma center provided salivary samples and completed PTSD and depressive symptom measures during days 0-13 of inpatient hospitalization. At 5-month follow-up, 368 patients (77 % male, 23 % female) completed the Clinician-Administered PTSD Scale for DSM-IV and the Self-rated Inventory of Depressive Symptomatology. Analyses focused on a latent inflammatory cytokine factor and C-reactive protein at baseline predicting 5-month PTSD and depression symptom outcomes and included baseline symptom levels as covariates. RESULTS: A latent factor representing proinflammatory cytokines was not related to 5-month PTSD or depressive symptom severity. Higher salivary CRP was related to greater PTSD symptom severity (ß = .10, p = .03) at 5-month follow-up and more severity in the following depressive symptoms: changes in weight and appetite, bodily complaints, and constipation/diarrhea (ß's from .14 to .16, p's from .004 -.03). CONCLUSION: In a primarily Latine and Black trauma patient sample, salivary CRP measured after traumatic injury was related to greater PTSD symptom severity and severity in several depressive symptom clusters. Our preliminary findings suggest that salivary or systemic CRP may be useful to include in models predicting post-trauma psychopathology.

Higher risk tumor features are not associated with higher nodal stage in patients with estrogen receptor-positive, node-positive breast cancer.

INTRODUCTION: Studies support omission of axillary lymph node dissection (ALND) for patients with sentinel node-positive disease, with ALND recommended for patients who present with clinically positive nodes. Here, we evaluate patient and tumor characteristics and pathologic nodal stage of patients with estrogen receptor-positive (ER +) breast cancer who undergo ALND to determine if differences exist based on nodal presentation. MATERIALS AND METHODS: Retrospective chart review from 2010 to 2019 defined three groups of patients with ER + breast cancer who underwent ALND for positive nodes: SLN + (positive node identified at SLN biopsy), cNUS (abnormal preoperative US and biopsy), and cNpalp (palpable adenopathy). Patients who received neoadjuvant chemotherapy or presented with axillary recurrence were excluded. RESULTS: Of 191 patients, 94 were SLN + , 40 were cNUS, and 57 were cNpalp. Patients with SLN + compared with cNpalp were younger (56 vs 64 years, p < 0.01), more often pre-menopausal (41% vs 14%, p < 0.01), and White (65% vs 39%, p = 0.01) with more tumors that were low-grade (36% vs 8%, p < 0.01). Rates of PR + (p = 0.16), levels of Ki67 expression (p = 0.07) and LVI (p = 0.06) did not differ significantly among groups. Of patients with SLN + disease, 64% had pN1 disease compared to 38% of cNUS (p = 0.1) and 40% of cNpalp (p = 0.01). On univariable analysis, tumor size (p = 0.01) and histology (p = 0.04) were significantly associated with pN1 disease, with size remaining an independent predictor on multivariable analysis (p = 0.02). CONCLUSION: Historically, higher risk features have been attributed to patients with clinically positive nodes precluding omission of ALND, but when restricting evaluation to patients with ER + breast cancer, only tumor size is associated with higher nodal stage.

Epigenetic Signatures Predict Pathologic Nodal Stage in Breast Cancer Patients with Estrogen Receptor-Positive, Clinically Node-Positive Disease.

BACKGROUND: Breast cancer patients with clinically positive nodes who undergo upfront surgery are often recommended for axillary lymph node dissection (ALND), yet more than half are found to have limited nodal disease (≤ 3 positive nodes, pN1) at surgery. In this study, we examined the efficiency of molecular classifiers in stratifying patients with clinically positive nodes to pN1 versus > pN1 disease. METHODS: We evaluated the clinical and epigenetic data of patients in The Cancer Genome Atlas with estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal carcinoma who underwent ALND for node-positive disease. Patients were divided into control (pN1, ≤ 3 positive nodes) and case (> pN1, > 3 positive nodes) groups. Machine learning algorithms were trained on 50% of the cohort and validated on the remaining 50% to identify DNA methylation signatures that predict > pN1 disease. Clinical variables and epigenetic signatures were compared. RESULTS: Controls (n = 34) and case (n = 24) cohorts showed similar mean age (56.4 ± 12.2 vs. 57.6 ± 16.7 years; p = 0.77), number of nodes removed (16.1 ± 7.3 vs. 17.5 ± 6.2; p = 0.45), tumor grade (p = 0.76), presence of lymphovascular invasion (p = 0.18), extranodal extension (p = 0.17), tumor laterality (p = 0.89), and tumor location (p = 0.42). The mean number of positive nodes was significantly different (1.76 ± 0.82, pN1; 8.83 ± 5.36, > pN1; p < 0.001). Three epigenetic signatures (EpiSig14, EpiSig13, EpiSig10) based on DNA methylation patterns of the primary tumors demonstrated high accuracy in predicting > pN1 disease (area under the curve 0.98). CONCLUSIONS: Epigenetic signatures have an excellent diagnostic accuracy for stratifying nodal disease in patients with clinically positive nodes. Validation of this tool is warranted and may provide an accurate and cost-effective method of identifying patients with predicted low nodal burden who could be spared the morbidity of ALND.

Assessing the Burden of Nodal Disease for Breast Cancer Patients with Clinically Positive Nodes: Hope for More Limited Axillary Surgery.

BACKGROUND: Omission of axillary lymph node dissection (ALND) is accepted for patients with one or two positive sentinel nodes, and studies are focusing on clinically node-positive patients who have been downstaged with neoadjuvant chemotherapy (NAC). Evidence is lacking for patients with positive nodes who undergo surgery upfront. These patients are assumed to have a higher burden of nodal disease such that ALND remains the standard of care. METHODS: Patients who underwent ALND for breast cancer between 2010 and 2019 at the authors' institution were retrospectively identified. Those with clinical N1 disease were included in the study. Patients who received NAC and those who had surgery for sentinel node positive disease or axillary recurrence were excluded. Clinical and pathologic factors associated with nodal stage were evaluated. RESULTS: Of 111 patients who met the inclusion criteria, 61.3% had a palpable node on exam, and 41.4% ultimately had pN1 disease. Most of the tumors were estrogen receptor (ER)-positive (91.5%), and 21.7% of the tumors were invasive lobular cancers. Lobular histology, tumor size, and metastasis size were associated with higher nodal stage. In the multivariable analysis, the patients with nodal metastasis larger than 10 mm had significantly lower odds of having pN1 disease (odds ratio 0.12; 95% confidence interval 0.02-0.69; p = 0.02). In a subset analysis of patients with palpable nodes, tumor size and histology remained significantly associated with nodal stage. CONCLUSION: More than 40% of breast cancer patients with clinically positive nodes had minimal nodal disease (pN1) at surgery. Additionally, palpable nodes on exam did not predict higher nodal stage. A subset of patients with clinically positive nodes may be identified who can potentially be spared the morbidity of ALND.

Drug Use is Associated with Delayed Advancement Along the HIV Care Continuum Among Transgender Women of Color.

Transgender women are impacted by elevated rates of HIV infection and drug use. This study investigated effects of drug use on HIV care outcomes among transgender women of color living with HIV who enrolled in a combined peer health navigation (PHN) and contingency management intervention (N = 129). At baseline, 71.3% reported any drug use in the past 6 months. Linkage to HIV care was delayed for users of any stimulant compared to non-users of stimulants, and for methamphetamine users compared to non-users of methamphetamine. Any drug use, relative to no drug use, was associated with fewer HIV care visits (IRR 0.50, 95% CI [0.30, 0.85]), but did not significantly impact ART adherence, or attaining an undetectable viral load. PHN sessions were positively related to the number of HIV care visits (IRR 1.20, 95% CI [1.07, 1.34]), especially for users of any stimulant and for methamphetamine users, to ART adherence (OR 2.54, 95% CI [1.67, 3.86]), and to virological suppression (OR 7.57, 95% CI [1.64, 34.94]). These findings demonstrate the value of assessing drug use as a possible barrier to HIV care.

The longitudinal relationship of school climate with adolescent social and emotional health.

BACKGROUND: Schools and school climate are thought to influence academic outcomes as well as child and adolescent development, health and well-being. We sought to examine the relationship between several aspects of the school climate with adolescent social-emotional health outcomes. METHODS: We analysed data from the Reducing Inequities through Social and Educational change Follow-up (RISE UP) Study, a longitudinal natural experimental study of Los Angeles high school students collected from 2013 to 2018. We analysed data on the portion of the sample that completed the baseline, 10th grade and 11th grade surveys (n=1114). Students reported their perceptions of school climate at 10th grade and social-emotional outcomes including grit, self-efficacy, depression, hopelessness, and stress at baseline (9th grade) and at 11th grade. Multivariable regressions adjusted for student and parental demographics and baseline social-emotional states tested associations between school climate and each outcome. RESULTS: Students who reported being in authoritative school environments in 10th grade, one that is highly supportive and highly structured, had subsequently higher levels of self-efficacy (p< 0.001) and grit (p=0.01). They also had fewer depressive symptoms (p=0.008), and less hopelessness (p = 0.01), stress at school (p=0.002) and stress about the future (p=0.03) reported in 11th grade. CONCLUSIONS: School climate, and particularly an authoritative school environment, is strongly associated with better social-emotional health among adolescents. Relationship with teachers and their disciplinary style may be a focus for future interventions to improve the social-emotional health of children.

Technology use to facilitate health care among young adult transgender women living with HIV.

Little is known about how young adult transgender women living with HIV use digital technologies to facilitate their health care. This study examined the use of digital technologies to search for health information and support HIV care among young adult transgender women living with HIV (N = 130) in Los Angeles County, California. About half used the Internet "all the time" to search for transgender-specific resources (TSR; 53.8%) and for sexual health information (SHI; 51.5%). Less than half (39.2%) received digital HIV care reminders and, of those taking ART medication (n = 63), 36.5% received digital medication reminders. Internet information search was associated with Hispanic/Latina ethnicity (TSR: OR = 0.23, 95% CI [0.09, 0.58]; SHI: OR = 0.29, 95% CI [0.12, 0.73]) and higher (≥ $500) past-month income (TSR: OR = 2.67, 95% CI [1.13, 6.34]; SHI: OR = 2.67, 95% CI [1.14, 6.26]); receiving digital medication reminders with post-secondary educational attainment (OR = 5.70, 95% CI [1.04, 31.19]) and higher income (OR = 6.73, 95% CI [1.52, 29.67]). Receiving analog, but not digital, HIV care reminders was associated with engagement in HIV care (OR = 2.37, 95% CI [1.13, 5.00]) and ART uptake (OR = 2.18, 95% CI [1.06, 4.48]. Digital technology use was common for health-related searches but not for supporting HIV care.

Associations Between Social Support and Social Media Use Among Young Adult Cisgender MSM and Transgender Women Living With HIV.

Social media platforms offer the opportunity to develop online social networks. Use of these platforms has been particularly attractive to younger sexual and gender minority individuals as well as those living with HIV. This cross-sectional study examined the perceived level of social support and associations with social media use among youth and young adult cisgender men who have sex with men (MSM) and transgender (trans) women living with HIV and examined these associations by gender identity. The study drew from baseline data collected from 612 cisgender MSM and 162 trans women enrolling in one of 10 demonstration sites that were part of a Health Resources and Services Administration Special Projects of National Significance initiative. The individual projects were designed to evaluate the potential for social media/mobile technology-based interventions to improve retention in care and HIV health outcomes. The data used in this study came from baseline surveys completed when participants enrolled in a site between October 2016 and May 2018. Results demonstrated that a significantly greater proportion of MSM than trans women participants reported the use of social media platforms (e.g., Facebook: MSM = 86%, trans women = 62%; Instagram: MSM = 65%, trans women = 35%). Furthermore, increased social media use improved perceptions of social support only among MSM participants (direct adjusted OR = 1.49) and not trans women participants (gender identity interaction term adjusted OR = 0.64). These results revealed that MSM participants perceived greater social benefit from the use of social media platforms than trans women, which could be a result of generalized online transphobia experienced by trans women. More nuanced data on various social media platforms, that is, anonymous versus profile-based, and group differences, are needed to better understand how social media platforms can be best utilized to optimize health care outcomes among sexual and gender minority youth and young adults living with HIV.

A Promising PrEP Navigation Intervention for Transgender Women and Men Who Have Sex with Men Experiencing Multiple Syndemic Health Disparities.

Transgender women and MSM experience many stigma-related syndemic conditions that exacerbate HIV incidence and prevalence rates. While PrEP is an effective biomedical intervention to reduce HIV transmission, uptake and adherence of PrEP is low among transgender women and MSM experiencing multiple syndemic health disparities. This study tested the feasibility, acceptability and effectiveness of A.S.K.-PrEP (AssistanceServicesKnowledge-PrEP), a five-session peer navigator program, designed to link transgender women and MSM to PrEP. From September 2016 to March 2018, 187 participants (transgender women = 58; MSM = 129) enrolled. Results demonstrated that approximately 90% of transgender women and MSM were linked to PrEP; MSM linked more quickly [KW χ2(1) = 10.9, p < .001]. Most transgender women (80%) and MSM (70%) reported they were still taking PrEP at the 90-day follow-up evaluation. Findings indicated that A.S.K.-PrEP is a promising intervention for PrEP linkage, uptake and preliminary adherence among transgender women and MSM.

Psychology of Habit.

As the proverbial creatures of habit, people tend to repeat the same behaviors in recurring contexts. This review characterizes habits in terms of their cognitive, motivational, and neurobiological properties. In so doing, we identify three ways that habits interface with deliberate goal pursuit: First, habits form as people pursue goals by repeating the same responses in a given context. Second, as outlined in computational models, habits and deliberate goal pursuit guide actions synergistically, although habits are the efficient, default mode of response. Third, people tend to infer from the frequency of habit performance that the behavior must have been intended. We conclude by applying insights from habit research to understand stress and addiction as well as the design of effective interventions to change health and consumer behaviors.

Tied to expectations: Predicting features speeds processing even under adverse circumstances.

When participants predict the upcoming stimulus in a randomized choice reaction task, a match between prediction and stimulus increases processing speed at a level similar to that observed in cueing studies with highly valid cues. This might be taken to suggest that people cannot help but fully use their self-generated, verbalized predictions for preparing task processing. Thus, we tested how flexibly participants can control formation and implementation of predictions. In Experiment 1, we varied validity and response-relevance of predictions. We observed that prediction effects on RT can be boosted by increasing validity, but prevail under adverse circumstances. This was not the case in a control group who read rather than predicted the feature words, suggesting that the effect was specific to predictions as such. Experiment 2 provided further evidence for limited control of participants over implementing and forming predictions. Participants were provided with practice on stimuli occurring with varying frequency, but neither learned to strategically choose predictions to maximize the number of match trials, nor did they reduce the amount of prediction-based preparation when predicting an infrequent stimulus. As sequential aftereffects of prediction match did not vary with validity, they were identified as an independent effect of verbalizing a response-relevant stimulus feature. The results are consistent with the view that the predicted stimulus feature is represented in the focus of attention in working memory and that the amount of implementation can be subject to weighting.

A neurocomputational model of automatic sequence production.

Most behaviors unfold in time and include a sequence of submovements or cognitive activities. In addition, most behaviors are automatic and repeated daily throughout life. Yet, relatively little is known about the neurobiology of automatic sequence production. Past research suggests a gradual transfer from the associative striatum to the sensorimotor striatum, but a number of more recent studies challenge this role of the BG in automatic sequence production. In this article, we propose a new neurocomputational model of automatic sequence production in which the main role of the BG is to train cortical-cortical connections within the premotor areas that are responsible for automatic sequence production. The new model is used to simulate four different data sets from human and nonhuman animals, including (1) behavioral data (e.g., RTs), (2) electrophysiology data (e.g., single-neuron recordings), (3) macrostructure data (e.g., TMS), and (4) neurological circuit data (e.g., inactivation studies). We conclude with a comparison of the new model with existing models of automatic sequence production and discuss a possible new role for the BG in automaticity and its implication for Parkinson's disease.

Optimizing an adaptive digital oral health intervention for promoting oral self-care behaviors: Micro-randomized trial protocol.

Dental disease continues to be one of the most prevalent chronic diseases in the United States. Although oral self-care behaviors (OSCB), involving systematic twice-a-day tooth brushing, can prevent dental disease, this basic behavior is not sufficiently practiced. Recent advances in digital technology offer tremendous potential for promoting OSCB by delivering Just-In-Time Adaptive Interventions (JITAIs)- interventions that leverage dynamic information about the person's state and context to effectively prompt them to engage in a desired behavior in real-time, real-world settings. However, limited research attention has been given to systematically investigating how to best prompt individuals to engage in OSCB in daily life, and under what conditions prompting would be most beneficial. This paper describes the protocol for a Micro-Randomized Trial (MRT) to inform the development of a JITAI for promoting ideal OSCB, namely, brushing twice daily, for two minutes each time, in all four dental quadrants (i.e., 2x2x4). Sensors within an electric toothbrush (eBrush) will be used to track OSCB and a matching mobile app (Oralytics) will deliver on-demand feedback and educational information. The MRT will micro-randomize participants twice daily (morning and evening) to either (a) a prompt (push notification) containing one of several theoretically grounded engagement strategies or (b) no prompt. The goal is to investigate whether, what type of, and under what conditions prompting increases engagement in ideal OSCB. The results will build the empirical foundation necessary to develop an optimized JITAI that will be evaluated relative to a suitable control in a future randomized controlled trial.

Response-mode shifts during sequence learning of macaque monkeys.

Incidental sequence learning has been conceptualized as involving a shift from stimulus-based to plan-based performance (e.g., Tubauet et al. in Journal of Experimental Psychology: General 136:43-63, 2007). We analyzed the response time (RT) data of two macaque monkeys that were trained for thousands of trials on a sequential reaching task in a study by Matsuzaka et al. in Journal of Neurophysiology 97, 1819-1832 (2007). The animals learned to respond predictively to a repeating 3-element sequence. During a transitional period, RT distributions were bimodal, indicating that the animals alternated between two processing modes. An analysis of trial-to-trial mode shifting probabilities provided preliminary evidence for a strategic process.

How sequence learning creates explicit knowledge: the role of response-stimulus interval.

Destrebecqz and Cleeremans (Psychon bull rev 8:343-350, 2001; Attention and implicit learning. John Benjamins Publishing Company, Amsterdam, pp 181-213, 2003) reported that increasing the response-stimulus interval (RSI) during incidental sequence learning improved participants' ability to discriminate old and new sequences in a recognition test. However, the original experimental design confounded RSI effects during training and test. I therefore repeated the experiment with an improved design in which RSI was varied systematically during the training phase and the recognition task. Participants learned a sequence of response locations either incidentally or intentionally. As a result, sequence recognition was not affected by the RSI manipulations in the group of incidental learners. With intentional learning instructions, recognition was unaffected by training RSI, but a long RSI in the test phase improved recognition performance over a short RSI. Response latencies while executing the test sequences indicated no effect of training RSI on sequence learning. However, sequence knowledge was expressed more readily when the RSI in the test phase matched the RSI in the training phase.

Understanding trajectories of underlying dimensions of posttraumatic psychopathology.

BACKGROUND: Research suggests four modal trajectories of psychological symptoms after traumatic injury: Resilient, Chronic, Delayed Onset, Recovery. However, most studies focus on symptoms of psychiatric disorders (e.g., posttraumatic stress disorder, depression), which are limited by heterogeneity and symptom overlap. We examined trajectories of cross-cutting posttraumatic symptom dimensions following traumatic injury and predictors of trajectory membership. METHODS: In this longitudinal study of 427 predominantly Hispanic/Latino traumatic injury survivors, posttraumatic psychopathology symptoms were assessed during hospitalization and approximately one and five months post-trauma. Using latent class growth analysis, we estimated trajectories of several posttraumatic symptom dimensions: re-experiencing, avoidance, anxious arousal, numbing, dysphoric arousal, loss, and threat. We then examined sociodemographic and trauma-related characteristics (measured during hospitalization) as predictors of trajectory membership for each dimension. RESULTS: Four trajectories (Resilient, Chronic, Delayed Onset, Recovery) emerged for all dimensions except loss and threat, which manifested three trajectories (Resilient, Chronic, Delayed Onset). Across dimensions, membership in the Chronic (vs. Resilient) trajectory was consistently predicted by unemployment (7 of 7 dimensions), followed by older age (3/7), female sex (3/7), and assaultive trauma (2/7). For several dimensions, unemployment also distinguished between participants who presented with similar symptom levels days after trauma, but then diverged over time. LIMITATIONS: Measures of posttraumatic symptom dimension constructs differed across assessments. CONCLUSIONS: This study provides evidence of distinct trajectories across transdiagnostic symptom dimensions after traumatic injury. Employment status emerged as the most important predictor of trajectory membership. Research is needed to better understand the etiologies and consequences of these posttraumatic symptom dimension trajectories.

Chaos in Schools and Its Relationship to Adolescent Risk Behaviors.

OBJECTIVE: Chaos in the home is associated with worse childhood behaviors. We hypothesize chaos in the school environment might also be associated with teen risk behaviors. METHODS: We analyzed data from the Reducing Inequities through Social and Educational change Follow-Up study, a natural experiment designed to examine the impact of high-performing schools on adolescent outcomes. Students reported the amount of noise, order, and control in their school environment and whether they engaged in substance use, fighting, school absenteeism, and delinquent behaviors. We conducted cross-lagged panel structural equation modeling to examine the relationship between school chaos at 10th grade with risk behaviors at 11th grade while simultaneously examining the relationship between behaviors at 10th grade with chaos at 11th grade. RESULTS: Among a sample of 1114 teens, 90% were Latinx and 40% were native English speakers. Students reporting more school chaos in 10th grade were more likely in 11th grade to report recent alcohol and cannabis use, physical fighting, school absenteeism, and delinquent behaviors in the last year. Cross-lagged structural equation model analyses indicate school chaos at 10th grade is linked to alcohol use and absenteeism at 11th grade, while fighting, absenteeism, and any delinquent behaviors at 10th grade are associated with more chaos at 11th grade. School engagement was not a mediating factor. CONCLUSIONS: Although causal relationships cannot be assumed, school chaos may be an important predictor of adolescent risk behaviors. Future studies should examine whether reducing school chaos leads to lower rates of adolescent risk behaviors.

Head & neck melanoma: A 22-year experience of recurrence following sentinel lymph node biopsy.

OBJECTIVE: To examine the clinicopathologic factors that contribute to regional and distant recurrence in intermediate to high risk head and neck melanoma patients after sentinel lymph node biopsy (SLNB). METHODS: This study is a retrospective review from an academic tertiary care center. Patients treated with SLNB for head and neck melanoma from 1997 to 2019 were reviewed and characterized by sentinel lymph node (SLN) status. Clinical variables were examined for the impact on regional and distant recurrence in SLNB-negative patients using univariable and multivariable Cox regression analysis. RESULTS: One hundred and fifty four patients were included. Of note, 127 (82.5 %) were men, and the average age was 61.3 years. Median follow-up was 68.6 weeks. Pathologic review of SLNs found 3.9% positive for metastatic melanoma; 96.1% were negative. Regional recurrence was significantly associated with tumor stage and age on multivariate analysis. A total of 4.5% of patients recurred in a previously labeled negative basin. Scalp subsite accounted for 30.5% of primary tumors and was more likely to yield a positive SLN on univariate analysis (P = .023). Tumor stage and age were significantly associated with distant metastasis on multivariable analysis (P = .026, P < .001 respectively). CONCLUSION: We report a number of prognostic trends in head and neck melanoma. SLN positivity was found more often in patients with a primary tumor of the scalp. Regional recurrence was significantly associated with age and tumor stage, whereas distant recurrence was significantly associated with tumor staging and scalp subsite. Scalp subsite was associated with an increased risk for nodal metastasis and distant recurrence. LEVEL OF EVIDENCE: 3.

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2-20 years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10-68 years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of 'classic' FD. The vast majority of patients in this cohort presented with symptoms of 'classic' FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of -1.88 mL/min/1.73 m2/yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis. While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease.

Predictive Significance of Serum Interferon-Inducible Protein Score for Response to Treatment in Systemic Sclerosis-Related Interstitial Lung Disease.

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, ß2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3ß) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. RESULTS: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). CONCLUSION: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.