Faculty Bibliography

Clinical diagnosis typically incorporates physical examination, patient history, various laboratory tests, and imaging studies but makes limited use of the human immune system's own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis, an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to severe acute respiratory syndrome coronavirus 2, influenza, and human immunodeficiency virus, highlight antigen-specific receptors, and reveal distinct characteristics of systemic lupus erythematosus and type-1 diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of immune responses.

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca²⁺ entry (SOCE) and T cell activation. T helper 1 (T_H1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T_H lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4⁺ T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE-NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.

BACKGROUND:Motoric cognitive risk (MCR) syndrome is a predementia syndrome characterized by subjective cognitive complaints and slow gait in the absence of dementia and mobility disability. Although past research has suggested that personality traits could play a significant role in the onset and progression of MCR among older adults, the exact relationships between specific personality profiles and MCR remain unclear. This study aimed to examine the relationship between personality profiles and MCR among community-dwelling older adults. METHODS:A cross-sectional study was conducted from March 2021 to January 2022. Personality traits, including openness, extraversion, agreeableness, conscientiousness and neuroticism, were measured using the 40-item brief version of the Chinese Big Five Inventory. The Latent profile analysis was used to identify personality profiles among these older adults who shared similar patterns of personality traits. The Lanza, Tan, and Bray's approach was employed to investigate the personality profile-specific differences in MCR prevalence. Furthermore, a stepwise multinomial logistic regression revealed unique population characteristics for different personality profiles. RESULTS: = 14.599, p = 0.002). Personality profile membership was characterized by different population characteristics. Notably, the anti-resilient profile was association with symptoms of depression (OR = 28.443, 95%CI = 11.095-72.912), while the reserved profile was linked with advanced age (OR = 1.031, 95%CI = 1.003-1.061). Overall, a low education level and poor sleep quality were the robust attribution factors. CONCLUSIONS:This study revealed that personality profiles may assist in identifying older adults at greater risk of MCR. Increased awareness and management of personality profiles may contribute to the prevention of MCR.

This editorial focuses on the seven studies published in the BMJ Mental Health topic collection Advances in Clinical Psychopharmacology in Children and Young People. Collectively, these articles provide evidence that informs key steps in the psychopharmacological management of children and adolescents with mental health or neurodevelopmental conditions. Papers in this collection contribute to strengthen evidence-based psychopharmacological practice. We look forward to further developments in the field, supported by adequate research funding.

OBJECTIVE:We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and nonstimulants. METHOD/METHODS:February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multilevel meta-analytic models were conducted with R 4.3.1. RESULTS:We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedge's g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. CONCLUSION/CONCLUSIONS:In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and nonstimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and nonpharmacological interventions is likely to further improve QoL in people with ADHD. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:From a prior dataset of a network meta-analysis, 17 randomized controlled trials (RCTs) were included in a meta-analysis to investigate if attention-deficit/hyperactivity disorder (ADHD) medication improves quality of life (QoL) in people with ADHD. The analysis showed that medications such as amphetamines, methylphenidate, and atomoxetine improved QoL compared to placebo, with moderate effect sizes. This study underscores the importance of ADHD medications, both stimulants and nonstimulants, not only in alleviating core ADHD symptoms but also in enhancing overall QoL for individuals with ADHD. STUDY PREREGISTRATION INFORMATION/UNASSIGNED:Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/; qvgps.

Pathogenic Enterobacter species are of increasing clinical concern due to the multidrug-resistant nature of these bacteria, including resistance to carbapenem antibiotics. Our understanding of Enterobacter virulence is limited, hindering the development of new prophylactics and therapeutics targeting infections caused by Enterobacter species. In this study, we assessed the virulence of contemporary clinical Enterobacter hormaechei isolates in a mouse model of intraperitoneal infection and used comparative genomics to identify genes promoting virulence. Through mutagenesis and complementation studies, we found two porin-encoding genes, ompC and ompD, to be required for E. hormaechei virulence. These porins imported clinically relevant carbapenems into the bacteria, and thus loss of OmpC and OmpD desensitized E. hormaechei to the antibiotics. Our genomic analyses suggest porin-related genes are frequently mutated in E. hormaechei, perhaps due to the selective pressure of antibiotic therapy during infection. Despite the importance of OmpC and OmpD during infection of immunocompetent hosts, we found the two porins to be dispensable for virulence in a neutropenic mouse model. Moreover, porin loss provided a fitness advantage during carbapenem treatment in an ex vivo human whole blood model of bacteremia. Our data provide experimental evidence of pathogenic Enterobacter species gaining antibiotic resistance via loss of porins and argue antibiotic therapy during infection of immunocompromised patients is a conducive environment for the selection of porin mutations enhancing the multidrug-resistant profile of these pathogens.

OBJECTIVES/OBJECTIVE:Despite significant therapeutic advances in psoriatic arthritis (PsA), many patients do not achieve remission and cycle through multiple biologic (b)- or targeted synthetic (ts)- DMARDs. Identifying the underlying reasons for repetitive therapeutic failure remains a knowledge gap. Here we describe prescribing patterns and characteristics of PsA patients with multi-b/tsDMARD failure at the NYU Psoriatic Arthritis Center. METHODS:Nine hundred sixty PsA patients were enrolled in an observational, longitudinal registry. Demographics, medical history, medication use, and psoriatic disease phenotype were collected. Multi-b/tsDMARD failure was defined as requiring ≥ 4 b/tsDMARDs. RESULTS:Seven hundred twenty-five patients (75%) used ≥ 1 b/tsDMARD during their disease course. The initial b/tsDMARDs prescribed were predominately anti-TNF agents. 166 (17%) patients had multi-b/tsDMARD failure. Compared to those requiring 1 b/tsDMARD, female sex (OR 2.3; 95%CI 1.4-3.8), axial disease (OR 2.1; 95% CI 1.2-3.6), depression (OR 2.0; 95%CI 1.1-3.7), and obesity (OR 1.7; 95%CI 1.0-2.8) were risk factors for multi-b/tsDMARD failure disease after adjustment for age, disease duration, sex, depression, smoking, obesity, and skin severity. Patients with multi-b/tsDMARD failure PsA also had increased disease activity at their clinical visit (i.e., swollen joint count, p = 0.005). CONCLUSION/CONCLUSIONS:In this cohort, 17% patients with PsA experienced multi-b/tsDMARD failure. These patients were more likely to be female, obese, and have higher rates of axial involvement and depression, along with higher active disease activity. This highlights the inflammatory and non-inflammatory drivers of multiple therapeutic failures, underscoring the need for precision medicine strategies and potential non-pharmacologic adjuvant therapies for patients with PsA to improve outcomes and quality of life.

The mediodorsal (MD) thalamus is a critical partner for the prefrontal cortex (PFC) in cognitive control. Accumulating evidence has shown that the MD regulates task uncertainty in decision making and enhance cognitive flexibility. However, the computational mechanism of this cognitive process remains unclear. Here we trained biologically-constrained computational models to delineate the mechanistic role of MD in context-dependent decision making. We show that the addition of a feedforward MD structure to the recurrent PFC increases robustness to low cueing signal-to-noise ratio, enhances working memory, and enables rapid context switching. Incorporating genetically identified thalamocortical connectivity and interneuron cell types into the model replicates key neurophysiological findings in task-performing animals. Our model reveals computational mechanisms and geometric interpretations of MD in regulating cue uncertainty and context switching to enable cognitive flexibility. Our model makes experimentally testable predictions linking cognitive deficits with disrupted thalamocortical connectivity, prefrontal excitation-inhibition imbalance and dysfunctional inhibitory cell types.

OBJECTIVES/OBJECTIVE:Hearing impairment is associated with delirium among ICU patients and a lack of functional recovery among older ICU survivors. We assessed the feasibility of using otoacoustic emissions (OAEs) testing to screen for preexisting hearing loss in the ICU. DESIGN/METHODS:Pilot study. SETTING/METHODS:Medical ICU at a tertiary medical center. PATIENTS/METHODS:All adults (age ≥ 18) and admitted to the medical ICU between November 29, 2021, and December 03, 2021, were eligible for the study. INTERVENTIONS/METHODS:OAE is a noninvasive, nonparticipatory tool that is used to screen for hearing loss by detecting intracochlear motion in response to auditory stimulation. The presence or absence of OAE was tested at six frequencies (1 k, 1.5 k, 2 k, 3 k, 4 k hertz). MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome of feasibility was defined a priori as completion of greater than or equal to 70% of attempted tests. Average time of test completion and barriers or facilitators were also measured as outcomes. A patient passed OAE testing if at least two of six frequencies were detected in at least one ear, suggesting they did not have moderate or severe hearing impairment (that would require an amplifier). Data were also gathered on demographics, delirium, ventilation, sedation, illness severity, and ambient noise. Of 31 patients approached, 23 (74.2%) underwent testing. Eight patients (25.8%) were unable to be tested, most commonly due to elevated ambient noise. Among the 18 patients with complete data, six patients screened positive for hearing loss. The average time for OAE test completion per ear was 152.6 seconds (sd = 97.6 s). CONCLUSIONS:OAE testing is a feasible method to screen for hearing loss in the ICU, including in nonparticipatory patients. Identification of hearing loss would facilitate improved communication through interventions such as amplifiers and accommodations. Future studies should evaluate whether identification and treatment of hearing loss in the ICU may reduce delirium and improve post-ICU recovery.

Multiparametric MRI of the bladder is highly accurate in the detection and local staging of bladder cancer. The Vesical Imaging Reporting and Data System (VI-RADS) scoring system has improved the diagnostic accuracy, reproducibility, and interpretability of bladder MRI in the assessment of the invasion of the muscularis propria. There are several technical details concerning bladder MRI that need to be strictly applied to obtain the highest possible diagnostic potential from the MRI. In addition, image evaluation, accurate interpretation, and reporting need to be standardized to optimize diagnostic accuracy and interreader agreement. This review describes the patient population for bladder MRI and discusses, with a practical approach, the correct acquisition protocol for optimal image quality using VI-RADS with reporting tips, pitfalls, and challenges for its clinical application. This review also discusses the latest evidence, clinical implications, current controversies, and future challenges, including gaps in knowledge, of the VI-RADS scoring system.