The Role of the Medial Prefrontal Cortex in Moderating Neural Representations of Self and Other in Primates.

As a frontal node in the primate social brain, the medial prefrontal cortex (MPFC) plays a critical role in coordinating one's own behavior with respect to that of others. Current literature demonstrates that single neurons in the MPFC encode behavior-related variables such as intentions, actions, and rewards, specifically for self and other, and that the MPFC comes into play when reflecting upon oneself and others. The social moderator account of MPFC function can explain maladaptive social cognition in people with autism spectrum disorder, which tips the balance in favor of self-centered perspectives rather than taking into consideration the perspective of others. Several strands of evidence suggest a hypothesis that the MPFC represents different other mental models, depending on the context at hand, to better predict others' emotions and behaviors. This hypothesis also accounts for aberrant MPFC activity in autistic individuals while they are mentalizing others.

Gene-Environment Interactions: My Unique Journey.

I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (a) discovery and characterization of the AHR/CYP1 axis, (b) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (c) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (d) discovery and characterization of the SLC39A8 gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.

A comprehensive review of protein-centric predictors for biomolecular interactions: from proteins to nucleic acids and beyond.

Proteins interact with diverse ligands to perform a large number of biological functions, such as gene expression and signal transduction. Accurate identification of these protein-ligand interactions is crucial to the understanding of molecular mechanisms and the development of new drugs. However, traditional biological experiments are time-consuming and expensive. With the development of high-throughput technologies, an increasing amount of protein data is available. In the past decades, many computational methods have been developed to predict protein-ligand interactions. Here, we review a comprehensive set of over 160 protein-ligand interaction predictors, which cover protein-protein, protein-nucleic acid, protein-peptide and protein-other ligands (nucleotide, heme, ion) interactions. We have carried out a comprehensive analysis of the above four types of predictors from several significant perspectives, including their inputs, feature profiles, models, availability, etc. The current methods primarily rely on protein sequences, especially utilizing evolutionary information. The significant improvement in predictions is attributed to deep learning methods. Additionally, sequence-based pretrained models and structure-based approaches are emerging as new trends.

How does genetic variation modify ND-CNV phenotypes?

Rare copy-number variants (CNVs) associated with neurodevelopmental disorders (NDDs), i.e., ND-CNVs, provide an insight into the neurobiology of NDDs and, potentially, a link between biology and clinical outcomes. However, ND-CNVs are characterised by incomplete penetrance resulting in heterogeneous carrier phenotypes, ranging from non-affected to multimorbid psychiatric, neurological, and physical phenotypes. Recent evidence indicates that other variants in the genome, or 'other hits', may partially explain the variable expressivity of ND-CNVs. These may be other rare variants or the aggregated effects of common variants that modify NDD risk. Here we discuss the recent findings, current questions, and future challenges relating to other hits research in the context of ND-CNVs and their potential for improved clinical diagnostics and therapeutics for ND-CNV carriers.

Effort expenditure modulates feedback evaluations involving self-other agreement: evidence from brain potentials and neural oscillations.

The influence of effort expenditure on the subjective value in feedback involving material reward has been the focus of previous research. However, little is known about the impact of effort expenditure on subjective value evaluations when feedback involves reward that is produced in the context of social interaction (e.g. self-other agreement). Moreover, how effort expenditure influences confidence (second-order subjective value) in feedback evaluations remains unclear. Using electroencephalography, this study aimed to address these questions. Event-related potentials showed that, after exerting high effort, participants exhibited increased reward positivity difference in response to self-other (dis)agreement feedback. After exerting low effort, participants reported high confidence, and the self-other disagreement feedback evoked a larger P3a. Time-frequency analysis showed that the high-effort task evoked increased frontal midline theta power. In the low (vs. high)-effort task, the frontal midline delta power for self-other disagreement feedback was enhanced. These findings suggest that, at the early feedback evaluation stage, after exerting high effort, individuals exhibit an increased sensitivity of subjective value evaluation in response to self-other agreement feedback. At the later feedback evaluation stage, after completing the low-effort task, the self-other disagreement feedback violates the individuals'high confidence and leads to a metacognitive mismatch.

How the Orthodox Features of Orthopoxviruses Led to an Unorthodox Mpox Outbreak: What We've Learned, and What We Still Need to Understand.

Orthopoxviruses have repeatedly confounded expectations in terms of the clinical illness they cause and their patterns of spread. Monkeypox virus (MPXV), originally characterized in the late 1950s during outbreaks among captive primates, has been recognized since the 1970s to cause human disease (mpox) in West and Central Africa, where interhuman transmission has largely been associated with nonsexual, close physical contact. In May 2022, a focus of MPXV transmission was detected, spreading among international networks of gay, bisexual, and other men who have sex with men. The outbreak grew in both size and geographic scope, testing the strength of preparedness tools and public health science alike. In this article we consider what was known about mpox before the 2022 outbreak, what we learned about mpox during the outbreak, and what continued research is needed to ensure that the global public health community can detect, and halt further spread of this disease threat.

The Causal Role of Temporoparietal Junction in Mediating Self-Other Mergence during Mentalizing.

Mentalizing is a core faculty of human social behaviors that involves inferring the cognitive states of others. This process necessitates adopting an allocentric perspective and suppressing one's egocentric perspective, referred to as self-other distinction (SOD). Meanwhile, individuals may project their own cognitive states onto others in prosocial behaviors, a process known as self-other mergence (SOM). It remains unclear how the two opposing processes coexist during mentalizing. We here combined functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) techniques with intranasal oxytocin (OTint) as a probe to examine the SOM effect in healthy male human participants, during which they attributed the cognitive states of decision confidence to an anonymous partner. Our results showed that OTint facilitated SOM via the left temporoparietal junction (lTPJ), but did not affect neural representations of internal information about others' confidence in the dorsomedial prefrontal cortex, which might be dedicated to SOD, although the two brain regions, importantly, have been suggested to be involved in mentalizing. Further, the SOM effect induced by OTint was fully mediated by the lTPJ activities and became weakened when the lTPJ activities were suppressed by rTMS. These findings suggest that the lTPJ might play a vital role in mediating SOM during mentalizing.SIGNIFICANCE STATEMENT Every human mind is unique. It is critical to distinguish the minds of others from the self. On the contrary, we often project the current mental states of the self onto others; that is to say, self-other mergence (SOM). The neural mechanism underlying SOM remains unclear. We here used intranasal oxytocin (OTint) as a probe to leverage SOM, which is typically suppressed during mentalizing. We revealed that OTint specifically modulated the left temporoparietal junction (lTPJ) neural activities to fully mediate the SOM effect, while suppressing the lTPJ neural activities by transcranial magnetic stimulations causally attenuated the SOM effect. Our results demonstrate that the lTPJ might mediate SOM during social interactions.

Metabolic effect of adrenaline infusion in people with type 1 diabetes and healthy individuals.

AIMS/HYPOTHESIS: As a result of early loss of the glucagon response, adrenaline is the primary counter-regulatory hormone in type 1 diabetes. Diminished adrenaline responses to hypoglycaemia due to counter-regulatory failure are common in type 1 diabetes, and are probably induced by exposure to recurrent hypoglycaemia, however, the metabolic effects of adrenaline have received less research attention, and also there is conflicting evidence regarding adrenaline sensitivity in type 1 diabetes. Thus, we aimed to investigate the metabolic response to adrenaline and explore whether it is modified by prior exposure to hypoglycaemia. METHODS: Eighteen participants with type 1 diabetes and nine healthy participants underwent a three-step ascending adrenaline infusion during a hyperinsulinaemic-euglycaemic clamp. Continuous glucose monitoring data obtained during the week before the study day were used to assess the extent of hypoglycaemia exposure. RESULTS: While glucose responses during the clamp were similar between people with type 1 diabetes and healthy participants, plasma concentrations of NEFAs and glycerol only increased in the group with type 1 diabetes (p<0.001). Metabolomics revealed an increase in the most common NEFAs (p<0.01). Other metabolic responses were generally similar between participants with type 1 diabetes and healthy participants. Exposure to hypoglycaemia was negatively associated with the NEFA response; however, this was not statistically significant. CONCLUSIONS/INTERPRETATION: In conclusion, individuals with type 1 diabetes respond with increased lipolysis to adrenaline compared with healthy participants by mobilising the abundant NEFAs in plasma, whereas other metabolic responses were similar. This may suggest that the metabolic sensitivity to adrenaline is altered in a pathway-specific manner in type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05095259.

Extensively Drug-Resistant Pseudomonas aeruginosa Outbreak Associated With Artificial Tears.

BACKGROUND: Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) are extensively drug-resistant bacteria. We investigated the source of a multistate CP-CRPA outbreak. METHODS: Cases were defined as a US patient's first isolation of P. aeruginosa sequence type 1203 with carbapenemase gene blaVIM-80 and cephalosporinase gene blaGES-9 from any specimen source collected and reported to the Centers for Disease Control and Prevention during 1 January 2022-15 May 2023. We conducted a 1:1 matched case-control study at the post-acute care facility with the most cases, assessed exposures associated with case status for all case-patients, and tested products for bacterial contamination. RESULTS: We identified 81 case-patients from 18 states, 27 of whom were identified through surveillance cultures. Four (7%) of 54 case-patients with clinical cultures died within 30 days of culture collection, and 4 (22%) of 18 with eye infections underwent enucleation. In the case-control study, case-patients had increased odds of receiving artificial tears versus controls (crude matched OR, 5.0; 95% CI, 1.1-22.8). Overall, artificial tears use was reported by 61 (87%) of 70 case-patients with information; 43 (77%) of 56 case-patients with brand information reported use of Brand A, an imported, preservative-free, over-the-counter (OTC) product. Bacteria isolated from opened and unopened bottles of Brand A were genetically related to patient isolates. Food and Drug Administration inspection of the manufacturing plant identified likely sources of contamination. CONCLUSIONS: A manufactured medical product serving as the vehicle for carbapenemase-producing organisms is unprecedented in the United States. The clinical impacts from this outbreak underscore the need for improved requirements for US OTC product importers.

Brain responses to self- and other- unfairness under resource distribution context: Meta-analysis of fMRI studies.

Under resource distribution context, individuals have a strong aversion to unfair treatment not only toward themselves but also toward others. However, there is no clear consensus regarding the commonality and distinction between these two types of unfairness. Moreover, many neuroimaging studies have investigated how people evaluate and respond to unfairness in the abovementioned two contexts, but the consistency of the results remains to be investigated. To resolve these two issues, we sought to summarize existing findings regarding unfairness to self and others and to further elucidate the neural underpinnings related to distinguishing evaluation and response processes through meta-analyses of previous neuroimaging studies. Our results indicated that both types of unfairness consistently activate the affective and conflict-related anterior insula (AI) and dorsal anterior cingulate cortex/supplementary motor area (dACC/SMA), but the activations related to unfairness to self appeared stronger than those related to others, suggesting that individuals had negative reactions to both unfairness and a greater aversive response toward unfairness to self. During the evaluation process, unfairness to self activated the bilateral AI, dACC, and right dorsolateral prefrontal cortex (DLPFC), regions associated with unfairness aversion, conflict, and cognitive control, indicating reactive, emotional and automatic responses. In contrast, unfairness to others activated areas associated with theory of mind, the inferior parietal lobule and temporoparietal junction (IPL-TPJ), suggesting that making rational judgments from the perspective of others was needed. During the response, unfairness to self activated the affective-related left AI and striatum, whereas unfairness to others activated cognitive control areas, the left DLPFC and the thalamus. This indicated that the former maintained the traits of automaticity and emotionality, whereas the latter necessitated cognitive control. These findings provide a fine-grained description of the common and distinct neurocognitive mechanisms underlying unfairness to self and unfairness to others. Overall, this study not only validates the inequity aversion model but also provides direct evidence of neural mechanisms for neurobiological models of fairness.

Bedaquiline Resistance after Effective Treatment of Multidrug-Resistant Tuberculosis, Namibia.

Bedaquiline is currently a key drug for treating multidrug-resistant or rifampin-resistant tuberculosis. We report and discuss the unusual development of resistance to bedaquiline in a teenager in Namibia, despite an optimal background regimen and adherence. The report highlights the risk for bedaquiline resistance development and the need for rapid drug-resistance testing.

Racial and Ethnic Disparities in Tuberculosis Incidence, Arkansas, USA, 2010-2021.

We conducted an epidemiologic assessment of disease distribution by race/ethnicity to identify subpopulation-specific drivers of tuberculosis (TB). We used detailed racial/ethnic categorizations for the 932 TB cases diagnosed in Arkansas, USA, during 2010-2021. After adjusting for age and sex, racial/ethnic disparities persisted; the Native Hawaiian/Pacific Islander (NHPI) group had the highest risk for TB (risk ratio 173.6, 95% CI 140.6-214.2) compared with the non-Hispanic White group, followed by Asian, Hispanic, and non-Hispanic Black. Notable racial/ethnic disparities existed across all age groups; NHPI persons 0-14 years of age were at a particularly increased risk for TB (risk ratio 888, 95% CI 403-1,962). The risks for sputum smear-positive pulmonary TB and extrapulmonary TB were both significantly higher for racial/ethnic minority groups. Our findings suggest that TB control in Arkansas can benefit from a targeted focus on subpopulations at increased risk for TB.

Mycobacterium senegalense Infection in Kidney Transplant Patient with Diabetes, Memphis, Tennessee, USA.

Fewer than 30 cases of Mycobacterium senegalense infection have been reported. We report a complicated case of M. senegalense infection in Memphis, Tennessee, in the southeastern United States. The patient's comorbidities of past organ transplant and insulin-dependent diabetes required delicate consideration of those health conditions to guide treatment.

Geographic Variation and Environmental Predictors of Nontuberculous Mycobacteria in Laboratory Surveillance, Virginia, USA, 2021-20231.

Because epidemiologic and environmental risk factors for nontuberculous mycobacteria (NTM) have been reported only infrequently, little information exists about those factors. The state of Virginia, USA, requires certain ecologic features to be included in reports to the Virginia Department of Health, presenting a unique opportunity to study those variables. We analyzed laboratory reports of Mycobacterium avium complex (MAC) and M. abscessus infections in Virginia during 2021-2023. MAC/M. abscessus was isolated from 6.19/100,000 persons, and 2.37/100,000 persons had MAC/M. abscessus lung disease. M. abscessus accounted for 17.4% and MAC for 82.6% of cases. Saturated vapor pressure was associated with MAC/M. abscessus prevalence (prevalence ratio 1.414, 95% CI 1.011-1.980; p = 0.043). Self-supplied water use was a protective factor (incidence rate ratio 0.304, 95% CI 0.098-0.950; p = 0.041). Our findings suggest that a better understanding of geographic clustering and environmental water exposures could help develop future targeted prevention and control efforts.

Newly Identified Mycobacterium africanum Lineage 10, Central Africa.

Analysis of genome sequencing data from >100,000 genomes of Mycobacterium tuberculosis complex using TB-Annotator software revealed a previously unknown lineage, proposed name L10, in central Africa. Phylogenetic reconstruction suggests L10 could represent a missing link in the evolutionary and geographic migration histories of M. africanum.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

Treatment Outcomes for Tuberculosis Infection and Disease Among Persons Deprived of Liberty, Uganda, 2020.

We report that unsuccessful treatment outcomes were 11.8% for tuberculosis (TB) disease and 21.8% for TB infection among persons deprived of liberty in Uganda Prisons Service facilities. Remedial efforts should include enhancing referral networks to ensure treatment continuity, strengthening data systems for complete outcome documentation, and prioritizing short-course treatment regimens.

Systematic Review of Scales for Measuring Infectious Disease-Related Stigma.

Infectious disease outbreaks are associated with substantial stigma, which can have negative effects on affected persons and communities and on outbreak control. Thus, measuring stigma in a standardized and validated manner early in an outbreak is critical to disease control. We reviewed existing scales used to assess stigma during outbreaks. Our findings show that many different scales have been developed, but few have been used more than once, have been adequately validated, or have been tested in different disease and geographic contexts. We found that scales were usually developed too slowly to be informative early during an outbreak and were published a median of 2 years after the first case of an outbreak. A rigorously developed, transferable stigma scale is needed to assess and direct responses to stigma during infectious disease outbreaks.

Costs of Digital Adherence Technologies for Tuberculosis Treatment Support, 2018-2021.

Digital adherence technologies are increasingly used to support tuberculosis (TB) treatment adherence. Using microcosting, we estimated healthcare system costs (in 2022 US dollars) of 2 digital adherence technologies, 99DOTS medication sleeves and video-observed therapy (VOT), implemented in demonstration projects during 2018-2021. We also obtained cost estimates for standard directly observed therapy (DOT). Estimated per-person costs of 99DOTS for drug-sensitive TB were $98 in Bangladesh (n = 719), $119 in the Philippines (n = 396), and $174 in Tanzania (n = 976). Estimated per-person costs of VOT were $1,154 in Haiti (87 drug-sensitive), $304 in Moldova (173 drug-sensitive), $452 in Moldova (135 drug-resistant), and $661 in the Philippines (110 drug-resistant). 99DOTS costs may be similar to or less expensive than standard DOT. VOT is more expensive, although in some settings, labor cost offsets or economies of scale may yield savings. 99DOTS and VOT may yield savings to local programs if donors cover infrastructure costs.

Chest Radiograph Screening for Detecting Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.