--Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in Pediatric Human Atrial Tissue.

Nearly 1% of babies are born with congenital heart disease (CHD) - many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (n=117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes (DEGs) revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower IKr expression in younger patients, a finding potentially tied to an increased amplitude of IKs that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.

Lateral prefrontal cortex controls interplay between working memory and actions.

Humans must often keep multiple task goals in mind, at different levels of priority and immediacy, while also interacting with the environment. We might need to remember information for an upcoming task while engaged in more immediate actions. Consequently, actively maintained working memory (WM) content may bleed into ongoing but unrelated motor behavior. Here, we experimentally test the impact of WM maintenance on action execution, and we transcranially stimulate lateral prefrontal cortex (PFC) to parse its functional contributions to WM-motor interactions. We first created a task scenario wherein human participants (both sexes) executed cued hand movements during WM maintenance. We manipulated the compatibility between WM and movement goals at the trial level and the statistical likelihood that the two would be compatible at the block level. We found that remembering directional words (e.g., 'left', 'down') biased the trajectory and speed of hand movements that occurred during the WM delay, but the bias was dampened in blocks when WM content predictably conflicted with movement goals. Then we targeted left lateral PFC with two different transcranial magnetic stimulation (TMS) protocols before participants completed the task. We found that an intermittent theta-burst protocol, which is thought to be excitatory, dampened sensitivity to block-level control demands (i.e., proactive control), while a continuous theta-burst protocol, which is thought to be inhibitory, dampened adaptation to trial-by-trial conflict (i.e., reactive control). Therefore, lateral PFC is involved in controlling the interplay between WM content and manual action, but different PFC mechanisms may support different time-scales of adaptive control.

Anterior thalamic nucleus local field potentials during focal temporal lobe epileptic seizures.

Objective: To analyze the local field potentials (LFPs) in patients with focal drug-resistant epilepsy (DRE) from the anterior nucleus of the thalamus (ANT) during inter-ictal state and seizure state. Method: ANT stereotactic EEG (SEEG) recordings were studied in four patients with focal temporal lobe epilepsy. SEEG data was classified as inter-ictal and ictal state and sub-categorized into electrographic (ESz), focal aware seizure (FAS), focal with impaired awareness (FIA), or focal to bilateral tonic-clonic seizure (FBTC). LFP was analyzed at 4 Hz, 8 Hz, 16 Hz, 32 Hz, high gamma (100 Hz), and ripples (200 Hz) using spectrogram analysis and a statistical comparison of normalized power spectral density (PSD) averaged during seizures versus pre-ictal baseline segments. Result: The LFP recordings were analyzed for 162 seizures (127 ESz, 23 FAS, 6 FIA, and 6 FBTC). Based on time-frequency data (spectrogram), a broad band of activity, occurring between 2 and 6 Hz and centered at 4 Hz, and thin-band activity occurring specifically at 8 Hz on the frequency spectrogram were observed during the inter-ictal state. Statistically significant changes in LFP-PSD were seen for FAS, FIA, and FBTC. We observed a significant gain in LFP at the lower frequency band during FAS at 4 Hz, FIA, and FBTC at 4, 8, and 16 Hz while also observing increases at higher frequencies during FBTC at 100 and 200 Hz and a decrease during FAS seizures at 32 Hz. In contrast, no significant change in LFP power was seen for electrographic seizures. Interpretation: Our observations from a limited dataset indicate that all clinical seizure types, but not electrographic seizures, caused a change in ANT-LFP based on the magnitude of the associated power spectral density (PSD). Future work will be needed to validate the use of ANT-LFP at these frequencies as accurate measurements of seizure occurrence and severity. This work represents a first step toward understanding ANT thalamic LFP patterns during focal seizures and developing adaptive DBS strategies.

Evaluating complete response rates and predictors in total neoadjuvant therapy for rectal cancer.

BACKGROUND: There is a paradigm shift in the management of locally advanced rectal cancer (LARC) from conventional neoadjuvant treatment to total neoadjuvant therapy (TNT). Despite its growing acceptance, there are limited studies that have examined its effects on disease presentation. In addition, it is important to determine the factors that play a role in complete response (CR). Our previous data from 119 patients revealed that the CR rate was 37%, and low rectal tumors and the absence of extramural vascular invasion (EMVI) were predictors of CR. Unfortunately, there continues to be a lack of data, and reliable markers are still needed to consistently identify the best respondents. Therefore, this study aimed to determine the factors associated with CR. Moreover, this study hypothesized that both predictive factors and the CR ratio might evolve over time because of the growing patient population. METHODS: This retrospective study included patients who completed TNT for LARC at our tertiary care center between 2015 and 2022. The primary outcome was to determine the predictors of CR. The secondary outcomes were the 2-year disease-free survival (DFS) rate and overall survival (OS) rate. CR consists of patients who sustained clinical CR (cCR) for at least 12 months under watch and wait or had pathologic CR (pCR) after surgery. RESULTS: Of 339 patients with LARC, 208 (61.3%) successfully completed TNT. Among 208 patients, 57 (27.4%) achieved cCR, and 166 (80.0%) sustained cCR without tumor regrowth after 1 year. The remaining 151 patients (72.6%) underwent surgery, and 42 patients had pCR. The final CR rate was 42.3%. The median age of the patients was 56 years (IQR, 49-66). Moreover, 132 participants (63.5%) were male, whereas 76 participants (36.5%) were female. The median tumor size was 4.95 cm (IQR, 3.60-6.43), with most tumors in the low rectum (119 [57.2%]). Based on the MRI findings, the mesorectal facia (MRF) involvement rate was 25.0% (n = 52), and EMVI was observed in 43 patients (20.7%). Low rectal tumors, the absence of MRF involvement, and the absence of EMVI were predictors of CR. With a median follow-up of 24.7 months, 2-year DFS and OS were significantly higher among patients with CR than among patients with incomplete response (91.3% vs 71.0% [P < .01] and 98.8% vs 90.2% [P = .03], respectively). CONCLUSION: An increasing CR rate was observed in our updated dataset compared with that in our previous study. In addition to previously identified predictors, low tumor location, and the absence of EMVI, the absence of MRF involvement was determined as a predictor of CR. Our findings offer valuable insights into clinical practice and help clinicians set clear expectations when counseling patients.

Timescales of learning in prefrontal cortex.

The lateral prefrontal cortex (PFC) in humans and other primates is critical for immediate, goal-directed behaviour and working memory, which are classically considered distinct from the cognitive and neural circuits that support long-term learning and memory. Over the past few years, a reconsideration of this textbook perspective has emerged, in that different timescales of memory-guided behaviour are in constant interaction during the pursuit of immediate goals. Here, we will first detail how neural activity related to the shortest timescales of goal-directed behaviour (which requires maintenance of current states and goals in working memory) is sculpted by long-term knowledge and learning - that is, how the past informs present behaviour. Then, we will outline how learning across different timescales (from seconds to years) drives plasticity in the primate lateral PFC, from single neuron firing rates to mesoscale neuroimaging activity patterns. Finally, we will review how, over days and months of learning, dense local and long-range connectivity patterns in PFC facilitate longer-lasting changes in population activity by changing synaptic weights and recruiting additional neural resources to inform future behaviour. Our Review sheds light on how the machinery of plasticity in PFC circuits facilitates the integration of learned experiences across time to best guide adaptive behaviour.

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium.

Background: Nearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. Methods: Right atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Results: Enrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling ( I NCX ) and repolarization ( I K1 ) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower I Kr expression in younger patients, a finding likely tied to the increased amplitude of I Ks triggered by elevated sympathetic activation in pediatric patients. Conclusion: This study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

Optimization and Local Cost-Effectiveness of Nasopharyngeal Carcinoma Screening Strategies in Southern China: Secondary Analysis of the Guangdong Randomized Trial.

BACKGROUND: Screening with anti-Epstein-Barr virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China. METHODS: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women aged 30-69). Seropositive subjects were rescreened annually for 5 years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial subcohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system. RESULTS: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (¥42,366/life-year, 0.52 GDP per capita). Screening for 5 to 15 years between ages 35 and 59 years met a willingness-to-pay threshold of 1.5 GDP/quality-adjusted life-years in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One-lifetime screen could reduce NPC mortality by approximately 20%. CONCLUSIONS: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region. IMPACT: These findings support population-based screening in southern China by defining the target population, cost-effectiveness, and optimized screening approach.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Defining putative tertiary sulci in lateral prefrontal cortex in chimpanzees using human predictions.

Similarities and differences in brain structure and function across species are of major interest in systems neuroscience, comparative biology, and brain mapping. Recently, increased emphasis has been placed on tertiary sulci, which are shallow indentations of the cerebral cortex that appear last in gestation, continue to develop after birth, and are largely either human or hominoid specific. While tertiary sulcal morphology in lateral prefrontal cortex (LPFC) has been linked to functional representations and cognition in humans, it is presently unknown if small and shallow LPFC sulci also exist in non-human hominoids. To fill this gap in knowledge, we leveraged two freely available multimodal datasets to address the following main question: Can small and shallow LPFC sulci be defined in chimpanzee cortical surfaces from human predictions of LPFC tertiary sulci? We found that 1-3 components of the posterior middle frontal sulcus (pmfs) in the posterior middle frontal gyrus are identifiable in nearly all chimpanzee hemispheres. In stark contrast to the consistency of the pmfs components, we could only identify components of the paraintermediate frontal sulcus (pimfs) in two chimpanzee hemispheres. Putative LPFC tertiary sulci were relatively smaller and shallower in chimpanzees compared to humans. In both species, two of the pmfs components were deeper in the right compared to the left hemisphere. As these results have direct implications for future studies interested in the functional and cognitive role of LPFC tertiary sulci, we share probabilistic predictions of the three pmfs components to guide the definitions of these sulci in future studies.

Comparison of Real-Time PCR and Digital PCR for Detection of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma.

Plasma Epstein-Barr virus (EBV) DNA is an established biomarker for endemic nasopharyngeal carcinoma. However, existing real-time quantitative PCR (qPCR) assays are limited by poor interlaboratory reproducibility. This is a barrier to biomarker integration into staging systems and management. It was hypothesized that EBV digital PCR (dPCR) would have similar sensitivity but improved precision relative to qPCR. Using the World Health Organization EBV standard and patient specimens, the NRG-HN001 BamHI-W qPCR, two commercial EBNA-1 qPCR assays, and two laboratory-developed dPCR assays amplifying the BamHI-W, EBNA-1, and EBER targets were compared. Testing was conducted in the North American reference laboratory for the NRG-HN001 randomized trial. The EBV dPCR assays achieved similar performance compared with qPCR. Although dPCR does not require quantitation standards, different dPCR thresholding algorithms yielded significant qualitative and quantitative variation. This was most evident with low levels of EBV DNA. No-template control-informed thresholding (ddpcRquant) mitigated false-positive/false-negative findings. The NRG-HN001 BamHI-W qPCR and laboratory-developed BamHI-W droplet dPCR offered higher sensitivity, lower limit of blank, higher precision at low plasma EBV DNA levels (≤1500 IU/mL), and higher overall agreement with clinical specimens versus single-copy qPCR/dPCR targets (EBNA-1/EBER). These data confirm the rationale for using the BamHI-W target to define prognostic thresholds and indicate that both qPCR and dPCR methods harmonized to the World Health Organization standard can provide the necessary analytical performance.

Recommendations for Epstein-Barr virus-based screening for nasopharyngeal cancer in high- and intermediate-risk regions.

A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)-based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.

Hominoid-specific sulcal variability is related to face perception ability.

The relationship among brain structure, brain function, and behavior is of major interest in neuroscience, evolutionary biology, and psychology. This relationship is especially intriguing when considering hominoid-specific brain structures because they cannot be studied in widely examined models in neuroscience such as mice, marmosets, and macaques. The fusiform gyrus (FG) is a hominoid-specific structure critical for face processing that is abnormal in individuals with developmental prosopagnosia (DPs)-individuals who have severe deficits recognizing the faces of familiar people in the absence of brain damage. While previous studies have found anatomical and functional differences in the FG between DPs and NTs, no study has examined the shallow tertiary sulcus (mid-fusiform sulcus, MFS) within the FG that is a microanatomical, macroanatomical, and functional landmark in humans, as well as was recently shown to be present in non-human hominoids. Here, we implemented pre-registered analyses of neuroanatomy and face perception in NTs and DPs. Results show that the MFS was shorter in DPs than NTs. Furthermore, individual differences in MFS length in the right, but not left, hemisphere predicted individual differences in face perception. These results support theories linking brain structure and function to perception, as well as indicate that individual differences in MFS length can predict individual differences in face processing. Finally, these findings add to growing evidence supporting a relationship between morphological variability of late developing, tertiary sulci and individual differences in cognition.

Modeling incomplete penetrance in long QT syndrome type 3 through ion channel heterogeneity: an in silico population study.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent because of incomplete penetrance of the mutation and variability of antiarrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 individuals with the O'Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation) and then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ΔKPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined by either the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-to-INa ratio are less susceptible. Furthermore, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that the balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.NEW & NOTEWORTHY An in silico population approach investigates the relationship between variability in ion channel expression and gain-of-function mutations in the voltage-gated sodium channel associated with the congenital disorder long QT syndrome type 3 (LQT3). We find that ion channel variability can contribute to incomplete penetrance of the mutation, with mutant-specific differences in ion channel conductances leading to susceptibility to proarrhythmic action potential duration prolongation or early afterdepolarizations.

Radiation Oncology Virtual Education Rotation (ROVER) 2.0 for Residents: Implementation and Outcomes.

The COVID-19 pandemic catalyzed the integration of a virtual education curriculum to support radiation oncologists in training. We report outcomes from Radiation Oncology Virtual Education Rotation (ROVER) 2.0, a supplementary virtual educational curriculum created for radiation oncology residents globally. A prospective cohort of residents completed surveys before and after the live virtual webinar sessions (pre- and post-surveys, respectively). Live sessions were structured as complex gray-zone cases across various core disease sites. Resident demographics and responses were summarized using means, standard deviations, and proportions. Nine ROVER sessions were held from October 2020 to June 2021. A total of 1487 registered residents completed the pre-survey, of which 786 attended the live case discussion and 223 completed post-surveys. A total of 479 unique radiation oncology residents (of which 95, n = 19.8%, were international attendees) from 147 institutions (national, n = 81, 55.1%; international, n = 66, 44.9%) participated in the sessions. There was similar participation across post-graduate year (PGY) 2 through 5 (range n = 86 to n = 105). Of the 122 unique resident post-surveys, nearly all reported learning through the virtual structure as "very easy" or "easy" (97.5%, n = 119). A majority rated the ROVER 2.0 educational sessions to be "valuable or "very valuable" (99.2%, n = 121), and the panelists-attendee interaction as "appropriate" (97.5%, n = 119). Virtual live didactics aimed at radiation oncology residents are feasible. These results suggest that the adoption of the ROVER 2.0 curricula may help improve radiation oncology resident education.

Clinician vs. imaging-based subthalamic nucleus deep brain stimulation programming.

INTRODUCTION: We sought to explore whether electrode visualization tools (EVT) can accurately predict the selection of optimal Deep Brain Stimulation (DBS) electrode contacts. METHODS: Twelve patients with Parkinson's disease (PD) undergoing STN-DBS at The Ohio State University were enrolled in a prospective analysis to evaluate the accuracy of EVT-based vs. standard DBS programming. EVTs were generated by the Surgical Information Sciences (SIS) system to develop a 3D model showing the implanted lead location relative to the STN. Then, imaging-based data were compared to the results of a standard monopolar review to evaluate concordance with clinical data and time spent selecting useable, non-useable, and borderline electrode contacts. RESULTS: A total of 18 DBS leads (n = 68 electrode contacts) were analyzed. The concordance between EVT and standard clinical programming expressed as the kappa coefficient was 0.65 (82.35% raw agreement) for non-useable, 0.52 for useable (64.71% raw agreement), and 0.52 for borderline (58.82% raw agreement). The average time spent determining whether an electrode contact was useable, non-useable, or borderline was 1.46 ± 0.76 min with EVT vs. 61.25 ± 17.47 with standard monopolar review. Eight different categories of side effects were identified, with facial pulling and speech difficulties being observed with the most frequency. The type of side effect observed was accurately predicted using EVT 90% of the time. CONCLUSIONS: This study demonstrates that next-generation EVT-based programming can be implemented into STN-DBS programming workflows with a considerable saving of time and effort spent in testing combinations of stimulation settings, particularly for the identification of non-useable electrode contacts.

Sulcal depth in prefrontal cortex: a novel predictor of working memory performance.

The neuroanatomical changes that underpin cognitive development are of major interest in neuroscience. Of the many aspects of neuroanatomy to consider, tertiary sulci are particularly attractive as they emerge last in gestation, show a protracted development after birth, and are either human- or hominoid-specific. Thus, they are ideal targets for exploring morphological-cognitive relationships with cognitive skills that also show protracted development such as working memory (WM). Yet, the relationship between sulcal morphology and WM is unknown-either in development or more generally. To fill this gap, we adopted a data-driven approach with cross-validation to examine the relationship between sulcal depth in lateral prefrontal cortex (LPFC) and verbal WM in 60 children and adolescents between ages 6 and 18. These analyses identified 9 left, and no right, LPFC sulci (of which 7 were tertiary) whose depth predicted verbal WM performance above and beyond the effect of age. Most of these sulci are located within and around contours of previously proposed functional parcellations of LPFC. This sulcal depth model outperformed models with age or cortical thickness. Together, these findings build empirical support for a classic theory that tertiary sulci serve as landmarks in association cortices that contribute to late-maturing human cognitive abilities.

Long-term learning transforms prefrontal cortex representations during working memory.

The role of the lateral prefrontal cortex (lPFC) in working memory (WM) is debated. Non-human primate (NHP) electrophysiology shows that the lPFC stores WM representations, but human neuroimaging suggests that the lPFC controls WM content in sensory cortices. These accounts are confounded by differences in task training and stimulus exposure. We tested whether long-term training alters lPFC function by densely sampling WM activity using functional MRI. Over 3 months, participants trained on both a WM and serial reaction time (SRT) task, wherein fractal stimuli were embedded within sequences. WM performance improved for trained (but not novel) fractals and, neurally, delay activity increased in distributed lPFC voxels across learning. Item-level WM representations became detectable within lPFC patterns, and lPFC activity reflected sequence relationships from the SRT task. These findings demonstrate that human lPFC develops stimulus-selective responses with learning, and WM representations are shaped by long-term experience, which could reconcile competing accounts of WM functioning.

Uncovering a tripartite landmark in posterior cingulate cortex.

Understanding brain structure-function relationships, and their development and evolution, is central to neuroscience research. Here, we show that morphological differences in posterior cingulate cortex (PCC), a hub of functional brain networks, predict individual differences in macroanatomical, microstructural, and functional features of PCC. Manually labeling 4511 sulci in 572 hemispheres, we found a shallow cortical indentation (termed the inframarginal sulcus; ifrms) within PCC that is absent from neuroanatomical atlases yet colocalized with a focal, functional region of the lateral frontoparietal network implicated in cognitive control. This structural-functional coupling generalized to meta-analyses consisting of hundreds of studies and thousands of participants. Additional morphological analyses showed that unique properties of the ifrms differ across the life span and between hominoid species. These findings support a classic theory that shallow, tertiary sulci serve as landmarks in association cortices. They also beg the question: How many other cortical indentations have we missed?

Posttreatment FDG-PET/CT Hopkins criteria predict locoregional recurrence after definitive radiotherapy for oropharyngeal squamous cell carcinoma.

BACKGROUND: Metabolic response assessment for oropharyngeal squamous cell carcinoma (OPSCC) aids in identifying locoregional persistence/recurrence (LRR). The Hopkins Criteria are a standardized qualitative response assessment system using posttreatment FDG-PET/CT. METHODS: We conducted a retrospective cohort study of patients with node-positive OPSCC treated with definitive (chemo)radiotherapy. We assessed Hopkins Criteria performance for LRR, then developed and validated a competing-risks model. RESULTS: Between 2004 and 2018, 259 patients were included with median follow-up of 43 months. The Hopkins Criteria sensitivity, specificity, negative predictive value, and accuracy were 68%, 88%, 95%, and 85%. The 36-month cumulative incidence of LRR was greater with positive scores (45% vs. 5%, HR 12.60, p < 0.001). PET/CTs performed ≤10 weeks after radiotherapy were associated with a four-fold increase in pathologically negative biopsies/surgeries (36% vs. 9%, p = 0.03). The AUC for LRR was 0.89 using a model integrating the Hopkins score. CONCLUSIONS: The Hopkins Criteria predict LRR with high accuracy for OPSCC response assessment.

Multiplex Epstein-Barr virus BALF2 genotyping detects high-risk variants in plasma for population screening of nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) exhibits unusual geographic restriction despite ubiquitous lifelong infection. Screening programs can detect most NPC cases at an early stage, but existing EBV diagnostics are limited by false positives and low positive predictive value (PPV), leading to excess screening endoscopies, MRIs, and repeated testing. Recent EBV genome-wide association studies (GWAS) suggest that EBV BALF2 variants account for more than 80% of attributable NPC risk. We therefore hypothesized that high-risk BALF2 variants could be readily detected in plasma for once-lifetime screening triage. METHODS: We designed and validated a multiplex genotyping assay to detect EBV BALF2 polymorphisms in human plasma. Targeted next-generation sequencing was used to validate this assay, conduct association studies with clinical phenotype, and longitudinally genotype plasma to assess within-host haplotype stability. We examined the association between NPC and BALF2 haplotypes in a large non-endemic population and three prior EBV GWAS. Finally, we estimated NPC mortality reduction, resource utilization, and cost-effectiveness of BALF2 variant-informed screening using a previously-validated cohort model. RESULTS: Following analytical validation, the BALF2 genotyping assay had 99.3% concordance with sequencing in a cohort of 24 NPC cases and 155 non-NPC controls. BALF2 haplotype was highly associated with NPC in this non-endemic population (I613V: odds ratio [OR] 7.9; V317M: OR 178.8). No other candidate BALF2 polymorphisms were significantly associated with NPC or hematologic disorders. Longitudinal genotyping revealed 97.8% within-host haplotype concordance, indicative of lifelong latent infection. In a meta-analysis of 755 NPC cases and 981 non-NPC controls, BALF2 I613V and V317M were significantly associated with NPC in both endemic and non-endemic populations. Modeled variant-informed screening strategies achieved a 46% relative increase in PPV with 7% decrease in effective screening sensitivity, thereby averting nearly half of screening endoscopies/MRIs among endemic populations in east/southeast Asia. CONCLUSIONS: EBV BALF2 haplotypes are temporally stable within hosts and can be readily detected in plasma via an inexpensive multiplex genotyping assay that offers near-perfect sequencing concordance. In endemic and non-endemic populations, I613V and V317M were highly associated with NPC and could be leveraged to develop variant-informed screening programs that mitigate false positives with small reductions in screening sensitivity.