Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Divvying up the pie: Tissue nutrient content is related to its parasite load.

The nutrient content of host resources can influence the abundance of parasites within an ecosystem, but linking specific nutrients in a host to the abundance of different parasite taxa remains a challenge. Here, we work to forge this link by quantifying the relationship between the nutrient content of specific infection sites and the abundance of multiple parasite taxa within the digestive tract of largemouth bass (Micropterus salmoides) collected from the Mississippi River. To generate a mechanistic understanding of these relationships, we tested four basic predictions: (1) the nutrient content of different host tissues (infection sites) varies within and across hosts, (2) the nutrient content of parasite genera differs from that of their host tissue(s), (3) the nutrient content of parasite genera differ from one another and (4) the nutrient content of host tissues is related to the nutrient content and abundance of parasite genera. We found support for each of these predictions. We found stoichiometric differences between the digestive tissues we examined. We also found that across hosts, intestine and pyloric caeca C:N ratios increased and %N decreased with fish condition factor. Both of the actively feeding parasitic genera we measured had lower C:N ratios compared to both their host tissue and other encysted/non-reproductive genera, suggesting the potential for N limitation of these parasites in the intestines or pyloric caeca of hosts. Consistent with this possibility, we found that the total number of actively feeding parasitic worms in the pyloric caeca increased with that tissue's N:P ratio (but was not related to host condition factor). Our results suggest that parasites encounter significant variation in nutrient content within and across hosts and that this variation may influence the abundance of actively feeding parasites. This work highlights the need for additional empirical comparisons of parasite stoichiometry across tissues and individual hosts.

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient's ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

Utility of Adult-Based Discoid Lateral Meniscus Diagnostic Criteria in a Pediatric Population.

Background: Commonly cited discoid lateral meniscus (DLM) imaging definitions are based on adult magnetic resonance imaging (MRI) measurements. This pathology commonly presents in pediatric populations; however, whether accepted adult measurements reliably apply to children and adolescents is unknown. Purpose/Hypothesis: This purposes of the study were to determine (1) the utility of applying adult-accepted MRI definitions of DLM to pediatric patients, (2) whether sex differences affect the applicability of the criteria, and (3) whether MRI magnet strength and/or tear presence affect MRI measurements for diagnosing DLM in pediatric patients. It was hypothesized that MRI criteria for DLM would be similar in adults and pediatric patients. Study Design: Case series; Level of evidence, 4. Methods: A total of 100 consecutive MRIs from pediatric patients with DLM were evaluated, with 91 scans included. Two study authors independently reviewed the MRIs, evaluating meniscal height and width on sagittal and coronal images, "bow tie signs" on sagittal images, tibial sagittal and coronal width, and tear presence. For analysis, MRI magnet strength was dichotomized into high (>1.5 T) and low (<1.5 T) groups. Results: The mean age of the patients at MRI evaluation was 12.3 ± 3.4 years; 51% of the patients were male, and 56% of the scans were of left knees. Included patients with DLM showed a mean of 3.68 bow tie signs, a sagittal total anterior to posterior meniscal width/tibial width ratio of 73%, a coronal meniscal width/tibial width ratio of 30%, and a coronal, transverse width of the lateral meniscus at the midportion of the meniscal body of 20.6 ± 7.7 mm. The MRI tesla strength of the images included in this study ranged from 0.3 to 3. It was determined that high- versus low-resolution MRI scans did not affect the inter- or intraobserver reliability of the MRI measurments (P > .05). However, several measurements showed improved intraclass correlation coefficients with increased tesla strength. Conclusion: This study confirms that pediatric patients with DLM, diagnosed by board-certified pediatric sports medicine orthopaedic surgeons, have measurements on MRI consistent with adult DLM diagnostic criteria. This finding held true regardless of sex or MRI tesla strength. Pediatric patients with DLM had >3 bow tie signs, >70% sagittal tibial plateau coverage, >14 mm coronal width, and >20% coronal tibial plateau coverage on MRI.

Prevalence of autoimmune diseases in patients with sickle cell disease: a single center retrospective analysis.

Not available.

The Royal College of Ophthalmologists' National ophthalmology database study of cataract surgery: Report 14, cohort analysis - the impact of CapsuleGuard® utilisation on cataract surgery posterior capsule rupture rates.

BACKGROUND/OBJECTIVES: The aim of this study was to investigate whether the use of the silicone tipped irrigation/aspiration (I/A) handpiece CapsuleGuard® (Bausch + Lomb, Laval, Canada) reduced rates of posterior capsule rupture (PCR) during cataract surgery. METHODS: Royal College of Ophthalmologists' National Ophthalmology Database (NOD) Cataract Audit data from 01/04/2010 and 31/03/2021 and Bausch + Lomb sales figures were combined to identify centres participating in national cataract audit who have routinely adopted the silicone tipped I/A handpiece, CapsuleGuard®. Data were included only from centres with eligible cataract operations recorded on the NOD both before and after adopting CapsuleGuard®. Review of the literature was undertaken to estimate the proportion of PCR that occurs during I/A, to evaluate the impact of adoption of CapsuleGuard® on PCR occurring in this phase of surgery. RESULTS: Within the study period, 267 371 eligible cataract operations were performed in 14 centres with >50 eligible operations both before and after adopting CapsuleGuard®. Within centres adopting CapsuleGuard®, the rate of PCR occurrence reduction was 16.4%. Before and after the adoption of CapsuleGuard® the median change of PCR was 21.7% reduction (IQR: 4.8% to 37.7% reduction). CONCLUSIONS: A reduction in the rate of PCR was seen after regular adoption of CapsuleGuard® during cataract operations. Review of published studies attributing PCR to various components of the cataract operation suggest around 25% of PCR may occur during I/A; adoption of CapsuleGuard may, therefore, be associated with avoidance of a substantial proportion of the PCR during that phase of surgery.

The Royal College of Ophthalmologists' National Ophthalmology Database Study of Cataract Surgery: Report 13, monitoring post-cataract surgery endophthalmitis rates-the rule of X.

BACKGROUND: Cataract surgical safety has improved over recent decades, with endophthalmitis rates before 2006 typically 0.13-0.15% compared with the most recent UK national estimate of 0.02%. There remains, however, substantial variation in reported rates from different centres. Due to the low event rate, this disparity may not be noticed and opportunities to improve therefore be missed. We propose a method of monitoring post-cataract endophthalmitis rates that would help centres with higher rates identify this. METHODS: A statistical tool, available to download or use online, permits comparison of local endophthalmitis rate with the estimated UK rate of 0.02%. Centres are encouraged to maintain a register of endophthalmitis cases, and when the number reaches a threshold (X cases), either in a certain time period or in a fixed number of procedures, then the centre can consider itself as an outlier and trigger local investigations to improve infection control. RESULTS: Example outputs are offered, such as for a unit doing 5000 cataracts annually, a value of X is suggested such that the third case of endophthalmitis (X = 3) in a 12-month period would give 85% confidence, the fourth case 90% confidence and the fifth case 95% confidence that the true endophthalmitis rate for that unit was higher than the national average. CONCLUSIONS: This statistical tool provides a basis for units to set a threshold number of cases of endophthalmitis within a given period that would trigger local processes, thus helping inform local monitoring processes for this rare but potentially catastrophic complication of cataract surgery.

Selection pressures on evolution of ribonuclease H explored with rigorous free-energy-based design.

Understanding natural protein evolution and designing novel proteins are motivating interest in development of high-throughput methods to explore large sequence spaces. In this work, we demonstrate the application of multisite λ dynamics (MSλD), a rigorous free energy simulation method, and chemical denaturation experiments to quantify evolutionary selection pressure from sequence-stability relationships and to address questions of design. This study examines a mesophilic phylogenetic clade of ribonuclease H (RNase H), furthering its extensive characterization in earlier studies, focusing on E. coli RNase H (ecRNH) and a more stable consensus sequence (AncCcons) differing at 15 positions. The stabilities of 32,768 chimeras between these two sequences were computed using the MSλD framework. The most stable and least stable chimeras were predicted and tested along with several other sequences, revealing a designed chimera with approximately the same stability increase as AncCcons, but requiring only half the mutations. Comparing the computed stabilities with experiment for 12 sequences reveals a Pearson correlation of 0.86 and root mean squared error of 1.18 kcal/mol, an unprecedented level of accuracy well beyond less rigorous computational design methods. We then quantified selection pressure using a simple evolutionary model in which sequences are selected according to the Boltzmann factor of their stability. Selection temperatures from 110 to 168 K are estimated in three ways by comparing experimental and computational results to evolutionary models. These estimates indicate selection pressure is high, which has implications for evolutionary dynamics and for the accuracy required for design, and suggests accurate high-throughput computational methods like MSλD may enable more effective protein design.

Gross and Histologic Placental Abnormalities Associated With Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. STUDY DESIGN: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. RESULTS: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P = .01). CONCLUSION: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

A tip-predominant distribution of villous intraepithelial lymphocytes is not specific to celiac disease in children with Marsh I lesions.

OBJECTIVES: To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). METHODS: Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. RESULTS: Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P = .31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P = .11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P = .80) half of each villus, respectively. CONCLUSIONS: The distribution of IELs in Marsh I lesions is not specific for CeD.

[Care for dying patients in the emergency department]. / Versorgung sterbender PatientInnen in der Notaufnahme.

Patients at the end of life frequently receive care in emergency departments. Emergency physicians are faced with caring for both patients who pass away suddenly following an acute illness or injury despite rescue efforts, as well as those who are dying from a chronic condition or high age. To provide proper care and respect the patients' wishes regarding invasive treatments, emergency physicians should be knowledgeable about advance directives and have effective communication skills when delivering bad news to patients and their family. In addition, a basic understanding of palliative care is necessary for physicians to effectively manage symptoms.

Cross-cultural differences in self-reported and behavioural emotional self-awareness between Japan and the UK.

OBJECTIVE: How we express and describe emotion is shaped by sociocultural norms. These sociocultural norms may also affect emotional self-awareness, i.e., how we identify and make sense of our own emotions. Previous studies have found lower emotional self-awareness in East Asian compared to Western samples using self-report measures. However, studies using behavioural methods did not provide clear evidence of reduced emotional self-awareness in East Asian groups. This may be due to different measurement tools capturing different facets of emotional self-awareness. RESULTS: To investigate this issue further, we compared the emotional self-awareness of Japanese (n = 29) and United Kingdom (UK) (n = 43) adults using the self-report Toronto Alexithymia Scale (TAS-20), alongside two behavioural measures - the Emotional Consistency Task (EC-Task) and the Photo Emotion Differentiation Task (PED-Task). Japanese adults showed higher TAS-20 scores than UK participants, indicating greater self-reported difficulties with emotional self-awareness. Japanese participants also had lower EC-Task scores than UK adults, indicating a lower ability to differentiate between levels of emotional intensity. PED-Task performance did not show clear group differences. These findings suggest that cross-cultural differences in emotional self-awareness vary with the task used, because different tasks assess distinct aspects of this ability. Future research should attempt to capture these different aspects of emotional self-awareness.

Direct measurement of the structural change associated with amorphous solidification using static scattering of coherent radiation.

In this paper, we demonstrate that the weak temperature dependence of the structure factor of supercooled liquids, a defining feature of the glass transition, is a consequence of the averaging of the scattering intensity due to angular averaging. We show that the speckle at individual wavevectors, calculated from a simulated glass former, exhibits a Debye-Waller factor with a sufficiently large temperature dependence to represent a structural order parameter capable of distinguishing liquid from glass. We also extract from the speckle intensities a quantity proportional to the variance of the local restraint, i.e., a direct experimental measure of the amplitude of structural heterogeneity.

The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors.

α5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the ß-carboline, methyl 6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.

Barriers and Facilitators to Optimal Fluoride Varnish Application.

OBJECTIVE: National guidelines recommend that all children under age six receive fluoride varnish (FV) in medical settings. However, application rates remain low. This study aimed to update understanding of barriers and facilitators to guideline concordant FV application. METHODS: We conducted virtual semi-structured interviews with a purposive sample (eg, FV application rates, geographic location, practice size and type) of pediatric primary care clinicians and medical assistants in Massachusetts between February 1 and June 30, 2022. The Consolidated Framework for Implementation Research (CFIR) served as the study's theoretical framework and data were analyzed using a modified grounded theory approach. RESULTS: Of the 31 participants, 90% identified as White and 81% as female. Major themes, which linked to four CFIR domains, included: variation in perceived adequacy of reimbursement; differences in FV application across practice types; variation in processes, protocols, and priorities; external accountability for quality of care; and potential levers for change. Important subthemes included challenges for small practices; role of quality measures in delivering guideline-concordant preventive oral health care; and desire for preventive care coordination with dentists. CONCLUSIONS: This study suggests that potential barriers and facilitators to guideline concordant FV application exist at multiple levels that may warrant further study. Examples include testing the effectiveness of quality measures for FV application and testing strategies for implementing consistent processes and protocols for improving FV application rates.

Reliability of whole mount radical prostatectomy histopathology as the ground truth for artificial intelligence assisted prostate imaging.

The development of artificial intelligence-based imaging techniques for prostate cancer (PCa) detection and diagnosis requires a reliable ground truth, which is generally based on histopathology from radical prostatectomy specimens. This study proposes a comprehensive protocol for the annotation of prostatectomy pathology slides. To evaluate the reliability of the protocol, interobserver variability was assessed between five pathologists, who annotated ten radical prostatectomy specimens consisting of 74 whole mount pathology slides. Interobserver variability was assessed for both the localization and grading of PCa. The results indicate excellent overall agreement on the localization of PCa (Gleason pattern ≥ 3) and clinically significant PCa (Gleason pattern ≥ 4), with Dice similarity coefficients (DSC) of 0.91 and 0.88, respectively. On a per-slide level, agreement for primary and secondary Gleason pattern was almost perfect and substantial, with Fleiss Kappa of .819 (95% CI .659-.980) and .726 (95% CI .573-.878), respectively. Agreement on International Society of Urological Pathology Grade Group was evaluated for the index lesions and showed agreement in 70% of cases, with a mean DSC of 0.92 for all index lesions. These findings show that a standardized protocol for prostatectomy pathology annotation provides reliable data on PCa localization and grading, with relatively high levels of interobserver agreement. More complicated tissue characterization, such as the presence of cribriform growth and intraductal carcinoma, remains a source of interobserver variability and should be treated with care when used in ground truth datasets.

A multimodal pain protocol for treatment of vaso-occlusive crisis in patients with sickle cell disease: Implementation and evaluation.

OBJECTIVES: Pain management during a vaso-occlusive crisis (VOC) for patients with sickle cell disease (SCD) remains a major challenge and strongly depends on opioids. We developed a multimodality pain protocol for rapid, opioid-sparing pain treatment of VOC and evaluated its feasibility. METHODS: Patients were included for evaluation if they were ≥18 years, diagnosed with SCD and visited the emergency department (ED) because of VOC between July 2018 and December 2020. Primary evaluation outcome was the feasibility of multimodal pain analgesia (i.e., the use of at least two analgesics with different underlying mechanisms of action). RESULTS: A total of 131 SCD patients visited the ED because of VOC with a total of 550 ED presentations, of which 377 were eventually hospitalised. A total of 508 (92.4%) ED presentations and 374 (99.2%) hospital admissions received multimodal pain treatment. Time to first administration of an opioid was median [IQR] 34.0 [21.0-62.0] minutes. CONCLUSION: The implementation of a pain protocol using multimodal analgesia for VOC in patients with SCD appeared to be feasible and facilitated rapid administration of opioids. Controlled trials are needed to investigate the effectiveness of multimodal analgesia on pain and should focus on patient reported outcome measures.

Intimately tracking NO2 pollution over the New York City - Long Island Sound land-water continuum: An integration of shipboard, airborne, satellite observations, and models.

Nitrogen dioxide (NO2) pollution remains a serious global problem, particularly near highly populated urbanized coasts that face increasing challenges with climate change. Yet, the combined impact of urban emissions, pollution transport, and complex meteorology on the spatiotemporal dynamics of NO2 along heterogeneous urban coastlines remains poorly characterized. Here, we integrated measurements from different platforms - boats, ground-based networks, aircraft, and satellites - to characterize total column NO2 (TCNO2) dynamics across the land-water continuum in the New York metropolitan area, the most populous area in the United States that often experiences the highest national NO2 levels. Measurements were conducted during the 2018 Long Island Sound Tropospheric Ozone Study (LISTOS), with a main goal to extend surface measurements beyond the coastline - where ground-based air-quality monitoring networks abruptly stop - and over the aquatic environment where peaks in air pollution often occur. Satellite TCNO2 from TROPOMI correlated strongly with Pandora surface measurements (r = 0.87, N = 100) both over land and water. Yet, TROPOMI overall underestimated TCNO2 (MPD = -12%) and missed peaks in NO2 pollution caused by rush hour emissions or pollution accumulation during sea breezes. Aircraft retrievals were in excellent agreement with Pandora (r = 0.95, MPD = -0.3%, N = 108). Stronger agreement was found between TROPOMI, aircraft, and Pandora over land, while over water satellite, and to a lesser extent aircraft, retrievals underestimated TCNO2 particularly in the highly dynamic New York Harbor environment. Combined with model simulations, our shipborne measurements uniquely captured rapid transitions and fine-scale features in NO2 behavior across the New York City - Long Island Sound land-water continuum, driven by the complex interplay of human activity, chemistry, and local scale meteorology. These novel datasets provide critical information for improving satellite retrievals, enhancing air quality models, and informing management decisions, with important implications for the health of diverse communities and vulnerable ecosystems along this complex urban coastline.

Dopaminergic and norepinephrinergic modulation of endogenous event-related potentials: A systematic review and meta-analysis.

Event-related potentials (ERPs) represent the cortical processing of sensory, motor or cognitive functions invoked by particular events or stimuli. A current theory posits that the catecholaminergic neurotransmitters dopamine (DA) and norepinephrine (NE) modulate a number of endogenous ERPs during various cognitive processes. This manuscript aims to evaluate a leading neurotransmitter hypothesis with a systematic overview and meta-analysis of pharmacologic DA and NE manipulation of specific ERPs in healthy subjects during executive function. Specifically, the frontally-distributed P3a, N2, and Ne/ERN (or error-related negativity) are supposedly modulated primarily by DA, whereas the parietally-distributed P3b is thought to be modulated by NE. Based on preceding research, we refer to this distinction between frontally-distributed DA-sensitive and parietally-distributed NE-sensitive ERP components as the Extended Neurobiological Polich (ENP) hypothesis. Our systematic review and meta-analysis indicate that this distinction is too simplistic and many factors interact with DA and NE to influence these specific ERPs. These may include genetic factors, the specific cognitive processes engaged, or elements of study design, i.e. session or sequence effects or data-analysis strategies.