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In the past 2 decades, health care has witnessed technological and pharmacological advancements leading to innovations in diabetes management. Despite these advances, published guidelines, and treatment algorithms, most people with diabetes remain above glycemic targets. Thus, the authors designed a novel care model aimed at improving several causative factors, including therapeutic inertia, limited access to endocrinology and cardiovascular specialists, time constraints, and complexity in incorporating clinical practice guidelines. The model involves collaboration between the diabetes specialty team and primary care providers (PCPs). The intervention reviewed uncontrolled diabetes data and the patient's electronic medical record (EMR) and sent personalized, evidence-based recommendations to the provider using the task function in the EMR. Other services (eg, diabetes education) were utilized to optimize patient care to achieve optimal glycemic targets and address cardiometabolic risk. The overall mean hemoglobin A1c (HbA1c) decreased pre-post intervention by almost 1%, and 52.1% (347 of 666) of the cohort had ≥-0.5% change in HbA1c post-intervention. All pathways exhibited a decrease in HbA1c. Team-based approaches to managing diabetes patient care were the most effective. The interventions effectively utilized the resources across the health system without placing additional load or burden on primary care or diabetes specialty care teams. In the future, the authors hope to address the limitations of the current gap caused by increasing diabetes numbers, decreasing availability of PCPs and endocrinologists, and fee-for-service models using the innovative specialty consultant-primary care connection and knowledge exchange offered by this novel model, which can only be sustained with payer's support.

Objective: As of January 26, 2022, the United States Medical Licensing Examination(USMLE) Step 1 score reporting will be changed from a numeric scoring system to pass/fail. Although the new scoring policy is expected to benefit medical students, there is concern that it will also amplify preexisting disadvantages and worsen disparities for students applying in the already-competitive plastic surgery match. Whether the reporting change will tangibly benefit applicants to plastic surgery has yet to be elucidated., Design: A cross-sectional survey was distributed to medical students and graduates via social media platforms. Data were analyzed using Student t test and Chi-squared statistic, with an alpha level set at 0.05., Setting: Data collection and analysis was performed at Johns Hopkins University School of Medicine., Participants: This study included a sample of 120 American Medical Trainees (AMTs) and International Medical Trainees (IMTs) who are interested in plastic surgery., Results: The plurality of respondents were against the new Step 1 score reporting (AMT: 40.7%; IMT: 44.3%), but differences existed between AMTs when compared to IMTs, especially regarding opinions about the reporting change on stress levels and competitiveness of highly competitive specialties. Regardless of training status, respondents felt that the pass/fail scoring system would increase their likelihood to engage with more research, dual apply, prioritize studying for Step 2 CK, and consider a dedicated research year., Conclusions: While a pass/fail reporting system for Step 1 may alleviate some stress for medical trainees, other issues arise that may perpetuate disparities and bias against students with little resources in the field of plastic surgery. Residency programs should offer anticipatory guidance regarding prioritization of aspects of application to ease this psychosocial and financial pressure, as well as help students reorganize their constrained time., (Copyright © 2022 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: The research agenda in pediatric hospital medicine has seldom considered the perspectives of young people, parents and caregivers, and health care professionals. Their perspectives may be useful in identifying questions on topics for research., Objective: To prioritize unanswered research questions in pediatric hospital medicine from the perspectives of young people, parents/caregivers, and health care professionals., Design, Setting, and Participants: Between August 4, 2020, and August 19, 2021, two online surveys and a virtual workshop were conducted, using modified Delphi technique and nominal group technique. Young people, parents/caregivers, and health care professionals with experiences in pediatric hospital medicine in Canada were included., Interventions: The established James Lind Alliance Priority Setting Partnership method was used. In phase 1, a survey collected unanswered questions regarding pediatric hospital medicine via 3 open-ended questions. Survey responses were used to develop summary questions that went through an evidence-checking process. Unanswered questions were brought to a phase 2 interim prioritization survey. The top 10 unanswered research questions in pediatric hospital medicine were established at the final priority setting workshop., Main Outcomes and Measures: Survey responses, top 10 research questions., Results: The phase 1 survey was completed by 188 participants (148 of 167 [89%] females; 17 of 167 [10%] males; mean [SD] age, 39.5 [12.4] years) and generated 495 unanswered research questions and comments, of which 58 were deemed out of scope. The remaining 437 responses were grouped into themes (eg, communication, shared decision-making, health service delivery, and health service management) and then refined to 75 unanswered research questions. Of these 75, only 4 questions had sufficient evidence. To make the number of questions in phase 2 manageable, 21 questions submitted by only 1 respondent were eliminated. Fifty unanswered research questions were included in the phase 2 survey, which was completed by 201 participants (165 of 186 [89%] females; 19 of 186 [10%] males; mean [SD] age, 40.0 [11.0] years). A short list of 16 questions-the top 10 questions from patient partners (youths, parents/caregivers) and clinicians-was presented at the final priority setting workshop and the top 10 questions were prioritized. The top 10 questions focused on the care of special inpatient populations (eg, children with medical complexity), communication, shared decision-making, support strategies in the hospital, mental health supports, shortening length of stay, and supporting Indigenous patients, parents/caregivers, and families., Conclusions and Relevance: This patient-oriented pediatric hospital medicine priority setting partnership identified the most important unanswered research questions focused on the care of children in the hospital. These questions provide a possible roadmap for research on areas deemed important to young people, parents/caregivers, and clinicians.

Objectives: To evaluate the growth and variation of electronic consultation, or e-consult, use in the Veterans Health Administration (VHA) across regions and specialties., Study Design: Observational cohort study using administrative data of all veterans who received an e-consult for 41 specialties across 1269 VHA medical centers and associated clinical sites from January 1, 2012, through December 31, 2018., Methods: Assessments included (1) the number and characteristics of all e-consults, (2) growth of e-consult use, (3) e-consults as a proportion of all consults by region and by specific specialty, (4) need for an in-person visit with the same specialty within 12 months after an e-consult, and (5) potential miles of driving saved for patients and mileage reimbursement costs avoided for VHA due to e-consult use., Results: Over the 7-year study period, VHA providers completed 3,117,998 e-consults (5.5% of all specialty consults). e-Consults increased by 309% for all specialties. By 2018, for 16 of 41 specialties, e-consults accounted for greater than 10% of all consults. Overall, 21.5% of e-consults resulted in an in-person visit with the same specialty within 12 months. On average, each e-consult resulted in approximately 84.3 (SD, 89.9; interquartile range, 25.1-115.0) miles in driving saved, equating to potential driving reimbursement savings of $46 million., Conclusions: Use of e-consults in the VHA grew substantially between 2012 and 2018, with variability across specialties. In-person follow-up after an e-consult was low, suggesting that e-consults may substitute for in-person visits and reduce considerable patient travel burden.

The infectious pandemics and epidemics of the past 200 years have caused millions of deaths. However, these devastating events have also led to creative thinking, imaginative experimentation and the evolution of medical care. As a result, the history of critical care medicine is entwined with the story of these global disasters. This article will take case studies from recent pandemics and epidemics and examine their impact on the development of anaesthesia and intensive care medicine.

From September-December 2017, the Mathematical Biosciences Institute at Ohio State University hosted a series of workshops on control theory in biology and medicine, including workshops on control and modulation of neuronal and motor systems, control of cellular and molecular systems, control of disease / personalized medicine across heterogeneous populations, and sensorimotor control of animals and robots. This special issue presents tutorials and research articles by several of the participants in the MBI workshops.

Objective Medically complex patients experience fragmented health care compounded by long wait times. The MedREACH program was developed to improve access and overall system experience for medically complex patients. Program description MedREACH is a novel primary-tertiary care collaborative demonstration program that features community nursing outreach, community specialist outreach, and a multi-specialty consultation clinic. Methods All 179 patients, referring primary care clinicians, and specialists involved were eligible to participate. Patient and clinician feedback were elicited by feedback surveys. Process measures were evaluated by participant retrospective chart reviews. Community nursing outreach patients completed the Goal Attainment Scale. Results Forty-eight patients and 22 clinicians consented to the feedback survey. About 75% of patients were seen within 2 weeks of referral. Patients spent an average of 3, 1.63, and 1.2 visits with the nursing outreach, multi-specialty clinic, and specialist outreach, respectively. Patients indicated a better medical experience, health enablement, and goals attainment. Family physicians felt more supported in the community management of medically complex patients and, overall, physicians felt MedREACH could improve collaborative care for medically complex patients. Qualitative analysis of clinician responses identified the need for increased mental health services. Discussion MedREACH demonstrates a patient-centered link between primary and tertiary care that could improve health care access and overall experience.

Objective: The past decade has seen significant paradigm shifts in the management of many retinal diseases. The goal of this study is to assess the effect these advances have had on the number of retinal specialists, and the differences in output between medical and surgical specialists at the population level., Design: Population-based analysis of surgical and medical retina therapeutic and diagnostic procedures among all ophthalmologists in Ontario, Canada, from April 1999 to March 2012., Participants: This study included all ophthalmologists with an Ontario license and receiving remuneration from the Ontario Health Insurance Plan (OHIP). Ophthalmologists were categorized as a surgical or medical retina specialist based on the type and volume of retina-specific procedures performed each year., Methods: The IntelliHealth database operated by the Ministry of Health and Long Term Care was used to obtain anonymized physician services, which has excellent accuracy for procedure performance., Results: The number of retina specialists grew from 9.7% to 14.4% of the ophthalmology workforce. The proportion of late-career retina specialists (>25 years since graduation) doubled but had no influence on procedure output. Almost all retina specialists (90%) practice in the region they graduated medical school, and most (65%) practice in counties with a population greater than 400,000 people. Over the study period, the mean number of photocoagulation and fluorescein angiography performed was significantly higher among surgical retina specialists. Scleral buckling declined by 55% over the study period, whereas the number of pars plana vitrectomies grew by 49%., Conclusions: The retina subspecialty is a growing area of ophthalmology and is mainly located in urban centres. There has been a dramatic shift in the types of procedures performed to treat medical and surgical diseases over the past decade. To our knowledge, this is the first study to quantify differences in diagnostic and procedure performance between the medical and surgical retina subspecialties., (Copyright © 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: There is a disparity of availability and cost of drugs in the community for palliative care patients through the Pharmaceutical Benefits Scheme (PBS) compared to those available to inpatients in public hospitals., Methods: The Joint Therapeutics Committee of the Australian and New Zealand Society of Palliative Medicine, Palliative Care Australia and the Clinical Oncological Society of Australia surveyed palliative care practitioners in Australia to compile a list of drugs they considered essential., Results: Drugs nominated generally had good levels of evidence for use in palliative care, although many practitioners still used some without evidence of benefit., Discussion: We are now working with the Commonwealth Department of Health and Ageing to agree on a list of drugs for specific palliative care indications. As a result, the first ever section in the PBS for a specific patient population has been created. There is a need for high quality studies in palliative care to determine the best drugs to add to the list.

Open day activities rarely give applicants a real sense of the practical and intellectual work that goes on in university chemistry departments. We devised an experiment for year 13 (age 17-18) students based on the size-dependent colours of gold nanoparticles and linked this to current research in diagnostic medicine. The experience was designed to demonstrate the benefits of nanotechnology but it did so through the allure of gold. (Contains 5 figures and 1 table.)

There is increasing interest in neurobiological methods for investigating the shared representation of action perception and production in early development. We explored the extent and regional specificity of EEG desynchronization in the infant alpha frequency range (6-9 Hz) during action observation and execution in 14-month-old infants. Desynchronization during execution was restricted to central electrode sites, while action observation was associated with a broader desynchronization across frontal, central, and parietal regions. The finding of regional specificity in the overlap between EEG responses to action execution and observation suggests that the rhythm seen in the 6-9 Hz range over central sites in infancy shares certain properties with the adult mu rhythm. The magnitude of EEG desynchronization to action perception and production appears to be smaller for infants than for adults and older children, suggesting developmental change in this measure.

There is a good deal of evidence that observing the actions of other people is associated with activation of the observer's motor system, which may reflect involvement of the mirror neuron system (MNS) in certain aspects of action processing in humans. Furthermore, variation in the extent of this activation appears to be partly dependent on individuals' experience with performing the observed actions. However, very little work has examined the processes through which the observation of unfamiliar actions--which are not in an observer's motor repertoire--might become associated with MNS activation. In the current study we examined differences in EEG desynchronization in alpha-range bands during action observation following very brief imitative experience with the observed actions, which were novel drawing movements. Compared to carrying out unrelated actions, brief imitative experience was specifically associated with a significantly larger desynchronization in the 11-13 Hz band at mid-frontal sites (F3 and F4) when a previously imitated action was viewed again. In addition, higher fidelity of imitation was significantly correlated with greater bilateral desynchronization of the lower mu band (8-10 Hz) at central sites (C3 and C4) during subsequent observation of the previously imitated action. Our findings point to the involvement of frontal cortical processing and the MNS in the early stages of imitative learning. (Contains 5 figures.)

The field of tissue engineering/regenerative medicine combines the quantitative principles of engineering with the principles of the life sciences toward the goal of reconstituting structurally and functionally normal tissues and organs. There has been relatively little application of tissue engineering efforts toward the organs of speech, voice, and hearing. The present manuscript describes a study that was conducted in which a biologic scaffold derived from porcine (pig) extracellular matrix (ECM) was used to repair the defect following a hemilaryngectomy procedure in dogs. The ECM-augmented repair was compared with a control standard strap muscle (STM) procedure. The animals were sacrificed after 24 weeks at which time anatomic and histologic analyses were conducted. The ECM repair resulted in a macroscopic and microscopic reconstruction of laryngeal tissue that was superior to that observed with the STM procedure. The importance of regenerated tissue having the same structural and functional characteristics of native tissue is emphasized. A discussion of the mechanisms of ECM remodeling is presented along with the implications of such remodeling in the repair of laryngeal structures. (Contains 7 figures.)

Abstract Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the left primary motor cortex, on modulation of resting state electroencephalography (rsEEG) power. We first conducted hypothesis-driven region-of-interest (ROI) analyses examining changes in alpha (8–12 Hz) and beta (13–21 Hz) bands over the left and right motor cortex. Additionally, we performed data-driven whole-brain analyses across a wide range of frequencies (1–50 Hz) and all electrodes. Finally, we assessed the reliability of TBS effects across two sessions approximately 1 month apart. None of the protocols produced significant group-level effects in the ROI. Whole-brain analysis revealed that cTBS significantly enhanced relative power between 19 and 43 Hz over multiple sites in both hemispheres. However, these results were not reliable across visits. There were no significant differences between EEG modulation by active and sham TBS protocols. Between-visit reliability of TBS-induced neuromodulatory effects was generally low-to-moderate. We discuss confounding factors and potential approaches for improving the reliability of TBS-induced rsEEG modulation.

Abstract Coral reefs are iconic ecosystems that support diverse, productive communities in both shallow and deep waters. However, our incomplete knowledge of cold-water coral (CWC) niche space limits our understanding of their distribution and precludes a complete accounting of the ecosystem services they provide. Here, we present the results of recent surveys of the CWC mound province on the Blake Plateau off the U.S. east coast, an area of intense human activity including fisheries and naval operations, and potentially energy and mineral extraction. At one site, CWC mounds are arranged in lines that total over 150 km in length, making this one of the largest reef complexes discovered in the deep ocean. This site experiences rapid and extreme shifts in temperature between 4.3 and 10.7 °C, and currents approaching 1 m s−1. Carbon is transported to depth by mesopelagic micronekton and nutrient cycling on the reef results in some of the highest nitrate concentrations recorded in the region. Predictive models reveal expanded areas of highly suitable habitat that currently remain unexplored. Multidisciplinary exploration of this new site has expanded understanding of the cold-water coral niche, improved our accounting of the ecosystem services of the reef habitat, and emphasizes the importance of properly managing these systems.

Abstract Animal venoms are rich sources of neuroactive compounds, including anti-inflammatory, antiepileptic, and antinociceptive molecules. Our study identified a protonectin peptide from the wasp Parachartergus fraternus' venom using mass spectrometry and cDNA library construction. Using this peptide as a template, we designed a new peptide, protonectin-F, which exhibited higher antinociceptive activity and less motor impairment compared to protonectin. In drug interaction experiments with naloxone and AM251, Protonectin-F's activity was decreased by opioid and cannabinoid antagonism, two critical antinociception pathways. Further experiments revealed that this effect is most likely not induced by direct action on receptors but by activation of the descending pain control pathway. We noted that protonectin-F induced less tolerance in mice after repeated administration than morphine. Protonectin-F was also able to decrease TNF-α production in vitro and modulate the inflammatory response, which can further contribute to its antinociceptive activity. These findings suggest that protonectin-F may be a potential molecule for developing drugs to treat pain disorders with fewer adverse effects. Our results reinforce the biotechnological importance of animal venom for developing new molecules of clinical interest.

Abstract Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one’s present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance—mindfulness and perspective-taking—can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1, N = 108 participants, 5492 observations; Study 2, N = 218 participants, 9994 observations). Study 2 presents a close replication with a fully remote delivery during the COVID-19 pandemic. During weeks when they received twice-a-day intervention reminders, individuals in the distancing interventions reported drinking less frequently than on control weeks—directionally in Study 1, and significantly in Study 2. Intervention reminders reduced drinking frequency but did not impact amount. We find that smartphone-based mindfulness and perspective-taking interventions, aimed to create psychological distance, can change behavior. This approach requires repeated reminders, which can be delivered via smartphones.

Babesiosis is a globally distributed parasitic infection caused by intraerythrocytic protozoa. The full spectrum of neurologic symptoms, the underlying neuropathophysiology, and neurologic risk factors are poorly understood. Our study sought to describe the type and frequency of neurologic complications of babesiosis in a group of hospitalized patients and assess risk factors that might predispose patients to neurologic complications. We reviewed medical records of adult patients who were admitted to Yale-New Haven Hospital, New Haven, Connecticut, USA, during January 2011–October 2021 with laboratory-confirmed babesiosis. More than half of the 163 patients experienced >1 neurologic symptoms during their hospital admissions. The most frequent symptoms were headache, confusion/delirium, and impaired consciousness. Neurologic symptoms were associated with high-grade parasitemia, renal failure, and history of diabetes mellitus. Clinicians working in endemic areas should recognize the range of symptoms associated with babesiosis, including neurologic.

Abstract Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called “non-responders”. We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.

Abstract Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Abstract Measurement and monitoring of pH are essential in both the industry and academia. It is therefore important to continue developing novel, low-cost pH sensors that provide increased accuracy over long periods of time. Particularly promising are sensors based on materials that show pH-dependent fluorescence intensity (FI) and lifetime (FL). Carbon dots (CDs) are emerging as promising candidates because of their low cost, ease of manufacturing, low toxicity, and negligible photobleaching. However, little has been done to quantify the FI and FL values of CDs. Here we report the characterisation of the pH-dependent FI and FL of four novel solvothermal synthesised CDs. The fifth CD is used as a reference sample and was synthesised following a published synthesis. The precursors for the CDs include disperse blue 1 dye, phloroglucinol, m-phenylenediamine (m-PD), N, and N-dimethylformamide (DMF). The average diameter size of the CDs ranges from 1.5 to 15 nm. An excitation wavelength of 452 nm with a bandwidth of 45 nm was used to quantify the fluorescence in the pH range 5–9. Three CDs show a decreasing trend in FI with pH, while two CDs show an increasing trend. None of the CDs shows strong FL dependence. The FL changes around 0.5 ± 0.2 ns across the tested pH range. We suggest that the differences in the fluorescence trends can be attributed to the precursors chosen for synthesising the CDs.

Abstract Objective Zambia has embarked on improving the diagnostic capacity by setting up high throughput and accurate machines in the testing process and introduction of dried blood spot (DBS) as a sample type. This was a cross sectional study to verify dried blood spot as a sample type for HIV viral load and early infant diagnosis (EID) on Hologic Panther platform and Evaluate the analytical performance (precision, linearity and measurement of uncertainty) of the Hologic Panther. Results The specificity and sensitivity of EID performance of Aptima Quant Dx assay on Hologic panther machine against the gold standard machine COBAS Taqman (CAP/CTM) was 100% with an overall agreement of 100%. The quantitative HIV Viral Load (VL) accuracy had a positive correlation of (0.96) obtained against the gold standard (plasma samples) run on COBAS4800 platform. Analytical performance of the Hologic panther machine was evaluated; Precision low positive repeatability 3.50154 and within lab 2.268915 at mean 2.88 concentration and precision high positive repeatability 1.116955 and within lab 2.010677 at mean 5.09 concentration were obtained confirming manufacturers claims. Uncertainty of measurement for this study was found to be ± 71 copies/ml. Linearity studies were determined and all points were within acceptable limits. We therefore recommend DBS as a sample type alternative to plasma for the estimation of HIV-1 viral load and EID diagnosis on the Hologic panther machine.

Abstract Background Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes. Methods In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13–31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing. Results In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (Pinteraction

Abstract It is unclear whether the high burden of COPD in rural areas is related to worse outcomes in patients with COPD or is because the prevalence of COPD is higher in rural areas. We assessed the association of rural living with acute exacerbations of COPD (AECOPDs)-related hospitalization and mortality. We retrospectively analyzed Veterans Affairs (VA) and Medicare data of a nationwide cohort of veterans with COPD aged ≥ 65 years with COPD diagnosis between 2011 and 2014 that had follow-up data until 2017. Patients were categorized based on residential location into urban, rural, and isolated rural. We used generalized linear and Cox proportional hazards models to assess the association of residential location with AECOPD-related hospitalizations and long-term mortality. Of 152,065 patients, 80,162 (52.7%) experienced at least one AECOPD-related hospitalization. After adjusting for demographics and comorbidities, rural living was associated with fewer hospitalizations (relative risk-RR = 0.90; 95% CI: 0.89–0.91; P

Abstract Background People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD. Methods We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

Abstract The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.

Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and hospitalization. Here, we asked whether mRNA vaccine–induced memory T cells limit lung SARS-CoV-2 replication and severe disease. We show that mice and humans receiving booster BioNTech mRNA vaccine developed potent CD8 T cell responses and showed similar kinetics of expansion and contraction of granzyme B/perforin-expressing effector CD8 T cells. Both monovalent and bivalent mRNA vaccines elicited strong expansion of a heterogeneous pool of terminal effectors and memory precursor effector CD8 T cells in spleen, inguinal and mediastinal lymph nodes, pulmonary vasculature, and most surprisingly in the airways, suggestive of systemic and regional surveillance. Furthermore, we document that: (a) CD8 T cell memory persists in multiple tissues for > 200 days; (b) following challenge with pathogenic SARS-CoV-2, circulating memory CD8 T cells rapidly extravasate to the lungs and promote expeditious viral clearance, by mechanisms that require CD4 T cell help; and (c) adoptively transferred splenic memory CD8 T cells traffic to the airways and promote lung SARS-CoV-2 clearance. These findings provide insights into the critical role of memory T cells in preventing severe lung disease following breakthrough infections with antibody-evasive SARS-CoV-2 variants.

Abstract To better understand functional morphological adaptations to high elevation (> 3000 m above sea level) life in both North American and African mountain-associated rodents, we used microCT scanning to acquire 3D images and a 3D morphometric approach to calculate endocranial volumes and skull lengths. This was done on 113 crania of low-elevation and high-elevation populations in species of North American cricetid mice (two Peromyscus species, n = 53), and African murid rodents of two tribes, Otomyini (five species, n = 49) and Praomyini (four species, n = 11). We tested two distinct hypotheses for how endocranial volume might vary in high-elevation populations: the expensive tissue hypothesis, which predicts that brain and endocranial volumes will be reduced to lessen the costs of growing and maintaining a large brain; and the brain-swelling hypothesis, which predicts that endocranial volumes will be increased either as a direct phenotypic effect or as an adaptation to accommodate brain swelling and thus minimize pathological symptoms of altitude sickness. After correcting for general allometric variation in cranial size, we found that in both North American Peromyscus mice and African laminate-toothed (Otomys) rats, highland rodents had smaller endocranial volumes than lower-elevation rodents, consistent with the expensive tissue hypothesis. In the former group, Peromyscus mice, crania were obtained not just from wild-caught mice from high and low elevations but also from those bred in common-garden laboratory conditions from parents caught from either high or low elevations. Our results in these mice showed that brain size responses to elevation might have a strong genetic basis, which counters an opposite but weaker environmental effect on brain volume. These results potentially suggest that selection may act to reduce brain volume across small mammals at high elevations but further experiments are needed to assess the generality of this conclusion and the nature of underlying mechanisms.

Abstract There has been an increase in Candida auris healthcare-associated infections, which result from cross-contamination from surfaces and equipment. In this study, we tested the efficacies of EPA-registered disinfectant towelettes products that are increasingly used for infection control against C. auris at a range of contact times following modifications to standard EPA protocol MB-33-00. Hydrogen peroxide (HP)-based disinfectant towelettes were more efficacious against C. auris than the quaternary ammonium chloride (QAC)-alcohol-based disinfectant towelettes irrespective of tested contact times. Thirty s contact time was significantly less effective in reducing C. auris compared to 1-, 2-, 3-, and 10-min contact times. However, there were no statistically significant differences in the level of disinfection among 1-min and longer contact times regardless of product chemistry. None of the products achieved a standard six-log10 reduction at any tested contact times. Overall, the HP-based disinfectant towelette was significantly more fungicidal than the QAC-alcohol-based disinfectant towelette. For all product types, 30 s contact time did not achieve the same level of disinfection as 1-min or longer contact times. Overall, disinfectant towelette efficacy is dependent upon product formulation and contact time.

Abstract Background Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation. Results Using The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration. Conclusions By combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.

Abstract The reduction pathway of nitrate (NO3 −) and nitrite (NO2 −) to nitric oxide (NO) contributes to regulating many physiological processes. To examine the rate and extent of dietary nitrate absorption and its reduction to nitrite, we supplemented rat diets with Na15NO3-containing water (1 g/L) and collected plasma, urine and several tissue samples. We found that plasma and urine showed 8.8- and 11.7-fold increases respectively in total nitrate concentrations in 1-day supplementation group compared to control. In tissue samples—gluteus, liver and eyes—we found 1.7-, 2.4- and 4.2-fold increases respectively in 1-day supplementation group. These increases remained similar in 3-day supplementation group. LC–MS/MS analysis showed that the augmented nitrate concentrations were primarily from the exogenously provided 15N-nitrate. Overall nitrite concentrations and percent of 15N-nitrite were also greatly increased in all samples after nitrate supplementation; eye homogenates showed larger increases compared to gluteus and liver. Moreover, genes related to nitrate transport and reduction (Sialin, CLC and XOR) were upregulated after nitrate supplementation for 3 days in muscle (Sialin 2.3-, CLC1 1.3-, CLC3 2.1-, XOR 2.4-fold) and eye (XOR 1.7-fold) homogenates. These results demonstrate that dietary nitrate is quickly absorbed into circulation and tissues, and it can be reduced to nitrite in tissues (and likely to NO) suggesting that nitrate-enriched diets can be an efficient intervention to enhance nitrite and NO bioavailability.

Abstract The global degradation of coral reefs is steadily increasing with ongoing climate change. Yet coral larvae settlement, a key mechanism of coral population rejuvenation and recovery, is largely understudied. Here, we show how the lipophilic, settlement-inducing bacterial pigment cycloprodigiosin (CYPRO) is actively harvested and subsequently enriched along the ectoderm of larvae of the scleractinian coral Leptastrea purpura. A light-dependent reaction transforms the CYPRO molecules through photolytic decomposition and provides a constant supply of hydrogen peroxide (H2O2), leading to attachment on the substrate and metamorphosis into a coral recruit. Micromolar concentrations of H2O2 in seawater also resulted in rapid metamorphosis, but without prior larval attachment. We propose that the morphogen CYPRO is responsible for initiating attachment while simultaneously acting as a molecular generator for the comprehensive metamorphosis of pelagic larvae. Ultimately, our approach opens a novel mechanistic dimension to the study of chemical signaling in coral settlement and provides unprecedented insights into the role of infochemicals in cross-kingdom interactions.

Abstract Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant specialized metabolites found mainly in members of the order Ranunculales, including opium poppy (Papaver somniferum), for which BIA biosynthetic pathways leading to the critical drugs morphine, noscapine, and sanguinarine have been elucidated. Sacred lotus (Nelumbo nucifera), in the order Proteales, accumulates medicinal BIAs in the proaporphine, aporphine, and bisbenzylisoquinoline structural subgroups with a prevalence of R enantiomers, opposed to the dominant S configuration occurring in the Ranunculales. Nevertheless, distinctive BIA biosynthetic routes in sacred lotus have not been explored. In planta labeling experiments and in vitro assays with recombinant enzymes and plant protein extracts showed that dopamine and 4-hydroxyphenylacetaldehyde derived from l-tyrosine serve as precursors for the formation of (R,S)-norcoclaurine in sacred lotus, whereas only (R)-norcoclaurine byproducts are favored in the plant by action of R-enantiospecific methyltransferases and cytochrome P450 oxidoreductases (CYPs). Enzymes responsible for the R-enantiospecific formation of proaporphine (NnCYP80Q1) and bisbenzylisoquinoline (NnCYP80Q2) scaffolds, and a methylenedioxy bridge introduction on aporphine substrates (NnCYP719A22) were identified, whereas additional aspects of the biosynthetic pathways leading to the distinctive alkaloid profile are discussed. This work expands the availability of molecular tools that can be deployed in synthetic biology platforms for the production of high-value alkaloids.

Abstract Gene duplication is a key first step in the process of expanding the functionality of a multigene family. In order to better understand the process of gene duplication and its role in the formation of new enzymes, we investigated recent duplication events in the M14 family of proteolytic enzymes. Within vertebrates, four of 23 M14 genes were frequently found in duplicate form. While AEBP1, CPXM1, and CPZ genes were duplicated once through a large-scale, likely whole-genome duplication event, the CPO gene underwent many duplication events within fish and Xenopus lineages. Bioinformatic analyses of enzyme specificity and conservation suggested a greater amount of neofunctionalization and purifying selection in CPO paralogs compared with other CPA/B enzymes. To examine the functional consequences of evolutionary changes on CPO paralogs, the four CPO paralogs from Xenopus tropicalis were expressed in Sf9 and HEK293T cells. Immunocytochemistry showed subcellular distribution of Xenopus CPO paralogs to be similar to that of human CPO. Upon activation with trypsin, the enzymes demonstrated differential activity against three substrates, suggesting an acquisition of new function following duplication and subsequent mutagenesis. Characteristics such as gene size and enzyme activation mechanisms are possible contributors to the evolutionary capacity of the CPO gene.

Abstract Introduction and objective Muscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy. Methods We performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC. Results High concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8–40.5; p

Abstract The scaling behaviour of agent-based computational models, to evaluate transmission risks of infectious diseases, is addressed. To this end we use an existing computational code, made available in the public domain by its author, to analyse the system dynamics from a general perspective. The goal being to obtain deeper insight into the system behaviour than can be obtained from considering raw data alone. The data analysis collapses the output data for infection numbers and leads to closed-form expressions for the results. It is found that two parameters are sufficient to summarize the system development and the scaling of the data. One of the parameters characterizes the overall system dynamics. It represents a scaling factor for time when expressed in iteration steps of the computational code. The other parameter identifies the instant when the system adopts its maximum infection rate. The data analysis methodology presented constitutes a means for a quantitative intercomparison of predictions for infection numbers, and infection dynamics, for data produced by different models and can enable a quantitative comparison to real-world data.

Abstract We aimed to identify hepatocellular carcinoma (HCC) patients who will respond to repetitive transarterial chemoembolization (TACE) to improve the treatment algorithm. Retrospectively, 61 patients (mean age, 65.3 years ± 10.0 [SD]; 49 men) with 94 HCC mRECIST target-lesions who had three consecutive TACE between 01/2012 and 01/2020 were included. Robust and non-redundant radiomics features were extracted from the 24 h post-embolization CT. Five different clinical TACE-scores were assessed. Seven different feature selection methods and machine learning models were used. Radiomics, clinical and combined models were built to predict response to TACE on a lesion-wise and patient-wise level as well as its impact on overall-survival prognostication. 29 target-lesions of 19 patients were evaluated in the test set. Response rates were 37.9% (11/29) on the lesion-level and 42.1% (8/19) on the patient-level. Radiomics top lesion-wise response prognostications was AUC 0.55–0.67. Clinical scores revealed top AUCs of 0.65–0.69. The best working model combined the radiomic feature LargeDependenceHighGrayLevelEmphasis and the clinical score mHAP_II_score_group with AUC = 0.70, accuracy = 0.72. We transferred this model on a patient-level to achieve AUC = 0.62, CI = 0.41–0.83. The two radiomics-clinical features revealed overall-survival prognostication of C-index = 0.67. In conclusion, a random forest model using the radiomic feature LargeDependenceHighGrayLevelEmphasis and the clinical mHAP-II-score-group seems promising for TACE response prognostication.

Abstract To identify a spoken word (e.g., dog), people must categorize the speech steam onto distinct units (e.g., contrast dog/fog,) and extract their combinatorial structure (e.g., distinguish dog/god). However, the mechanisms that support these two core functions are not fully understood. Here, we explore this question using transcranial magnetic stimulation (TMS). We show that speech categorization engages the motor system, as stimulating the lip motor area has opposite effects on labial (ba/pa)- and coronal (da/ta) sounds. In contrast, the combinatorial computation of syllable structure engages Broca’s area, as its stimulation disrupts sensitivity to syllable structure (compared to motor stimulation). We conclude that the two ingredients of language—categorization and combination—are distinct functions in human brains.

Abstract Background Many migraine patients do not respond adequately to conventional preventive treatments and are therefore described as treatment/medically resistant or difficult to treat cases. Calcitonin gene-related peptide monoclonal antibodies are a relatively novel molecular treatment for episodic and chronic migraine that have been shown to be effective in short duration clinical trials in approximately 40–50% of all chronic migraine patients. Patient Related Outcome Measures (PROM) or Quality of Life (QoL) questionnaires are used to help measure response to treatment in migraine. Although some open label extension studies have become available for erenumab, there is a lack of real-world data pertaining to quality of life in the medium to long-term for chronic and treatment resistant migraine patients. Methods A total of 177 treatment resistant CM patients were started on erenumab (70 mg or 140 mg subcutaneous injection every 4 weeks) in our three specialist Headache Clinics. Of these, 174 had their first injection between December 2018 and October 2019. All patients were evaluated with the following PROM: the Headache Impact Test− 6, Migraine Associated Disability Assessment test and Migraine-Specific QoL Questionnaire, before starting treatment with erenumab and at intervals of 3–12 months after starting treatment. The decision to continue treatment was based on subjective clinical improvement of at least 30% (as reported by the patient), supported with diaries and QoL questionnaires. We present here the QoL measurements for this group of 177 patients. Prior preventive migraine treatments included conventional oral prophylactic medications (such as topiramate, candesartan, propranolol, or amitriptyline), at least two cycles of PREEMPT protocol onabotulinumtoxin A or (in a small number of cases) neuromodulation with single pulse Transcranial Magnetic Stimulation. Results Of the 177 patients who started treatment with erenumab, 68/177 (38.4%) stopped during the first year, either due to lack of efficacy (no significant benefit or only minimal improvement) and/or possible side effects. 109/177 (61.6%) patients reported clinically significant improvement after 6–12 months and wished to stay on treatment. Twelve of these 109 patients subsequently stopped treatment in the period between 1 year and up to June 2021 (mainly due to a worsening of their migraine). Therefore, a total of 97/177 patients (54.8%) remained on treatment as of June 2021 (duration of treatment 17–30 months, median of 25 months). Conclusion Approximately 55% of treatment resistant or difficult to treat CM patients who trialled erenumab in our clinics reported a subjective benefit and were still on treatment after 17–30 months.

Abstract Detection of viruses by RNA and DNA sequencing has improved the understanding of the human virome. We sought to identify blood viral signatures through secondary use of RNA-sequencing (RNA-seq) data in a large study cohort. The ability to reveal undiagnosed infections with public health implications among study subjects with available sequencing data could enable epidemiologic surveys and may lead to diagnosis and therapeutic interventions, leveraging existing research data in a clinical context. We detected viral RNA in peripheral blood RNA-seq data from a COPD-enriched population of current and former smokers. Correlation between viral detection and both reported infections and relevant disease outcomes was evaluated. We identified Hepatitis C virus RNA in 228 subjects and HIV RNA in 30 subjects. Overall, we observed 31 viral species, including Epstein-Barr virus and Cytomegalovirus. We observed an enrichment of Hepatitis C and HIV infections among subjects reporting liver disease and HIV infections, respectively. Higher interferon expression scores were observed in the subjects with Hepatitis C and HIV infections. Through secondary use of RNA-seq from a cohort of current and former smokers, we detected peripheral blood viral signatures. We identified HIV and Hepatitis C virus (HCV), highlighting potential public health implications for the approach described this study. We observed correlations with reported infections, chronic infection outcomes and the host transcriptomic response, providing evidence to support the validity of the approach.

Abstract Neopterin, a product of activated white blood cells, is a marker of nonspecific inflammation that can capture variation in immune investment or disease-related immune activity and can be collected noninvasively in urine. Mounting studies in wildlife point to lifetime patterns in neopterin related to immune development, aging, and certain diseases, but rarely are studies able to assess whether neopterin can capture multiple concurrent dimensions of health and disease in a single system. We assessed the relationship between urinary neopterin stored on filter paper and multiple metrics of health and disease in wild geladas (Theropithecus gelada), primates endemic to the Ethiopian highlands. We tested whether neopterin captures age-related variation in inflammation arising from developing immunity in infancy and chronic inflammation in old age, inflammation related to intramuscular tapeworm infection, helminth-induced anti-inflammatory immunomodulation, and perturbations in the gastrointestinal microbiome. We found that neopterin had a U-shaped relationship with age, no association with larval tapeworm infection, a negative relationship with metrics related to gastrointestinal helminth infection, and a negative relationship with microbial diversity. Together with growing research on neopterin and specific diseases, our results demonstrate that urinary neopterin can be a powerful tool for assessing multiple dimensions of health and disease in wildlife.

Abstract Insight impairment contributes significantly to morbidity in psychiatric disorders. The neurologic concept of anosognosia, reflecting deficits in metacognitive awareness of illness, is increasingly understood as relevant to psychopathology, but has been little explored in psychiatric disorders other than schizophrenia. We explored anosognosia as an aspect of insight impairment in n = 71 individuals with DSM-5 hoarding disorder. We used a standardized clutter severity measure to assess whether individuals with hoarding disorder underreport home clutter levels relative to independent examiners. We then explored whether underreporting, as a proxy for anosognosia, is predicted by clinical or neurocognitive behavioral measures. We found that individuals with hoarding disorder underreport their clutter, and that underreporting is predicted by objective severity of clutter. In an n = 53 subset of participants, we found that underreporting is predicted by altered performance on tests of cognitive control and inhibition, specifically Go/No-Go and Stroop tests. The relation of underreporting to objective clutter, the cardinal symptom of hoarding disorder, suggests that anosognosia may reflect core pathophysiology of the disorder. The neurocognitive predictors of clutter underreporting suggest that anosognosia in hoarding disorder shares a neural basis with metacognitive awareness deficits in other neuropsychiatric disorders and that executive anosognosia may be a transdiagnostic manifestation of psychopathology.