bluuebunny/crossref_metadata_2025 huggingface dataset:
What Do Medicaid Members Want From Their Health Plan?
Authors: McQueen Amy , Von Nordheim David , Thompson Tess , Manley Kayla , Pool Albert J. , Kreuter Matthew W.
Published: February 2024

Purpose of Study:

Managed care organizations (MCOs) provide case management services to address unmet health and social needs among their members. Few studies have examined factors influencing members' decision to participate in these programs. The purpose of the present study was to describe the life circumstances of Medicaid members offered case management, what they wanted from their MCO, and their perceptions of case management and barriers to participation. Results will inform practice to raise the awareness, engagement, and impact of case management programs.

Primary Practice Setting(s):

Case management offered through a Midwestern Medicaid MCO.

Methodology and Sample:

Adult members who had been offered case management services in the 6 months preceding the study were eligible for the study. Fifteen people from each strata were recruited: members who engaged with case management, declined it, or declined it initially but later engaged (N = 45). Participants completed a qualitative interview by phone and a brief health survey online.

Results:

Across strata, only 22 participants recalled engagement with case management. Members described a variety of life challenges (e.g., chronic health conditions, caregiver responsibilities, and limited finances) and services they desired from their MCO (e.g., stipends for over-the-counter health expenses, improved transportation services, and caregiver assistance). Participants identified direct communication, emotional support, and referrals for resources as benefits of case management.
Virtual Interprofessional Education
Authors: Smith Leslie M. , Jacob Julie , Prush Nicholas , Groden Sheryl , Yost Elizabeth , Gilkey Stephanie , Turkelson Carman , Keiser Megan
Published: February 2024

Purpose of Study:

This study assessed the effectiveness of a virtual interprofessional education (IPE) discharge planning simulation, focusing on collaborative patient education, and recommendations for hospital discharge.

Primary Practice Setting:

An acute care hospital.

Methodology and Sample:

The study utilized a virtual IPE discharge planning simulation for health care students from six different programs. The simulation involved prebriefing, icebreaker, team meeting, patient interaction, and debriefing. Assessment included pre- and post-IPE surveys that included the Interprofessional Education Collaborative (IPEC) Competency Self-Assessment Tool, and video analysis using the Modified McMaster-Ottawa Rating Scale.

Results:

Student participants from diverse health care programs (n =143) included nursing (n = 20), occupational therapy (n = 21), physical therapy (n = 42), physician assistant (n = 38), respiratory therapy (n = 3), and social work (n = 19). All programs except respiratory therapy showed significant improvement in IPEC Competency scores post-IPE, with positive outcomes for understanding other professions' roles. Students' self-reported perceptions of team performance were rated highly in various categories. Video analysis demonstrated strong interrater reliability for team scores.

Implications for Case Management Practice:

Effective hospital discharge planning is vital for cost reduction and patient care improvement. IPE emphasizes collaborative learning among health care students. Previous studies highlight positive outcomes from IPE discharge planning, including virtual formats. This virtual IPE discharge planning simulation significantly improved students' understanding and collaboration competencies, evident in increased IPEC scores across five professions.
Race, Ethnicity, and Intensive Care Utilization for Common Pediatric Diagnoses: U.S. Pediatric Health Information System 2019 Database Study
Authors: Slain Katherine N. , Hall Matt , Akande Manzilat , Thornton J. Daryl , Pronovost Peter J. , Berry Jay G.
Published: February 2024

OBJECTIVES:

Racial and ethnic disparities in healthcare delivery for acutely ill children are pervasive in the United States; it is unknown whether differential critical care utilization exists.

DESIGN:

Retrospective study of the Pediatric Health Information System (PHIS) database.

SETTING:

Multicenter database of academic children’s hospitals in the United States.

PATIENTS:

Children discharged from a PHIS hospital in 2019 with one of the top ten medical conditions where PICU utilization was present in greater than or equal to 5% of hospitalizations.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Race and ethnicity categories included Asian, Black, Hispanic, White, and other. Primary outcomes of interest were differences in rate of PICU admission, and for children requiring PICU care, total hospital length of stay (LOS). One-quarter (n= 44,200) of the 178,134 hospital discharges included a PICU admission. In adjusted models, Black children had greater adjusted odds ratio (aOR [95% CI]) of PICU admission in bronchiolitis (aOR, 1.08 [95% CI, 1.02–1.14];p= 0.01), respiratory failure (aOR, 1.18 [95% CI, 1.10–1.28];p< 0.001), seizure (aOR, 1.28 [95% CI, 1.08–1.51];p= 0.004), and diabetic ketoacidosis (DKA) (aOR, 1.18 [95% CI, 1.05–1.32];p= 0.006). Together, Hispanic, Asian, and other race children had greater aOR of PICU admission in five of the diagnostic categories, compared with White children. The geometric mean (±sd) hospital LOS ranged from 47.7 hours (± 2.1 hr) in croup to 206.6 hours (± 2.8 hr) in sepsis. After adjusting for demographics and illness severity, children from families of color had longer LOS in respiratory failure, pneumonia, DKA, and sepsis.

CONCLUSIONS:

The need for critical care to treat acute illness in children may be inequitable. Additional studies are needed to understand and eradicate differences in PICU utilization based on race and ethnicity.
Two-Team Transanal Total Mesorectal Excision and En Bloc Resection of the Lateral Pelvic Lymph Nodes, Main Iliac Vessels, and Pelvic Plexus for Locally Advanced Rectal Cancer With Lateral Lymph Node Metastasis
Authors: Shioi Ikuma , Ogawa Hiroomi , Hosoi Nobuhiro , Yamaguchi Arisa , Watanabe Takayoshi , Nakazawa Nobuhiro , Shibasaki Yuta , Shiraishi Takuya , Osone Katsuya , Okada Takuhisa , Sano Akihiko , Sakai Makoto , Sohda Makoto , Shirabe Ken , Saeki Hiroshi
Published: February 2024

Background:

Here, we describe the precise surgical technique for a novel procedure involving 2-team transanal total mesorectal excision with en bloc lateral pelvic lymph node (LPLN) dissection combined with resection of the involved main internal iliac vessels and pelvic plexus.

Methods:

From September 2020 to May 2023, 4 patients underwent the procedure at our hospital.

Results:

The operation time and blood loss were 272 to 412 minutes and 10 to 124 mL, respectively. No patients required conversion to open surgery or exhibited Clavien-Dindo grade III or worse postoperative complications, although 2 developed grade II urinary dysfunction. All surgical margins were negative.

Conclusions:

Our novel 2-team method can facilitate safe and satisfactory surgery, even for highly advanced rectal cancer. The transanal approach offers excellent visibility and operability, even during LPLN and adjacent structure dissection. Furthermore, initial dissection of the distal branches of the iliac vessels prevents excessive lymphatic tissue congestion, facilitating easier, and clearer dissection.
A New Step-Up Dual Endoscopic Approach for Large-Size Infected Pancreatic Necrosis: Percutaneous Endoscopic Necrosectomy Followed by Transluminal Endoscopic Drainage/Necrosectomy
Authors: Mangiafico Santi , Bertani Helga , Pigò Flavia , Russo Salvatore , Lupo Marinella , Cocca Silvia , Grande Giuseppe , Germani Ugo , Manta Raffaele , Conigliaro Rita
Published: February 2024

Background:

Acute pancreatitis in 10% to 20% of cases can be associated with necrosis of the pancreatic gland, peripancreatic tissue, or both. We report a case series of a new endoscopic approach to treat infected pancreatic necrosis (IPN).

Patients and Methods:

Consecutive patients with IPN, extending from the perigastric area up to the paracolic gutters or into the pelvis, were prospectively studied from January 2017 to June 2022. The treatment protocol was radiologic percutaneous drainage as the first step, followed by fully covered metal stent placement (FC-SEMS) in the track of the catheter. Percutaneous endoscopic necrosectomy (PEN) was performed 2 to 4 days later using a flexible endoscope through the percutaneous tract. About 2 to 4 weeks later, when a matured sac was visible, EUS-guided endoscopic transluminal drainage (ETD) with lumen-apposing metal stents (LAMS) was performed. Control of sepsis with resolution of collection(s) was the primary outcome measure.

Results:

We included 18 patients, males in 50% of cases with age 60±12 years old. Most frequent cause of pancreatitis was biliary (7 cases) followed by alcoholic in 6 cases; in 3 cases pancreatitis was caused by hyperlipemia and in 2 cases was idiopathic. Mean size of WON was 18±2 cm. For PEN, SEMSs used were esophageal FC-SEMS. LAMS used for ETD were Hot Axios, Hot Spaxus and Nagistent. Mean time of endoscopic intervention for PEN and ETD was 18±3 and 37±4 days, respectively. In 5 cases adverse events occurred: 3 cases of overinflations resolved with introduction of Verres needles in abdomen. In 2 cases postprocedural GI bleeding required endoscopic intervention. In all cases control of sepsis was reached together with resolution of collections. No cases of deaths were observed.

Conclusions:

Step-up percutaneous and transluminal endoscopic necrosectomy therapy is an effective strategy for large-size IPN with combined central and peripheral necrosis.
Invasive Fungal Infections in Inpatient Solid Organ Transplant Recipients With COVID-19: A Multicenter Retrospective Cohort
Authors: Permpalung Nitipong , Chiang Teresa Po-Yu , Manothummetha Kasama , Ostrander Darin , Datta Kausik , Segev Dorry L. , Durand Christine M. , Mostafa Heba H. , Zhang Sean X. , Massie Allan B. , Marr Kieren A. , Avery Robin K.
Published: February 2024

Background.

The prevalence and outcomes of COVID-19-associated invasive fungal infections (CAIFIs) in solid organ transplant recipients (SOTRs) remain poorly understood.

Methods.

A retrospective cohort study of SOTRs with COVID-19 admitted to 5 hospitals within Johns Hopkins Medicine was performed between March 2020 and March 2022. Cox regression multilevel mixed-effects ordinal logistic regression was used.

Results.

In the cohort of 276 SOTRs, 22 (8%) developed IFIs. The prevalence of CAIFIs was highest in lung transplant recipients (20%), followed by recipients of heart (2/28; 7.1%), liver (3/46; 6.5%), and kidney (7/149; 4.7%) transplants. In the overall cohort, only 42 of 276 SOTRs (15.2%) required mechanical ventilation; these included 11 of 22 SOTRs (50%) of the CAIFI group and 31 of 254 SOTRs (12.2%) of the no-CAIFI group. Compared with those without IFIs, SOTs with IFIs had worse outcomes and required more advanced life support (high-flow oxygen, vasopressor, and dialysis). SOTRs with CAIFIs had higher 1-y death-censored allograft failure (hazard ratio 1.65.116.4, P = 0.006) and 1-y mortality adjusting for oxygen requirement (adjusted hazard ratio 1.12.45.1, P < 0.001), compared with SOTRs without CAIFIs.

Conclusions.

The prevalence of CAIFIs in inpatient SOTRs with COVID-19 is substantial. Clinicians should be alert to the possibility of CAIFIs in SOTRs with COVID-19, particularly those requiring supplemental oxygen, regardless of their intubation status.
Disparities in Liver Transplantation for Nonalcoholic Steatohepatitis in Women
Authors: Becker Erica C. , Siddique Osama , O’Sullivan David M. , Dar Wasim , Einstein Michael , Morgan Glyn , Emmanuel Bishoy , Sotil Eva U. , Richardson Elizabeth , Serrano Oscar K.
Published: February 2024

Background.

Nonalcoholic steatohepatitis (NASH) is the fastest-growing indication for liver transplantation (LT). Sex disparities among patients with cirrhosis on the LT waitlist are well known. We wanted to understand these disparities further in women with end-stage liver disease patients listed for NASH cirrhosis in a contemporary cohort.

Methods.

We used data from the Scientific Registry of Transplant Recipients to assess sex racial, and ethnic differences in NASH patients listed for LT. Adults transplanted from August 1997 to June 2021 were included. Inferential statistics were used to evaluate differences with univariate and multivariate comparisons, including competitive risk analysis.

Results.

During the study time period, we evaluated 12 844 LT for NASH cirrhosis. Women were transplanted at a lower rate (46.5% versus 53.5%; P < 0.001) and higher model for end-stage liver disease (MELD) (23.8 versus 22.6; P < 0.001) than men. Non-White women were transplanted at a higher MELD (26.1 versus 23.1; P < 0.001) than White women and non-White male patients (26.1 versus 24.8; P < 0.001). Graft and patient survivals were significantly different (P < 0.001) between non-White women and White women and men (White and non-White).

Conclusions.

Evaluation of LT candidates in the United States demonstrates women with NASH cirrhosis have a higher MELD than men at LT. Additional disparities exist among non-White women with NASH as they have higher MELD and creatinine at LT compared with White women. After LT, non-White women have worse graft and patient survival compared with men or White women. These data indicate that non-White women with NASH are the most vulnerable on the LT waitlist.
First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation
Authors: Viklicky Ondrej , Slatinska Janka , Janousek Libor , Rousse Juliette , Royer Pierre-Joseph , Toutain Pierre-Louis , Cozzi Emanuele , Galli Cesare , Evanno Gwenaelle , Duvaux Odile , Bach Jean-Marie , Soulillou Jean-Paul , Giral Magali , Vanhove Bernard , Blancho Gilles
Published: February 2024

Background.

Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti-N-glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models.

Methods.

This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1. In an ascending dose cohort (n = 5), a primary kidney transplant recipient at low immunologic risk (panel reactive antibody [PRA] < 20%), received LIS1 for 5 d at either 0.6, 1, 3, 6, or 8 mg/kg. After each patient completed treatment, the data safety monitoring board approved respective dose escalation. In the therapeutic dose cohort (n = 5) in patients with PRA <50% without donor specific antibodies, 2 patients received 8 mg/kg and 3 patients 10 mg/kg.

Results.

CD3+ T cell depletion <100/mm3 at day 2 was observed in all patients who received 6, 8, and 10 mg/kg of LIS1. The terminal half-life of LIS1 was 33.7 d with linearity in its disposition. Lymphocyte repopulation was fast and pretransplant lymphocyte subpopulation counts recovered within 2–4 wk. LIS1 was well tolerated, neither cytokine release syndrome nor severe thrombocytopenia or leukopenia were noticed. Antibodies to LIS1 were not detected.

Conclusions.

In this first-in-human trial, genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T cell depletion in low- and medium-risk kidney transplant recipients.
Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials
Authors: Hurst Daniel J. , Padilla Luz , Merlocco Anthony , Rodger Daniel , Bobier Christopher , Gray William H. , Sorabella Robert , Cooper David K. C. , Pierson Richard N.
Published: February 2024

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available. Scientific and clinical developments in xenotransplantation appear likely to permit cardiac xenotransplantation clinical trials in adults in the coming years. The ethical issues around xenotransplantation of the heart and other organs and tissues have recently been examined, but to date, only limited literature is available on the ethical issues that are attendant with pediatric heart xenotransplantation. Here, we summarize the ethical issues, focusing on (1) whether cardiac xenotransplantation should proceed in adults or children first, (2) pediatric recipient selection for initial xenotransplantation trials, (3) special problems regarding informed consent in this context, and (4) related psychosocial and public perception considerations. We conclude with specific recommendations regarding ethically informed design of pediatric heart xenotransplantation trials.
Efficient Generation of Protein Pockets with PocketGen
Authors: Zhang Zaixi , Shen Wan Xiang , Liu Qi , Zitnik Marinka
Published: February 2024

Designing protein-binding proteins is critical for drug discovery. However, the AI-based design of such proteins is challenging due to the complexity of ligand-protein interactions, the flexibility of ligand molecules and amino acid side chains, and sequence-structure dependencies. We introduce PocketGen, a deep generative model that simultaneously produces both the residue sequence and atomic structure of the protein regions where ligand interactions occur. PocketGen ensures consistency between sequence and structure by using a graph transformer for structural encoding and a sequence refinement module based on a protein language model. The bilevel graph transformer captures interactions at multiple scales, including atom, residue, and ligand levels. To enhance sequence refinement, PocketGen integrates a structural adapter into the protein language model, ensuring that structure-based predictions align with sequence-based predictions. PocketGen can generate high-fidelity protein pockets with superior binding affinity and structural validity. It operates ten times faster than physics-based methods and achieves a 95% success rate, defined as the percentage of generated pockets with higher binding affinity than reference pockets. Additionally, it attains an amino acid recovery rate exceeding 64%.
A method for correcting systematic error in PO2measurement to improve measures of oxygen supply capacity
Authors: Timpe A.W. , Seibel B.A
Published: February 2024

An organism’s oxygen supply capacity (α) can be measured as a ratio of the metabolic rate (MR) and the critical oxygen partial pressure (Pc). However, this metric is sensitive to errors in the measurement of PO2, especially at low PO2where the ratio of instrument error to environmental oxygen is magnified. Consequently, the oxygen supply capacity of animals, particularly those that evolved in low-oxygen environments, may appear unnaturally high and variable. Here, we present a method to correct for instrumental calibration error and use simulated and literature datasets to demonstrate how it can be usedpost hocto diagnose error in, correct the magnitude of, and reduce the variability in repeat measures of the oxygen supply capacity.
Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue
Authors: Boda Madison R , Otieno Lavender A , Smith Ashleigh E , Goldsworthy Mitchell R , Sidhu Simranjit K
Published: February 2024

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra– and inter-individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 minutes. Fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate fatigue in young healthy individuals.
Evaluating generalizability of artificial intelligence models for molecular datasets
Authors: Ektefaie Yasha , Shen Andrew , Bykova Daria , Marin Maximillian , Zitnik Marinka , Farhat Maha
Published: February 2024

Deep learning has made rapid advances in modeling molecular sequencing data. Despite achieving high performance on benchmarks, it remains unclear to what extent deep learning models learn general principles and generalize to previously unseen sequences. Benchmarks traditionally interrogate model generalizability by generating metadata based (MB) or sequence-similarity based (SB) train and test splits of input data before assessing model performance. Here, we show that this approach mischaracterizes model generalizability by failing to consider the full spectrum of cross-split overlap,i.e., similarity between train and test splits. We introduce SPECTRA, a spectral framework for comprehensive model evaluation. For a given model and input data, SPECTRA plots model performance as a function of decreasing cross-split overlap and reports the area under this curve as a measure of generalizability. We apply SPECTRA to 18 sequencing datasets with associated phenotypes ranging from antibiotic resistance in tuberculosis to protein-ligand binding to evaluate the generalizability of 19 state-of-the-art deep learning models, including large language models, graph neural networks, diffusion models, and convolutional neural networks. We show that SB and MB splits provide an incomplete assessment of model generalizability. With SPECTRA, we find as cross-split overlap decreases, deep learning models consistently exhibit a reduction in performance in a task- and model-dependent manner. Although no model consistently achieved the highest performance across all tasks, we show that deep learning models can generalize to previously unseen sequences on specific tasks. SPECTRA paves the way toward a better understanding of how foundation models generalize in biology.
Helical grooves on the surfaces of microtrichia in European Hornets: Functional significance for antipodal relation between right and left hindwings
Authors: Inoué Sayako , Sato Hisako , Yamagishi Akihiko
Published: February 2024

The surface structures of microtrichia on the hindwings ofVerspa Crabro(European hornets) were observed by scanning electron microscopy (SEM). Helical grooves were seen in the microtrichia on both the ventral and dorsal sides. Their helical orientation varied spatially across the wing surface but were the same in the ventral and dorsal surfaces. Notably the grooves wound antipodally between the left and right wings. The observed chirality relation might be related to the effective anti-wetting of hindwings. The results demonstrated the importance of microscopic chirality in understrading the functions of insect wings.
Supplementary motor area disinhibition during motor sequence learning: A TMS-EEG study
Authors: Thong Sophie , Doery Elizabeth , Biabani Mana , Rogasch Nigel C. , Chong Trevor T. -J. , Hendrikse Joshua , Coxon James P.
Published: February 2024

Background

In primary motor cortex, changes in excitatory and inhibitory neurotransmission (E:I balance) accompany motor sequence learning. In particular, there is an early reduction in inhibition (i.e., disinhibition). The supplementary motor area (SMA) is a key brain region involved in the learning of sequences, however the neurophysiological mechanisms within SMA which support motor sequence learning remain poorly understood. Disinhibition may also occur in SMA, but this possibility remains unexamined.

Objective

We investigated disinhibition within SMA during motor sequence learning using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG).

Methods

Twenty-nine healthy adults practiced a sequential motor task. TMS-evoked potentials (TEPs) resulting from SMA stimulation were measured with EEG before, during, and after practice. The N45 TEP peak was our primary measure of disinhibition. Furthermore, the slope of aperiodic EEG activity was included as an additional E:I balance measure.

Results

Significant improvements in task performance (i.e., learning) occurred with practice. We observed smaller N45 amplitudes during early learning relative to baseline (bothp< .01), indicative of disinhibition. Intriguingly, aperiodic exponents increased as learning progressed and were associated with greater sequence learning (p< .05).

Conclusion

Our results show disinhibition within SMA during the planning phase of motor sequence learning and thus provide novel understanding on the neurophysiological mechanisms within higher-order motor cortex that accompany new sequence learning.
Components of Mnemonic Metacognition Constitutionally Supported by High Gamma Activity Between the Precuneus and Hippocampus
Authors: Pan Kai , Guo Xinxia , Zheng Zhe , Zhu Zhoule , Wu Hemmings , Zhu Junming , Ye Hongyi , Cai Yudian , Santos-Pata Diogo , Zhang Jianmin , Kwok Sze Chai , Jiang Hongjie
Published: February 2024

Metacognition, the ability to introspectively monitor one’s own performance, remains an area with poorly understood neural mechanisms, particularly regarding the intercommunication among various brain regions. Recent studies have identified the precuneus as a key region in mnemonic metacognitive tasks, while the hippocampus is recognized for its role in memory function. This study aimed to investigate the role of the precuneus and hippocampus in mnemonic metacognition by utilizing intracranial electrode recordings from patients with intractable epilepsy to analyze the correlational dynamics between these regions. Our findings revealed that high gamma activity serve as a key feature in both the precuneus and hippocampus for confidence judgment. Based on signal detection theory (SDT), we discovered that high gamma activity in the precuneus is significantly linked to type 2 sensitivity (meta-d’), while hippocampal high gamma activity was primarily linked to type 1 sensitivity (d’). Additionally, the correlation between high gamma activity in the hippocampus and precuneus was exclusively related to type 2 sensitivity (meta-d’). Temporal analysis indicated that the hippocampus is initially engaged for the memory process, followed by its joint engagement together with the precuneus for confidence generation. These findings elucidate the distinct electrophysiological roles of the hippocampus and precuneus in mnemonic metacognition, providing deeper insights into the neural mechanisms underlying this cognitive process.
mRNA-delivered consensus allergens induce a neutralizing IgG response against food and pollen allergens
Authors: Møiniche Mark , Johansen Kristoffer H. , Parrón-Ballesteros Jorge , Corneliussen Josefine K. , Eriksen Helena Højsted , Kringelum Jens Vindahl , Hadrup Sine Reker , Luengo Olga , Cardona Victoria , Bartra Joan , Pascal Mariona , Turnay Javier , Villalba Mayte , Münter Rasmus , Jenkins Timothy P. , Laustsen Andreas H. , Rivera-de-Torre Esperanza
Published: February 2024

Pollen-food allergy syndrome (PFAS) affects a significant proportion of the global population with a major health and socioeconomic impact. Patients are generally treated against the major sensitized allergen which does not warrant protection against cross-reactive allergens, leading to long and ineffective treatment regimens. For food allergies, patient guidelines rely on source avoidance, leading to dietary restrictions and reduced quality of life - in particular for those suffering from PFAS. To overcome these limitations, we introduce a novel allergy immunotherapy (AIT) approach utilizing consensus allergens and mRNA technology to achieve broader, safer, and faster desensitization in PFAS patients. We first designed a consensus allergen of orthologs of non-specific Lipid Transfer Proteins (cnsLTP-1) representing a broad spectrum of nsLTP allergens prevalent in food and pollen sources. CnsLTP-1 was delivered to naïve BALB/c mice using mRNA-lipid nanoparticles (mRNA-LNP) as vehicle, or by a traditional protein formulation, to assess if it elicits broad protection against allergens from different sources. Immunization with both mRNA-LNP and protein formulations demonstrated that cnsLTP-1-specific IgGs could be induced, whilst the mRNA-LNP formulation notably avoided the induction of allergen-specific IgEs. The induced antibodies were capable of recognizing and binding to a variety of nsLTPs, and effectively blocked the binding of allergens by allergic patient serum IgEs. This study thus demonstrates that the presented AIT strategy, based on mRNA-LNP technology and consensus allergens, could find clinical utility by addressing the limitations of current AIT. Further development of this technology platform could pave the way for more effective and patient-friendly treatments for PFAS and other cross-reactive allergies.
Evidence for a trade-off between glyphosate resistance and anti-grazer defence in green algaChlamydomonas reinhardtii
Authors: Hansson Erika M , Childs Dylan Z , Beckerman Andrew P
Published: February 2024

The widespread and persistent use of herbicides has both selected for dramatically increased levels of herbicide resistance in the weed populations they were designed to control, and increased contamination of non-target ecosystems.

Experimental evolution using microbes offers the opportunity to explore basic evolutionary theory, including testing for the existence of intrinsic and extrinsic fitness trade-offs, connecting them to the patterns observed in both natural and agricultural populations.

We used green algaChlamydomonas reinhardtiiadapted to high and moderate levels of glyphosate to test for an extrinsic cost to glyphosate resistance in the form of a trade-off with clumping, the inducible anti-grazer defence deployed against gape-limited micrograzers. Through exposing the algae to freshwater rotiferBrachionus calyciflorusas well as their isolated info-chemicals, we test whether glyphosate resistance affects ability to deploy defences as well as ability to withstand grazing compared to control populations.

We find an increase in variation rather than uni-directional effect of glyphosate treatment, with treated populations exhibiting both lower and higher degree of anti-grazer defence compared to controls. Furthermore, our data suggests there are at least three different glyphosate resistant phenotypes present, with two conferring different extrinsic costs in the form of tradeoff with anti-grazer defence.

Our study indicates that extrinsic costs to glyphosate resistance may be context dependent in this system, possibly only being present at particular stages in the adaptation process or with particular resistance mechanisms.
ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis
Authors: Chung Allen , Chang Hyun K. , Pan Huize , Bashore Alexander C. , Shuck Karissa , Matias Caio V. , Gomez Juliana , Yan Hanying , Li Mingyao , Bauer Robert C.
Published: February 2024

Human genetic studies have repeatedly associatedADAMTS7with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury and that the proatherogenicity of ADAMTS7, a secreted protein, is due to its catalytic activity. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types expressADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and foundADAMTS7expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specificAdamts7conditional knockout and transgenic mice. Conditional knockout ofAdamts7in either cell type is insufficient to reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and decreased fibrous cap formation. RNA-sequencing in SMCs revealed an upregulation of lipid uptake genes typically assigned to macrophages. Subsequent experiments demonstrated that ADAMTS7 increases SMC oxLDL uptake through increased CD36 levels. Furthermore,Cd36expression is increased due to increased levels of PU.1, a transcription factor typically associated with myeloid fate determination. In summary,Adamts7expression in either SMCs or ECs promotes SMC foam cell formation and atherosclerosis. In SMCs, ADAMTS7 promotes oxLDL uptake via increased PU.1 andCd36expression, thereby increasing SMC foam cell formation and atherosclerosis.
Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia
Authors: Wen Kailong , Shi Zhuoyue , Yu Peijia , Mo Lillian , Sullere Shivang , Yang Victor , Westneat Nate , Beeler Jeff A , McGehee Daniel S , Doiron Brent , Zhuang Xiaoxi
Published: February 2024

Loss of dopamine neurons causes motor deterioration in Parkinson’s disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m6A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion ofYthdf1in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinson’s disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.
Genome concentration limits cell growth and modulates proteome composition inEscherichia coli
Authors: Mäkelä Jarno , Papagiannakis Alexandros , Lin Wei-Hsiang , Lanz Michael C. , Glenn Skye , Swaffer Matthew , Marinov Georgi K. , Skotheim Jan M. , Jacobs-Wagner Christine
Published: February 2024

Defining the cellular factors that drive growth rate and proteome composition is essential for understanding and manipulating cellular systems. In bacteria, ribosome concentration is known to be a constraining factor of cell growth rate, while gene concentration is usually assumed not to be limiting. Here, using single-molecule tracking, quantitative single-cell microscopy, and modeling, we show that genome dilution inEscherichia colicells arrested for DNA replication limits total RNA polymerase activity within physiological cell sizes across tested nutrient conditions. This rapid-onset limitation on bulk transcription results in sub-linear scaling of total active ribosomes with cell size and sub-exponential growth. Such downstream effects on bulk translation and cell growth are near-immediately detectable in a nutrient-rich medium, but delayed in nutrient-poor conditions, presumably due to cellular buffering activities. RNA sequencing and tandem-mass-tag mass spectrometry experiments further reveal that genome dilution remodels the relative abundance of mRNAs and proteins with cell size at a global level. Altogether, our findings indicate that chromosome concentration is a limiting factor of transcription and a global modulator of the transcriptome and proteome composition inE. coli. Experiments inCaulobacter crescentusand comparison with eukaryotic cell studies identify broadly conserved DNA concentration-dependent scaling principles of gene expression.
Bayesian Hierarchical Hypothesis Testing in Large-Scale Genome-Wide Association Analysis
Authors: Samaddar Anirban , Maiti Tapabrata , de los Campos Gustavo
Published: February 2024

Variable selection and large-scale hypothesis testing are techniques commonly used to analyze high-dimensional genomic data. Despite recent advances in theory and methodology, variable selection and inference with highly collinear features remain challenging. For instance, collinearity poses a great challenge in Genome-Wide Association Studies (GWAS) involving millions of variants, many of which may be in high linkage disequilibrium. In such settings, collinearity can significantly reduce the power of variable selection methods to identify individual variants associated with an outcome. To address such challenges, we developed a Bayesian Hierarchical Hypothesis Testing (BHHT)–a novel multi-resolution testing procedure that offers high power with adequate error control and fine-mapping resolution. We demonstrate through simulations that the proposed methodology has a power-FDR performance that is competitive with (and in many scenarios better than) state-of-the-art methods. Finally, we demonstrate the feasibility of using the proposed methodology with big data to map risk variants for serum urate using data (n∼300,000) on phenotype and ultra-high-dimensional genotypes (∼15 million SNPs) from the UK-Biobank. Our results show that the proposed methodology leads to many more discoveries than those obtained using traditional feature-centered inference procedures. The article is accompanied by open-source software that implements the methods described in this study using algorithms that scale to biobank-size ultra-high-dimensional data.
Reactivated past decisions repel early sensory processing and attract late decision-making
Authors: Luo Minghao , Zhang Huihui , Luo Huan
Published: February 2024

Automatic shaping of perception by past experiences is common in many cognitive functions, reflecting the exploitation of temporal regularities in environments. A striking example is serial dependence, i.e., current perception is biased by previous trials. However, the neural implementation of its operational circle in human brains remains unclear. In two experiments with Electroencephalography (EEG) / Magnetoencephalography (MEG) recordings and delayed-response tasks, we demonstrate a two-stage ’repulsive-then-attractive’ past-present interaction mechanism underlying serial dependence. First, past-trial reports serve as a prior to be reactivated during both encoding and decision-making. Crucially, past reactivation interacts with current information processing in a two-stage manner: repelling and attracting the present during encoding and decision-making, and arising in the sensory cortex and prefrontal cortex, respectively. Finally, while the early stage occurs automatically, the late stage is modulated by task and predicts bias behavior. Our findings might also illustrate general mechanisms of past-present influences in neural operations.
CD34-positive monocytes are highly susceptible to HIV-1
Authors: Takahashi Naofumi , Noyori Osamu , Komohara Yoshihiro , Eltalkhawy Youssef M. , Hirayama Masatoshi , Yoshida Ryoji , Nakayama Hideki , Kuroda Marcelo J. , Nomura Takushi , Ishii Hiroshi , Matano Tetsuro , Gatanaga Hiroyuki , Oka Shinichi , Takiguchi Masafumi , Suzu Shinya
Published: February 2024

HIV-1 persists in cellular reservoirs despite effective combined antiretroviral therapy (cART). CD4+T cells are a well-known reservoir, but there is evidence suggesting that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is not fully understood which subsets of monocytes are preferentially infected in vivo. Here, we show that a monocyte fraction expressing a stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In cART-untreated viremic individuals, the CD34+fraction increased in the percentage in total monocytes, and harbored higher copies of proviral DNA than the major subset. Consistent with this, the CD34+fraction expressed HIV-1 receptors CD4 and CCR5 at higher levels and HIV-1 restriction factors MX2 and SAMHD1 at lower levels. Interestingly, proviral DNA was still detectable in the CD34+fraction of cART-treated virologically suppressed individuals. CD34+monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed in peripheral blood. Moreover, CD34+monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Collectively, our findings raise the new possibility that lymph node CD34+monocytes, which originate from the circulation, are infected with HIV-1 owing to their high susceptibility to HIV-1, and return to circulation, which explains the detection of proviral DNA in peripheral CD34+monocytes even after long-term cART.
Development and Validation of a Deep Learning Model for Detecting Signs of Tuberculosis on Chest Radiographs among US-bound Immigrants and Refugees
Authors: Lee Scott , Fox Shannon , Smith Raheem , Skrobarcek Kimberly A. , Keyserling Harold , Phares Christina R. , Lee Deborah , Posey Drew L.
Published: February 2024

Immigrants and refugees seeking admission to the United States must first undergo an overseas medical exam, overseen by the US Centers for Disease Control and Prevention (CDC), during which all persons ≥15 years old receive a chest x-ray to look for signs of tuberculosis. Although individual screening sites often implement quality control (QC) programs to ensure radiographs are interpreted correctly, the CDC does not currently have a method for conducting similar QC reviews at scale.

We obtained digitized chest radiographs collected as part of the overseas immigration medical exam. Using radiographs from applicants 15 years old and older, we trained deep learning models to perform three tasks: identifying abnormal radiographs; identifying abnormal radiographs suggestive of tuberculosis; and identifying the specific findings (e.g., cavities or infiltrates) in abnormal radiographs. We then evaluated the models on both internal and external testing datasets, focusing on two classes of performance metrics: individual-level metrics, like sensitivity and specificity, and sample-level metrics, like accuracy in predicting the prevalence of abnormal radiographs.

A total of 152,012 images (one image per applicant; mean applicant age 39 years) were used for model training. On our internal test dataset, our models performed well both in identifying abnormalities suggestive of TB (area under the curve [AUC] of 0.97; 95% confidence interval [CI]: 0.95, 0.98) and in estimating sample-level counts of the same (−2% absolute percentage error; 95% CIC: −8%, 6%). On the external test datasets, our models performed similarly well in identifying both generic abnormalities (AUCs ranging from 0.89 to 0.92) and those suggestive of TB (AUCs from 0.94 to 0.99). This performance was consistent across metrics, including those based on thresholded class predictions, like sensitivity, specificity, and F1 score.

Strong performance relative to high-quality radiological reference standards across a variety of datasets suggests our models may make reliable tools for supporting chest radiography QC activities at CDC.
Carboxylated graphene: A novel approach for enhanced IgA-SARS-CoV-2 electrochemical biosensing
Authors: Freire Luciana de Souza , Ruzo Camila Macena , Salgado Barbara Batista , Gandarilla Ariamna María Dip , Barcelay Yonny Romaguera , Tavares Ana P.M. , Nobre Francisco Xavier , Lalwani Pritesh , Astofi-Filho Spartaco , Brito Walter Ricardo
Published: February 2024

Biosensors comprise devices that use a material of biological nature as receptors connected to transducers, these devices are capable of capturing biorecognition signals, called a primary signal, and converting it to a measurable signal. In this study, we report the synthesis of carboxylated graphene (CG) through a carboxylation method in acid medium and further characterization of the materials by different techniques such as scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), Raman spectroscopy, thermal gravimetric analysis (TGA), and X-ray diffraction (DRX). Also, the surface of the screen-printed carbon electrodes (SPCEs) was modified with CG for subsequent immobilization of N-protein of SARS-CoV-2, which allowed the detection of antibodies (IgA-SARS-CoV-2). The electrical properties and response of the biosensor were investigated using electrochemical techniques (cyclic voltammetry and electrochemical impedance spectroscopy). Through the chemical characterization techniques, it was possible to confirm the success of the CG synthesis process. The biosensor fabricated shown to be able to detect IgA-SARS-CoV-2 in the range of 1:1000 to1:200 v/v in phosphate buffer solution (PBS) and the limit of detection calculated was 1:1601 v/v. this perspective they comprise a wide range of applications due to its advantages, such as the possibility of a shorter response time, reproducibility, the miniaturization of detection devices such as the use of screen-printed electrodes, the use of small amounts of sample, the high sensitivity and specificity, low limits of detection and the integration of nano materials that make it possible to improve the detected signal.