bluuebunny/crossref_metadata_2025 huggingface dataset:
The ideational robustness of bureaucracy
Authors: Sørensen Eva , Torfing Jacob
Published: May 2024

To better understand why bureaucracy is still going strong despite a century of scorn, this article asks: How has the bureaucratic governance paradigm managed to achieve its ideational robustness in the face of consecutive waves of criticism and societal challenges? This question is answered by studying the combination of a broad range of ideational robustness strategies that have enabled bureaucracy to weather the storm and stay relevant and praiseworthy in the eyes of public governors. The article describes the core components of the bureaucratic governance paradigm and reviews four consecutive waves of criticism before explaining the ideational changes that have enabled the relative stability of public bureaucracy based on the adaptation and innovation of its content and scope. In addition to summarizing key debates about public bureaucracy, the article develops six ideational robustness strategies that may be used to study other core ideas in public governance.
Trajectories of actigraphy-derived sleep duration, quality, and variability from childhood to adolescence: downstream effects on mental health
Authors: Thompson Morgan J , Gillis Brian T , Hinnant J Benjamin , Erath Stephen A , Buckhalt Joseph A , El-Sheikh Mona
Published: May 2024

Study Objectives

We examined growth trajectories of four actigraphy-derived sleep parameters (sleep minutes, sleep efficiency, and variability in sleep minutes and efficiency across a week of assessments) across childhood and adolescence and examined individual differences in trajectories according to participants’ race/ethnicity and sex. We also assessed the predictive effect of growth trajectories of sleep parameters on growth trajectories of mental health outcomes and moderation by race and sex.

Method

Youth (N = 199, 49% female, 65% white, 32% black, 3% biracial) and their parents participated in five waves of data (M ages were 9, 10, 11, 17, and 18 across waves). Participants were from a diverse range of socioeconomic backgrounds.

Results

Across participants, sleep minutes, sleep efficiency, and variability in sleep minutes and efficiency demonstrated significant linear change across childhood and adolescence. Whereas sleep duration shortened over time, sleep efficiency improved. Youth exhibited increases in night-to-night variability in sleep minutes and reductions in night-to-night variability in sleep efficiency. Highlighting the importance of individual differences, some race- and sex-related effects emerged. Black youth and male youth experienced steeper declines in their sleep duration across development relative to their respective counterparts. Black youth also demonstrated smaller improvements in sleep efficiency and greater variability in sleep efficiency compared to white youth. Finally, trajectories of sleep efficiency and variability in sleep minutes predicted trajectories of internalizing symptoms and externalizing behaviors.

Conclusions

Findings showed significant changes in developmental trajectories of four sleep parameters across childhood and adolescence. We discuss the empirical and translational implications of the findings.
The Greek Executive State Model: A Paradigm for Better Legislation
Authors: Xanthaki Helen
Published: May 2024

This paper presents and critically assessed the implementation of the executive state model in Greek law-making, and identifies the elements of the model that are transferable elsewhere. The first four years of extensive legislative reforms in application of the executive state model have produced tangible innovations fertile to better law-making. But the real challenge, the change of legislative mentality, resists.
PFAS and their association with the increased risk of cardiovascular disease in postmenopausal women
Authors: Arredondo Eve Alicia , Tunc Elif , Mehta Dhruv , Yoo Jin Young , Yilmaz Huriye Erbak , Emren Sadık Volkan , Akçay Filiz Akyıldız , Madak Erdogan Zeynep
Published: May 2024

Cardiovascular diseases (CVDs) are one of the major causes of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence CVD risk. Per- and polyfluoroalkyl substances (PFASs) are a class of highly fluorinated chemicals used in household consumer and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorobutanesulfonic acid in postmenopausal women from our previously established CVD study. We used liquid chromatography with tandem mass spectrometry, supported by machine learning approaches, and the detection and quantification of serum metabolites and proteins. Here, we show that PFOS can be a good predictor of coronary artery disease, whereas PFOA can be an intermediate predictor of coronary microvascular disease. We also found that the PFAS levels in our study are significantly associated with inflammation-related proteins. Our findings may provide new insight into the potential mechanisms underlying the PFAS-induced risk of CVDs in this population.

This study shows that exposure to PFOA and PFOS is associated with an increased risk of cardiovascular disease in postmenopausal women. PFOS and PFOA levels correlate with amino acids and proteins related to inflammation. These circulating biomarkers contribute to the etiology of CVD and potentially implicate a mechanistic relationship between PFAS exposure and increased risk of cardiovascular events in this population.
Bringing light into deep-sea biodiversity: a systematic revision and molecular phylogeny of the genus Scaphander Montfort, 1810 (Gastropoda: Cephalaspidea), with a focus on the Indo-Pacific
Authors: Siegwald Justine , Malaquias Manuel António E
Published: May 2024

Scaphander is a genus of mostly deep-sea, soft-bottom gastropods distributed nearly worldwide. Its taxonomic history is complex, with 32 species currently accepted, most based on shells only. In this work, we revise the diversity and systematics of Scaphander, with a focus on the Indo-Pacific region, using a detailed morphological study and molecular phylogenetics. Conchological and anatomical characters, such as digestive and male reproductive systems were compared, and original descriptions and type material were investigated. Additionally, molecular species delimitation methods were used, such as Assemble Species by Automatic Partitioning (ASAP) based on the gene cytochrome c oxidase subunit I, and the multispecies coalescent method Species Tree And Classification Estimation, Yarely (STACEY) based on a dataset of five gene markers. Thirty-three Scaphander species were recognized worldwide, 10 still based only on shells. Five species are here described as new to science, namely Scaphander amygdalus sp. nov., Scaphander cornus sp. nov., Scaphander obnubilus sp. nov., Scaphander semicallus sp. nov. and Scaphander solomonensis sp. nov. The most diverse region is the Western Pacific (17 species), followed by the Atlantic (12 species) and the Indian Ocean (7 species).
High-Dose Buprenorphine Initiation: A Scoping Review
Authors: Wong Stanley , Fabiano Nicholas , Webber Declan , Kleinman Robert A.
Published: May 2024

Objective

The aim of the study is to review and synthesize the literature on high-dose buprenorphine initiation (>12-mg total dose on day of initiation).

Methods

A scoping review of literature about high-dose buprenorphine initiation was conducted. MEDLINE, Embase, PsycINFO, and Cochrane Central were searched. Randomized controlled trials, prospective and retrospective cohort studies, and case studies/reports published in English before February 13, 2023, were included.

Results

Fifteen studies reporting outcomes from 580 high-dose buprenorphine initiations were included. Eight studies were in inpatient settings, 3 in emergency departments, 3 in outpatient settings, and 1 in a first-responder setting. Four studies reported high-dose initiations among individuals exposed to fentanyl. There were no reported events of fatal or nonfatal overdose or respiratory depression, although adverse event reporting was inconsistent in published reports. The most reported side effects with high-dose buprenorphine initiation were nausea or vomiting (n = 17) and precipitated withdrawal (n = 7). The most serious reported adverse event was hypotension requiring oral hydration (n = 2). Most studies reported improvements in subjective or objective withdrawal symptoms. The duration of follow-up ranged from none to 8 months.

Conclusions

High-dose buprenorphine initiation has not been associated with reported cases of overdose or respiratory depression. However, the current literature about high-dose buprenorphine is limited by inconsistent side effect reporting, limited power to detect rare safety events such as respiratory depression, limited follow-up data, and few comparison studies between high-dose and regular initiation protocols. Further prospective data are needed to evaluate the safety and effectiveness of this initiation strategy.
Success of Ultra-low Dose Radiation Therapy for Primary Cutaneous B-cell Lymphoma
Authors: Onyewadume Louisa , McClelland Shearwood
Published: May 2024

Objectives:

Primary cutaneous B-cell lymphoma (PCBCL) is a relatively rare disease, associated with 5-year overall survival of nearly 95% when treated with external beam radiation therapy (EBRT) alone. However, standard EBRT doses yield acute skin toxicity in more than 70% of patients and grade 3 to 4 acute skin toxicity in nearly 10% of patients. Consequently, the PCBCL treatment paradigm is shifting towards lower EBRT doses. This study evaluates our early experience with ultra-low dose EBRT (total dose of 4 Gy in 2 fractions) for PCBCL.

Methods:

Four biopsy-confirmed PCBCL lesions (1 anterior thigh and 3 chest) in 2 male patients were treated with 2 Gy×2 fraction EBRT using electrons through a clinical setup. The anterior thigh lesion was treated using a clamshell to protect the scrotum from scatter dose. Treatment was achieved using 9 MeV electrons to the 85% isodose line using no bolus, with follow-up every 4 months and potential retreatment if no visible response at 8 to 9 months.

Results:

All lesions demonstrated a response to EBRT by 4 months, visibly manifesting as flattening with changes in pigmentation. At the last follow-up (20, 20, 16.5, and 4 mo, respectively), all lesions had flattened with no evidence of local recurrence and no skin toxicity.

Conclusions:

Treatment of PCBCL with ultra-low dose EBRT to 4 Gy total dose in 2 fractions provides durable local control with zero skin toxicity. These results are encouraging for both the success of treatment and the potential to use similarly low doses for retreatment should patients exhibit local recurrence.
Developing Parametric and Nonparametric Models for Model-Informed Precision Dosing: A Quality Improvement Effort in Vancomycin for Patients With Obesity
Authors: Hughes Maria-Stephanie A. , Hughes Jasmine H. , Endicott Jeffrey , Langton Meagan , Ahern John W. , Keizer Ron J.
Published: May 2024

Background:

Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity.

Methods:

Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using Pmetrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset.

Results:

In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24–89 years), and a median BMI of 46.3 kg/m2 (range: 40–70.3 kg/m2). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were −6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients).

Conclusions:

Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.
Temporal Profile of Serum Neurofilament Light (NF-L) and Heavy (pNF-H) Level Associations With 6-Month Cognitive Performance in Patients With Moderate-Severe Traumatic Brain Injury
Authors: Trifilio Erin , Bottari Sarah , McQuillan Leah E. , Barton David J. , Lamb Damon G. , Robertson Claudia , Rubenstein Richard , Wang Kevin K. , Wagner Amy K. , Williamson John B.
Published: May 2024

Objective:

Identification of biomarkers of cognitive recovery after traumatic brain injury (TBI) will inform care and improve outcomes. This study assessed the utility of neurofilament (NF-L and pNF-H), a marker of neuronal injury, informing cognitive performance following moderate-to-severe TBI (msTBI).

Setting:

Level 1 trauma center and outpatient via postdischarge follow-up.

Participants:

N = 94. Inclusion criteria: Glasgow Coma Scale score less than 13 or 13-15 with clinical evidence of moderate-to-severe injury traumatic brain injury on clinical imaging. Exclusion criteria: neurodegenerative condition, brain death within 3 days after injury.

Design:

Prospective observational study. Blood samples were collected at several time points post-injury. Cognitive testing was completed at 6 months post-injury.

Main Measures:

Serum NF-L (Human Neurology 4-Plex B) pNF-H (SR-X) as measured by SIMOA Quanterix assay. Divided into 3 categorical time points at days post-injury (DPI): 0-15 DPI, 16-90 DPI, and >90 DPI. Cognitive composite comprised executive functioning measures derived from 3 standardized neuropsychological tests (eg, Delis-Kaplan Executive Function System: Verbal Fluency, California Verbal Learning Test, Second Edition, Wechsler Adult Intelligence Scale, Third Edition).

Results:

pNF-H at 16-90 DPI was associated with cognitive outcomes including a cognitive-executive composite score at 6 months (β = −.430, t
34 = −3.190, P = .003).

Conclusions:

Results suggest that “subacute” elevation of serum pNF-H levels may be associated with protracted/poor cognitive recovery from msTBI and may be a target for intervention. Interpretation is limited by small sample size and including only those who were able to complete cognitive testing.
Impact of Early Personal Resources on Long-Term Psychosocial Outcomes After Moderate-to-Severe Traumatic Brain Injury: A Systematic Review
Authors: Bray Emily Alice , Hogan Christy , Mitchell Jessie , Geraghty Timothy , Ownsworth Tamara
Published: May 2024

Objective:

To investigate the relationship between preinjury or early personal resources and long-term psychosocial outcomes following moderate-to-severe traumatic brain injury (TBI) and examine evidence for the stability of personal resources over time.

Methods:

The review protocol was registered with the International Register of Systematic Reviews (PROSPERO, Registration No. CRD4202341056). A search of PsycINFO, Cumulative Index to Allied Health Literature (CINAHL), MEDLINE, Scopus, and Web of Science was conducted from inception to February 23, 2023, for longitudinal studies involving adults with moderate-to-severe TBI that examined: (1) the relationship between preinjury or early personal resources (measured ≤6 months postinjury) and later psychosocial outcomes or (2) stability of personal resources over time with a minimum reassessment interval of 3 months. Two reviewers independently assessed eligibility and rated methodological quality of studies using a checklist informed by Strengthening the Reporting of Observational Studies in Epidemiology.

Results:

A narrative synthesis was conducted on 14 eligible articles summarizing 12 studies (N = 826). Nine studies examined the impact of preinjury or early personal resources on long-term psychosocial outcomes, most typically at 12 months postdischarge. Out of 9 studies 7 indicated that self-reported preinjury or early personal resources, including productive coping, higher self-esteem and resilience, and lower neuroticism, were associated with better psychosocial outcomes. Evidence from 7 studies examining the stability of personal resources over time was generally mixed, with personality changes (eg, neuroticism, conscientiousness, and extraversion) more evident from informant ratings than self-ratings.

Conclusion:

Preinjury or early personal resources may influence later psychosocial outcomes after TBI. Further research is needed to investigate the stability of personal resources and factors mediating or moderating change across the adjustment trajectory.
Growing the Neonatal Nurse Practitioner Workforce Through Mentoring
Authors: Baker Lela A. , Moss Colleen , Bordelon Curry , Savin Michele K.
Published: May 2024

Objective:

The purpose of this article is to highlight evidence specific to the neonatal nurse practitioner (NNP) workforce related to successful mentoring programs. Specifically, the authors of this article explored recent evidence of mentorship to improve job satisfaction and retention of the NNP workforce.

Background:

NNPs are valuable members of neonatal healthcare team. Because of the aging NNP workforce, methods to recruit, train, mentor, develop, and retain new NNPs are imperative.

Methods:

Using a quality appraisal tool from the PRISMA extension for scoping reviews, articles were identified through electronic database searches using search terms related to mentoring, nurse practitioners, recruitment, and retention. Studies published in English between 2013 and 2023 were included. Peer-reviewed quantitative and qualitative articles were synthesized and critically appraised by 4 reviewers.

Results:

The authors identified 46 articles with a focus on mentoring in nursing of which 12 articles include mentoring for nurse practitioners. Research indicates that mentoring relationships are valuable in many healthcare roles and professions. Evidence is limited indicating the impact of mentoring in the highly specialized role of the NNP.

Conclusion:

Mentoring is an invaluable component of professional nursing and counters incivility while advancing competency, job satisfaction, and retention. Additional research is needed regarding NNP-specific mentoring programs.
68Ga-PSMA-11 PET/CT in Cherry Hemangiomas
Authors: Betech-Antar Vicky , Urtasun-Iriarte César , Rosales Juan J. , Barrio-Piqueras Miguel , Rodriguez-Fraile Macarena
Published: May 2024

A 63-year-old man was remitted for a 68Ga-PSMA-11 PET/CT scan due to biochemical recurrence with a PSA of 0.32 ng/mL 1 year after radical prostatectomy of locally advanced Gleason 6 (3 + 3) ISUP 2 pT3a pN0 prostate cancer. 68Ga-PSMA-11 PET/CT showed multiple cutaneous and subcutaneous uptake foci in the upper body. Physical examination revealed numerous dome-shaped, ruby-red papules. These were consistent with a previous diagnosis of cutaneous hemangiomas. Cherry hemangiomas (also known as Campbell de Morgan spots) are the most common type of benign vascular proliferation of the skin. Due to the nonspecific 68Ga-PSMA-11 uptake of vascular lesions, careful interpretation should be considered in order to avoid a potential pitfall in nonmalignant conditions.
Relationship Between Pericarotid Fat Density and Pathology-Based Carotid Plaque Risk Characteristics
Authors: Dai An , Yao Weinan , Lei Jing , Yan Limin , Dang Lei , Zhao Haijun , Gu Jingshun , Li Jun , Nie Ying , Zheng Mengru , Wang Dongchun , Wang Qingwen
Published: May 2024

Objectives:

In this study, the authors aimed to evaluate the relationship between pericarotid fat density (PFD) and pathologic carotid plaque risk characteristics.

Methods:

The authors retrospectively evaluated 58 patients (mean age: 66.66 ± 7.26 y, 44 males) who were subjected to both carotid endarterectomy and carotid artery computed tomography angiography (CTA) at the authors’ institution. The computed tomography values of the adipose tissue around the most severe stenosis carotid artery were measured, and the removed plaques were sent to the Department of Pathology for American Heart Association (AHA) classification. The Wilcoxon signed-rank test was used to detect the difference in PFD values between the operative and nonoperative sides. According to carotid plaque risk characteristics, the associations between PFD and 4 different risk characteristic subgroups were analyzed. The Student t test and χ2 test were used to compare differences between different risk subgroups. Receiver operating characteristic curve analysis was used to evaluate the predictive efficacy of PFD for carotid plaque risk characteristics.

Results:

The operative side had higher mean Hounsfield units (HU) values compared with the nonoperative side (P < 0.001). The AHA VI and the intraplaque hemorrhage (IPH) subgroups had higher mean HU values compared with the non-AHA VI and the non-IPH subgroups (P < 0.05). Male patients presented with IPH more than female patients (P = 0.047). The results of receiver operating characteristic curve analysis showed that the mean HU value (operative side; area under the curve: 0.729, Sensitivity (SE): 59.26%, Specificity (SP): 80.65%, P = 0.003) had a certain predictive value for diagnosing high-risk VI plaques. Pericarotid fat density ≥ −68.167 HU is expected to serve as a potential cutoff value to identify AHA VI and non-AHA VI subgroups.

Conclusion:

PFD was significantly associated with vulnerable plaques, high-risk AHA VI plaques, and IPH, which could be an indirect clinical marker for vulnerable plaques.
Microvascular Decompression Plus Partial Resection of Trigeminal Nerve Motor Root for Hemimasticatory Spasm Combined With Hemifacial Atrophy: A Good Choice or Not?
Authors: Zhang Weifeng , Zhao Weiguo , Cai Yu
Published: May 2024

Hemimasticatory spasm (HMS) combined with hemifacial atrophy is a rare clinical entity with an unclear etiology. The authors report a 58-year-old female suffering from HMS and hemifacial atrophy, which performed microvascular decompression plus partial resection of the trigeminal nerve motor root, which is the first report in worldwide. The vascular compression of the trigeminal nerve motor root was found in surgery, the authors completed the aforementioned surgical method. The symptoms of HMS disappeared after surgery but recurred after 8 months.
Evaluation of Regio Temporalis in 3 Steps in Terms of Interventional Procedures
Authors: Ok Fatma , Coşkun Osman , Yiğit Mehmet , Kale Ayşin , Sağ Fatma Beyza
Published: May 2024

Regio temporalis is a site where botulinum neurotoxin is applied for various medical reasons, such as migraine, bruxism, and myofascial pain syndrome. The region is also one of the target regions in flap surgery. This study aimed to define the region topographically. In addition, it was aimed to reveal the intramuscular nerve distribution of the temporalis.11 fixed cephalus (cadaver head) and 2 fresh cephalus were used. The lateral canthus of the eye was marked as point A, and the middle of the ear tragus as point B. The transverse and vertical distances of the branching point of the superficial temporal artery to the A and B points were measured. Transverse distances of the superficial temporal artery and superficial temporal vein to A and B points were measured. The muscle was examined in 5 equal parts (L0–L1–L2–L3–L4), and each part’s vertical muscle and tendon lengths were examined. Intramuscular nerve density was demonstrated by applying the modified Sihler staining to fresh temporalis’. Superficial temporal artery had an average transverse distance of 8.56±1.9 mm in women and 12.56±1.94 mm in men from the middle of the ear tragus. The artery was 64.21±5.59 mm posterior in females and 63.48±6.53 mm in males from the lateral canthus of the eye. Our study determined that the branching point of the superficial temporal artery was below the upper level of the arcus zygomaticus in 10% of cases and above it in 90% of cases. In our study, the L2 point had the highest vertical muscle length at 45.67 mm, while the L3 point had the highest vertical tendon length at 41.25 mm. The point where the muscle length had the highest ratio with 1.49 compared to the tendon length, was the L2 point. The temporalis’ for which the modified Sihler staining was applied was examined in 5 quadrants. It was determined that the nerve densities were in the second and third quadrants from anterior to posterior. The distance of superficial landmarks to neurovascular structures is extremely important in interventions to the regio temporalis. Considering the average distances given in our study is important in avoiding damage in surgical procedures and not injecting into vascular structures. The point where the muscle length had the highest ratio of 1.49 compared to the tendon length was the L2 point. The area in line with this point is the most suitable area for injection. The L2 point is also the most suitable area for injection as it has the highest muscle length. Since the nerve densities were observed in the modified Sihler staining applied temporalis’ 2 and 3 quadrants from anterior to posterior, botulinum neurotoxin injections to these areas will give more effective results.
New Tools for Data Harmonization and Their Potential Applications in Organ Transplantation
Authors: Tabatabaei Hosseini Seyed Amir , Kazemzadeh Reza , Foster Bethany Joy , Arpali Emre , Süsal Caner
Published: May 2024

In organ transplantation, accurate analysis of clinical outcomes requires large, high-quality data sets. Not only are outcomes influenced by a multitude of factors such as donor, recipient, and transplant characteristics and posttransplant events but they may also change over time. Although large data sets already exist and are continually expanding in transplant registries and health institutions, these data are rarely combined for analysis because of a lack of harmonization. Promoted by the digitalization of the healthcare sector, effective data harmonization tools became available, with potential applications also for organ transplantation. We discuss herein the present problems in the harmonization of organ transplant data and offer solutions to enhance its accuracy through the use of emerging new tools. To overcome the problem of inadequate representation of transplantation-specific terms, ontologies and common data models particular to this field could be created and supported by a consortium of related stakeholders to ensure their broad acceptance. Adopting clear data-sharing policies can diminish administrative barriers that impede collaboration between organizations. Secure multiparty computation frameworks and the artificial intelligence (AI) approach federated learning can facilitate decentralized and harmonized analysis of data sets, without sharing sensitive data and compromising patient privacy. A common image data model built upon a standardized format would be beneficial to AI-based analysis of pathology images. Implementation of these promising new tools and measures, ideally with the involvement and support of transplant societies, is expected to produce improved integration and harmonization of transplant data and greater accuracy in clinical decision-making, enabling improved patient outcomes.
How to Set up and Run a Bad Bugs Bookclub group: resources and recommendations
Authors: Verran Joanna
Published: May 2024

The Bad Bugs Bookclub is a public engagement initiative that enables scientists (microbiologists) and non-scientists to discuss the role of infectious disease and microorganisms in novels of fiction. The bookclub began in 2009 but since 2020 the meetings have taken place online, enabling international membership and occasional author participation. The bookclub has been shown through peer-reviewed publications to have impact and value to its members. For each book (the number now exceeds 100) a reading guide (questions to provoke discussion) and a meeting report (narrative of the discussion) have been produced. Previously hosted on a website, the reading guides from this rich archive and resource are now presented alongside this paper which provides tips on how to run a similar reading group.
Simulating pedigrees ascertained on the basis of observed IBD sharing
Authors: Jewett Ethan M. ,   the 23andMe Research Team
Published: May 2024

1.

In large genotyping datasets, individuals often have thousands of distant cousins with whom they share detectable segments of DNA identically by descent (IBD). The ability to simulate these distant relationships is important for developing and testing methods, carrying out power analyses, and performing population genetic analyses. Because distant relatives are unlikely to share detectable IBD segments by chance, many simulation replicates are needed to sample IBD between any given pair of distant relatives. Exponentially more samples are needed to simulate observable segments of IBD simultaneously among multiple pairs of distant relatives in a single pedigree. Using existing pedigree simulation methods that do not condition on the event that IBD is observed among certain pairs of relatives, the chances of sampling shared IBD patterns that reflect those observed in real data ascertained from large genotyping datasets are vanishingly small, even for pedigrees of modest size. Here, we show how to sample recombination breakpoints on a fixed pedigree while conditioning on the event that specified pairs of individuals share at least one observed segment of IBD. The resulting simulator makes it possible to sample genotypes and IBD segments on pedigrees that reflect those ascertained from biobank scale data.
A homozygousATP2A2variant alters sarcoendoplasmic reticulum Ca2+-ATPase 2 function in skeletal muscle and causes a novel vacuolar myopathy
Authors: Llansó Laura , Ravenscroft Gianina , Aceituno Cristina , Gutiérrez Antonio , Parmar Jevin , Gallano Pia , Caballero-Ávila Marta , Carbayo Álvaro , Vesperinas Ana , Collet Roger , Blanco Rosa , Laing Nigel , Hove-Madsen Leif , Gallardo Eduard , Olivé Montse
Published: May 2024

Background

Sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), encoded byATP2A2, is a key protein involved in intracellular Ca2+homeostasis. The transcript SERCA2a is predominantly expressed in cardiac muscle and in type I myofibers, while SERCA2b is ubiquitously expressed including in skin cells. To date, variants in this gene were reported to be the cause of Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to primary skeletal muscle disease. We describe four patients suffering from a novel hereditary myopathy caused by a homozygous missense variant inATP2A2.

Methods

We studied a family with four affected individuals suffering from an adult-onset progressive skeletal myopathy. We performed a comprehensive evaluation of the clinical phenotype, serum CK levels, muscle MRI, and muscle biopsy, with genetic workup by means of gene panel sequencing followed by whole genome sequencing and segregation analysis. Immunohistochemistry and western blot (WB) to evaluate SERCA2 and SERCA1 expression in skeletal muscle was performed. We evaluated kinetics of Ca2+handling following caffeine exposure or voltage-induced sarcolemma depolarization in patient myoblasts and myotubes, compared to healthy controls.

Results

Four siblings in their fifties developed in early adulthood symmetric proximal weakness in lower limbs, which was slowly progressive over time. They had no skin or cardiac involvement. Biopsy findings in two affected individuals showed small vacuoles restricted to type I myofibers. Ultrastructural analysis showed dilation and proliferation of T-tubules, swelling of sarcoplasmic reticulum and autophagic vacuoles. Genome sequencing revealed a homozygous variant inATP2A2(c.1117G>A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested SERCA2 mislocalization in patient myofibers compared to controls. WB did not show changes in the amount or molecular weight of the protein.In vitrofunctional studies revealed delayed sarcoendoplasmic reticulum Ca2+reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation with caffeine or depolarization.

Conclusions

We report a novel adult-onset vacuolar myopathy caused by a homozygous variant inATP2A2, resulting in a pure skeletal muscle phenotype with a limb-girdle distribution. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca2+dysregulation in slow-twitch skeletal myofibers highly support the pathogenicity of the variant.
Role of Lamin A/C on dendritic cell function in antiviral immunity
Authors: Herrero-Fernandez Beatriz , Bris Raquel Gómez , Zapero Marina Ortega , Saez Angela , Iborra Salvador , Zorita Virginia , Quintas Ana , Vazquez Enrique , Dopazo Ana , Sánchez-Madrid Francisco , Arribas Silvia Magdalena , Granado Jose Maria Gonzalez
Published: May 2024

Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing -CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primaryVaccinia virus(VACV) infection. Remarkably,in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naïve CD4 T cells. Lamin A/C deletion induces alterations in NFκB nuclear localization, thereby influencing NFκB-dependent transcription. Furthermore, lamin A/C ablation modifies the epigenetic signature of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and elucidates the molecular mechanisms through which lamin A/C modulates DC function via epigenetic and transcriptional regulation.
Imaging of MAP kinase dynamics reveals endocytic regulation of pulsatile signalling and network re-wiring in response to targeted therapy in EGFR-mutant non-small cell lung cancer
Authors: Le Marois Alix , Bailey Sasha , Hooper Steven , Kumar Sunil , Sparks Hugh , Alexandrov Yuriy , Caswell Deborah , Frӧhlich Fabian , Schlegelmilch Karin , Valand Karishma , Martin Matthew , Narvaez Ana , Swanton Charles , Downward Julian , Dunsby Christopher , French Paul , Sahai Erik
Published: May 2024

A better understanding of the signalling mechanisms underlying transitions from drug-sensitive to drug-tolerant states is required to overcome therapy failure. We combined single-cell biosensor imaging with functional perturbations to investigate the regulation of oncogenic signalling in EGFR-mutant lung adenocarcinoma. We find that despite the constant presence of the mutant oncogene, ERK signalling exhibits pulsatile dynamics, with pulse characteristics determined by the endocytic machinery. Analysis of drug-tolerant persisters (DTPs) revealed that, after an initial phase of complete pathway shut-down, signalling was rewired leading to renewed ERK pulses that drive cell cycle progression. FAK- and SRC-regulated adhesion complexes replace mutant EGFR as the driver of reactivated ERK pulses in DTPs, yet they remain controlled by the membrane trafficking machinery. We show that DTPs rely on additional survival pathways including YAP signalling, and that the phosphatase PTPRS represents a key node in therapy resistant cells, coordinating regulation of ERK, the cytoskeleton, and YAP.
Lysineless HiBiT and NanoLuc Tagging Systems as Alternative Tools Monitoring Targeted Protein Degradation
Authors: Lin Hanfeng , Riching Kristin , Lai May Poh , Lu Dong , Cheng Ran , Qi Xiaoli , Wang Jin
Published: May 2024

Target protein degradation (TPD) has emerged as a revolutionary approach in drug discovery, leveraging the cell’s intrinsic machinery to selectively degrade disease-associated proteins. Proteolysis-Targeting Chimeras (PROTACs) exemplify this strategy, exploiting heterobifunctional molecules to induce ubiquitination and subsequent degradation of target proteins. The clinical advancement of PROTACs underscores their potential in therapeutic intervention, with numerous projects progressing through clinical stages. However, monitoring subtle changes in protein abundance induced by TPD molecules demands highly sensitive assays. Nano-luciferase (nLuc) fusion proteins, or the NanoBiT technology derived from it, offer a robust screening platform due to their high sensitivity and stability. Despite these advantages, concerns have arisen regarding potential degradation artifacts introduced by tagging systems due to the presence of lysine residues on them, prompting the development of alternative tools. In this study, we introduce HiBiT-RR and nLucK0, variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that HiBiT-RR maintains similar sensitivity and binding affinity with the original HiBiT. Moreover, the comparison between nLucWTand nLucK0constructs reveals variations in degradation patterns induced by certain PROTAC molecules, emphasizing the importance of choosing appropriate tagging systems to ensure the reliability of experimental outcomes in studying protein degradation processes.
SS18::SSX redistributes BAF chromatin remodelers selectively to activate and repress transcription
Authors: Li Jinxiu , Li Li , Smith-Fry Kyllie , Wilmot Zaki F. , Carroll Lara , Morrison Linda , Ge Xinyi , Nelson Mary , Hill Lesley A. , Zhang Xiaoyang , Nielsen Torsten O. , Hirst Martin , Underhill T. Michael , Cairns Bradley R. , Jones Kevin B.
Published: May 2024

Synovial sarcoma (SyS) is driven by the expression of a chromosomal translocation-generated SS18::SSX fusion oncoprotein1,2. This oncoprotein fuses the SSX carboxy terminal tail that binds ubiquitylated histone H2A (H2AK119ub)3–6to the SS18 component of both canonical (CBAF) and non-canonical (GBAF, GLTSCR1-containing) BAF-family chromatin remodeling complexes7–11, wherein SS18::SSX reprograms the epigenetic landscape. Mice that express SS18::SSX develop tumors that faithfully recapitulate human SyS histopathologically and molecularly12–14, allowing dissection of transcriptional reprogrammingin vivo15,16. Here, we show that SS18::SSX redistributes GBAF complexes broadly to promoters and distal enhancers decorated by H2AK119ub, which uncharacteristically lack the transcription-silencing trimethylation of H3K27 that otherwise accompanies H2AK119ub. Fusion-GBAF instead associates with H2AK119ub and transcription-enabling H3K4 trimethylation (promoters), monomethylation (distal enhancers), and H3K27 acetylation (both). CBAF with the fusion redistributes away from typical loci, avoids H2AK119ub-bearing regions, and instead narrowly flanks transcription start sites (TSSs), co-distributed with polybromo BAF (PBAF). Accelerated tumorigenesis in our SyS mouse model followed deletion ofSmarcb1(PBAF and CBAF),Pbrm1(PBAF-specific), andArid1aorArid1b(CBAF-specific). While tumors lackingArid1a or Arid1bretained SyS character, loss ofSmarcb1orPbrm1resulted in tumors lacking SyS features. These findings suggest that SyS transcriptional reprogramming includes both improper GBAF localization and gene activation at H2AK119ub-bearing regulatory regions and improper gene silencing through loss of CBAF.
Effects of alcohol consumption and tobacco smoking on the composition of the ensemble of drug metabolizing enzymes and transporters in human liver
Authors: Gaither Kari A. , Singh Dilip Kumar , Yue Guihua , Trudeau Julia , Ponraj Kannapiran , Davydova Nadezhda Y. , Lazarus Philip , Davydov Dmitri R. , Prasad Bhagwat
Published: May 2024

We examined the effect of alcohol consumption and smoking on the abundance of drug-metabolizing enzymes and transporters (DMET) in human liver microsomes (HLM) isolated from liver tissues of 94 donors. Global proteomics analysis was performed and DMET protein levels were analyzed in relation to alcohol consumption levels, smoking history, and sex using non-parametric tests (p-value ≤ 0.05; cutoff of 1.25-fold change, FC). The examination of the alcohol-induced changes was further enforced by correlational analysis, where we used arbitrary alcohol consumption grade (ACG) scaling from 0 to 4 to establish a set of protein markers. We elaborated a provisional index of alcohol exposure (PIAE) based on a combination of relative abundances of four proteins (ER chaperone HSPA5, protein disulfide isomerases PDIA3 and P4HB, and cocaine esterase CES2) best correlating with ACG. The PIAE index was then used to find its correlations with the abundances of DMET proteins. Our results demonstrate considerable alcohol-induced changes in composition of the pool of cytochrome P450 enzymes in HLM. We observed significantly increased abundances of CYP2E1, CYP2B6, CYP2J2, and NADPH-cytochrome P450 reductase. In contrast, CYP1A2, CYP2C8, CYP2C9, CYP4A11, and cytochrome b5protein levels were downregulated. Significant alteration in abundances of UDP-glucuronosyltransferase (UGT) were also detected, comprising of elevated UGT1A6, UGT1A9, and UGT2A1, and reduced UGT1A3, UGT1A4, UGT2B7, UGT2B10, and UGT2B15 levels. Important alcohol-induced changes were also observed in the expression of non-CYP and non-UGT DMET. Additionally, tobacco smoke was associated with elevated CYP1A2, UGT1A6, UGT2A1, and UGT2B4 and decreased FMO3, FMO4, and FMO5 levels.
Ecological Momentary Assessments of Trauma-Related Intrusive Memories: Potential Clinical Utility
Authors: Pollmann Yara , Clancy Kevin J. , Devignes Quentin , Ren Boyu , Kaufman Milissa , Rosso Isabelle M.
Published: May 2024

As the global prevalence of trauma rises, there is a growing need for accessible and scalable treatments for trauma-related disorders like posttraumatic stress disorder (PTSD). Trauma-related intrusive memories (TR-IMs) are a central PTSD symptom and a target of exposure-based therapies, gold-standard treatments that are effective but resource-intensive. This study examined whether a brief ecological momentary assessment (EMA) protocol assessing the phenomenology of TR-IMs could reduce intrusion symptoms in trauma-exposed adults.

Participants (N=131) experiencing at least 2 TR-IMs per week related to a DSM-5 criterion A trauma completed a 2-week EMA protocol during which they reported on TR-IM properties three times per day, and on posttraumatic stress symptoms at the end of each day. Longitudinal symptom measurements were entered into linear mixed-effects models to test the effect of Time on TR-IMs.

Over the 2-week EMA protocol, intrusion symptom severity (cluster B scores) significantly declined (t = −2.78, p = 0.006), while other symptom cluster scores did not significantly change. Follow-up analyses demonstrated that this effect was specific to TR-IMs (t = −4.02, p < 0.001), and was not moderated by survey completion rate, total PTSD symptom severity, or ongoing treatment.

Our findings indicate that implementing an EMA protocol assessing intrusive memories could be an effective trauma intervention. Despite study limitations like its quasi-experimental design and absence of a control group, the specificity of findings to intrusive memories argues against a mere regression to the mean. Overall, an EMA approach could provide a cost-effective and scalable treatment option targeting intrusive memory symptoms.
A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma
Authors: Pilcher William C. , Yao Lijun , Gonzalez-Kozlova Edgar , Pita-Juarez Yered , Karagkouni Dimitra , Acharya Chaitanya R. , Michaud Marina E , Hamilton Mark , Nanda Shivani , Song Yizhe , Sato Kazuhito , Wang Julia T. , Satpathy Sarthak , Ma Yuling , Schulman Jessica , D’Souza Darwin , Jayasinghe Reyka G. , Cheloni Giulia , Bakhtiari Mojtaba , Pabustan Nick , Nie Kai , Foltz Jennifer A. , Saldarriaga Isabella , Alaaeldin Rania , Lepisto Eva , Chen Rachel , Fiala Mark A. , Thomas Beena E , Cook April , Dos Santos Junia Vieira , Chiang I-ling , Figueiredo Igor , Fortier Julie , Slade Michael , Oh Stephen T. , Rettig Michael P. , Anderson Emilie , Li Ying , Dasari Surendra , Strausbauch Michael A , Simon Vernadette A ,   Immune Atlas Consortium, Rahman Adeeb H , Chen Zhihong , Lagana Alessandro , DiPersio John F. , Rosenblatt Jacalyn , Kim-Schulze Seunghee , Dhodapkar Madhav V , Lonial Sagar , Kumar Shaji , Bhasin Swati S , Kourelis Taxiarchis , Vij Ravi , Avigan David , Cho Hearn J , Mulligan George , Ding Li , Gnjatic Sacha , Vlachos Ioannis S , Bhasin Manoj
Published: May 2024

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.