bluuebunny/crossref_metadata_2025 huggingface dataset:
The contribution of porins to enterobacterial drug resistance
Authors: Davin-Regli Anne , Pagès Jean-Marie , Vergalli Julia
Published: August 2024

In Enterobacteriaceae, susceptibility to cephalosporins and carbapenems is often associated with membrane and enzymatic barrier resistance. For about 20 years, a large number of Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae presenting ß-lactam resistance have been isolated from medical clinics. In addition, some of the resistant isolates exhibited alterations in the outer membrane porin OmpC-OmpF orthologues, resulting in the complete absence of gene expression, replacement by another porin or mutations affecting channel properties. Interestingly, for mutations reported in OmpC-OmpF orthologues, major changes in pore function were found to be present in the gene encoding for OmpC. The alterations were located in the constriction region of the porin and the resulting amino acid substitutions were found to induce severe restriction of the lumen diameter and/or alteration of the electrostatic field that governs the diffusion of charged molecules. This functional adaptation through porins maintains the entry of solutes necessary for bacterial growth but critically controls the influx of harmful molecules such as β-lactams at a reduced cost. The data recently published show the importance of understanding the underlying parameters affecting the uptake of antibiotics by infectious bacteria. Furthermore, the development of reliable methods to measure the concentration of antibiotics within bacterial cells is key to combat impermeability-resistance mechanisms.
In vitro evaluation of ganaplacide/lumefantrine combination against Plasmodium falciparum in a context of artemisinin resistance
Authors: Manaranche Jeanne , Laurent Marion , Tressieres Roxane , Nguyen Michel , Salim Maryam , Ouji Manel , Reyser Thibaud , Egwu Chinedu O , Robert Anne , Augereau Jean-Michel , Benoit-Vical Françoise , Paloque Lucie
Published: August 2024

Background

Ganaplacide, also known as KAF156, is among the new antimalarial drug candidates that have successfully reached Phase III clinical trials, and is proposed in combination with lumefantrine. This combination could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs. Indeed, the African continent, where the malaria burden is the highest, is currently experiencing worrying multiple emergences and spread of artemisinin resistance, which urges for the exploration of the antiparasitic properties of KAF156 in this context.

Objectives and methods

The objectives of this work were firstly to evaluate the risk of cross-resistance between artemisinins and KAF156 alone, and in combination with lumefantrine, using a panel of artemisinin-resistant strains carrying different pfk13 mutations and markers of other antiplasmodial drug resistances; secondly to explore in vitro the relevance of combining KAF156 and lumefantrine with artemisinins, based on the model of triple ACTs.

Results

Our results highlighted that KAF156 activity was not impaired by mutations in pfk13, pfcrt, pfmdr1, pfmdr2, pfdhps and pfdhfr genes or by pfmdr1 amplification. Moreover, we demonstrated that KAF156 alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent.

Conclusions

All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible.
Assessment of intermediate-term mortality following pancreatectomy for cancer
Authors: Janczewski Lauren M , Visenio Michael R , Joung Rachel Hae-Soo , Yang Anthony D , Odell David D , Danielson Elizabeth C , Posner Mitchell C , Skolarus Ted A , Bentrem David J , Bilimoria Karl Y , Merkow Ryan P
Published: August 2024

Background

Pancreatic cancer remains highly lethal, and resection represents the only chance for cure. Although patients are counseled regarding short-term (0-3 months) mortality, little is known about mortality 3-6 months (intermediate-term) following surgery. We assessed predictors of intermediate-term mortality, evaluated hospital-level variation, and developed a nomogram to predict intermediate-term mortality risk.

Methods

Patients undergoing pancreatic cancer resection were identified from the National Cancer Database (2010-2020). Multivariable logistic regression identified predictors of intermediate-term mortality and assessed differences between short-term and intermediate-term mortality. Multinomial regression grouped by intermediate-term mortality quartiles evaluated hospital-level variation. A neural network model was constructed to predict intermediate-term mortality risk. All statistical tests were 2-sided.

Results

Of 45 297 patients, 3974 (8.9%) died within 6 months of surgery of which 2216 (5.1%) were intermediate-term. Intermediate-term mortality was associated with increasing T category, positive nodes, lack of systemic therapy, and positive margins (all P < .05) compared with survival beyond 6 months. Compared with short-term mortality, intermediate-term mortality was associated with treatment at high-volume hospitals, positive nodes, neoadjuvant systemic therapy, adjuvant radiotherapy, and positive margins (all P < .05). Median intermediate-term mortality rate per hospital was 4.5% (interquartile range [IQR] = 2.6-6.5). Highest quartile hospitals had decreased odds of treatment with neoadjuvant systemic therapy, neoadjuvant radiotherapy, and adjuvant radiotherapy (all P < .05). The neural network nomogram was highly accurate (accuracy = 0.9499; area under the receiver operating characteristics curve = 0.7531) in predicting individualized intermediate-term mortality risk.

Conclusion

Nearly 10% of patients undergoing pancreatectomy for cancer died within 6 months, of which one-half occurred in the intermediate term. These data have real-world implications to improve shared decision making when discussing curative-intent pancreatectomy.
Sustainable treatment success of an Os naviculare syndrome using conservative measures, infiltration therapy, and shock waves
Authors: Andresen Julian Ramin , Radmer Sebastian , Puchner Stephan E
Published: August 2024

Medial plantar foot pain can have various causes, and the painful Os tibiale externum should be considered in the differential diagnosis. A reliable diagnosis can be made through physical examination and multimodal imaging. We report on a 53-year-old man with severe, load-dependent pain consistent with an accessory navicular syndrome, caused by a pes planovalgus, which consecutively induced focal inflammation and tenosynovitis of the tibialis posterior tendon. Multifactorial conservative measures, including infiltration therapy, provided only moderate symptom relief. A final shockwave therapy ultimately led to a sustainable symptom relief.
Peanut phytobezoar: an unusual cause for small bowel obstruction
Authors: Sealey Andrew J , Lau Ngee-Soon
Published: August 2024

Bezoars are indigestible masses of material forming within the gastrointestinal system. Phytobezoars are the most common subtype consisting of plant matter such as fibre, skins, and seeds. Rarely they present causing small bowel obstruction (SBO) and may be difficult to distinguish from faecalization on imaging. Here we present the case of a man in his 70s who rapidly consumed an expiring bag of peanuts and subsequently developed a SBO due to formation of a peanut phytobezoar. After failing conservative management, he required emergency surgery with intentional enterotomy to milk out the bezoar. This case highlights the importance of maintaining a broad differential and thorough history taking in patients presenting with SBO.
Methodology and Definitions
Authors: Romano Cesare PR , Boggio Andrea
Published: August 2024

This chapter first describes the methodology followed and the sources used to prepare a historical account of the emergence and codification of the right to science, to map the right to science in contemporary legal instruments—mostly international but also national constitutions—and to determine the normative content of the right to science. Then, key terms at the core of the relationship between science and human rights are defined. These include “freedoms,” “rights,” “entitlements,” “science,” “scientific knowledge,” “scientific progress and advancement,” and “benefits.” The chapter also provides a disambiguation of science and culture, science and technology, science and pseudoscience, and science and the sciences.
The Right to Responsible Scientific Progress (Scientific Responsibility)
Authors: Romano Cesare PR , Boggio Andrea
Published: August 2024

Arguing that scientific responsibility is part of the normative content of the right to science, this chapter describes the normative basis and content of the second cluster of rights within the right to science: the right to responsible science. This right imposes two duties on scientists: to respect scientific integrity and to responsible anticipation. The chapter discusses how respect for scientific integrity requires scientists to adhere to the norms of research integrity and scientific citizenry and how the duty to responsible anticipation includes the duty to respect research participants and to anticipate the benefits and harms of scientific progress and its applications. The steps that scientists must implement to discharge both duties are also discussed. The chapter then looks at the role of states in ensuring adherence to scientific responsibility standards and proposes indicators for monitoring adherence.
The Right to Benefit from Scientific Progress
Authors: Romano Cesare PR , Boggio Andrea
Published: August 2024

This chapter presents the normative basis and content of the fourth cluster of rights within the right to science: to benefit from scientific progress. This right contains five rights: to access scientific knowledge; to anticipation and monitoring of impacts; to the development of beneficial applications; to the diffusion of and access to applications; and to policies aligned with scientific evidence. Framing scientific science as a global public good, the argument identifies the human rights standards that require that scientific knowledge and applications be made widely accessible to the public. It also critically assesses the precautionary principle as a regulatory tool to protect society from the harmful impacts of science and proposes the principle of prudence as better fitting human rights standards. The duty of policymakers to adhere to these standards and to adopt policies aligned with scientific evidence are also discussed. The chapter closes by proposing indicators to monitor compliance with these standards.
The Future of the Right to Science
Authors: Romano Cesare PR , Boggio Andrea
Published: August 2024

This chapter reflects on the status of the human right to science and looks into its future. Arguing that the right has been mostly overlooked in its potential to govern science, technology, and innovation, the chapter proposes ways in which policymakers, scholars, and practitioners can engage with the right to ensure the realization of its full potential. Further work needs to be done to translate right-to-science principles into standards of conduct to guide science, technology, and innovation policy. Additionally, policymakers, scholars, and practitioners must strengthen the monitoring of States’ adherence to the right-to-science standards and ensure opportunities for claims based on the right to science to be adjudicated in court. To this end, constitutional, statutory, and regulatory frameworks must be adapted to better incorporate right-to-science principles. This chapter proposes the negotiation and adoption of a global treaty in support of science. Such a treaty could help entrenching and deepening the normative content of the right to science. A sketch of the content of the proposed treaty is provided. The chapter also identifies future initiatives at the level of regional systems. It concludes by reiterating the value of framing science as a global public good and by inviting the international community to adopt the right to science as the leading framework to govern science, technology, and innovation, internationally and domestically.
Designing a Culture of Ethical Practice in Healthcare
Authors: Fitzgerald Heather , Rushton Cynda Hylton
Published: August 2024

Healthcare is reeling from escalating complexity, competing interests, and patients challenged by increasingly diverse and severe health conditions. Clinicians, including nurses, feel external pressures and inner conflicts about their ability to practice in ways that reflect their professional values. Clinicians and the people they serve are reporting disengagement and despair in an ever-chaotic culture that reflects societal disempowering norms and systems. A new paradigm is needed that leverages core ethical values, shifts patterns that undermine integrity, produces impactful, sustainable results, and offers a vision of hope for the future. This chapter applies a model of full-spectrum change to create a culture of ethical practice in healthcare. Key shifts that are necessary to begin the process of individual and organizational transformation are highlighted, including perspectives, recognition of patterns that are no longer working, and using design principles to produce strategic results. Promising practices to enable these shifts and exemplars from healthcare settings engaged in this work are highlighted.
Effectiveness of Sucrose Analgesia in Newborns Undergoing Painful Medical Procedures
Authors: Osborn David
Published: August 2024

Pain management guidelines promoted the widespread use of sucrose. However, there were concerns that few painful procedures had been evaluated and that sucrose may raise blood glucose levels in newborns of diabetic mothers. Taddio et al. randomized 240 healthy newborns of nondiabetic and diabetic mothers undergoing intramuscular injection, venipuncture, or heel-lance to oral sucrose 24% or water placebo. Overall mean pain scores were lower among newborns who received sucrose than among those who received placebo (mean difference –1.3; 95% confidence interval –2.0 to –0.6). There was no difference in the incidence of adverse effects or mean blood glucose levels.
Reduction of Maternal–Infant Transmission of Human Immunodeficiency Virus Type 1 With Zidovudine Treatment
Authors: van Kaam Anton H. , Onland Wes
Published: August 2024

Maternal–infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). Animal studies demonstrate that zidovudine may prevent or alter maternal–infant transmission of HIV. This study randomized 477 pregnant, HIV-infected women (CD4+ T-lymphocyte count >200) between 14 and 34 weeks’ gestation to an antepartum, intrapartum, and neonatal treatment regimen with zidovudine or placebo. HIV infection status was known for 363 births and showed a 67.5% (95% confidence interval 40.7 to 82.1, p = 0.00006) relative risk reduction in HIV transmission in favor of the zidovudine group. Minimal short-term toxic effects were observed.
A Randomized Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy
Authors: Foglia Elizabeth
Published: August 2024

Cerebral palsy (CP) is a leading cause of chronic childhood disability, with risk increasing with lower gestational ages. Early evidence suggested magnesium sulfate may be neuroprotective for infants born preterm. This randomized trial enrolled 2,241 women at risk of imminent preterm delivery between 24 and 31 weeks’ gestation. Patients were randomized to intravenous magnesium sulfate versus placebo therapy. There was no difference in the primary outcome of infant death or moderate or severe cerebral palsy at 2 years corrected age. However surviving infants born to mothers randomized to magnesium sulfate were significantly less likely to be diagnosed with moderate or severe cerebral palsy.
Understanding Implicit Bias and Responding to Microaggressions
Authors: Estime Stephen R. , Williams Brian H.
Published: August 2024

Implicit biases are unconscious associations about groups of people that can manifest as actions expressing prejudice, which can unwittingly perpetuate discrimination and are known as microaggressions. An understanding of implicit bias and microaggressions is an important skills for functioning as an effective leader in healthcare. Given the role of physicians as leaders who navigate difficult social and clinical interactions, these principles are especially pertinent. An understanding of one’s personal biases allows for improved communication in high-stakes interactions, may lead to better health outcomes and patient–provider interactions, and is a core component of professionalism. Addressing implicit bias at the individual level demands the acknowledgment that everyone harbors biases, that feedback is an important mechanism to uncover bias, and that adjusting one’s actions will allow for better future interactions in an increasingly complex world. At the institutional level, systems that address implicit bias can be achieved by a commitment from leadership to address bias at all levels to empower workers who may otherwise not be engaged and to offer pertinent and timely training to improve institutional diversity.
Cultural Sensitivity in the Healthcare Workplace
Authors: Mulaikal Teresa A. , Hastie Maya Jalbout
Published: August 2024

Culture can be defined as the intricate set of beliefs, values, and practices that impact personal choices. Physician–patient relationships, which are key determinants in achieving health equity, are impacted by the multicultural social context in which healthcare providers practice. Accordingly, physicians’ cultural sensitivity and competence can be developed to improve patient experiences and outcomes. Cultural competence relies in part on developing the skills for empathetic and respectful communications. In addition, organizational and structural factors perpetuate healthcare disparities. In this chapter, communications with patients and their families are explored in the context of end-of-life discussions and goals-of-care settings. Cultural sensitivity should be introduced during medical education and residency training and should be considered an important aspect of professional development.
Do Not Resuscitate and Physician Orders for Life-Sustaining Treatment
Authors: Berkman Emily , Clark Jonna D. , Lewis-Newby Mithya
Published: August 2024

Respecting patient autonomy is a requirement of ethical medical practice. When patients lack decision-making capacity, treatment decisions should be made based on previously documented patient preferences or through surrogate decision-makers. In an emergency, if a patient’s wishes are unknown and a surrogate decision-maker is unavailable, the default position is to provide all medically appropriate therapies. Adult patients have the right to forgo life-sustaining therapies. Ideally, conversations eliciting patient goals, educating regarding prognosis, and discussing potential benefits, burdens and alternatives take place within a trusting patient–clinician relationship over time, and decisions to forgo specific treatments should be documented by adult patients and their healthcare providers. Advance directives are legal documents that describe treatment preferences and/or identify a durable power of attorney for healthcare. They allow competent adults to make decisions for themselves for future care should they lose capacity. In contrast, physician orders for life-sustaining therapies forms are intended for patients who are frail or terminally ill. They apply to current care and describe preferences that apply across all medical environments. Regardless of format, written legal documentation that describes patient wishes best allows clinicians to honor individual preferences. In cases of discordance regarding treatment preferences, state specific mediation processes should be followed. Ethics committee consultation can be helpful or necessary.
Medical Aid in Dying
Authors: Sweet Ashley L. , Blanke Charles D.
Published: August 2024

This chapter on medical aid in dying (MAID) examines a growing end-of-life option, which has been legalized in 11 US jurisdictions. It defines MAID and distinguishes this practice from euthanasia. It reviews the eligibility criteria for accessing MAID in the United States and appraises these criteria in the specific case of a patient with the progressive neurodegenerative condition amyotrophic lateral sclerosis (ALS). It also summarizes key ethical arguments for and against MAID, and it assists readers, regardless of their own personal views on the ethical permissibility of this end-of-life option, in evaluating and responding to patient requests for MAID.
Documentation Disputes in the Medical Record
Authors: Kirsch Rachel , Stadler Michael E.
Published: August 2024

The passing of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 created national standards for the protection of an individual’s sensitive health information to provide patients with increased control over their personal health information (PHI). A parallel movement in medicine to digitize health records led to the universal adoption of various health information technology platforms, including electronic health records (EHR). The EHR has streamlined care and enhanced transparency, allowing patients to engage more actively with their own health information. However, much of the information in the EHR is entered by healthcare workers and therefore potentially liable to human error. Requesting an amendment to a medical record is a HIPAA-mandated patient right that all covered entities must respect. A patient’s PHI remains confidential and is only legally accessible to the patient, their designated representatives, and those directly involved in their care. In addition, proper documentation is important for patient safety because other providers caring for the patient depend on the accuracy of this information. Similarly, other institutions, such as health or life insurers, rely on this information to appropriately assess an individual’s overall health risks. Patients may therefore desire and request a change to their PHI within the EHR. Clinicians, hospitals, and health systems must know how to appropriately address these requests.
Goal-Directed and Habitual Behaviors
Authors: Hernandez Ledia F. , Obeso Ignacio
Published: August 2024

Driving a car, handwriting, and riding a bicycle are examples of the many human actions that have been established as instrumental through two fundamental behavioral selection mechanisms: the goal-directed system and the habitual system. There are segregated loops connecting brain region coding and involved in each of these behavioral domains. The brain regions involved in both kinds of behavior have been highly conserved from an evolutionary point of view. Habitual behavior has been retained across evolution and, in the case of certain adaptive responses, almost without alteration among species. This chapter reviews classical and recent studies that highlight the main mechanisms and brain networks supporting goal-directed and habitual behaviors across species, with a focus on evolutionary perspectives on important biological hierarchies. Finally, it raises the possibility that dopaminergic dysfunction in certain brain diseases (such as addiction and Parkinson’s disease) is associated with a pathological involvement of these critical behavioral control systems.
The Properties of Cortico-motoneuronal Connections and Their Evolutionary Significance for Amyotrophic Lateral Sclerosis
Authors: Lemon Roger N.
Published: August 2024

The evolutionary significance of amyotrophic lateral sclerosis (ALS) is apparent from the fact that it is a uniquely human disease. It is a disorder affecting both descending corticospinal projections and the motoneurons which they influence. Direct, cortico-motoneuronal projections from the motor cortex to the cranial and spinal motoneurons are a subdivision of the primate corticofugal and corticospinal systems and have been strongly implicated in ALS. This chapter will review the key structural and functional properties of the cortico-motoneuronal system, emphasizing the late evolutionary development of this system and its unique importance for human motor skills such as gesture and tool manufacture and tool usage. Studying the vulnerability of the cortico-motoneuronal system to ALS might help in understanding and even treating this devastating disease.
Williams Syndrome and Autism
Authors: August Isabel , Semendeferi Katerina
Published: August 2024

Certain human disorders, such as Williams syndrome (WS) and autism spectrum disorders (ASD), are known to affect social behaviors. WS is a rare neurodevelopmental disorder caused by deletion of approximately 25 genes on chromosome band 7q11.23, and WS individuals are typically described as hypersocial. ASD is a much more common group of heterogeneous disorders generally characterized by hyposociality. In WS total brain volume is decreased, while in ASD total brain volume is increased, in early development. Both disorders are characterized by microstructural changes throughout the brain, and this chapter focuses on changes in the prefrontal cortex and amygdala, regions which have been subject to recent evolutionary change in humans. This chapter reviews the neuroanatomical profiles of these two disorders in an evolutionary context before concluding with a brief discussion of how animal and stem cell models can be used to explore the cellular and molecular mechanisms underlying their neuroanatomical profiles.
Prenatal Diagnosis
Authors: Phillips Amber Mathiesen , Roy Kali Bogaard
Published: August 2024

Prenatal diagnosis is the term used to describe a set of tests that are designed to determine whether a specific genetic condition is present in a fetus. This chapter provides a detailed description of the procedures as well as the types of testing options available for prenatal diagnosis. The two techniques for prenatal diagnosis, amniocentesis and chorionic villus sampling, are described in detail, including their procedures, risks, limitations, and their use in twin/multiple gestations. The prenatal diagnosis testing options are also described in detail, including karyotype, fluorescence in situ hybridization (FISH), microarray, targeted testing, single-gene testing, panel testing, whole exome, and genome sequencing as well as alpha-fetoprotein (AFP) and acetylcholinesterase (AChE) level testing. The chapter also includes images of karyotype, FISH, and microarray test results and reviews the indications for prenatal diagnostic testing.
Epilepsy and systemic disease
Authors: Dugan Patricia
Published: August 2024

This chapter examines the association of epilepsy with a diverse array of multiorgan diseases, particularly neurocutaneous disorders, connective tissue diseases, and systemic vasculitides. It reviews epilepsy in the setting of tuberous sclerosis complex, neurofibromatosis type 1, Sturge–Weber syndrome, systemic lupus erythematosus, Sjögren syndrome, scleroderma, Ehlers–Danlos syndrome, Wegener’s granulomatosis, Behçet’s disease, type 1 diabetes mellitus, and cardiovascular disease. The chapter also describes the possible shared underlying mechanisms responsible for both epilepsy and the varied systemic manifestations of these diseases, such as direct immunological effects on the brain, aberrant vasculature, and abnormal cell proliferation. Specific treatment strategies are also outlined, which may involve optimizing management of the underlying disorder.
Attention
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

Attention is the active or passive focusing of consciousness on the external world and the inner life. Attention is active when externally focused, and it is passive when focusing on the flow of internal events. Attention may be voluntary or involuntary. It is voluntary when effort is focused on an internal or external event by choice or intention, and it is involuntary when an event or object attracts attention without deliberate conscious choice or intentional effort. This chapter discusses the definition of attention and its characteristics; describes genes and attentional networks; reviews anatomic substrates for attention, summarizing development neuroimaging studies; considers attention and self-regulation in infancy and child development; discusses attention training in childhood; and reviews neurodevelopmental disorders characterized by attention deficits.
Temperament
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

Temperament is defined as constitutionally based individual differences in reactivity and self-regulation. Temperament describes the initial state from which personality develops and is essential to understanding the origins of personality development. The infant’s brain is not a blank slate at birth to be shaped by parenting; children differ from infancy and afterwards in their temperament. Neurobiologically, temperament links individual differences in behavior to underlying neural networks. This chapter reviews the role of temperament and personality in socioemotional development from a developmental perspective. The chapter includes a historical introduction to temperament and a review of various definitions of temperament. It addresses the effects of temperament on others, the neurobiology of temperament, temperament and cognition, and the assessment of temperament in children with developmental disabilities.
Autism Spectrum Disorder
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

From its beginnings, “autism” has been a term that focused on a neurodevelopmental disorder with deficits in social communication and restricted and repetitive patterns of behavior, interests, and activities. Recent developmental research has focused on deficits in social understanding, repetitive behaviors, affective development, social cognition, and interpersonal reciprocity. This chapter reviews the history, definition and classification, epidemiology, clinical features, etiologies (genetic and environmental), natural history, neurobiology, and treatment of autism spectrum disorders. It focuses on the spectrum of social communicative and social interaction deficits in autism spectrum disorder and examines the underlying neurobiology. The major emphasis is on social understanding and the development of social awareness and repetitive behavior from a neurobiological and a social interactional perspective.
Diverse Origins of Near-Identical Antifreeze Proteins in Unrelated Fish Lineages Provide Insights Into Evolutionary Mechanisms of New Gene Birth and Protein Sequence Convergence
Authors: Rives Nathan , Lamba Vinita , Cheng C H Christina , Zhuang Xuan
Published: August 2024

Determining the origins of novel genes and the mechanisms driving the emergence of new functions is challenging yet crucial for understanding evolutionary innovations. Recently evolved fish antifreeze proteins (AFPs) offer a unique opportunity to explore these processes, particularly the near-identical type I AFP (AFPI) found in four phylogenetically divergent fish taxa. This study tested the hypothesis of protein sequence convergence beyond functional convergence in three unrelated AFPI-bearing fish lineages. Through comprehensive comparative analyses of newly sequenced genomes of winter flounder and grubby sculpin, along with available high-quality genomes of cunner and 14 other related species, the study revealed that near-identical AFPI proteins originated from distinct genetic precursors in each lineage. Each lineage independently evolved a de novo coding region for the novel ice-binding protein while repurposing fragments from their respective ancestors into potential regulatory regions, representing partial de novo origination—a process that bridges de novo gene formation and the neofunctionalization of duplicated genes. The study supports existing models of new gene origination and introduces new ones: the innovation–amplification–divergence model, where novel changes precede gene duplication; the newly proposed duplication–degeneration–divergence model, which describes new functions arising from degenerated pseudogenes; and the duplication–degeneration–divergence gene fission model, where each new sibling gene differentially degenerates and renovates distinct functional domains from their parental gene. These findings highlight the diverse evolutionary pathways through which a novel functional gene with convergent sequences at the protein level can evolve across divergent species, advancing our understanding of the mechanistic intricacies in new gene formation.
Long-term effects on fertility after central nervous system cancer: A systematic review and meta-analysis
Authors: Pape Janna , Gudzheva Tanya , Beeler Danijela , Weidlinger Susanna , Vidal Angela , Furtwängler Rhoikos , Karrer Tanya , von Wolff Michael
Published: August 2024

Background

Central nervous system (CNS) cancer represents a common group of solid tumors in childhood and young adults, and less frequently in adults aged 30–40. Due to treatment advancements with increasing survival rates, disorders of the hypothalamus-pituitary axis have become increasingly relevant for patients’ future fertility plans. Most guidelines recommend that physicians should counsel their patients about fertility prognosis before initiating gonadotoxic therapy. However, for fertility preservation measures, gonadal toxicity as the only relevant risk factor has not yet been systematically reviewed.

Methods

A systematic literature search was performed in MEDLINE, Embase, and Cochrane in January 2024. The systematic review included studies of patients who had undergone treatment for all types of malignant CNS cancer. The outcomes were defined as clinically relevant gonadal toxicity as well as preserved fertility. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Results

The qualitative analysis included 31 studies with a total of 4590 patients after CNS cancer. The overall pooled prevalence of gonadal toxicity was found to be 20% (95% confidence intervals [CI]: 10%–34%). Preserved fertility was present in 75% (95% CI: 64%–83%) of the patients and was maintained after at least 5 years following treatment (75%, 95% CI: 46%–91%).

Conclusions

This initial meta-analysis provides a basis for fertility counseling after diverse CNS cancer treatments. Due to the high heterogeneity of the study population and lack of individual patient data on fertility outcomes, it is not possible to provide an exact estimation of the fertility prognosis following a specific treatment. Thus, fertility preservation measures should still be recommended.
Utility of Cerebrospinal Fluid Unstimulated Interferon-Gamma (IRISA-TB) as a Same-Day Test for Tuberculous Meningitis in a Tuberculosis-Endemic, Resource-Poor Setting
Authors: Randall Philippa , Mutsvangwa Junior , Nliwasa Marriott , Wilson Lindsay , Makamure Beauty , Makambwa Edson , Meldau Richard , Dheda Keertan , Munyati Shungu , Siddiqi Omar , Corbett Elizabeth , Esmail Ali
Published: August 2024

Background

Tuberculous meningitis (TBM) mortality is high and current diagnostics perform suboptimally. We evaluated the diagnostic performance of a DNA-based assay (GeneXpert Ultra) against a new same-day immunodiagnostic assay that detects unstimulated interferon-gamma (IRISA-TB).

Methods

In a stage 1 evaluation, IRISA-TB was evaluated in biobanked samples from Zambia (n = 82; tuberculosis [TB] and non-TBM), and specificity in a South African biobank (n = 291; non-TBM only). Given encouraging results, a stage 2 evaluation was performed in suspected TBM patients from Zimbabwe and Malawi (n = 668). Patients were classified as having definite, probable or possible TBM, or non-TBM based on their microbiological results, cerebrospinal fluid (CSF) chemistry, and whether they received treatment.

Results

In the stage 1 evaluation, sensitivity and specificity of IRISA-TB were 75% and 87% in the Zambian samples, and specificity was 100% in the South African samples. In the stage 2 validation, IRISA-TB sensitivity (95% confidence interval [CI]) was significantly higher than Xpert Ultra (76.2% [55.0%–89.4%] vs 25% [8.9%–53.3%]; P = .0048) when trace readouts were considered negative. Specificity (95% CI) was similar for both assays (91.4% [88.8%–93.4%] vs 86.9% [83.4%–89.8%]). When the Xpert Ultra polymerase chain reaction product was verified by sequencing, the positive predictive value of trace readouts in CSF was 27.8%. Sensitivity of IRISA-TB was higher in human immunodeficiency virus (HIV)–infected versus uninfected participants (85.8% vs 66.7%).

Conclusions

As a same-day rule-in test, IRISA-TB had significantly better sensitivity than Xpert Ultra in a TB/HIV-endemic setting. An immunodiagnostic approach to TBM is promising, and further studies are warranted.
Parametrized Post-Newtonian Test of Black Hole Spacetime for Galactic Center Massive Black Hole Sgr A*: Formulation and χ2 Fitting
Authors: Saida Hiromi , Matsui Sena A , Takeuchi Tsutomu T , Nishiyama Shogo , Saitou Rio , Takamori Yohsuke , Takahashi Masaaki
Published: August 2024

We have performed a parametrized post-Newtonian (PPN) test of a black hole spacetime using observational data of the star S0-2/S2 orbiting the massive black hole at our galactic center Sgr A$^{\ast \, }$. After introducing our PPN model of black hole spacetime, we report the result of $\chi ^2$ fitting of the PPN model with the observational data. A new finding through our PPN model is the detectability of the gravitational lens effect on the null geodesics connecting S0-2 and the observer under the present observational uncertainties, if a PPN parameter is about one order larger than the value for the general relativity case. On the other hand, the effect of black hole spin on S0-2’s motion is not detectable. Thus, our present PPN test is performed with spherically symmetric vacuum black hole spacetime. The resultant value of the PPN parameter, which corresponds to the minimum $\chi ^2$, implies that the gravitational field of Sgr A$^{\ast \, }$ is not of the Schwarzschild metric or that there exists a sufficient amount of dark matters around Sgr A$^{\ast \, }$ to be detected by present telescopes. However, the difference between the minimum $\chi ^2$ and the $\chi ^2$ of the Schwarzschild case is not large enough to ensure the statistical significance of the non-Schwarzschild result. A more precise statistical analysis than $\chi ^2$ statistics is necessary to extract statistically significant information on the gravitational field of Sgr A$^{\ast \, }$ from the present observational data. We will report a result by a Bayesian analysis in our next paper.
Enhancing the immunomodulatory osteogenic properties of Ti-Mg alloy by Mg2+-containing nanostructures
Authors: Liang Luxin , Lin Zhengjun , Duan Ziqing , Agbedor Solomon-Oshioke , Li Ning , Baker Ian , Wang Bing , Liu Tang , Wu Hong
Published: August 2024

Facilitating an appropriate immune response is crucial for promoting bone tissue regeneration upon biomaterial implantation. In this study, the Mg2+-containing nanostructures on the surface of Ti-1.25Mg alloy were prepared by a one-step hydrothermal reaction method via regulating pH value to enhance the immunomodulatory osteogenic properties of Ti-Mg alloys. In neutral (HT7) or alkaline (HT9) hydrothermal treatment (HT) solution, the size of MgTiO3 nanostructures formed on the surface of Ti-1.25Mg alloy is smaller than that in acidic HT solution (HT5), and lamellar Mg(OH)2 nanostructures are found in HT7 and HT9. In addition, the sample surface has a lower roughness and higher wettability with increasing pH value. The Mg2+-containing nanostructures on the Ti-1.25Mg alloy inhibited inflammatory response by promoting the polarization of M2 macrophages, thereby promoting osteogenesis in vitro. The micro-CT and histological assessment proved that the regeneration of bone defect was faster in HT7 than the Ti-1.25Mg in vivo. Mechanically, Mg2+-containing nanostructures can mediate the immune response of macrophages via upregulating integrins α5β1 and inhibiting Toll-like receptors (TLR-4), subsequently inhibiting the NF-κB signaling pathway. Overall, osteoimmunity-regulating Mg2+-containing nanostructures on Ti-1.25Mg present a promising biomaterial for bone repair.
Disease characteristics and medications use in idiopathic inflammatory myopathy: a multi-centre prospective observational study of decentralized remote vs. traditional clinic enrolment
Authors: Keret Shiri , Silva Raisa Lomanto , Chandra Tanya , Gkiaouraki Eugenia , Pongtarakulpanit Nantakarn , Sriram Shreya , Moghadam-Kia Siamak , Oddis Chester V , Aggarwal Rohit
Published: August 2024

Objectives

Idiopathic inflammatory myopathies (IIM) are rare and characterized by heterogeneous manifestations and clinical trajectories. Utilizing tele-research methods has the potential to improve participant recruitment and advance the understanding of the disease. We aimed to evaluate disease characteristics in IIM patients throughout the USA and compare these parameters between patients recruited remotely through mobile application or website vs those recruited locally in myositis clinics.

Methods

‘Myositis Patient Centered Tele-Research’ (My PACER) is a multicentre prospective observational study of US IIM subjects, competitively recruited through traditional in-person clinic visits [centre-based cohort (CBC)] and remotely using mobile application or website and social media [tele-research cohort (TRC)]. Data collection comprised baseline demographic and clinical variables, encompassing symptoms, organ involvement, diagnostic tests results and medication use.

Results

The study included 120 IIM patients, 82 in the TRC and 38 in the CBC. The average age was 55 ± 13.4, 75% females and 81% Caucasians. Both cohorts exhibited similar demographic characteristics. Overall, 41% dermatomyositis, 27% polymyositis, 23% anti-synthetase syndrome, and 9% necrotizing myositis patients were enrolled, with comparable subtypes prevalence among cohorts (P = 0.85). The groups demonstrated similarities in multiple clinical factors, including muscle enzymes, diagnostic delay, employment status, various patient and physician-reported outcomes, functional tests, and the frequency of abnormal findings in chest CT, pulmonary function tests and electromyography. TRC patients received biologics and csDMARDs more frequently (P < 0.001 and P = 0.013, respectively).

Conclusion

Tele-research recruitment yielded a patient cohort resembling traditionally recruited patients demographically and clinically, indicating its effectiveness for robust and diverse patient recruitment in clinical studies.
“I know when to stop”: sentinels and counterstrategies against drowsy driving in narcolepsy and idiopathic hypersomnia
Authors: Beguin Elsa , Maranci Jean Baptiste , Leu-Semenescu Smaranda , Dodet Pauline , Gales Ana , Oudiette Delphine , Andrillon Thomas , Arnulf Isabelle
Published: August 2024

Study Objectives

To collect prodromal symptoms experienced by participants with narcolepsy and idiopathic hypersomnia (considered “hypersomnolence experts”) prior to drowsy driving and counterstrategies used to maintain alertness.

Methods

Systematic, face-to-face interview (using a semi-structured questionnaire), including clinical measures, frequency of car accidents/near misses, and symptoms experienced before impending drowsy driving episodes and counterstrategies.

Results

Among 61 participants (32 with narcolepsy, 29 with idiopathic hypersomnia; 56 drivers), 61% of drivers had at least one lifetime accident/near miss. They had a higher sleepiness score (14 ± 4 vs. 11 ± 5, p < .04) than those without an accident/near miss, but no other differences in demographics, driving experience, medical conditions, symptoms, sleep tests, and treatment. All but three participants experienced prodromal symptoms of drowsy driving, which included postural and motor changes (86.9%: axial hypotonia—e.g. eyelid droop, stereotyped movements), cognitive impairment (53.3%: automatic steering, difficulty concentrating/shifting, dissociation, mind wandering, dreaming), sensory (65%: paresthesia, pain, stiffness, heaviness, blunted perceptions such as a flat dashboard with loss of 3D, illusions and hallucinations), and autonomic symptoms (10%, altered heart/breath rate, penile erection). Counterstrategies included self-stimulation from external sources (pain, cold air, music, drinks, and driving with bare feet), motor changes (upright posture and movements), and surprise (sudden braking).

Conclusions

Drowsy driving symptoms can result from “local” NREM, entry in N1 sleep, and hybrid wake/REM sleep states. These rich qualitative insights from participants with narcolepsy and idiopathic hypersomnia, as well as sophisticated counterstrategies, can be gathered to reduce the crash risk in this population, but also in inexperienced healthy drivers.
Closed-loop auditory stimulation targeting alpha and theta oscillations during rapid eye movement sleep induces phase-dependent power and frequency changes
Authors: Jaramillo Valeria , Hebron Henry , Wong Sara , Atzori Giuseppe , Bartsch Ullrich , Dijk Derk-Jan , Violante Ines R
Published: August 2024

Study Objectives

Alpha and theta oscillations characterize the waking human electroencephalogram (EEG) and can be modulated by closed-loop auditory stimulation (CLAS). These oscillations also occur during rapid eye movement (REM) sleep, but their function here remains elusive. CLAS represents a promising tool to pinpoint how these brain oscillations contribute to brain function in humans. Here we investigate whether CLAS can modulate alpha and theta oscillations during REM sleep in a phase-dependent manner.

Methods

We recorded high-density EEG during an extended overnight sleep period in 18 healthy young adults. Auditory stimulation was delivered during both phasic and tonic REM sleep in alternating 6-second ON and 6-second OFF windows. During the ON windows, stimuli were phase-locked to four orthogonal phases of ongoing alpha or theta oscillations detected in a frontal electrode.

Results

The phases of ongoing alpha and theta oscillations were targeted with high accuracy during REM sleep. Alpha and theta CLAS induced phase-dependent changes in power and frequency at the target location. Frequency-specific effects were observed for alpha trough (speeding up) and rising (slowing down) and theta trough (speeding up) conditions. CLAS-induced phase-dependent changes were observed during both REM sleep substages, even though auditory evoked potentials were very much reduced in phasic compared to tonic REM sleep.

Conclusions

This study provides evidence that faster REM sleep rhythms can be modulated by CLAS in a phase-dependent manner. This offers a new approach to investigating how modulation of REM sleep oscillations affects the contribution of this vigilance state to brain function.