bluuebunny/crossref_metadata_2025 huggingface dataset:
Navigating Communication Conflicts Among the Healthcare Team
Authors: Costa Deena Kelly , Manojlovich Milisa
Published: August 2024

This chapter presents a case study that forms the discussion of strategies to navigate communication conflicts. Ineffective communication is an ongoing problem in healthcare despite decades of research and is associated with adverse patient events. Communication is a complex, iterative process, and the complexity increases as the number of people involved in a communication exchange grows. Healthcare teams must learn to navigate numerous barriers to achieve effective communication, including contextual, intrapersonal, and interpersonal factors, all of which are apparent in the case. Teams can use different conflict resolution styles (i.e., competing, collaborating, avoiding, compromising, accommodating) to resolve communication conflicts when they inevitably occur. To improve conflict resolution and the team’s ability to provide high-quality care in any and all healthcare settings, teams must be aware of particular factors that predispose them to communication conflicts as well as their own individual needs, communication styles, and conflict management styles.
Addressing and Managing Disruptive Physician Behaviors
Authors: Rosenstein Alan H.
Published: August 2024

Disruptive behavior is a difficult problem to address in an effective manner because it is not a traditional credentialing assessment of clinical competency but about professionalism. Organizations should have policies in place that define appropriate behavioral standards as well as a clear process to deal with disruptive events. There needs to be a consistent method for incident review that maintains confidentiality with protection from retaliation. All events should be reviewed in an unbiased and professional manner with well-documented discussion, recommendations, and action items. The organization must resist the temptation for inaction, particularly if the offending provider brings a large volume of patients and revenue to the organization. For minor infrequent disturbances, an informal chat may be sufficient, while formal remediation programs and counseling may be necessary for more severe cases.
Developing a Culture of Wellness
Authors: Pilarski Alicia , Apps Jennifer N.
Published: August 2024

Wellness is composed of interdependent dimensions including physical, emotional, intellectual, social, spiritual, vocational, financial, and environmental. Achieving wellness is an active process and unique for each individual. Individuals who demonstrate resilience are less likely to suffer from burnout. Organizational strategies need to address solutions at the individual level but also within work units in the organization as a whole and across dimensions including workload demands, efficiency and resources, meaning within work, values, autonomy and flexibility, support at work and work life integration. Organizational commitment to well-being is the most important step, and organizational culture must be well-defined. Once the culture has been analyzed there must be awareness of the need to change, a desire to support the change, knowledge of how to change, and the ability to demonstrate skills and behavior which need to be reinforced to make changes stick. Communication and involvement of senior leadership is essential.
Surviving a Bad Outcome
Authors: Zielinski Ruth , Drummond Nora , Roosevelt Lee
Published: August 2024

For most, if not all, healthcare providers, there will be cases that result in a bad outcome. In these circumstances, a natural reaction may be to blame others on the healthcare team or even the patient. Communicating the bad news to the patient and/or family can be challenging and ultimately increases the risk of litigation if handled improperly. For healthcare providers, it is important to have healthy coping strategies and support to avoid excessive vicarious trauma and posttraumatic stress disorder. This chapter presents a case where a nurse-midwife is caring for a patient who is also a friend, which adds an additional element of complexity when there is a bad outcome.
Disclosure of Medical Errors
Authors: Reno Jennifer Prettyman
Published: August 2024

This chapter examines situations where medical errors occur and that warrant disclosure, along with the process by which such disclosure can be conducted successfully. The author reviews the role of the attending physician as well as other healthcare providers in the process while also focusing on the dynamics between the healthcare providers and the patient and/or family members to whom the disclosure is made. Tips are provided for effective communication to the patient and/or family members, with an emphasis on transparency, disclosure, and apologies related to medical errors. Finally, the author directs attention to the psychological impact of medical errors and disclosure on healthcare professionals.
Billing Compliance
Authors: Roke Daniel
Published: August 2024

Reimbursement is the underlying fuel for the practice of medicine. Clinicians dedicate themselves to the expert application of an extensive knowledge base and procedural skills, but all this effort is for naught without payments from insurers. Reimbursement is the result of teamwork between clinicians, on one hand, and coders and billers, on the other. Compliance with coding and billing regulations and guidelines is important for financially recognizing the critical clinical work done by healthcare providers. Noncompliance with these same regulations and guidelines can lead to poor reimbursement and/or adverse legal consequences. The many rules from the multitude of government and private insurance providers make an exhaustive review difficult, but this chapter outlines a broad set of guidelines that address the most common areas of billing compliance.
Conscientious Objection in Medical Practice
Authors: Van Norman Gail A.
Published: August 2024

This chapter examines controversies regarding the moral integrity of medical practitioners and their rights to refuse to treat. It examines how conscientious objection in medical care creates conflicts between practitioners and challenges the core principle in the practice of medicine that expects the practitioner to set aside personal interests in favor of their patients. Different perspectives on “conscience” that affect practitioners’ willingness or unwillingness to allow conscientious objection to certain types of care are reviewed. This chapter discusses potential limitations on the rights of healthcare providers to be accommodated in a conscientious objection. It also discusses several approaches to conscientious objection, including allowing all conscientious objection in medical care, disallowing conscientious objection in medical care altogether, and accommodating conscientious objectors who meet certain criteria, such as being willing to refer patients to a “willing provider” or accepting specific job limitations.
Parens Patriae
Authors: Gish Bryan , Robins Berklee
Published: August 2024

In the vast majority of circumstances, parents make medical decisions for their children that are concordant with the medical recommendations they are offered. Similarly, for patients who lack decision-making capacity or legal competence, surrogate decision-makers and guardians generally make decisions that are in agreement with medical advice and are believed to be what the patient would choose for themselves if they were able. This is commonly known as choosing what is in a patient’s best interests or, at a minimum, choosing among a set of reasonable choices. Sometimes the medical team may believe that the parents, legal guardians, or other surrogate decision-makers are not making reasonable decisions or are actually harming or neglecting those for whom they should be advocates. The doctrine of parens patriae refers to the legal principle which authorizes the state (government authority) to intervene to safeguard the rights and health of an individual who cannot exercise their own right to autonomy. In the case of medical decision-making, this ranges from authorizing medical care, to, in extreme cases, terminating the legal authority of an individual to make medical decisions for a child or adult patient who is at risk.
Death by Neurological Criteria
Authors: Peramunage Dasun
Published: August 2024

Death by neurological criteria, or “brain death” as it is often incorrectly called, has long been recognized as an irreversible process that, much like cardiopulmonary failure, is incompatible with life. Advances in critical care medicine have allowed for the ongoing support of cardiac and pulmonary function despite catastrophic and irrecoverable neurological injury. Though the diagnosis has been widely recognized by the medical community, evidence shows that despite the existence of published and reviewed societal guidelines for determining death by neurological criteria, there are many inconsistencies in the practice of evaluating and confirming this diagnosis. Given its permanence, it is important that a consistent and methodical approach be applied to all patients for whom this diagnosis is being considered. Determining death has significant legal and ethical implications for the patient and their family. In this chapter, the author demystifies the process of making this important determination.
Bloom’s Taxonomy
Authors: Pla Raymond A. , Cohen Ira Todd
Published: August 2024

The affective domain of Bloom’s taxonomy delineates the powerful effect of emotional engagement in fostering deep learning and appreciation of concepts and skills. Feelings and attitudes shape the values that learners attach to new material. These values may be internalized and incorporated into their practices and integrated into the learner’s value system. The cognitive and psychomotor domains may be more deeply engaged, fostering deeper and enduring learning, driven by the attitude that learning this material is deeply beneficial. The affective domain consists of five levels: Receiving, Responding, Valuing, Organizing, and Internalization (Characterization). As in the cognitive domain, verbs describing observable behaviors are associated with each category and can be used to create learning objectives for educational activities.
Adult Learning Theory
Authors: Wilson Rebecca D. , Sneddon Christopher
Published: August 2024

Andragogy, the art and science of helping adults learn, gained popularity in the 1970s, often based on Malcolm Knowles assumptions regarding adults as learners. This non-neuropsychological learning theory posits that adults see themselves as self-directed learners, can call on their prior experience as a resource for learning, and are motivated by the desire to improve in a social role and therefore are more problem- rather than subject-focused. Adults are more likely to engage when they are intrinsically motivated to learn. Although these assumptions may not hold across all adults at all times, it is a valuable framework for educators to use in determining approaches to teaching adults and addressing issues that may arise in self-direction, prior experience, and motivation.
How to Give an Excellent Virtual Presentation
Authors: De Gagne Jennie C. , O’Brien Stacey
Published: August 2024

During the COVID-19 pandemic, users of all ages and backgrounds were forced to adapt to virtual platforms, and the use of these platforms soared. Consequently, virtual platforms are increasingly meeting new expectations but also requiring new skills of presenters. To develop engaging presentations, presenters must possess knowledge of specific platforms as well as skills to utilize available resources creatively. The benefits of virtual presentations are numerous and exciting, and difficulties can generally be mitigated by capable presenters. The information in this chapter can help presenters improve their ability to provide excellent virtual presentations by identifying techniques to maintain engagement during virtual presentations.
Brain Diseases Associated with Unstable Repeats
Authors: Shelly Katharine E. , Allen Emily G. , Jin Peng
Published: August 2024

Tandem repeat elements are both abundant and dynamic in the human genome. Since 1991, repeat expansions have been shown to cause many neurological diseases, and a vast and intricate body of research has emerged, detailing the ways these elements influence neuronal and central nervous system functions. Variable number tandem repeats reveal the evolutionary roots of some repetitive elements that are unique to the human genome and were established through insertion and deletion events. Short tandem repeats (STRs), commonly mapped within many genomic loci, are the focus for expansions associated with neurological disorders. An overview of the nearly 50 repeat expansion diseases associated with STRs is provided. Finally, the technological advances that accelerated the discovery of polymorphic repeats in the genome are discussed and contextualized. Their utility and continued evolution will provide new insights and excitement in the next era of TR research.
Introduction
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

The introduction provides explanations of the nature, causes, and treatment of intellectual and developmental disabilities. It offers a history of the way intellectual developmental impairments have been perceived and highlights the many advances that have been made over the years. The Introduction also highlights Leo Kanner’s the contribution to this field of study.
Assessment, Interview, and Behavior Rating Scales
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

The assessment process in developmental neuropsychiatry requires a comprehensive evaluation of the individual child and their family. Three approaches are involved: (a) clinical assessment, which includes current and past family history, individual and family clinical interviews, and mental status examination of the child; (b) semistructured and structured interviews, questionnaires, behavior checklists, and rating scales; and (c) standardized tests, including psychological and neurological examinations. Background knowledge in normal child development, child psychopathology, diagnostic classification, and the specific tests used is a prerequisite. In dealing with developmental psychopathology, knowledge of the specific syndromes and their natural history is essential. This chapter discusses the rationale for the clinical interview, procedures involved in psychiatric interviewing, the psychiatric history, the psychiatric examination, behavior rating scales and checklists, the clinical case formulation, treatment planning, and prognosis.
Emotion
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

Emotions are essential to evolutionary adaptation and survival. Emotion is the term generally used to describe physiological and psychosomatic concomitants of mood. Emotional states have been categorized according to type, intensity, and duration. The response to emotional experience is an adaptive one with three components: the physiologic reaction (e.g., increased heart rate), the behavioral reaction (e.g., fight or flight), and subjective feeling (e.g., fear). 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.
Specific Learning Disorders
Authors: Harris James C. , Coyle Joseph T.
Published: August 2024

Neurodevelopmental disorders are disorders of brain development and lifelong with early age of onset. They are distinct from acquired brain disorders resulting from trauma. To make these diagnoses, problems applying key academic skills to learning have an onset during the developmental period and must have persisted for at least 6 months despite targeted interventions. Such learning impairments, if not treated, increase the later risk for emotional and behavior disorders. Academic impairments may involve reading, spelling, mathematics, and written expression. This chapter reviews the history, epidemiology, definition and classification, assessment, etiology (genetics and neuroimaging), comorbid psychiatric disorders and treatment for impairments in reading, hyperlexia, spelling, mathematics, and written expression.
Focused Perioperative Nutritional Supplementation Reduces Wound Complications in Patients Undergoing Spinal Fusion Surgery
Authors: Como Christopher J. , Setliff Joshua C. , Dalton Jonathan F. , Tang Yunting Melissa , Oyekan Anthony A. , Hua Kimberly , Byrne Kevin , Sadhwani Shaan , Spitnale Michael , Russell Kira L. , Wawrose Richard , Lee Joon Y. , Shaw Jeremy D.
Published: August 2024

Study Design:

Retrospective cohort study

Objective:

To evaluate intensive postoperative nutritional supplementation on wound healing complications and outcomes after spinal fusion surgery.

Background:

Poor nutritional status leads to inferior postoperative outcomes by increasing mortality and predisposing patients to infection and wound healing complications. While perioperative nutritional supplementation has shown promise in mitigating these risks, there is a paucity of literature regarding specific nutritional routines in spinal fusion surgery.

Methods:

A retrospective analysis was conducted on patients who underwent spinal fusion surgery between 2019 and 2022. Demographic and nutritional data, including preoperative prealbumin levels (PAB) and postoperative supplemental diet, were examined. Primary endpoints included wound complications, with secondary outcomes assessing Oswestry Disability Index (ODI) and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Health (PH) scores. Statistical analyses included unpaired t-tests and Chi-squared/Fischer’s exact tests with significance set at P<0.05.

Results:

Patients receiving the supplemental diet (n=229) demonstrated fewer wound complications (7% vs. 21%, P=0.004) and reoperations (3% vs. 11%, P=0.016) compared to those without supplementation (n=56). No significant differences were observed in preoperative or postoperative PROMIS PH or ODI scores. Patients with normal preoperative PAB had more wound complications without the supplemental diet (5% vs. 18%, P=0.025). A similar trend was seen in the patients with low preoperative PAB (12% vs. 26%, P=0.12).

Conclusion:

Postoperative nutritional supplementation significantly reduces wound complications after spinal fusion surgery in a cost-effective manner. This study underscores the modifiability of certain perioperative risk factors and suggests that nutritional strategies can mitigate potential complications.
Abnormal brain-heart electrophysiology in mild and severe orthostatic hypotension
Authors: Cheng Yingzhe , Huang Peilin , Lin Lin , Zhang Jiejun , Cheng Yahui , Zheng Jiahao , Wang Yanping , Pan Xiaodong
Published: August 2024

Introduction:

This study investigated the changes in cardiocerebral electrophysiology in patients with mild orthostatic hypotension (MOH) and severe orthostatic hypotension (SOH) and their relationship with the severity of orthostatic hypotension, psychiatric symptoms, and cognitive dysfunction.

Methods:

This study included 72 nonorthostatic hypotension (NOH), 17 with MOH, and 11 with SOH. Seated resting-state heart rate variability (HRV) and quantitative electroencephalogram parameters were synchronized and recorded. HRV measures in the time and frequency domains were analyzed, along with the peak frequency and power of the brain waves.

Results:

Abnormal neuronal activity was found in FP1 in patients with MOH, whereas it was more widespread in FP1, FP2, and O2 in patients with SOH (P < 0.05). Cardiac and cerebral electrophysiological abnormalities were significantly associated with orthostatic hypotension severity, psychiatric symptoms, and cognitive dysfunction.

Conclusion:

Abnormal EEG activity in patients are mainly manifested in the prefrontal and occipital lobes, especially in patients with SOH. These results may help patients to better understand the mechanisms underlying orthostatic hypotension severity and psychiatric and cognitive impairment in orthostatic hypotension.
Molecular typing of reduced susceptibility of Acinetobacter calcoaceticus–baumannii complex to Chlorhexidine in Turkey by pulsed-field gel electrophoresis
Authors: Tozluyurt Abdullah
Published: August 2024

Introduction. The global spread of Acinetobacter spp., particularly the Acinetobacter calcoaceticusbaumannii (ACB) complex, has led to its recognition as a significant pathogen by the World Health Organization (WHO). The increasing resistance of the ACB complex to multiple antibiotics presents a challenge for treatment, necessitating accurate antibiotic susceptibility profiling after isolation.

Hypothesis or gap statement. There is limited understanding of the antimicrobial resistance and chlorhexidine, a biocide, susceptibility profiles of ACB complex strains, especially in clinical settings in Turkey.

Aim. This study aimed to identify ACB complex strains recovered from various clinical specimens at Hacettepe University Hospitals in Ankara, Turkey, in 2019, and to assess identification, their antibiotic and chlorhexidine susceptibility profiles, and genomic relatedness.

Methodology. Eighty-two ACB complex strains were identified using MALDI-TOF MS. Susceptibility testing to 12 antibiotics was conducted using the disc diffusion method, and colistin, chlorhexidine susceptibility was assessed using the broth microdilution technique, following the latest EUCAST and CLSI guidelines. ACB complex members with reduced chlorhexidine sensitivity were further analyzed by pulsed-field gel electrophoresis (PFGE) for bacterial typing.

Results. Among the isolates, 1.2% were multidrug-resistant (MDR), 73.2% were extensively drug-resistant (XDR), and 12.2% were pandrug-resistant (PDR). Carbapenem resistance was found in 86.7% of MDR, PDR, and XDR strains. Colistin resistance was observed in 15.8% of isolates, and 18.2% exhibited decreased susceptibility to chlorhexidine. PFGE revealed seven different clones among strains with reduced chlorhexidine sensitivity, indicating vertical transmission within the hospital.

Conclusion. This study highlights the reduced susceptibility to chlorhexidine in ACB complex members and provides epidemiological insights into their spread. The findings underscore the importance of screening for antimicrobial resistance and biocide susceptibility profiles to effectively manage healthcare-associated infections.
Cell wall arabinogalactan is responsible for Fungitell® cross reactivity in nocardiosis
Authors: Mariller Christophe , Letowski Pascal , Chang Wei-Ting , Lowary Todd L. , Ulrich Marc , Faure Karine , Loridant Séverine , Sendid Boualem , Wallet Frédéric , Poulain Daniel , Hazzan Marc , Frimat Marie , Guerardel Yann , Titecat Marie
Published: August 2024

Nocardiosis is a serious infection in immunosuppressed patients, especially transplant recipients. The slow-growing phenotype of the bacterium and the variety of symptoms complicate diagnosis and delay antimicrobial therapy, which results in high mortality rates despite effective treatments. Incidentally, some nocardiosis patients test positive in fungal diagnostics that detect (1,3) β−D-glucan (the Fungitell® assay), but the basis for this cross-reactivity remains unknown. We demonstrate that nocardial cell wall arabinogalactan is a cryptic antigen responsible for cross reactivity in the Fungitell® assay and that this antigen is revealedin vivofollowing bacterial cell lysis. We further show that the reactivity results from β-glucose substitution of the galactan domain, a modification specific to Nocardia, and identify the optimal antigen as a tetramer of the trisaccharide repeating unit. By providing structural evidence for Fungitell® cross-reactivity during nocardiosis, this work paves the way for developing specific diagnostic tools that are presently lacking.
Perception/action coupling in children with autism: insights from looking time and pupil dilation measurements
Authors: Clavaud-Seon Nicole , Guillon Quentin , Vergne Judith , Sonié Sandrine , Schmitz Christina
Published: August 2024

The objective of this study was to characterize, through indices extracted from eye-tracking measurements, the spontaneous distinction of videos of daily actions with a variable perception/action coupling, depending on whether, for the same action, the video was presented in the forward reading direction (strong coupling), or in the backward reading direction (weaker coupling). 17 pairs of videos of daily actions performed by adults were viewed by 36 typically developing children and 28 children with ASD aged 7-18 years. During the exposure phase, they watched two videos of the same action (forward and backward) presented successively, before looking at these two videos in competition, in a second visual preference phase. During the exposure phase, all participants paid similar general attention to each of the videos. We found greater pupillary dilation for backward than forward actions in both groups, but significantly less in the ASD group. In the visual preference phase, both groups showed significantly greater looking times for backward actions over forward ones, with no difference between groups. If TD children perceived the kinematics of the backward videos as violating their expectations given the strong perception/action coupling they had already built over that action, on the contrary, the lower increased in pupil dilation found in ASD children could reflect altered perception/action coupling. This study confirms the validity of looking time and pupil dilation as behavioral and physiological markers that could be used in a 10-mn eye-tracking test to explore perception/action coupling in childhood and in ASD.

Lay summary

People with ASD often have difficulty understanding the actions of others. The fine understanding of actions requires a coupling between the action we observe, and its representation stored in our memory. This process might be challenged in autism. Here we used a 10-mn eye-tracking test to explore perception/action coupling in ASD. Participants were watching videos of daily actions. Looking time and pupil dilation were measured while participants watched videos of daily actions, and were found to be relevant indexes.
Evaluation of EUROSCORE II to determine the prognosis of patients with moderate-to-severe aortic stenosis: a long-term retrospective study
Authors: Cai Xianzhen , Hu Danchun , Yan Baoxin , Chen Jinhao , Li Weiwen , Lin Ying , Lin Run , Ye Junjun , Huang Xiaojun , Xie Bin , Zhuang Xiaodong , Chen Jianying , Li Jilin
Published: August 2024

Background and Aims

Aortic stenosis (AS) was a prevalent heart valve disease whose morbidity and mortality can be reduced by aortic valve replacement (AVR) . EUROSCORE II assesses the perioperative mortality of severe AS patients undergoing AVR. This study explored EUROSCORE II’s prognostic value for long-term all-cause mortality of Chinese patients with moderate-to-severe AS and determined whether AVR affects this.

Methods

Allocated to four groups following the EUROSCORE II (cut-off value of 4%) and whether performed AVR, 544 patients with moderate-to-severe AS were enrolled. Baseline data, Kaplan–Meier, Cox regression and subgroup analysis were used to analyse the relationship between EUROSCORE II and participants’ all-cause mortality. Furthermore, ROC analysis determining the optimal cut-off value of EUROSCORE II was utilized.

Results

During a median follow-up of 41.4 months, 177 (21.5%) participants reached the endpoint, with higher risks (EUROSCORE II ≥4%) and no AVR exhibited significantly increased all-cause mortality rates compared to other groups (55.4% vs. 6.5%, 13.4%, and 32.7%; P<0.001). Kaplan-Meier curves confirmed these findings (log-rank test P<0.001). Cox regression analysis revealed a 6.891-fold higher risk (HR, 6.891; 95% CI, 3.083-15.401; P<0.001) in patients without AVR with higher EUROSCORE II. The adjusted model (P<0.01) and subgroup analyses (without AVR P=0.001; with AVR P=0.029) supported EUROSCORE II’s prognostic value for all-cause mortality. The optimal EUROSCORE II cut-off for predicting all-cause mortality in patients without AVR was 2.23% (AUC 0.675).

Conclusions

EUROSCORE II (cut-off value 4%) and AVR independently impact the long-term prognosis of patients with moderate-to-severe AS.
THE POTENTIAL ROLE OF TAURINE IN ACETAMINOPHEN HEPATOTOXIC INDUCED RATS
Authors: Babalola Isaac Olamide , Adekunle Habeeb Kehinde , Adigun Muhammed Damola
Published: August 2024

Taurine demonstrates an important cytoprotective function in the body, regulating oxidative and inflammation in various conditions. Taurine is actively synthesized in the hepatocyte, moreover, it confers protection to oxidative mediated injury in the liver. Acetaminophen, which has been shown to trigger oxidative related liver damage, is administered in its hepatotoxic dose to rats in this study. The preventive and regulatory role of taurine is investigated in this study. Twenty five adult male wistar rats were grouped into 5 distinct groups labeled the positive control group, negative control group, groups administered with taurine 12 hours prior acetaminophen administration, simultaneously with acetaminophen and an hour after acetaminophen was administered. The study indicated that taurine significantly reduced acetaminophen-induced liver injury in an in vivo rat model. Adding taurine either 12 hours before or at the time of acetaminophen treatment effectively prevented hepatocyte necrosis. Moreover, administering taurine 1 hour after the onset of acetaminophen-induced hepatotoxicity significantly improved liver injury, as evidenced by reduced hepatocyte necrosis, possibly through its unique cytoprotective properties such as antioxidant activity.
BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma
Authors: Clark Courtney , Barzegar Behrooz Amir , da Silva Rosa Simone C. , Jacobs Joadi , Weng Xiaohui , Srivastava Abhay , Vitorino Rui , Ande Sudharsan Rao , Ravandi Amir , Dhingra Sanjiv , Pecic Stevan , Miller Donald , Shojaei Shahla , Ghavami Saeid
Published: August 2024

Temozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed a TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences in cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R and non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced apoptosis, while TMZ-R cells-maintained viability. Autophagy flux was completely inhibited in TMZ-R cells, indicated by LC3βII and SQSTM1 accumulation. BCL2L13, which showed higher expression in TMZ-R cells, demonstrated increased interaction with Ceramide Synthase 6 (CerS6) and reduced interaction with Ceramide Synthase 2 (CerS2) in TMZ-NR cells. BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation in TMZ-R cells while increasing it in TMZ-NR cells. These changes contributed to altered ceramide profiles, where TMZ-R cells displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1. Our findings highlight BCL2L13 and altered ceramide metabolism as potential therapeutic targets to overcome TMZ resistance in GB.
Improved genetic discovery and fine-mapping resolution through multivariate latent factor analysis of high-dimensional traits
Authors: Zhou Feng , Astle William J , Butterworth Adam S , Asimit Jennifer L
Published: August 2024

Genome-wide association studies (GWAS) of high-dimensional traits, such as molecular phenotypes or imaging features, often use univariate approaches, ignoring information from related traits. Biological mechanisms generating variation in high-dimensional traits can be captured parsimoniously through GWAS of a smaller number of latent factors from factor analysis. Here, we introduce a zero-correlation multi-trait fine-mapping approach, flashfmZero, for any number of latent factors. In our application to 25 latent factors derived from 99 blood cell traits in the INTERVAL cohort, we show how GWAS of latent factors enables detection of signals that have sub-threshold associations with several blood cell traits. FlashfmZero resulted in 99% credible sets with the same size or fewer variants than those for blood cell traits in 87% of our comparisons, and all latent trait fine-mapping credible sets were subsets of those from flashfmZero. These analysis techniques give enhanced power for discovery and fine-mapping for many traits.
Genetically encoded fluorescent reporter for polyamines
Authors: Sharma Pushkal , Kim Colin Y. , Keys Heather R. , Imada Shinya , Joseph Alex B. , Ferro Luke , Kunchok Tenzin , Anderson Rachel , Yilmaz Omer , Weng Jing-Ke , Jain Ankur
Published: August 2024

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson’s disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson’s disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
SynPull: a novel method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy
Authors: Kedia Shekhar , Fertan Emre , Wu Yunzhao , Zhang Yu P. , Meisl Georg , Lam Jeff Y. L. , Wiseman Francis , McEwan William A. , Quaegebeur Annelies , Spillantini Maria Grazia , Danial John S. H. , Klenerman David
Published: August 2024

Synaptic dysfunction is one of the primary hallmarks of both Alzheimer’s and Parkinson’s disease, leading to cognitive and behavioural decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptic dysfunction. However, the methodology for studying the small (sub-diffraction limit) and soluble aggregates -often called oligomers, formed by these proteins is limited. Here we describe SynPull, a novel method combining single-molecule pulldown, super-resolution microscopy, and advanced computational analyses, in order to reliably study the quantity and morphology of the oligomeric alpha-synuclein, beta-amyloid, and AT8-positive tau aggregates in synaptosomes harvested from post-mortem human brain samples and mouse models. Using SynPull, we show that AT8-positive tau is the predominant aggregate type in AD, with significantly more aggregates compared to the control samples, yet the aggregate size does not differ between disease and control samples. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in dementia, which can help further understand the disease mechanisms causing synaptic dysfunction.

Abstract Figure

Graphical abstract.

Human post-mortem orbitofrontal cortex samples from subjects with neuropathological diagnosis of Alzheimer’s and Parkinson’s disease, as well as age-matched controls cut into ∼300 mg sections, and MI2, APPNL-G-F, P301S, and C57Bl/6J mouse brains were first homogenised in synaptosome buffer using a Dounce homogeniser and then filtered and centrifuged to separate nuclei and organelles from the synaptic fragments. Then, the isolated synaptosomes were incubated on the SiMPull surface with anti-neurexin antibody overnight, followed by fixation and permeabilisation. Imaging antibodies against beta-amyloid, alpha-synuclein, and AT8-positive tau were added to the samples anddSTORM imaging was performed to super-resolve the aggregates.
Optimization of Seizure Prevention by Cannabidiol (CBD)
Authors: Bhandari Bidhan , Naeini Sahar Emami , Rezaee Sholeh , Rogers Hannah M , Khodadadi Hesam , Bosomtwi Asamoah , Seyyedi Mohammad , MacKinnon Neil J , Dhandapani Krishnan M , Salles Évila Lopes , Hess David C , Yu Jack C , Moore-Hill Debra , Vale Fernando L. , Wang Lei P , Baban Babak
Published: August 2024

Objective

Cannabidiol (CBD) is one of the most prominent non-psychotropic cannabinoids with known therapeutic potentials. Based on its anti-seizure efficacy, the first cannabis derived, pharmaceutical grade CBD-based medication was approved in the USA in 2018 for the treatment of seizures in patients 2 years and older. Despite the effectiveness in reducing seizures, there remain several major questions on the optimization of CBD therapy for epilepsy such as the optimal dosage, composition, and route of delivery, which are the main objective of this current study.

Methods

We evaluated the antiseizure effects of CBD through different compositions, routes of delivery, and dosages in a pre-clinical model. We used a kainic acid-induced epilepsy model in C57BL/6 mice, treated them with placebo and/or CBD through inhalation, oral and injection routes. We used CBD broad spectrum (inhaled and injection) versus CBD isolate formulations. We employed the Racine scaling system to evaluate the severity of the seizures, flow cytometry for measuring Immune biomarkers and neurotrophic factors, and histologic analysis to examine and compare the groups.

Results

Our findings showed that all forms of CBD reduced seizures severity. Among the combination of CBD tested. CBD broad spectrum via inhalation was the most effective in the treatment of epileptic seizures (p<0.05) compared to other forms of CBD treatments.

Conclusion

Our data suggest that route and CBD formulations affect its efficacy in the prevention of epileptic seizures. Inhaled broad spectrum CBD showed a potential superior effect compared to other delivery routes and CBD formulations in the prevention of epileptic seizures, warrants further research.
RESPIRATORY SYNCYTIAL VIRUS NON-STRUCTURAL PROTEIN EXPRESSION ARE LIMITED IN NEUTROPHILS
Authors: Thornhill Elena M , Verhoeven David
Published: August 2024

Respiratory Syncytial Virus (RSV) is a negative stranded RNA virus with a high incidence of secondary bacterial infections. RSV contains two broad immune inhibitory proteins Ns1 and Ns2 which are not present in any other viruses of the Mononegavirales Order. Here we report that expression of Ns2 is attenuated during RSV infection of neutrophils and that RSV is indeed infecting neutrophils rather than simply being phagocytosed by them. Infection was determined by intracellular staining and coinfection studies of uninfected Hep2 cells. The significant attenuation of Ns2 in vivo along with the low abundance of coinfected cells indicates that RSV infection is likely functionally non permissive in in vivo infection. The implications of RSV infection of neutrophils may explain the previously observed phenomenon of decreased phagocytosis in neutrophils exposed to RSV and the lack of Ns2 expression within neutrophils may provide avenues of study to attenuate viral infection through therapy development.
Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty
Authors: Mak Jonathan K.L. , Qin Chenxi , Kuukka Anna ,   FinnGen, Hägg Sara , Lin Jake , Jylhävä Juulia
Published: August 2024

Frailty is a clinically relevant phenotype with significant gaps in our understanding of its etiology. We performed a genome-wide association study of frailty in FinnGen (N=500,737) and replicated the signals in the UK Biobank (N=429,463) using polygenic risk scores (PRSs). We prioritized genes through proteomics integration (N∼45,000; UK Biobank) and colocalization of protein quantitative trait loci. Frailty was measured using the Hospital Frailty Risk Score (HFRS). We observed 1,588 variants associated with frailty (p<5×10-8) of which 1,242 were novel, i.e., previously unreported for any trait. The associations mapped to 106 genes of which 31 were novel. PRS replication validated the signals (β=0.074,p<2×10-16). Cell type enrichment analysis indicated expression in neuronal cells. Protein levels ofKHK,CGREF1,MET,ATXN2,ALDH2,NECTIN2,APOC1,APOEandFOSBwere associated with HFRS, whereas colocalized signals were observed withinAPOEandBRAP. Our results reveal novel genetic contributions and causal candidate genes for frailty.
The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease
Authors: Mahajan Abhimanyu , Morrow Christopher B , Seemiller Joseph , Mills Kelly A , Pontone Gregory M
Published: August 2024

Background

Motor and non-motor fluctuations adversely impact quality of life in Parkinson’s disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations.

Objectives

We sought to evaluate the effect of dysautonomia on motor and non-motor fluctuations in PD

Methods

Two hundred subjects with PD were evaluated in both “on” and “off” dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Multivariable logistic regression was performed to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from ON to OFF states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine agonist LEDD.

Results

Subjects with dysautonomia had greater odds of clinically meaningful change in motor features (OR 3.0), cognition (OR 3.4) and anxiety (OR 4.3) compared to those without dysautonomia.

Conclusions

Dysautonomia may be a contributory mechanism behind fluctuations in PD. The exact nature of this relationship deserves further evaluation.
The public health co-benefits of strategies consistent with net-zero emissions: a systematic review of quantitative studies
Authors: Moutet Léo , Bernard Paquito , Green Rosemary , Milner James , Haines Andy , Slama Rémy , Temime Laura , Jean Kévin
Published: August 2024

Moving toward net-zero emission societies is projected to provide health co-benefits, yet their magnitude is not well documented and may be context-specific. Synthesizing the evidence on these co-benefits could enhance the engagement of decision-makers and populations in climate mitigation actions. We performed a systematic review including 58 quantitative studies exploring 125 scenarios. Across air quality, physical activity and dietary changes pathways, substantial health co-benefits were found, with half of scenarios showing a mortality reduction by more than 1.5%, in addition to benefits directly related to climate stabilization. However, these co-benefits varied with explored emission sectors, decarbonization levers, modelling approaches and locations. Among studies including a cost-benefit analysis, 11 of 13 estimated that monetized benefits outweighed the costs of implementing climate policies. This review highlights the need for a standardised framework to assess and compare health impacts of climate mitigation actions across sectors, and confirms that achieving net-zero goals supports far-reaching public health policies.
The role of protein shape in multiphasic separation within condensates
Authors: Pandey Vikas , Hosokawa Tomohisa , Hayashi Yasunori , Urakubo Hidetoshi
Published: August 2024

Liquid–liquid phase separation (LLPS) of biological macromolecules leads to the formation of various membraneless organelles. LLPS can not only form homogenous condensates but also multilayered and multiphase condensates, which can mediate complex cellular functions. However, the factors that determine the topological features of multiphase condensates are not fully understood. Herein, we focused on Ca2+/calmodulin-dependent protein kinase II (CaMKII), a major postsynaptic protein that undergoes various forms of LLPS with other postsynaptic proteins, and present a minimalistic computational model that reproduces these forms of LLPS, including a form of two-phase condensates, phase-in-phase (PIP) organization. Analyses of this model revealed that the competitive binding of two types of client proteins is required for the PIP formation. The PIP only formed when CaMKII had high valency and a short linker length. Such CaMKII proteins exhibited a low surface tension, a modular structure, and slow diffusion. These properties are consistent with the functions required by CaMKII to store information at the synaptic level. Thus, the computational modeling reveals new structure–function relationships for CaMKII as a synaptic memory unit.
Impact of intragenicNRXN1deletions on early cortical development
Authors: Dutan Lucia , Gatford Nicholas J. F. , Carneiro Thaise , Nagy Roland , Higgs Victoria ,   APEX Consortia, Massrali Aicha , Paul Arkoprovo , Fasolino Maria , Zhou Zhaolan , Flinter Frances A , Adhya Dwaipayan , Bucan Maja , Baron-Cohen Simon , Srivastava Deepak P.
Published: August 2024

Background

Deletions inNRXN1are strongly associated with neurodevelopmental and psychiatric conditions. While exonic deletions are well-studied, intragenic deletions, particularly in intron 5, are less understood and generally consider benign. Recent studies show exonic deletions impact isoform diversity during neurodevelopment, affecting neurogenesis and neuronal function. However, whether intragenic deletions impact isoform expression and neurodevelopment remains underexplored.

Methods

We used hiPSCs from typically developing individuals (control) and those withNRXN1intron 5 deletions to study neurodevelopment. HiPSCs were differentiated towards a cortical fate, withNRXN1isoform expression, molecular differences, and neuronal morphology examined.

Results

We observed distinctNRXN1isoform expression dynamics during early neurodevelopment, with two expression peaks post-neuronal induction andNRXN1βbeing most highly expressed. BothNRXN1deletion and control lines showed similar acquisition of regional and cell fate identity, but significant differences inNRXN1isoform expression were observed between deletion and control lines, and between deletion lines. RNA sequencing revealed genotype-dependent alterations, particularly in pathways related to synaptic function and neuronal morphology. Consistent with these findings,NRXN1deletion lines exhibited altered dendrite outgrowth, with variations between deletion lines.

Conclusions

Our results indicate a potential role for intron 5 in controllingNRXN1isoform expression during neurodevelopment. Alterations in gene expression profiles, correlated with morphological changes, suggest a role forNRXN1isoforms in shaping dendritic morphology. Molecular and cellular differences observed between lines with identical intronic deletions suggest that additional factors, such as genetic background or biological sex, may also play an important role in these phenotypes. Collectively, these findings indicate thatNRXN1intronic deletions are not benign, influencing isoform expression, cellular phenotypes, and neurodevelopment.