bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the genomic landscape of HIV-associated lymphoma reveals heterogeneity across histological subtypes
Authors: Hybel Trine Engelbrecht , Sørensen Emma Frasez , Enemark Marie Hairing , Hemmingsen Jonas Klejs , Simonsen Anita Tranberg , Lauridsen Kristina Lystlund , Møller Michael Boe , Pedersen Court , Pedersen Gitte , Obel Niels , Larsen Carsten Schade , d’Amore Francesco , Hamilton-Dutoit Stephen , Stougaard Magnus , Vase Maja Ølholm , Ludvigsen Maja
Published: August 2024

Objective:

Individuals with HIV experience an increased risk of lymphoma, making this an important cause of death among people with HIV. Nevertheless, little is known regarding the underlying genetic aberrations, which we therefore set out to characterize.

Design:

We conducted next-generation panel sequencing to explore the mutational status of diagnostic lymphoma biopsies from 18 patients diagnosed with lymphoma secondary to HIV infection.

Methods:

Ion Torrent next-generation sequencing was performed with an AmpliSeq panel on diagnostic lymphoma biopsies from HIV-associated B-cell lymphomas (n = 18), comprising diffuse large B-cell lymphoma (n = 9), classic Hodgkin lymphoma (n = 6), Burkitt lymphoma (n = 2), follicular lymphoma (n = 1), and marginal zone lymphoma (n = 1). The panel comprised 69 lymphoid and/or myeloid-relevant genes, in which either the entire coding sequence or a hotspot region was sequenced.

Results:

Among the 18 lymphomas, we detected 213 variants. The number of detected mutations ranged from 4 to 41 per tumor distributed among 42 genes, including both exonic and intronic regions. The most frequently mutated genes included KMT2D (67%), TNFAIP3 (50%), and TP53 (61%). Notably, no gene was found to harbor variants across all the HIV-associated lymphomas, nor did we find subtype-specific variants. While some variants were shared among patients, most were unique to the individual patient and were often not reported as malignant genetic variants in databases.

Conclusion:

Our findings demonstrate genetic heterogeneity across histological subtypes of HIV-associated lymphomas and thus help elucidate the genetics and pathophysiological mechanisms underlying the disease.
A case of primary small cell neuroendocrine carcinoma of the submandibular gland
Authors: Lee Yeongrok , Kim Do Hyeon , Park Jae Hong
Published: August 2024

Small cell neuroendocrine carcinoma (SmCC) is rarely found in the head and neck region. With most cases having been reported in the larynx, SmCC of the salivary glands remains a rare clinical entity. Similar to that in the lung and larynx, SmCC of the salivary glands has an aggressive nature associated with strong metastatic potential, although its prognosis is relatively better. The authors experienced a case of a 50-year-old male patient who presented with a submandibular mass. After surgical excision, histopathologic and immunohistochemical examination confirmed the mass to be primary small cell neuroendocrine carcinoma of the submandibular gland. The patient received postoperative chemoradiation and has remained disease-free during 36 months of follow-up.
Repeat Exchange Autologous Cranioplasty for Recurrent Benign Osteoma: Meta-analysis and Literature Review
Authors: Drayton Ka’la D. , Dang Huy Q. , Rivera Echevarría Aranza , Martin Jonathan E. , Weiner Howard L. , Hughes Christopher
Published: August 2024

Osteomas are benign bony lesions that can occur throughout the craniofacial skeleton. Surgical excision can be an effective treatment, as recurrence is relatively uncommon. Outside of incomplete resection, causes of recurrence are poorly documented, especially in the pediatric population. Exchange cranioplasty is an autologous reconstructive surgical option for patients of all ages, and it can be effective in the treatment of large calvarial osteomas. Recurrent lesions of the cranioplasty site have not been well described in the literature, with only 3 documented reports. In this study, we present a unique case of a recurrent osteoma at the site of a prior exchange cranioplasty. The authors also provide a systematic review of the literature for recurrent osteomas and highlight causes and conclusions for these lesions. Utilizing the PRISMA guidelines, a systematic review of articles published across databases was performed to identify accounts of recurrent osteomas at prior cranioplasty sites. Our systematic review illustrates that recurrent osteomas overlying different cranioplasty biomaterials is a rare entity and is due to incomplete resection of the galea and periosteum during the index procedure. Biomaterial selection for the pediatric population requires careful consideration before reconstruction. Though limited by 3 articles previously published and without a direct link to recurrence, long-term studies are needed to further guide biomaterial selection in the pediatric population to evaluate potential recurrences.
An Innovative Methodology: The Submental Island Flap Offers Enhanced Soft Tissue Coverage to the Vascularized Iliac Crest Flap
Authors: Dou Chun-Bo , Yu Ming-Yang , Jia Jun , Yu Zi-Li
Published: August 2024

The vascularized iliac crest flap has garnered widespread acclaim within the field of mandibular reconstruction attributable to its sufficient bone mass and congruent curved morphology. However, when the precise orientation of the iliac crest is imperative during mandibular reconstruction and there exists an accompanying defect within the oral soft tissue, the indispensability of an additional flap to facilitate concurrent defect repair becomes evident. In such instances, the submental island flap emerges as an exemplary candidate.
Large Rhinolith in Nasal Cavity and Extension to Maxillary Sinus in a Cocaine User
Authors: Delamura Izabela F. , Murai Melissa K. , Panigali Olavo A. , Polo Tárik O.B. , Bassi Ana P.F. , Faverani Leonardo P.
Published: August 2024

Although rhinoliths are rare, they deserve attention and should be considered in the differential diagnoses of calcified lesions that can affect the nasal cavity and maxillary sinus region. This article reports a case of a large rhinolith in the nasal cavity caused by cocaine use. Initially, the patient denied drug use, leaving several uncertainties regarding the diagnosis, including recurrent sinusitis. However, after the histopathologic results, the patient admitted to previous cocaine use, emphasizing the importance of honesty in the medical history to guide diagnostic hypotheses, as well as the awareness of the diagnostic possibility of a rhinolith to assist in treatment.
VASCULAR ENDOTHELIAL DYSFUNCTION IMPROVEMENTS IN PATIENTS WITH UREMIA USING PENTOXIFYLLINE-SUPPRESSING NLRP3 EXPRESSIONS AND HMGB1 RELEASE
Authors: Li Ruikun , Zhang Xue , Xu Yuanqin , Feng Tao
Published: August 2024

This study aimed to investigate the protective effect of pentoxifylline (PTX) on vascular endothelial dysfunction in uremia. The human aortic endothelial cells (HAECs) required for the experiments were all obtained from the National Collection of Authenticated Cell Cultures (Salisbury, UK). The permeability of HAECs was assessed. Each group had six samples. Compared with the healthy volunteer group, HAEC proliferation in the 20% uremia group was significantly inhibited after 72 h (P < 0.001), co-localization of nucleotide-binding domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3 (NLRP3) and apoptosis-associated speck-like (ASC) protein induced by uremic serum was enhanced (P < 0.01) and high mobility group box 1 (HMGB1) release was increased (0.594 ± 0.057, P = 0.03). The co-immunoprecipitation of NLRP3, ASC, and HMGB1 induced by uremic toxin was also enhanced (P < 0.01), and PTX inhibited this phenomenon. The expression of NLRP3 (0.810 ± 0.032, P = 0.02) and caspase-1 (0.580 ± 0.041, P = 0.03) was increased, whereas the expression of ZO-1 (0.255 ± 0.038, P = 0.03) and VE-cadherin (0.0546 ± 0.053, P = 0.02) was decreased in the uremia group; compared with the healthy volunteer group, treated with PTX (NLRP3, 0.298 ± 0.042, P = 0.03; caspase-1, 0.310 ± 0.021, P = 0.03; ZO-1, 0.412 ± 0.028, P = 0.02; VE-cadherin, 0.150 ± 0.034, P = 0.02) and MCC950 (NLRP3, 0.432 ± 0.022, P = 0.03; caspase-1, 0.067 ± 0.031, P > 0.05; ZO-1, 0.457 ± 0.026, P = 0.03; VE-cadherin, 0.286 ± 0.017, P = 0.03) these lessened this trend. Pentoxifylline promoted the HAEC permeability mediated by uremic toxins (1.507 ± 0.012, P = 0.02). In conclusion, PTX enhances the release of HMGB1, which is dependent on NLRP3 activation, and consequently exerts positive effects on interconnecting proteins, ultimately leading to an improvement in vascular permeability.
PANAXADIOL SAPONIN ALLEVIATES LPS-INDUCED CARDIOMYOPATHY SIMILAR TO DEXAMETHASONE VIA IMPROVING MITOCHONDRIAL QUALITY CONTROL
Authors: Yang Zhaoyun , Gao Yan , Li Dongyang , Zhao Lijing , Du Yanwei
Published: August 2024

Septic cardiomyopathy is linked to a dysregulation in mitochondrial integrity and elevated mortality rates, for which an efficacious treatment remains elusive. PDS is a panaxadiol saponin extracted from ginseng stem and leaf. This study identified the protective effects of PDS and DEX in LPS-induced cardiomyopathy and explored the mechanism of them treating LPS-induced cardiomyopathy from the perspectives of mitochondrial quality control. DEX and PDS enhance antioxidant defense by degrading Keap1 to activate Nrf2; activate mitochondrial occurrence protein PGC-1α and fusion protein OPA1, Mfn1, and Mfn2 expression; and inhibit phosphorylation of mitochondrial fission protein Drp1, aiming to maintain normal structure and function of mitochondrial, thereby preserving oxidative phosphorylation capacity. In summary, our findings highlighted the protective efficacy of PDS and DEX in maintaining mitochondrial in LPS-induced cardiomyopathy, and mechanism improving mitochondrial quality control at least in part by promoting Nrf2 activation.
TARGETED TEMPERATURE MANAGEMENT AT 36°C IMPROVES SURVIVAL AND PROTECTS TISSUES BY MITIGATING THE DELETERIOUS INFLAMMATORY RESPONSE FOLLOWING HEMORRHAGIC SHOCK
Authors: Choi Arom , Woo Ji Sun , Park Yoo Seok , Kim Ju Hee , Chung Yong Eun , Lee Sojung , Beom Jin Ho , You Je Sung
Published: August 2024

Hemorrhagic shock (HS) is a life-threatening condition with high mortality rates despite current treatments. This study investigated whether targeted temperature management (TTM) could improve outcomes by modulating inflammation and protecting organs following HS. Using a rat model of HS, TTM was applied at 33°C and 36°C after fluid resuscitation. Surprisingly, TTM at 33°C increased mortality, while TTM at 36°C significantly improved survival rates. It also reduced histological damage in lung and kidney tissues, lowered serum lactate levels, and protected against apoptosis and excessive reactive oxygen species production. TTM at 36°C inhibited the release of high mobility group box 1 protein (HMGB1), a key mediator of inflammation, and decreased proinflammatory cytokine levels in the kidneys and lungs. Moreover, it influenced macrophage behavior, suppressing the harmful M1 phenotype while promoting the beneficial M2 polarization. Cytokine array analysis confirmed reduced levels of proinflammatory cytokines with TTM at 36°C. These results collectively highlight the potential of TTM at 36°C as a therapeutic approach to improve outcomes in HS. By addressing multiple aspects of injury and inflammation, including modulation of macrophage responses and cytokine profiles, TTM at 36°C offers promising implications for critical care management after HS, potentially reducing mortality and improving patient recovery.
Impact of Intrapatient Immunosuppression Variability in Liver Transplantation Outcomes: A Systematic Review and Meta-analysis
Authors: Lattimore Sherene , Chambers Anastasia , Angeli-Pahim Isabella , Shrestha Abhishek , Eke Benjamin O. , Pomputius Ariel , Bylund Carma , Gregory Megan E. , Zarrinpar Ali
Published: August 2024

Background.

To investigate the impact of intrapatient variability (IPV) in the levels of immunosuppressant drugs on health outcomes after liver transplantation.

Methods.

A comprehensive systematic review and meta-analysis were conducted, examining literature from MEDLINE/PubMed, Embase, Web of Science, Cochrane Reviews, and Cochrane CENTRAL.

Results.

The analysis focused on acute rejection, graft survival, acute kidney injury, and cancer risk as health outcomes. Of 2901 articles screened, 10 met the inclusion criteria. The results indicate a 19% reduction in the risk of acute rejection in patients with lower IPV (RR = 0.81; 95% confidence interval, 0.66-0.99), although 6 studies found no significant association between high IPV and acute rejection. Contrasting results were observed for graft survival, with 1 study indicating worse outcomes for high IPV, whereas another reported no significant difference. High IPV was consistently associated with acute kidney injury across 3 studies. One study suggested a link between high IPV and hepatocellular carcinoma, although a meta-analysis for these outcomes was not feasible.

Conclusions.

These findings point to a marginal but statistically significant association between high IPV and an increased risk of acute rejection, highlighting the importance of precise management of immunosuppressive drugs in liver transplant recipients to enhance patient outcomes.
Impact of Dialysis Time on Long-term Outcomes in HLA-identical Living Donor Kidney Transplant Recipients
Authors: Ferreira Evelyn S. , Requião-Moura Lucio , Nakamura Mônica R. , Foresto Renato Demarchi , Medina Pestana José , Tedesco-Silva Hélio
Published: August 2024

Background.

Dialysis vintage is associated with worse outcomes after kidney transplantation. The reasons behind this observation include immunological and nonimmunological risk factors. To mitigate the influence of immunological factors, we examined the association between time on dialysis and clinical outcomes in a cohort of HLA-identical kidney transplant recipients.

Methods.

This retrospective study included 13 321 kidney transplant recipients between 1999 and 2016, of whom 589 were HLA identical followed for at least 5 y. Patient and graft survivals were compared according to dialysis time (<12 or >12 mo) using the log-rank test and Cox regression analysis. We compared surgical complications, cytomegalovirus infection, acute rejection, disease recurrence, and the trajectories of estimated glomerular filtration rate (eGFR).

Results.

Median time on dialysis was 15 mo; 9.2% of patients received preemptive transplants, and 55.3% of patients were on dialysis for >12 mo. After a median follow-up time of 154 mo, there were no differences in unadjusted and adjusted patient and graft survivals (1, 5, 10, and 15 y) between the 2 groups. There were no differences in the incidence of surgical complications (6.2% versus 3.1%), acute rejection (6.1% versus 7.7%), cytomegalovirus infection (7.6% versus 4.0%), and disease recurrence (4.2% versus 4.0%), respectively. There were no differences in mean eGFR during 5 y or in the proportion of patients with an eGFR <30 mL/min at 5 y (9.9% versus 9.2%).

Conclusions.

In this low immunological risk cohort of HLA-identical kidney transplant recipients, we did not observe any association between dialysis vintage on patient survival and graft survival.
G2019S Mutation of Leucine-Rich Repeat Kinase 2 Is a Cause of Lewy Body Dementia in Patients With North African Ancestors
Authors: Segers Kurt , Benoit Florence , Levy Sophie , Martinet Valérie , Schulz Joachim G. , Bertrand Frédéric , De Bourgoing Gabrielle , Tatillo Chiara , Praet Jean-Philippe , Vandernoot Isabelle , Desmyter Laurence , Peyrassol Xavier , Kehagias Pashalina , Smits Guillaume , Dumoulin Baptiste , Besse-Hammer Tatiana , Dachy Bernard , Surquin Murielle
Published: August 2024

Background:

Mutations in the LRRK2 gene are the most common genetic cause of Parkinson disease but are believed to play no significant role in Lewy body disease (LBD).

Objectives:

As the frequency of G2019S LRRK2 mutation is extremely high in North African patients with Parkinson disease, we postulate that the high prevalence of LBD in North Africa might be due to the same mutation because LBD and Parkinson disease share many clinical, pathological, and genetic features.

Methods:

We screened patients with LBD or prodromal LBD for the G2019S mutation of LRRK2.

Results:

A total of 162 patients were tested for the mutation, which was present in 5 of the 47 patients with North African ancestors. This is a much higher prevalence (10.6%) than in healthy North African subjects (1.45%) but lower than in North African patients with Parkinson disease (36% to 39%). Carriers tended to develop more often orthostatic hypotension and swallowing problems.

Conclusions:

Where previous studies in European and North American patients found no link between LRRK2 mutations and LBD, we found an LRRK2 mutation associated with Lewy body disease, namely the G2019S mutation that might be restricted to patients with North African ancestors. Our study illustrates the need to introduce ethnic diversity as stratifying factor in the analysis of genetic causes of neurodegenerative disorders. The current development of disease-modifying drugs modulating LRRK2 kinase activity could justify to screen North African patients with LBD for the G2019S LRRK2 mutation.
Interpreting Histopathology Reports of Temporal Artery Biopsies Positive for Giant Cell Arteritis (GCA): A Single-Center Retrospective Study
Authors: McDonald Heather , Phillips Christian , Shah Minj , Margolin Edward
Published: August 2024

Background:

The gold standard for diagnosing giant cell arteritis (GCA) is temporal artery biopsy (TAB). However, specific histopathologic findings on biopsy reports are rarely considered in the context of the patient's clinical presentation. The purpose of this study was to analyze the correlation of specific biopsy findings with the clinical presentation of patients with GCA.

Methods:

Retrospective chart review of patients with a clinical and histopathologic diagnosis of GCA at a single tertiary care neuro-ophthalmology practice from January 2014 to September 2023. Histopathologic findings on TAB were recorded for each patient, along with clinical history, examination, and treatment. Continuous variables were reported as mean values with standard deviations (SD), while categorical variables were described as percentages. Correlation coefficients with P-values were used to evaluate the relationship between biopsy findings and clinical data.

Results:

A total of 53 patients were included. TAB specimens ranged in length from 0.6 to 3.4 cm, with a statistically significant correlation coefficient between specimen length and total number of positive findings on the biopsy report. A positive correlation coefficient that approached statistical significance was found between the presence of lymphocytes in the biopsy and permanent vision loss (R = 0.253, P-value 0.054), which occurred in 27 patients. Patients were treated with steroids prebiopsy for an average of 9 days; there was no statistically significant correlation between the duration of steroid treatment and the presence of specific histopathologic findings other than involvement of the intima.

Conclusions:

The results of this study demonstrate that (1) longer temporal artery biopsy specimens are significantly correlated with a higher number of findings on biopsy reports; (2) the presence of arterial stenosis, eosinophils, and lymphocytes correlated with permanent vision loss or degree of vision loss; and (3) the duration of steroid treatment had a significant inverse correlation with intimal involvement but did not affect other histopathologic findings seen with GCA. This retrospective observational study provides clinicians with an approach to understanding the nuances of the histopathologic findings on their patient's TAB report.
Does Electroencephalography Seizure Duration Account for an Adequate Treatment of Magnetic Seizure Therapy for Schizophrenia?
Authors: Jiang Jiangling , Li Jin , Xu Yuanhong , Zhang Bin , Sheng Jianhua , Liu Dengtang , Wang Wenzheng , Yang Fuzhong , Guo Xiaoyun , Li Qingwei , Zhang Tianhong , Tang Yingying , Jia Yuping , Wang Jijun , Li Chunbo
Published: August 2024

Objectives

A seizure lasting >15 s has been considered to indicate treatment for magnetic seizure therapy (MST), a modification of electroconvulsive therapy (ECT), without much validation. This study aimed to investigate whether this seizure duration was suitable for the treatment of schizophrenia.

Methods

Altogether, 34 and 33 in-patients with schizophrenia received 10 sessions of MST and ECT, respectively. Clinical symptoms were assessed using the Positive and Negative Symptom Scale at baseline and at the 4-week follow-up. Electroencephalogram (EEG) was monitored during each MST or ECT treatment using bifrontal electrodes.

Results

The proportion of participants who achieved the 15-second threshold was only 28.6% in the MST group, with a significant difference between responders and nonresponders. For patients receiving MST, the average EEG seizure duration correlated with the percentage of Positive and Negative Symptom Scale reduction (t
(32) = 2.51, P = 0.017, uncorrected; t
(32) = 2.00, P = 0.055, corrected with clinical characteristics). The average EEG seizure duration predicted the clinical response at a trend level (Z = 1.76, P = 0.078) with an optimal cutoff of 11.3 seconds. All patients in the ECT group achieved the 15-second threshold. However, their average EEG seizure duration was uncorrelated with clinical improvement.

Conclusions

The duration of EEG seizures may be associated with the antipsychotic effects of MST. This association may have been influenced by various clinical and technical factors. More research is needed to define the specific criteria for adequate MST in schizophrenia in order to achieve personalized dosing.
Developing power plant materials using the life cycle lens
Authors: Quadling Amanda , Bowden David , Hardie Chris , Vasanthakumaran Arti
Published: August 2024

The Spherical Tokamak for Energy Production (STEP) environment will include magnetic, thermal, mechanical and environmental loads far greater than those seen in the Joint European Torus campaigns of the past decade or currently contemplated for ITER. Greater still are the neutron peak dose rates of 10
−6
displacements per atom, per second, which in-vessel materials in STEP are anticipated to be exposed to. Reduced activation and high-fluence resilience therefore dominate the materials strategy to support the STEP Programme. The latter covers the full life cycle from downselected compositions and new microstructural developments to irradiation-informed modelling and end-of-life strategies. This article discusses how the materials downselection is oriented in plant power trade-off space, outlines the development of an advanced ferritic-martensitic structural steel, describes the ‘Design by Fundamentals’ mesoscale modelling approach and reports some of the waste mitigation routes intended to make STEP operations as sustainable as possible.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Context-Dependent Modulations of Subthalamo-Cortical Synchronization during Rapid Reversals of Movement Direction in Parkinson’s Disease
Authors: Winkler Lucie , Butz Markus , Sharma Abhinav , Vesper Jan , Schnitzler Alfons , Fischer Petra , Hirschmann Jan
Published: August 2024

The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts.

To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable.

We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. On the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients revealing brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition.

In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Further, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.

Significance Statement

Beta synchrony between motor cortex and the subthalamic nucleus is intensified when instructional cues within a continuous motor sequence become less predictable, calling for more cautious behavior.
Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO)
Authors: Bigler Melina , Vaucher Malina , Wiederkehr Manuel , Brülisauer Sophia , Albrich Werner C. , Dräger Sarah , Gisler Valentin , Akers Isabel , Mäusezahl Daniel
Published: August 2024

Background

The long-term effects of Legionnaires’ disease beyond the acute infection and their impact on healthcare utilisation remain poorly understood. We present the rationale and study design of a matched prospective observational cohort study (LongLEGIO) aimed at investigating the persistent sequelae on patients’ health, well-being, and health service use following community-acquired Legionnaires’ disease, compared to other bacterial pneumonias that tested negative forLegionella.

Methods

Patients with Legionnaires’ disease and other bacterialLegionellatest-negative pneumonia are recruited from secondary and tertiary care hospitals and matched for sex, age, hospital-level and date of diagnosis. Semi-structured interviews were conducted at baseline (shortly after the pneumonia diagnosis) and at two, six and 12 months following appropriate antibiotic therapy. Baseline assessments capture pre-existing conditions, illness experience, and disease severity, while follow-up assessments evaluate long-term symptoms, healthcare utilisation, quality of life (EQ-5D-5L), and social/work impacts. Data on case management and the disease severity are extracted from patient records.

Results

A total of 59 patients with community-acquired Legionnaires’ disease and 60 patients with other bacterialLegionellatest-negative pneumonia were enrolled. Both cohorts were representative of their respective condition. Key differences between Legionnaires’ disease and non-Legionellabacterial pneumonia patient groups emerged in terms of comorbidities, pneumonia severity, and self-reported quality of life. These differences will be accounted for in future analyses as part of theLongLEGIOstudy.

Conclusions

TheLongLEGIOstudy will advance ongoing research on post-acute infection syndromes and provide a robust data foundation for more accurate assessments of the disease burden associated with Legionnaires’ disease.
A comprehensiveSchizosaccharomyces pombeatlas of physical transcription factor interactions with proteins and chromatin
Authors: Skribbe Merle , Soneson Charlotte , Stadler Michael B. , Schwaiger Michaela , Sreechakram Vishnu N. Suma , Iesmantavicius Vytautas , Hess Daniel , Moreno Eliza Pandini Figueiredo , Braun Sigurd , Seebacher Jan , Smallwood Sebastien A. , Bühler Marc
Published: August 2024

Transcription factors (TFs) are key regulators of gene expression, yet many of their targets and modes of action remain unknown. InSchizosaccharomyces pombe, one-third of TFs are solely homology-predicted, with few experimentally validated. We created a comprehensive library of 89 endogenously taggedS. pombeTFs, mapping their protein and chromatin interactions using immunoprecipitation-mass spectrometry and chromatin immunoprecipitation sequencing. Our study identified protein interactors for half the TFs, with over a quarter potentially forming stable complexes. We discovered DNA binding sites for most TFs across 2,027 unique genomic regions, revealing motifs for 38 TFs and uncovering a complex regulatory network of extensive TF cross- and autoregulation. Characterization of the largest TF family revealed conserved DNA sequence preferences but diverse binding patterns, and identified a repressive heterodimer, Ntu1/Ntu2, linked to perinuclear gene localization. Our TFexplorer webtool makes all data interactively accessible, offering new insights into TF interactions and regulatory mechanisms with broad biological relevance.

HIGHLIGHTS

Comprehensive strain library of endogenously taggedS. pombeTFs

Experimentally determined atlas of TF interactions with proteins and chromatin

TFexplorer web application for interactive exploration of TF interactomes

Identification of repressive Nattou complex linked to perinuclear gene localization
A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1
Authors: Soles Alyssa , Grittner Jessica , Douglas Kaia , Yang Praseuth , Barnett Ryan , Chau Christine , Cosiquien Roj , Duvick Lisa , Rainwater Orion , Serres Shannah , Orr Harry , Dougherty Brendan , Cvetanovic Marija
Published: August 2024

Spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in theATAXIN-1 (ATXN1)gene, is characterized by motor dysfunction, cognitive impairment, and death from compromised swallowing and respiration. To delineate specific cell types that contribute to respiratory dysfunction, we utilized the floxed conditional knock-inf-ATXN1146Q/2Qmouse. Whole body plethysmography during spontaneous respiration and respiratory challenge showed thatf-ATXN1146Q/2Qmice exhibit a spontaneous respiratory phenotype characterized by elevated respiratory frequency, volumes, and respiratory output. Consequently, the ability off-ATXN1146Q/2Qmice to increase ventilation during the challenge is impaired. To investigate the role of mutantATXN1expression in neural and skeletal muscle lineages,f-ATXN1146Q/2Qmice were bred toNestin-CreandActa1-Cremice respectively. These analyses revealed that the abnormal spontaneous respiration inf-ATXN1146Q/2Qmice involved two aspects: a behavioral phenotype in which SCA1 mice exhibit increased motor activity during respiratory testing and functional dysregulation of central respiratory control centers. Both aspects of spontaneous respiration were partially ameliorated by removing mutantATXN1from neural, but not skeletal muscle, cell lineages.
Insilicocharacterisation of PAL homologs and metabolomic profiling of shade response indicates potential presence of PTALs and Tyr as a probable precursor of lignin biosynthesis in conifers
Authors: Ranade Sonali Sachin , García-Gil María Rosario
Published: August 2024

Norway spruce and Scots pine show enhanced lignin synthesis under shade along with differential expression of defense-related genes that renders disease resilience. In general, phenylalanine (Phe) is the precursor for lignin synthesis in plants and tyrosine (Tyr) forms an additional lignin precursor in grasses. Phenylalanine ammonia-lyase (PAL) and tyrosine ammonia-lyase (TAL) from lignin biosynthesis pathway use either Phe or Tyr as precursors for lignin production, respectively. Grasses possess bifunctional phenylalanine/tyrosine ammonia-lyase (PTAL) that potentially can use both Phe and Tyr for lignin biosynthesis. Metabolomic profiles of seedlings revealed a relatively higher amount of Phe and Tyr under shade in Scots pine, while Norway spruce showed differential regulation of only Tyr under shade. Sequence analysis and phylogeny of PAL homologs in the two conifers coupled with correlation of up-regulation of precursors for lignin synthesis (Phe/Tyr) and enhanced lignin synthesis along with differential expression of PAL homologs under shade, suggests potential presence of PTALs in conifers, which is novel. Exome sequence analysis revealed latitudinal variation in allele frequencies of SNPs from coding regions of putative PAL and PTAL in Norway spruce, which may impact enzyme activity affecting lignin synthesis. Metabolomic analysis additionally identified metabolites involved in plant immunity, defense and stress response.
Boosting Proteasome Activity: A Novel Mechanism of NMDAR Blockers Against Neurodegeneration
Authors: Sahin Fikret , Gunel Aslihan , Atasoy Buse Turegun , Guler Ulku , Salih Bekir , Kuzu Isunsu , Taspinar Mehmet , Cinar Ozgur , Kahveci Selda
Published: August 2024

NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer’s and Parkinson’s. In a mouse model, ketamine administration notably altered brain synaptic protein profiles within two hours, downregulating proteins linked to neurodegenerative conditions. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling—a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, crucial as proteasome activity declines with age leading to protein aggregation and disease symptoms. The elucidation of the mechanistic pathways underlying the therapeutic effects of NMDAR antagonists holds promise for developing new treatment strategies for brain diseases, including schizophrenia, Alzheimer’s, and Parkinson’s.
Silver chimaera genome assembly and identification of the holocephalan sex chromosome sequence
Authors: Teramura Akinori , Kadota Mitsutaka , Hirase Shotaro , Kuraku Shigehiro , Kikuchi Kiyoshi
Published: August 2024

Cartilaginous fishes are divided into holocephalans and elasmobranchs, and comparative studies involving them are expected to elucidate how variable phenotypes and distinctive genomic properties were established in those ancient vertebrate lineages. To date, molecular-level studies on holocephalans have concentrated on the family Callorhinchidae, with a chromosome-scale genome assembly ofCallorhinchus miliiavailable. In this study, we focused on the most species-rich holocephalan family Chimaeridae and sequenced the genome of its member, silver chimaera (Chimaera phantasma). We report the first chromosome-scale genome assembly of the Chimaeridae, with high continuity and completeness, which exhibited a large intragenomic variation of chromosome lengths, which is correlated with intron size. This pattern is observed more widely in vertebrates and at least partly accounts for cross-species genome size variation. A male-female comparison identified a silver chimaera genomic scaffold with a double sequence depth for females, which we identify as an X chromosome fragment. This is the first DNA sequence-based evidence of a holocephalan sex chromosome, suggesting a male heterogametic sex determination system. This study, allowing the first chromosome-level comparison among holocephalan genomes, will trigger in-depth understanding of the genomic diversity among vertebrates as well as species’ population genetic structures based on the genome assembly of high completeness.
Level of Cognitive Functioning among Elderly Patients in Urban area of Bangladesh: A Cross-Sectional Study
Authors: Imran Joynal Abedin , Saha Pradip Kumar , Ria Marzana Afrooj , Sarwar Syeda Saika , Konok Jannatul Ferdous
Published: August 2024

Bangladesh is experiencing rapid urbanization and an increasing elderly population, particularly in urban areas. Cognitive decline is a common issue among elderly populations worldwide. This study aims to investigate the current state of cognitive decline among urban-dwelling older adults in Bangladesh to inform effective healthcare plans and programs. This cross-sectional study employed systematic random sampling among 150 participants at the outpatient department of NITOR in Dhaka, Bangladesh. Data were collected using a pretested structured standard questionnaire, and cognitive function was assessed with the Rowland Universal Dementia Assessment Scale (RUDAS). The study revealed a linear association between cognitive function and factors such as level of educational status, and history of eye sight problem. Conversely, age and diabetes showed an adverse correlation with cognitive function. Moreover, factors such as age, educational level and diabetes remained significant predictors of cognitive function in multivariate analysis. Cognitive impairment is significantly more common among the elderly in Bangladesh, with cognitive abilities being affected by a range of factors such as age, education level, diabetes, and vision issues.
Cost-Effectiveness Analysis of Deep Brain Stimulation for the Treatment of Alcohol Use Disorder and Alcoholic Liver Disease
Authors: Abiola O.A. , Lehmann C. , Moussawi K. , Jalal H.
Published: August 2024

Background

Alcohol use disorder (AUD) is a major public health concern and cause of mortality and morbidity. Alcohol-associated liver disease (ALD) is a debilitating complication of AUD, mitigated by abstinence from alcohol use. Deep brain stimulation (DBS) is emerging as a potential treatment for AUD. However, its cost-effectiveness compared to the standard medical treatment is unclear.

Objective

To estimate the cost-effectiveness of DBS compared to medical management for patients with AUD and ALD.

Methods

We utilized a decision analytic model based on published literature to conduct a cost-effectiveness analysis of costs and health outcomes for DBS and medical management in patients with AUD and ALD. We also carried out a threshold analysis to determine the probability of success necessary for DBS to be cost-effective. Costs were measured in 2024 US dollars and effectiveness in quality-adjusted life years (QALYs). We used a time horizon of 1-2 years and adopted a societal perspective.

Results

Our results show that for AUD patients in general, DBS is not cost-effective at any DBS success rate. However, for advanced ALD patients, defined as fibrosis stage 3 or beyond DBS becomes cost-effective. For these patients, DBS is cost-effective over a two-year period at a $100,000 willingness-to-pay threshold at DBS success rates greater than 53%. For advanced decompensated ALD patients, DBS is cost-effective over a one-year period at DBS success rate greater than 35%.

Conclusion

Should it prove efficacious, DBS may be cost-effective for patients with AUD and ALD. Thus, future randomized controlled trials to evaluate its efficacy are warranted.
Leveraging Large Language Models for Identifying Interpretable Linguistic Markers and Enhancing Alzheimer’s Disease Diagnostics
Authors: Mo Tingyu , Lam Jacqueline C. K. , Li Victor O. K. , Cheung Lawrence Y. L.
Published: August 2024

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. Early detection of AD is crucial for timely disease intervention. This study proposes a novel LLM frame-work, which extracts interpretable linguistic markers from LLM models and incorporates them into supervised AD detection models, while evaluating their model performance and interpretability. Our work consists of the following novelties: First, we design in-context few-shot and zero-shot prompting strategies to facilitate LLMs in extracting high-level linguistic markers discriminative of AD and NC, providing interpretation and assessment of their strength, reliability and relevance to AD classification. Second, we incorporate linguistic markers extracted by LLMs into a smaller AI-driven model to enhance the performance of downstream supervised learning for AD classification, by assigning higher weights to the high-level linguistic markers/features extracted from LLMs. Third, we investigate whether the linguistic markers extracted by LLMs can enhance theaccuracy and interpretability of the downstream supervised learning-based models for AD detection. Our findings suggest that the accuracy of the LLM-extracted linguistic markers-led supervised learning model is less desirable as compared to their counterparts that do not incorporate LLM-extracted markers, highlighting the tradeoffs between interpretability and accuracy in supervised AD classification. Although the use of these interpretable markers may not immediately lead to improved detection accuracy, they significantly improve medical diagnosis and trustworthiness. These interpretable markers allow healthcare professionals to gain a deeper understanding of the linguistic changes that occur in individuals with AD, enabling them to make more informed decisions and provide better patient care.
Genomic Surveillance and Evolutionary Dynamics of Influenza A Virus in Sri Lanka
Authors: Pramanayagam Jayadas Tibutius Thanesh , Jeewandara Chandima , Senadheera Bhagya , Kuruppu Heshan , Wickramanayake Rivindu , Bary Farha , Wijewickrama Ananda , Manilgama Suranga , Gamage Manouri , Perera Nilanka , Ogg Graham S. , Malavige Gathsaurie Neelika
Published: August 2024

Background

Influenza A has been named as a priority pathogen by the WHO due to the potential to cause pandemics. Genomic sequencing of influenza strains is important to understand the evolution of the influenza strains and also to select the appropriate influenza vaccines to be used in the different influenza seasons in Sri Lanka. Therefore, we sought to understand the molecular epidemiology of the influenza viruses in the Western Province of Sri Lanka, including mutational analysis to investigate the evolutionary dynamics.

Methodology

A total of 349 individuals presenting with fever and respiratory symptoms were enrolled in this study from November 2022 to May 2024. Nasopharyngeal and oropharyngeal specimens were collected and screened using quantitative PCR to detect Influenza A, Influenza B, and SARS-CoV-2. Subtyping and genomic sequencing was carried out on influenza A strains using Oxford Nanopore Technology.

Results

Influenza A was detected in 49 (14 %) patients, influenza B in 20 (5.7%) and SARS-CoV-2 in 41 (11.7%). Co-infections were observed in five participants. The phylogenetic analysis assigned the H1N1 HA gene sequences within the 6B.1A.5a.2a clade. The HA gene of the H1N1 sequences in 2023 were assigned as belonging to the subclades C.1, C.1.2, and C.1.8, while the 2024 sequences were assigned to subclades C.1.8 and C.1.9. The H3N2 sequences from 2023 were assigned to the 3C.2a1b.2a.2a.1b clade and subclade G.1.1.2, while the 2024 sequences were assigned to the 3C.2a1b.2a.2a.3a.1 clade and subclade J.2. The K54Q, A186T, Q189E, E224A, R259K, K308R, I418V, and X215A amino acid substitutions were seen in the H1N1 in the 2023 and 2024 sequences. The 2024 H1N1 sequences additionally exhibited further substitutions, such as V47I, I96T, T120A, A139D, G339X, K156X, and T278S.

Conclusion

In this first study using genomic sequencing to characterize the influenza A strains in Sri Lanka, which showed different influenza A viruses circulating in an 18-month period. As the Sri Lankan strains also had certain mutations of unknown significance, it would be important to continue detailed surveillance of the influenza strains in Sri Lanka to choose the most suitable vaccines for the population and the timing of vaccine administration.
Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD
Authors: Ahmadi Armin , Valencia Ana P. , Begue Gwénaëlle , Norman Jennifer E. , Fan Sili , Durbin-Johnson Blythe P. , Jenner Bradley N. , Campbell Matthew D. , Reyes Gustavo , Kapahi Pankaj , Himmelfarb Jonathan , de Boer Ian H. , Marcinek David J. , Kestenbaum Bryan R. , Gamboa Jorge L. , Roshanravan Baback
Published: August 2024

Background

Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD.

Methods

We conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m2). We assessed changes in the blood transcriptome using 3’-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer.

Results

The (mean±SD) age, eGFR, and BMI of the participants were 61±11 years, 37±9 mL/min/1.73m2, and 28±5 kg/m2respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, –0.12, 95% CI of –0.24 to –0.01 pg/mL) and CRP (estimated difference, –0.11, 95% CI of –0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, –0.16 and –0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes.

Conclusion

Six weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.