bluuebunny/crossref_metadata_2025 huggingface dataset:
Coupled social and ecological change drove the historical extinction of the California grizzly bear (
Ursus arctos californicus
)
Authors: Mychajliw Alexis M. , Adams Andrea J. , Brown Kevin C. , Campbell Beau T. , Hardesty-Moore Molly , Welch Zoë S. , Page Henry M. , Southon John R. , Cooper Scott D. , Alagona Peter S.
Published: January 2024

Large carnivores (order Carnivora) are among the world's most threatened mammals due to a confluence of ecological and social forces that have unfolded over centuries. Combining specimens from natural history collections with documents from archival records, we reconstructed the factors surrounding the extinction of the California grizzly bear (
Ursus arctos californicus
), a once-abundant brown bear subspecies last seen in 1924. Historical documents portrayed California grizzlies as massive hypercarnivores that endangered public safety. Yet, morphological measurements on skulls and teeth generate smaller body size estimates in alignment with extant North American grizzly populations (approx. 200 kg). Stable isotope analysis (
δ
13
C,
δ
15
N) of pelts and bones (
n
= 57) revealed that grizzlies derived less than 10% of their nutrition from terrestrial animal sources and were therefore largely herbivorous for millennia prior to the first European arrival in this region in 1542. Later colonial land uses, beginning in 1769 with the Mission era, led grizzlies to moderately increase animal protein consumption (up to 26% of diet), but grizzlies still consumed far less livestock than otherwise claimed by contemporary accounts. We show how human activities can provoke short-term behavioural shifts, such as heightened levels of carnivory, that in turn can lead to exaggerated predation narratives and incentivize persecution, triggering rapid loss of an otherwise widespread and ecologically flexible animal.
Pharmaceutical pollution alters the cost of bacterial infection and its relationship to pathogen load
Authors: Aulsebrook Lucinda C. , Wong Bob B. M. , Hall Matthew D.
Published: January 2024

The relationship between pathogen proliferation and the cost of infection experienced by a host drives the ecology and evolution of host–pathogen dynamics. While environmental factors can shape this relationship, there is currently limited knowledge on the consequences of emerging contaminants, such as pharmaceutical pollutants, on the relationship between a pathogen's growth within the host and the damage it causes, termed its virulence. Here, we investigated how exposure to fluoxetine (Prozac), a commonly detected psychoactive pollutant, could alter this key relationship using the water flea
Daphnia magna
and its bacterial pathogen
Pasteuria ramosa
as a model system. Across a variety of fluoxetine concentrations, we found that fluoxetine shaped the damage a pathogen caused, such as the reduction in fecundity or intrinsic growth experienced by infected individuals, but with minimal change in average pathogen spore loads. Instead, fluoxetine modified the relationship between the degree of pathogen proliferation and its virulence, with both the strength of this trade-off and the component of host fitness most affected varying by fluoxetine concentration and host genotype. Our study underscores the potential for pharmaceutical pollution to modify the virulence of an invading pathogen, as well as the fundamental trade-off between host and pathogen fitness, even at the trace amounts increasingly found in natural waterways.
Temporal cluster-based organization of sleep spindles underlies motor memory consolidation
Authors: Boutin Arnaud , Gabitov Ella , Pinsard Basile , Boré Arnaud , Carrier Julie , Doyon Julien
Published: January 2024

Sleep benefits motor memory consolidation, which is mediated by sleep spindle activity and associated memory reactivations during non-rapid eye movement (NREM) sleep. However, the particular role of NREM2 and NREM3 sleep spindles and the mechanisms triggering this memory consolidation process remain unclear. Here, simultaneous electroencephalographic and functional magnetic resonance imaging (EEG-fMRI) recordings were collected during night-time sleep following the learning of a motor sequence task. Adopting a time-based clustering approach, we provide evidence that spindles iteratively occur within clustered and temporally organized patterns during both NREM2 and NREM3 sleep. However, the clustering of spindles in trains is related to motor memory consolidation during NREM2 sleep only. Altogether, our findings suggest that spindles' clustering and rhythmic occurrence during NREM2 sleep may serve as an intrinsic rhythmic sleep mechanism for the timed reactivation and subsequent consolidation of motor memories, through synchronized oscillatory activity within a subcortical–cortical network involved during learning.
Rediscovery and systematics of the enigmatic genus
Helicostoa
reveals a new species of sessile freshwater snail with remarkable sexual dimorphism
Authors: Zhang Le-Jia , Shi Zi-Ang , Chen Zhe-Yu , von Rintelen Thomas , Zhang Wei , Lou Zheng-Jie
Published: January 2024

Helicostoa sinensis
E. Lamy, 1926 is a unique freshwater gastropod species with a sessile habit. This enigmatic species was first found cemented on river limestones from China about 120 years ago and described together with the genus. It was never collected again and has been considered monotypic. Here, we report the rediscovery of
Helicostoa
from several rivers in China, and describe a second species of this genus based on a comprehensive study. In addition to the unique sessile habit of both species, the new
Helicostoa
species presents one of the most remarkable cases of sexual dimorphism within molluscs. Only the adult female is sessile and the original aperture of the female is sealed by shell matter or rock, while an opening on the body whorl takes the function of the original aperture. The male is vagile, with a normal aperture. Our results confirm the recently suggested placement of
Helicostoa
within the family Bithyniidae. The sessility of
Helicostoa
species is considered as an adaption to the limestone habitat in large rivers. The extreme sexual dimorphism and secondary aperture of females are considered as adaptations to overcome the obstacles for mating and feeding that come with a sessile life style.
Spatio-temporal variability in transmission risk of human schistosomes and animal trematodes in a seasonally desiccating East African landscape
Authors: Starkloff Naima C. , Angelo Teckla , Mahalila Moses P. , Charles Jenitha , Kinung'hi Safari , Civitello David J.
Published: January 2024

Different populations of hosts and parasites experience distinct seasonality in environmental factors, depending on local-scale biotic and abiotic factors. This can lead to highly heterogeneous disease outcomes across host ranges. Variable seasonality characterizes urogenital schistosomiasis, a neglected tropical disease caused by parasitic trematodes (
Schistosoma haematobium
). Their intermediate hosts are aquatic
Bulinus
snails that are highly adapted to extreme rainfall seasonality, undergoing prolonged dormancy yearly. While
Bulinus
snails have a remarkable capacity for rebounding following dormancy, we investigated the extent to which parasite survival within snails is diminished. We conducted an investigation of seasonal snail schistosome dynamics in 109 ponds of variable ephemerality in Tanzania from August 2021 to July 2022. First, we found that ponds have two synchronized peaks of schistosome infection prevalence and observed cercariae, though of lower magnitude in the fully desiccating than non-desiccating ponds. Second, we evaluated total yearly schistosome prevalence across an ephemerality gradient, finding ponds with intermediate ephemerality to have the highest infection rates. We also investigated dynamics of non-schistosome trematodes, which lacked synonymity with schistosome patterns. We found peak schistosome transmission risk at intermediate pond ephemerality, thus the impacts of anticipated increases in landscape desiccation could result in increases or decreases in transmission risk with global change.
The genomic architecture of continuous plumage colour variation in the European barn owl (
Tyto alba
)
Authors: Cumer Tristan , Machado Ana Paula , San-Jose Luis M. , Ducrest Anne-Lyse , Simon Céline , Roulin Alexandre , Goudet Jérôme
Published: January 2024

The maintenance of colour variation in wild populations has long fascinated evolutionary biologists, although most studies have focused on discrete traits exhibiting rather simple inheritance patterns and genetic architectures. However, the study of continuous colour traits and their potentially oligo- or polygenic genetic bases remains rare in wild populations. We studied the genetics of the continuously varying white-to-rufous plumage coloration of the European barn owl (
Tyto alba
) using a genome-wide association approach on the whole-genome data of 75 individuals. We confirmed a mutation at the melanocortin-1-receptor gene (
MC1R)
is involved in the coloration and identified two new regions, located in super-scaffolds 9 and 42. The combination of the three regions explains most of the colour variation (80.37%, 95% credible interval 58.45–100%). One discovered region, located in the sex chromosome, differs between the most extreme colorations in owls sharing a specific
MC1R
genotype. This region may play a role in the colour sex dimorphism of this species, possibly in interaction with the autosomal
MC1R
. We thus provide insights into the genetic architecture of continuous colour variation, pointing to an oligogenic basis with potential epistatic effects among loci that should aid future studies understanding how continuous colour variation is maintained in nature.
Distance functions of carabids in crop fields depend on functional traits, crop type and adjacent habitat: a synthesis
Authors: Boetzl Fabian A. , Sponsler Douglas , Albrecht Matthias , Batáry Péter , Birkhofer Klaus , Knapp Michal , Krauss Jochen , Maas Bea , Martin Emily A. , Sirami Clélia , Sutter Louis , Bertrand Colette , Baillod Aliette Bosem , Bota Gerard , Bretagnolle Vincent , Brotons Lluís , Frank Thomas , Fusser Moritz , Giralt David , González Ezequiel , Hof Anouschka R. , Luka Henryk , Marrec Ronan , Nash Michael A. , Ng Katherina , Plantegenest Manuel , Poulin Brigitte , Siriwardena Gavin M. , Tscharntke Teja , Tschumi Matthias , Vialatte Aude , Van Vooren Laura , Zubair-Anjum Muhammad , Entling Martin H. , Steffan-Dewenter Ingolf , Schirmel Jens
Published: January 2024

Natural pest and weed regulation are essential for agricultural production, but the spatial distribution of natural enemies within crop fields and its drivers are mostly unknown. Using 28 datasets comprising 1204 study sites across eight Western and Central European countries, we performed a quantitative synthesis of carabid richness, activity densities and functional traits in relation to field edges (i.e. distance functions). We show that distance functions of carabids strongly depend on carabid functional traits, crop type and, to a lesser extent, adjacent non-crop habitats. Richness of both carnivores and granivores, and activity densities of small and granivorous species decreased towards field interiors, whereas the densities of large species increased. We found strong distance decays in maize and vegetables whereas richness and densities remained more stable in cereals, oilseed crops and legumes. We conclude that carabid assemblages in agricultural landscapes are driven by the complex interplay of crop types, adjacent non-crop habitats and further landscape parameters with great potential for targeted agroecological management. In particular, our synthesis indicates that a higher edge–interior ratio can counter the distance decay of carabid richness per field and thus likely benefits natural pest and weed regulation, hence contributing to agricultural sustainability.
Conflict-reducing innovations in development enable increased multicellular complexity
Authors: Howe Jack , Cornwallis Charlie K. , Griffin Ashleigh S.
Published: January 2024

Obligately multicellular organisms, where cells can only reproduce as part of the group, have evolved multiple times across the tree of life. Obligate multicellularity has only evolved when clonal groups form by cell division, rather than by cells aggregating, as clonality prevents internal conflict. Yet obligately multicellular organisms still vary greatly in ‘multicellular complexity’ (the number of cells and cell types): some comprise a few cells and cell types, while others have billions of cells and thousands of types. Here, we test whether variation in multicellular complexity is explained by two conflict-suppressing mechanisms, namely a single-cell bottleneck at the start of development, and a strict separation of germline and somatic cells. Examining the life cycles of 129 lineages of plants, animals, fungi and algae, we show using phylogenetic comparative analyses that an early segregation of the germline stem-cell lineage is key to the evolution of more cell types, driven by a strong correlation in the Metazoa. By contrast, the presence of a strict single-cell bottleneck was not related to either the number of cells or the number of cell types, but was associated with early germline segregation. Our results suggest that segregating the germline earlier in development enabled greater evolutionary innovation, although whether this is a consequence of conflict reduction or other non-conflict effects, such as developmental flexibility, is unclear.
Nephrogenic diabetes insipidus in a geriatric patient affected by SARS-CoV-2: complexity of a diagnosis, complexity of a virus
Authors: Corich Maria Ada , Niero Michele , Corich Lucia , Ferretti Elisabetta , De Colle Paolo , Bernardi Stella , Ceschia Giuliano , Sanson Gianfranco , Zanetti Michela
Published: January 2024

Background. Coronavirus Disease-19 (COVID-19) has an important impact on the kidney through direct and indirect damage mechanisms. Most previous studies have highlighted lesions caused by this virus in the early segments of the nephron. However, due to the antigenic characteristics of the virus with almost ubiquitous receptors, and the molecular release it triggers, the distal segments of the nephron could also be affected.
Methods. A 71 years old man with a respiratory failure in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pneumonia presented the typical symptoms of diabetes insipidus after about 20 days of hospitalization. The water deprivation test led to the diagnosis of nephrogenic diabetes insipidus.
The etiological study was complex particularly because due to the patient’s previous lithium therapy.
Results. The sequence of pathognomonic events typical of diabetes insipidus associated with anamnestic, clinical and laboratory evidences supported strongly the diagnosis of nephrogenic diabetes insipidus due to SARS-CoV-2, rather than to other etiologies.
Conclusions. The collecting duct could represent a target for SARS-CoV-2 infection, directly or indirectly as a result of lesions of upstream portions of the nephron which would cascade into the distal segment. Other molecules, besides angiotensin 2 converting enzyme, might be involved in facilitating the viral aggression. The complexity of the geriatric patient shows the importance of a comprehensive approach which integrates a careful monitoring of clinical signs and symptoms,  laboratory and instrumental tests. This is especially important in the context of SARS-CoV-2 infection and in the management of its unexpected complications.
Halomicrococcus gelatinilyticus sp. nov. and Halosimplex aquaticum sp. nov., halophilic archaea isolated from saline soil and an inland solar saltern
Authors: Hu Yao , Ma Xue , Li Xin-Xin , Tan Shun , Cheng Mu , Hou Jing , Cui Heng-Lin
Published: January 2024

Two extremely halophilic archaeal strains, GSLN9T and XZYJT29T, were isolated from the saline soil in different regions of western China. Both strains GSLN9T and XZYJT29T have two 16S rRNA genes with similarities of 95.1 and 94.8 %, respectively. Strain GSLN9T was mostly related to the genus

Halomicrococcus

based on 16S rRNA (showing 91.0–96.0 % identities) and rpoB′ genes (showing 92.0 % identity). Strain XZYJT29T showed 92.1–97.6 % (16S rRNA gene) and 91.4–93.1 % (rpoB′ gene) sequence similarities to its relatives in the genus

Halosimplex

, respectively. The polar lipid profile of strain GSLN9T included phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me), phosphatidylglycerol sulphate (PGS), sulphated mannosyl glucosyl diether (S-DGD-1) and sulphated galactosyl mannosyl glucosyl diether (S-TGD-1), mostly similar to that of

Halomicrococcus hydrotolerans

H22T. PA, PG, PGP-Me, S-DGD-1 (S-DGD-PA), S2-DGD, S-TGD-1 and an unidentified glycolipid were detected in strain XZYJT29T; this polar lipid composition is similar to those of members of the genus

Halosimplex

. The average nucleotide identity, digital DNA–DNA hybridization and average amino acid identity values between these two strains and their relatives of the genera

Halomicrococcus

and

Halosimplex

were no more than 82, 27 and 80 %, respectively, much lower than the thresholds for species demarcation. Other phenotypic characterization results indicated that strains GSLN9T and XZYJT29T can be differentiated from the current species of the genera

Halomicrococcus

and

Halosimplex

, respectively. These results revealed that strains GSLN9T (=CGMCC 1.15215T=JCM 30842T) and XZYJT29T (=CGMCC 1.15828T=JCM 31853T) represent novel species of

Halomicrococcus

and

Halosimplex

, for which the names Halomicrococcus gelatinilyticus sp. nov. and Halosimplex aquaticum sp. nov. are proposed.
“That’s part of the culture:” A peer-to-peer study of reporting student mistreatment
Authors: Chen Alissa S. , Yau Bernice , Montgomery Kelsey B. , Dubuque Nicole , McDowelle Dana , Berg David , Holt Stephen R.
Published: January 2024

Introduction

Forty percent of graduating medical students report experiencing student mistreatment; however, most cases go unreported.

Methods

Peer-to-peer, semi-structured interviews with current medical students were conducted to understand medical students’ experiences with mistreatment and reporting. These interviews were inductively coded, and themes were identified to elucidate reasons students do and do not report mistreatment.

Results

Twenty-one students were interviewed who described a total of 34 mistreatment incidents. Four main groups of factors that students consider when deciding to report mistreatment were identified: personal, situational, structural, and climate. Personal factors were intrinsically tied to the participant, including their feelings or concerns about mistreatment. Situational factors related to the act of mistreatment, such as who the perpetrator was or the actions of bystanders. Structural factors included elements of the reporting system. Climate factors were concerns related to how the institution viewed mistreatment and the student’s place in medical education.

Discussion

This peer-to-peer study revealed four main groups of factors, all of which are influenced by the culture of the institution. Participants were impacted by the inactions of witnesses and their personal sense of justice. An approach to facilitating reporting of student mistreatment must be grounded in improving the culture of medical education.
Comparative Analysis of Three Surveys on Primary Care Providers’ Experiences with Interoperability and Electronic Health Records
Authors: Hendrix Nathaniel , Maisel Natalya , Everson Jordan , Patel Vaishali , Bazemore Andrew , Rotenstein Lisa S. , Holmgren A Jay , Krist Alex H. , Adler-Milstein Julia , Phillips Robert L.
Published: January 2024

Objective

This study compared primary care physicians’ self-reported experiences with Electronic Health Records’ (EHR) interoperability, as reported across three surveys: the 2022 Continuous Certification Questionnaire (CCQ) from the American Board of Family Medicine, the 2022 University of California San Francisco’s (UCSF) Physician Health IT Survey, and the 2021 National Electronic Health Records Survey (NEHRS).

Materials and Methods

We used descriptive analyses to identify differences between survey pairs. To account for weighting in NEHRS and UCSF, we assessed the significance of differences using the Rao-Scott corrected chi-square test.

Results

CCQ received 3,991 responses, UCSF received 1,375 from primary care physicians, and NEHRS received 858 responses from primary care physicians. Response rates were 100%, 3.6%, and 18.2%, respectively. Substantial and largely statistically significant differences in response were detected across the three surveys. For instance, 22.2% of CCQ respondents said it was very easy to document care in their EHR, compared to 15.2% in NEHRS, and 14.8% in the UCSF survey. Approximately one-third of respondents across surveys said documenting care in their EHR was somewhat or very difficult. The surveys captured different respondent types with CCQ respondents trending younger, and NEHRS respondents more likely to be in private practice.

Discussion

All surveys pointed to room for improvement in EHR usability and interoperability. The differences observed, likely driven by differences in survey methodology and response bias, were likely substantial enough to impact policy decisions.

Conclusion

Diversified data sources, such as those from specialty boards, may aid in capturing physicians’ experiences with EHRs and interoperability.
Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers
Authors: Lane Roger M. , Darreh-Shori Taher , Junge Candice , Li Dan , Yang Qingqing , Edwards Amanda L. , Graham Danielle L. , Moore Katrina , Mummery Catherine J.
Published: January 2024

Background

We wished to examine the impact of the K-variant ofbutyrylcholinesterase(BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) inAPOE4carriers.

Methods

In 45 patients, aged 50-74 years, with cerebrospinal fluid (CSF) biomarker confirmed mild AD, recruited into a clinical trial (NCT03186989), baseline demographics, disease characteristics, and biomarkers were evaluated byBCHE-KandAPOE4allelic status.

Results

InAPOE4carriers (N = 33), mean age-at-diagnosis of AD inBCHE-Kcarriers (n = 11) was 6.4 years earlier than inBCHE-Knoncarriers (n = 22,P <.001, ANOVA). InAPOE4noncarriers (N = 12) there was no similar influence ofBCHE-K. InAPOE4carriers with versus those withoutBCHE-K, mean age-at-baseline was over 6 years earlier and accompanied by slightly higher amyloid and tau accumulations. A predominant amyloid, limited tau pathophysiology, and limbic-amnestic phenotype was exemplified byAPOE4homozygotes withBCHE-K. Multiple regression analyses demonstrated association of amyloid accumulation withAPOE4carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng,P <.001), and less tau (p-tau181,P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL,P= .002), more synaptic injury (Ng,P <.001), and higher levels of glial activation (YKL-40,P= .01).

Conclusion

Findings concern the genetic architecture of prognosis in early AD, that is fundamental for patients and the design of clinical trials, and that is less well established than the genetics of susceptibility. In mild AD patients aged less than 75 years, the mean age-at-diagnosis of AD inAPOE4carriers was reduced by over 6 years inBCHE-Kcarriers versus noncarriers. Functional activation of glia may explain much of the effects ofAPOE4andBCHE-Kon the phenotype of early AD.
Left ventricular trabecular layer operates at high ejection fraction: implications for pump function assessment in excessive trabeculation
Authors: Visoiu Ionela Simona , Rimbas Roxana Cristina , Nicula Alina Ioana , Vinereanu Dragos , Jensen Bjarke
Published: January 2024

Aims

Numerous diagnostic criteria for excessive trabeculation (ET), or so-called “noncompaction”, score the extent of the trabecular layer, yet whether the trabeculations themselves have a negative or positive impact on pump function is largely unknown. This study aimed to measure the ejection fraction (EF) of the trabecular layer and its impact on pump function assessment.

Methods and results

We retrospectively analyzed cardiac magnetic resonance (CMR) findings in patients with ET of the left ventricle (LV). The LV was labelled into four regions: compact wall, central cavity (CC), trabeculations, and intertrabecular recesses (IR). For each label we calculated the systolic fractional volume change (SFVC) in short-axis images (n=15) and systolic fractional area change (SFAC) in 4-chamber images (n=30), by dividing end-systolic to end-diastolic values. We measured the EF of IR, CC, and total cavity (TC). Three methods to calculate EF of the TC were compared: trabeculations included (per guidelines), IR excluded (Jacquier criterion), trabeculations contoured and excluded (contour-EF).

The SFVC and SFAC of the compact wall were similar with SFVC and SFAC of trabeculations (both P>0.05). In contrast, the IR were more diminished in systole by comparison with the CC, having lower SFVC (39±17% vs. 56±16%, P<0.001) and SFAC (37±22% vs. 72±12%, P<0.001). EF of the IR was also greater than EF of the CC (61±17% vs. 44±16%, P<0.001). Excluding IR from the TC or including trabeculations underestimates the contour-EF (44±16% and 40±12%, respectively, vs. 51±16%; both P<0.001).

Conclusions

The trabecular layer has a high EF. Values of key prognostic indicators are better when this is accounted for.

Graphical Abstract

EF, ejection fraction; LVEF, left ventricular ejection fraction; SAX, short-axis; 4c, 4 chamber. *P<0001
The antidepressant effects of vaporized N,N-Dimethyltryptamine: a preliminary report in treatment-resistant depression
Authors: Falchi-Carvalho Marcelo , Barros Handersson , Bolcont Raynara , Laborde Sophie , Wießner Isabel , Silva Sérgio Ruschi B. , Montanini Daniel , Barbosa David C. , Teixeira Ewerton , Florence-Vilela Rodrigo , Almeida Raissa , de Macedo Rosana K. A. , Arichelle Flávia , Pantrigo Érica J. , Arcoverde Emerson , Galvão-Coelho Nicole , Araujo Draulio B. , Palhano-Fontes Fernanda
Published: January 2024

Introduction

N,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD).

Methods

Six TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing.

Results

Significant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was −22 points and −17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission.

Discussion

The rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments.

Clinical Trial registration

Clinicaltrials.govNCT06094907
Quantification of Cerebrospinal Fluid Tumor DNA in Lung Cancer Patients with Suspected Leptomeningeal Carcinomatosis
Authors: Azad Tej D. , Nanjo Shigeki , Jin Michael C. , Chabon Jacob J. , Kurtz David M. , Chaudhuri Aadel A. , Connolly Ian D. , Hui Angela Bik-Yu , Liu Chih Long , Merriott David , Ko Ryan , Yoo Christopher , Carter Justin , Chen Emily , Bonilla Rene , Hata Akito , Katakami Nobuyuki , Irie Kei , Yano Seiji , Okimoto Ross , Bivona Trever G. , Newman Aaron M. , Iv Michael , Nagpal Seema , Gephart Melanie Hayden , Alizadeh Ash A. , Diehn Maximilian
Published: January 2024

Introduction

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring neoplastic processes of the central nervous system. We hypothesize that analysis of CSF-tDNA in patients with advanced lung cancer improves the sensitivity of leptomeningeal disease (LMD) diagnosis and enables central nervous system response monitoring.

Methods

We applied CAPP-Seq using a lung cancer-specific sequencing panel to 81 CSF, blood, and tissue samples from 24 patients with advanced lung cancer who underwent lumbar puncture (LP) for suspected LMD. A subset of the cohort (N = 12) participated in a prospective clinical trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment with.

Results

CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%;P< 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45;P= 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1;P= 0.02). Among patients with progression on targeted therapy, resistance mutations, such asEGFRT790M andMETamplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2,P= 0.009).

Conclusions

Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA may improve the sensitivity of LMD diagnosis, enable improved prognostication, and drive therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
The Solute Carrier Family 26 Member 9 Is a Modifier of the Rapidly Progressing Cystic Fibrosis Associated with F508del CFTR Mutations
Authors: Luo Shiyu , Rollins Stuart , Schmitz-Abe Klaus , Tam Amy , Li Qifei , Shi Jiahai , Lin Jasmine , Wang Ruobing , Agrawal Pankaj B.
Published: January 2024

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease vary shown that modifier genes influence disease severity and clinical course. We previously reported epithelial sodium channel (ENaC) genes as modifiers of disease severity in long-term non-progressors sharing deltaF508 homozygous forCFTRgenotype. Here we describe the opposite, modifier genes that may be associated with rapidly progressing CF (RPCF) in a cohort of patients with the shared deltaF508 homozygous genotype. We have identified three rare missenseSLC26A9variants in four individuals (out of six) deemed to have RPCF: c.229G>A; p.G77S (present in two patients), c.1885C>T; p.P629S and c.2546G>A; p.R849Q. By analyzing publicly available single cell sequencing dataset from LungMAP, we revealed that bothSLC26A9andCFTRmRNA are highly enriched in Alveolar type 2 (AT2) cells, with a few (greater than 1%) in respiratory airway secretory (RAS) cells and ionocytes. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the ion transportation capability of SLC26A9. The enrichment of rare and potentially deleteriousSLC26A9mutations in patients with RPCF suggestsSLC26A9is a modifier gene associated with RPCF.
Depletion of effector regulatory T cells drives major response to induction dual immune checkpoint blockade
Authors: Jiang Xianli , Rudqvist Nils-Petter , Jiang Bo , Ye Shengbin , He Shan , Liang Qingnan , Dou Jinzhuang , Williams Michelle , Dunn Joe Dan , Johnson Jason M. , Akagi Keiko , Xiao Weihong , Liang Shaoheng , Elayavalli Satvik , Sun Baohua , Cuentas Edwin Roger Parra , Ferrarotto Renata , Garden Adam , Fuller Clifton , Reddy Jay , Gross Neil , Lango Miriam , Leung Cheuk Hong , Liu Suyu , Liu Diane , Lee J Jack , Curran Michael A. , Phan Jack , Chen Ken , Gillison Maura L.
Published: January 2024

In a phase 2 trial, local-regionally advanced HPV-positive oropharyngeal carcinoma (OPC) patients received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Co-primary endpoints achieved included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histological response rate. Single-cell profiling revealed responders had higher baseline intratumoral tissue-resident memory (TRM) CD8+T cells and NK cells expressing Fc Gamma Receptor IIIa (FCGR3A). Decreases in effector regulatory T (eTreg) cells, which highly expressedCTLA4, occurred only in responders, suggesting ipilimumab-dependent depletion byFCGR3A+NK cells. eTreg depletion correlated with increased Interferon Gamma (IFNG)+effector CD8+T cells. CD8+T-cell clonotypes transitioned from TRM to effector memory andIFNG+effector cells in responders, whereas clonotypes transitioned to exhausted TRM and proliferating cells in nonresponders. We conclude that eTreg depletion is critical for major response to induction dual immune checkpoint blockade.
Using clinical text to refine unspecific condition codes in Dutch general practitioner EHR data
Authors: Seinen Tom M , Kors Jan A , van Mulligen Erik M , Fridgeirsson Egill , Verhamme Katia MC , Rijnbeek Peter R
Published: January 2024

Objective

Observational studies using electronic health record (EHR) databases often face challenges due to unspecific clinical codes that can obscure detailed medical information, hindering precise data analysis. In this study, we aimed to assess the feasibility of refining these unspecific condition codes into more specific codes in a Dutch general practitioner (GP) EHR database by leveraging the available clinical free text.

Methods

We utilized three approaches for text classification—search queries, semi-supervised learning, and supervised learning—to improve the specificity of ten unspecific International Classification of Primary Care (ICPC-1) codes. Two text representations and three machine learning algorithms were evaluated for the (semi-)supervised models. Additionally, we measured the improvement achieved by the refinement process on all code occurrences in the database.

Results

The classification models performed well for most codes. In general, no single classification approach consistently outperformed the others. However, there were variations in the relative performance of the classification approaches within each code and in the use of different text representations and machine learning algorithms. Class imbalance and limited training data affected the performance of the (semi-)supervised models, yet the simple search queries remained particularly effective. Ultimately, the developed models improved the specificity of over half of all the unspecific code occurrences in the database.

Conclusions

Our findings show the feasibility of using information from clinical text to improve the specificity of unspecific condition codes in observational healthcare databases, even with a limited range of machine-learning techniques and modest annotated training sets. Future work could investigate transfer learning, integration of structured data, alternative semi-supervised methods, and validation of models across healthcare settings. The improved level of detail enriches the interpretation of medical information and can benefit observational research and patient care.
Effect ofAPOEε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI-DAD
Authors: Wang Yi Zhe , Zhao Wei , Moorjani Priya , Gross Alden L. , Zhou Xiang , Dey Aparajit B. , Lee Jinkook , Smith Jennifer A. , Kardia Sharon L.R.
Published: January 2024

BACKGROUND

We investigated effects ofAPOEε4 and its interactions with sociodemographic characteristics on cognitive measures in 2,563 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD).

METHODS

Linear regression models were used to assess the association betweenAPOEε4 and global- and domain-specific cognitive function. Effect modification by age, sex, and education were explored using cross-product interaction terms and subgroup analyses.

RESULTS

APOEε4 was inversely associated with most cognitive measures. This association was stronger in the older age group (age >68) for general cognitive function, orientation, and language/fluency, as well as in females for memory and language/fluency. Interaction betweenAPOEε4 and education was mostly nonsignificant.

DISCUSSION

APOEε4 is associated with lower cognitive function in South Asians from India, with a more pronounced impact observed in females and older individuals.
Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 × 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D Trial) in adults with cystic fibrosis
Authors: Sivapiromrat Alisa K. , Suppakitjanusant Pichatorn , Wang Yanling , Binongo Jose , Hunt William R. , Gewirtz Andrew , Alvarez Jessica A. , Hu Chengcheng , Weinstein Samuel , Jathal Ishaan , Ziegler Thomas R. , Tangpricha Vin
Published: January 2024

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3(50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3weekly; 3) combined oral vitamin D3weekly and oral prebiotic inulin daily; and 4) oral vitamin D3placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.
Noradrenergic modulation of saccades in Parkinson’s disease
Authors: Orlando Isabella F. , Hezemans Frank H. , Ye Rong , Murley Alexander G. , Holland Negin , Regenthal Ralf , Barker Roger A. , Williams-Gray Caroline H. , Passamonti Luca , Robbins Trevor W. , Rowe James B. , O’Callaghan Claire
Published: January 2024

Noradrenaline is a powerful modulator of cognitive processes, including action-decisions underlying saccadic control. Changes in saccadic eye movements are common across neurodegenerative diseases of ageing, including Parkinson’s disease. With growing interest in noradrenergic treatment potential for non-motor symptoms in Parkinson’s disease, the temporal precision of oculomotor function is advantageous to assess the effects of this modulation. Here we studied the effect of 40 mg atomoxetine, a noradrenaline reuptake inhibitor, in nineteen people with idiopathic Parkinson’s disease using a single dose, randomised double-blind crossover placebo-controlled design. Twenty-five healthy adult participants completed the assessments to provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity and accuracy of saccades, and resting pupil diameter, were measured. Increased pupil diameter on the drug confirmed its expected effect on the locus coeruleus ascending arousal system. Atomoxetine improved key aspects of saccade performance: prosaccade latencies were faster and the saccadic main sequence was normalised. These improvements were accompanied by increased antisaccade error rates on the drug. Together these findings suggest a shift in the speed-accuracy trade-off for visuo-motor decisions in response to noradrenergic treatment. Our results provide new evidence to substantiate a role for noradrenergic modulation of saccades, and based on known circuitry we advance the hypothesis that this reflects modulation at the level of the locus coeruleus–superior colliculus pathway. Given the potential for noradrenergic treatment of non-motor symptoms of Parkinson’s disease and related conditions, the oculomotor system can support the assessment of cognitive effects without limb-motor confounds on task performance.
Large language models in simplifying radiological reports: systematic review
Authors: Artsi Yaara , Sorin Vera , Konen Eli , Glicksberg Benjamin S. , Nadkarni Girish , Klang Eyal
Published: January 2024

Objectives

Simplifying medical information to make it understandable for patients, specifically in the case of radiology reports, is challenging. It requires time and effort from medical personnel. This systematic review focuses on the application of large language models (LLMs) in generating simplified radiological imaging reports, as well as answering patient inquiries regarding radiological procedures.

Materials and Methods

The authors searched for studies published up to January 2024. Search terms focused on LLMs generated simplified radiological reports and answers to patient inquiries regarding radiological procedures. MEDLINE was used as a search database.

Results

Overall, eight studies published between May 2023 and November 2023 were included. All studies showed that LLMs can produce simplified medical information for patients. Four studies (50%) used GPT-3.5, Two studies (25%) conducted a comparative analysis between GPT-3.5 and GPT-4. One study (12.5%) examined Microsoft Bing. One study (12.5%) utilized GPT-4. Four studies (50%) used LLMs to simplify radiological reports. Four studies (50%) used LLMs to answer patient questions regarding radiological procedures. Only two studies (25%) used patients to evaluate the LLMs output. One study (12.5%) compared their initial prompt with optimized prompt. Five studies (62.5%) showed missing, inaccurate and potentially harmful AI outputs.

Conclusion

LLMs can be used to simplify medical imaging reports and procedures, for improved patient comprehension. However, their limitations cannot be ignored. Further study in this field is essential and more conclusive evidence is needed.
Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection
Authors: Günther Theresa , Schöfbänker Michael , Lorentzen Eva Ulla , Romberg Marie-Luise , Hennies Marc Tim , Neddermeyer Rieke , Müller Marlin Maybrit , Mellmann Alexander , Lenz Georg , Stelljes Matthias , Hrincius Eike Roman , Vollenberg Richard , Ludwig Stephan , Tepasse Phil-Robin , Kühn Joachim Ewald
Published: January 2024

Neutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the intra-host evolution and the humoral immune response in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81.

Bamlanivimab treatment early in infection was associated with the emergence of the bamlanivimab escape mutation S:S494P. Ten days before virus elimination, additional mutations within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S were observed, of which the triple mutant S:Delta141-4 E484K S494P became dominant. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test (pVNT), surrogate VNT (sVNT), and immunoglobulin-capture EIA showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in a massive increase of Omicron-reactive antibodies.

In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the emergence of escape variants with known epidemiological relevance.
The Impact of Electronic Order Communications on Laboratory Turnaround Times in Acute Hospital Care
Authors: Gallier S. , Zou X. , Evison F. , Hodson J. , Atia J. , Webster C , Garrick M. , Coleman J. , Pankhurst T. , Ball S. , Nirantharakumar K. , Sapey E.
Published: January 2024

Objective

To examine the impact of computerised physician order entry (CPOE) systems upon laboratory turnaround times (LTAT), namely the time from recording the collection of a blood sample to the results being reported, within a large acute hospital.

Materials and methods

1,810,311 blood samples taken between 1stJanuary 2014 and 31stDecember 2019 were included. Changes in LTAT over the 24 months pre- and 18 months post-CPOE implementation were analysed using a segmented regression approach. The primary analysis assessed the median LTAT across the whole hospital, with secondary analyses assessing subgroups defined by clinical settings.

Results

CPOE implementation was associated with a step-change reduction in the median LTAT of 31.7 minutes (95% CI: 25.5-37.9, p<0.001). This was sustained over eighteen months post- implementation of CPOE despite the number of samples increasing by an average of 31% in this post-implementation period. Analysis by broad clinical specialty found all subgroups of wards considered to have a significant reduction in LTAT post-CPOE, either in the form of a step-change reduction, or an increasing rate of change.

Discussion and Conclusion

The implementation of CPOE within an acute hospital improves the average LTAT over a prolonged period, despite an increase in the number of samples collected. This could improve care efficiencies. Understanding the likely reduction in LTAT also provides information to support an economic evaluation of the implementation of such a system into a new setting.