bluuebunny/crossref_metadata_2025 huggingface dataset:
A pediatric teletrauma program pilot project: Improves access to pediatric trauma care and timely assessment of pediatric traumas
Authors: Eldredge R. Scott , Moore Zachary , Smith Julia , Barnes Kasey , Norton Sidney P. , Larsen Kezlyn , Padilla Benjamin E. , Swendiman Robert A. , Fenton Stephen J. , Russell Katie W.
Published: January 2024

BACKGROUND

Geographic location is a barrier to providing specialized care to pediatric traumas. In 2019, we instituted a pediatric teletrauma program in collaboration with the Statewide Pediatric Trauma Network at our level 1 pediatric trauma center (PTC). Triage guidelines were provided to partnering hospitals (PHs) to aid in evaluation of pediatric traumas. Our pediatric trauma team was available for phone/video trauma consultation to provide recommendations on disposition and management. We hypothesized that this program would improve access and timely assessment of pediatric traumas while limiting patient transfers to our PTC.

METHODS

A retrospective cohort study was conducted at the PTC between January 2019 and May 2023. All pediatric trauma patients younger than 18 years who had teletrauma consults were included. We also evaluated all avoidable transfers without teletrauma consults defined as admission for less than 36 hours without an intervention or imaging as a comparison group.

RESULTS

A total of 151 teletrauma consults were identified: 62% male and median age of 8 years (interquartile range [IQR], 4–12 years). Teletrauma consults increased from 12 in 2019 to 100 in 2022 to 2023, and the number of PHs increased from 2 to 32. Partnering hospitals were 15 to 554 miles from the PTC, with a median distance of 34 miles (IQR, 28–119 miles). Following consultation, we recommended discharge (34%), admission (29%), or transfer to PTC (35%). Of those who were not transferred, 3% (3 of 97) required subsequent treatment at the PTC. Nontransferred teletrauma consults had a higher percentage of TBI (61% vs. 31%, p < 0.001) and were from farther distances (40 miles [IQR, 28–150 miles] vs. 30 miles [IQR, 28–50 miles], p < 0.001) compared with avoidable transferred patients without a teletrauma consult.

CONCLUSION

Teletrauma consult is a safe and viable addition to a pediatric trauma program faced with providing care to a large geographical catchment area. The pediatric teletrauma program provided management recommendations to 32 PHs and avoided transfer in approximately 63% of cases.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Update on Outcomes of a Novel Pathway for Thoracic Surgery Training
Authors: Potts John R , Klingensmith Mary E , Merrill Walter H
Published: January 2024

BACKGROUND:

The Joint Surgery-Thoracic Surgery (JS-TS) pathway began as a pilot program to grant both general surgery (GS) residency and thoracic surgery (TS) fellowship credit for 12 months of the PGY-4 and 5 years. This review updates the outcomes of this novel program.

STUDY DESIGN:

GS and TS programs in all approved JS-TS institutions were contacted for data collection, including JS-TS enrollee demographics and GS and TS case logs (CLs). National GS and TS CL data, and program and institutional data were publicly available. Enrollee case numbers were compared with those of their contemporaries. The American Board of Surgery and American Board of Thoracic Surgery provided certification data. Only enrollees who completed GS through 2019 were included.

RESULTS:

There were 90 JS-TS enrollees in 14 institutions. Two enrollees withdrew and 1 had not completed TS at the time of data collection leaving 87 for analysis. GS CLs were available for all 87 enrollees. TS CLs were available for all 62 enrollees who completed fellowship in 2016 or later. In GS, enrollees recorded fewer cases than their contemporary PGY-5s nationally in all domains except thoracic and endocrine. In TS, mean enrollee case numbers exceeded those of national contemporaries in every major category. Sixty-two JS-TS enrollees have achieved American Board of Surgery certification. Eighty-two enrollees are American Board of Thoracic Surgery certified with 5 currently in the certification process.

CONCLUSIONS:

The JS-TS pathway has proven a successful alternative route for TS training and could be a blueprint for other specialties considering novel avenues to specialty training.
Impact of Prehospital Exsanguinating Airway-Breathing-Circulation Resuscitation Sequence on Patients with Severe Hemorrhage
Authors: Ritondale Joseph , Piehl Mark , Caputo Sydney , Broome Jacob , McLafferty Bryant , Anderson Augustus , Belding Cameron , Tatum Danielle , Duchesne Juan ,   for the Damage Control Resuscitation Study Group
Published: January 2024

BACKGROUND:

At the 2023 ATLS symposium, the priority of circulation was emphasized through the “x-airway-breathing-circulation (ABC)” sequence, where “x” stands for exsanguinating hemorrhage control. With growing evidence from military and civilian studies supporting an x-ABC approach to trauma care, a prehospital advanced resuscitative care (ARC) bundle emphasizing early transfusion was developed in our emergency medical services (EMS) system. We hypothesized that prioritization of prehospital x-ABC through ARC would reduce in-hospital mortality.

STUDY DESIGN:

This was a single-year prospective analysis of patients with severe hemorrhage. These patients were combined with our institution’s historic controls before prehospital blood implementation. Included were patients with systolic blood pressure (SBP) less than 90 mmHg. Excluded were patients with penetrating head trauma or prehospital cardiac arrest. Two-to-one propensity matching for x-ABC to ABC groups was conducted, and the primary outcome, in-hospital mortality, was compared between groups.

RESULTS:

A total of 93 patients (x-ABC = 62, ABC = 31) met the inclusion criteria. There was no difference in patient age, sex, initial SBP, initial Glasgow Coma Score, and initial shock index between groups. When compared with the ABC group, x-ABC patients had significant improvement in vitals at emergency department admission. Overall mortality was lower in the x-ABC group (13% vs 47%, p < 0.001). Multivariable regression revealed that prehospital circulation-first prioritization was independently associated with decreased in-hospital mortality (odds ratio 0.15, 95% CI 0.04 to 0.54, p = 0.004).

CONCLUSIONS:

This is the first analysis to demonstrate a prehospital survival benefit of x-ABC in this subset of patient with severe injury and hemorrhagic shock. Standardization of prehospital x-ABC management in this patient population warrants special consideration.
Females counter-sing, but response to male song differs by sex in Alston's singing mouse
Authors: Tripp Joel A. , Phelps Steven M.
Published: January 2024

Vocal display behaviours are common throughout the animal kingdom, play important roles in both courtship and aggression, and are frequent subjects of behavioural research. Although females of many species vocalize, an overwhelming fraction of behavioural research has focused on male display. We investigated vocal display behaviours in female singing mice (
Scotinomys teguina
), small muroid rodents in which both sexes produce songs consisting of trills of rapid, downward frequency sweeps. Previous research established that male singing mice increase song production and engage in precisely timed counter-singing behaviour in response to playback of conspecific male song. We tested whether female singing mice also increased their rate of singing in response to playback of male song, whether they counter-sing, and whether there are sexual dimorphisms in song effort. Our results demonstrate that much like males, female singing mice increase their song effort and counter-sing in response to playback of male song; however, females sing fewer and shorter songs compared to males. This study further informs the understanding of female vocal behaviour and establishes the singing mouse as a valuable model for investigating female vocal display.
Ray Freeman. 6 January 1932—1 May 2022
Authors: Keeler James , Morris FRS Gareth A.
Published: January 2024

Ray Freeman pioneered many of the important advances in the technique of liquid-state nuclear magnetic resonance spectroscopy: he changed fundamentally the ways in which chemists and structural biologists use NMR. Born in Nottingham, he was an undergraduate chemistry student at Oxford after National Service working with radar, and completed his Part II and doctoral research with Rex Richards (FRS 1959). After brief spells with Anatole Abragam (ForMemRS 1983) in Saclay, France, and at the National Physical Laboratory in Teddington, he worked for 10 years in the research department of Varian Associates, Palo Alto, USA. He was appointed as lecturer in physical chemistry and tutorial fellow of Magdalen College, Oxford, in 1973, and subsequently promoted to Aldrichian praelector. In 1987 he was appointed to the John Humphrey Plummer chair at the University of Cambridge, where he remained active in research long after his retirement in 1999, publishing his last paper at the age of 84.
Finite element modelling of sound transmission in the Weberian apparatus of zebrafish (
Danio rerio
)
Authors: Marcé-Nogué Jordi , Liu Juan
Published: January 2024

Zebrafish, an essential vertebrate model, has greatly expanded our understanding of hearing. However, one area that remains unexplored is the biomechanics of the Weberian apparatus, crucial for sound conduction and perception. Using micro-computed tomography (μCT) bioimaging, we created three-dimensional finite element models of the zebrafish Weberian ossicles. These models ranged from the exact size to scaled isometric versions with constrained geometry (1 to 10 mm in ossicular chain length). Harmonic finite element analysis of all 11 models revealed that the resonance frequency of the zebrafish's Weberian ossicular chain is approximately 900 Hz, matching their optimal hearing range. Interestingly, resonance frequency negatively correlated with size, while the ratio of peak displacement and difference of resonance frequency between tripus and scaphium remained constant. This suggests the transmission efficiency of the ossicular chain and the homogeneity of resonance frequency at both ends of the chain are not size-dependent. We conclude that the Weberian apparatus's resonance frequency can explain zebrafish's best hearing frequency, and their biomechanical characteristics are not influenced by isometric ontogeny. As the first biomechanical modelling of atympanic ear and among the few non-human ear modelling, this study provides a methodological framework for further investigations into hearing mechanisms and the hearing evolution of vertebrates.
Advantages of the classical thermodynamic analysis of single—and multi-component Langmuir monolayers from molecules of biomedical importance—theory and applications
Authors: Dynarowicz-Latka Patrycja , Wnętrzak Anita , Chachaj-Brekiesz Anna
Published: January 2024

The Langmuir monolayer technique has been successfully used for decades to model biological membranes and processes occurring at their interfaces. Classically, this method involves surface pressure measurements to study interactions within membrane components as well as between external bioactive molecules (e.g. drugs) and the membrane. In recent years, surface-sensitive techniques were developed to investigate monolayers
in situ
; however, the obtained results are in many cases insufficient for a full characterization of biomolecule-membrane interactions. As result, description of systems using parameters such as mixing or excess thermodynamic functions is still relevant, valuable and irreplaceable in biophysical research. This review article summarizes the theory of thermodynamics of single- and multi-component Langmuir monolayers. In addition, recent applications of this approach to characterize surface behaviour and interactions (e.g. orientation of bipolar molecules, drug-membrane affinity, lateral membrane heterogeneity) are presented.
Comparative transcriptome analysis of the antenna and proboscis reveals feeding state-dependent chemosensory genes in
Eupeodes corollae
Authors: Chen Ruipeng , Ai Dong , Wang Guirong , Wang Bing
Published: January 2024

The physiological state of an insect can affect its olfactory system. However, the molecular mechanism underlying the effect of nutrition-dependent states on odour-guided behaviours in hoverflies remains unclear. In this study, comparative transcriptome analysis of the antenna and proboscis from
Eupeodes corollae
under different feeding states was conducted. Compared with the previously published antennal transcriptome, a total of 32 novel chemosensory genes were identified, including 4 ionotropic receptors, 17 gustatory receptors, 9 odorant binding proteins and 2 chemosensory proteins. Analysis of differences in gene expression between different feeding states in male and female antennae and proboscises revealed that the expression levels of chemosensory genes were impacted by feeding state. For instance, the expression levels of
EcorOBP19
in female antennae,
EcorOBP6
in female proboscis, and
EcorOR6
,
EcorOR14
,
EcorIR5
and
EcorIR84a
in male antennae were significantly upregulated after feeding. On the other hand, the expression levels of
EcorCSP7
in male proboscis and
EcorOR40
in male antennae were significantly downregulated. These findings suggest that nutritional state plays a role in the adaptation of hoverflies' olfactory system to food availability. Overall, our study provides important insights into the plasticity and adaptation of chemosensory systems in hoverflies.
Reply to: Erosive balanitis caused by Staphylococcus haemolyticus in a healthy, circumcised adult male
Authors: Kravvas Georgios , Watchorn Richard , Bunker Christopher Barry
Published: January 2024

n/a
A practical guide and Galaxy workflow to avoid inter-plasmidic repeat collapse and false gene loss in Unicycler’s hybrid assemblies
Authors: Schäfer Lea , Jehle Johannes A. , Kleespies Regina G. , Wennmann Jörg T.
Published: January 2024

Generating complete, high-quality genome assemblies is key for any downstream analysis, such as comparative genomics. For bacterial genome assembly, various algorithms and fully automated pipelines exist, which are free-of-charge and easily accessible. However, these assembly tools often cannot unambiguously resolve a bacterial genome, for example due to the presence of sequence repeat structures on the chromosome or on plasmids. Then, a more sophisticated approach and/or manual curation is needed. Such modifications can be challenging, especially for non-bioinformaticians, because they are generally not considered as a straightforward process. In this study, we propose a standardized approach for manual genome completion focusing on the popular hybrid assembly pipeline Unicycler. The provided Galaxy workflow addresses two weaknesses in Unicycler’s hybrid assemblies: (i) collapse of inter-plasmidic repeats and (ii) false loss of single-copy sequences. To demonstrate and validate how to detect and resolve these assembly errors, we use two genomes from the

Bacillus cereus

group. By applying the proposed pipeline following an automated assembly, the genome sequence quality can be significantly improved.
How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis
Authors: Holmes Rachel , Duan Hongzhe , Bagley Olivia , Wu Deqing , Loika Yury , Kulminski Alexander , Yashin Anatoliy , Arbeev Konstantin , Ukraintseva Svetlana
Published: January 2024

The ε4 allele of theAPOEgene (APOE4)is known for its negative association with human longevity, however, the mechanism is unclear.APOE4was also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here we explore the role of aging changes in weight in the connection betweenAPOE4and longevity, using a Causal Mediation Analysis (CMA) approach to uncovering mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis, whether the association ofAPOE4with reduced survival to age 85+ is mediated by key characteristics of age-trajectories of weight, such as age at reaching peak values, and slope of the decline in weight afterwards. Mediation effects were evaluated by the Total Effect (TE), Natural Indirect Effect, and Proportion Mediated. Controlled Direct Effect and Natural Direct Effect are also reported. The CMA results suggest thatAPOE4carriers have 19%-22% (TE p=0.019-0.038) lower chances of surviving to age 85 and beyond in part because they reach peak values of weight at younger ages, and their weight declines faster afterwards, compared to non-carriers. This finding is in line with the idea that detrimental effect ofAPOE4on longevity is in part related to accelerated physical aging of ε4 carriers.
Generalisable functional imaging classifiers of schizophrenia have multifunctionality as trait, state, and staging biomarkers
Authors: Kawashima Takahiko , Yamashita Ayumu , Yoshihara Yujiro , Kobayashi Yuko , Okada Naohiro , Kasai Kiyoto , Huang Ming-Chyi , Sawa Akira , Yoshimoto Junichiro , Yamashita Okito , Murai Toshiya , Miyata Jun , Kawato Mitsuo , Takahashi Hidehiko
Published: January 2024

Schizophrenia spectrum disorder (SSD) is one of the top causes of disease burden; similar to other psychiatric disorders, SSD lacks widely applicable and objective biomarkers. This study aimed to introduce a novel resting-state functional connectivity (rs-FC) magnetic resonance imaging (MRI) biomarker for diagnosing SSD. It was developed using customised machine learning on an anterogradely and retrogradely harmonised dataset from multiple sites, including 617 healthy controls and 116 patients with SSD. Unlike previous rs-FC MRI biomarkers, this new biomarker demonstrated a notable accuracy rate of 77.3% in an independent validation cohort, including 404 healthy controls and 198 patients with SSD from seven different sites, effectively mitigating across-scan variability. Importantly, our biomarker specifically identified SSD, differentiating it from other psychiatric disorders. Our analysis identified 47 important FCs significant in SSD classification, several of which are involved in SSD pathophysiology. Beyond their potential as trait markers, we explored the utility of these FCs as both state and staging markers. First, based on aggregated FCs, we built prediction models for clinical scales of trait and/or state. Thus, we successfully predicted delusional inventory scores (r=0.331, P=0.0177), but not the overall symptom severity (r=0.128, P=0.178). Second, through comprehensive analysis, we uncovered associations between individual FCs and symptom scale scores or disease stages, presenting promising candidate FCs for state or staging markers. This study underscores the potential of rs-FC as a clinically applicable neural phenotype marker for SSD and provides actionable targets to neuromodulation therapies.
Phase angle clusters in bioimpedance: An alternative to body mass index
Authors: Jesús Fuentes Sebio Ma
Published: January 2024

Abstract

Background

The “Body Mass Index” (BMI) or “Quetelet Index” is the most widely used tool to diagnose the degree of obesity. Anyone can calculate it, with no other tools than a scale and a measuring rod. However, its accuracy in predicting body fat percentage is low. The aim of this study is to find an alternative to BMI that is more reliable, accessible and easily applicable in daily clinical practice.

Methods

Using the K-means method (an unsupervised classification algorithm), we performed aclusteranalysis of the two phase angles obtained with bioimpedance analysis (BIA) of 641 women with different health status. BMI, age, diseases, treatments and any other data other than the phase angle values of the participants were not taken into account.

Results

Theclustersgenerated by the K-means algorithm do not coincide with the BMI categories, nor with the predetermined division of individuals into healthy and pathological.

The K-means clustering algorithm identified new patterns that provide information on the greater or lesser predisposition of different individuals to suffer from diseases, taking as a reference their pathological peers in the samecluster.

Conclusions

The categories generated by the K-means algorithm based on the phase angles obtained by BIA classify individuals according to their health status independently of other variables such as age or BMI.
Immune checkpoint inhibitor response in sarcomas associates with immune infiltrates and increased expression of transposable elements and viral response pathways
Authors: Nacev Benjamin A. , Bradic Martina , Woo Hyung Jun , Richards Allison L. , Kelly Ciara M. , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary L. , Chi Ping , Movva Sujana , Maki Robert , Slotkin Emily K. , Rosenbaum Evan , Avutu Viswatej , Chan Jason E. , Banks Lauren , Adamson Travis , Singer Samuel , Antonescu Cristina R. , Tap William D. , Donoghue Mark T.A. , D’Angelo Sandra P.
Published: January 2024

Response to immune checkpoint inhibition (ICI) in sarcoma is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. One potential mechanism is epigenetic de-repression of transposable elements (TEs), which stimulates antitumor immunity. Here, we used transcriptomic data to assign immune-hot versus immune-cold status to 67 pre-treatment biopsies of sarcomas from patients treated on ICI trials. Progression-free survival and overall response was superior in the immune-hot group. Expression of TEs and epigenetic regulators significantly predicted immune-hot status in a regression model in which specific TE subfamilies andIKZF1, a chromatin-interacting transcription factor, were significantly contributory. TE andIKZF1expression positively correlated with tumor immune infiltrates, inflammatory pathways, and clinical outcomes. Key findings were confirmed in a validation cohort (n=190). This work suggests that TE andIKZF1expression warrant investigation as predictive biomarkers for ICI response and as therapeutic targets in sarcomas.
A Method to Redesign and Simplify Schedules of Assessment and Quantify the Impacts. Applications to Merck Protocols
Authors: Cummings Steven R. , Chetham Scott , Lee Andy
Published: January 2024

The growing complexity of biopharmaceutical sponsored trials has adverse impacts on increased burdens on participants, clinical sites, and sponsors, including greater difficulty recruiting and retaining participants, difficulty engaging sites to participate in trials, excessive cost of trials, and increased cycle times. The schedule of assessments (SoAs) is the origin of and blueprint for complexity that is often generated by copying and pasting from previous SoAs. We developed an approach, termed Lean Design, for redesigning SoAs, restarting SoAs from ‘ground zero’, challenging the addition of assessments using several principles of trial design. We employed a system, the Faro Trial Designer Tool, to quantify the impacts of changes in an SoA to provide real-time feedback to the team and sponsor. We applied the approach in workshops with teams for six clinical trials in various stages of design and implementation. The approach resulted in recommendation for substantial savings in participant and site staff time, costs, and complexity of the trials. Application of this approach to very early stages of protocol design has the potential to reduce the complexity of biopharmaceutical sponsored trials and its consequences.
Effects of Diazepam on Hippocampal Blood Flow in People at Clinical High Risk for Psychosis
Authors: Livingston Nicholas R. , Kiemes Amanda , Devenyi Gabriel A. , Knight Samuel , Lukow Paulina B. , Jelen Luke A. , Reilly Thomas , Dima Aikaterini , Nettis Maria Antonietta , Casetta Cecilia , Agyekum Tyler , Zelaya Fernando , Spencer Thomas , Micheli Andrea De , Fusar-Poli Paolo , Grace Anthony A. , Williams Steve C.R. , McGuire Philip , Egerton Alice , Chakravarty M. Mallar , Modinos Gemma
Published: January 2024

Background

Elevated hippocampal perfusion has been observed in people at clinical high-risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that prophylactic treatment with diazepam during adolescence can prevent the development of psychosis-relevant phenotypes. Here we examined whether diazepam normalises hippocampal perfusion in CHR-P individuals.

Methods

Using a randomised, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with MRI on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labelling and sampled in native space using participant-specific hippocampus/subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-one healthy controls (HC) were scanned using the same acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield.

Results

Under the placebo condition, CHR-P individuals (mean[±SD] age: 24.1[±4.8] years, 15F) showed significantly elevated rCBF compared to HC (mean[±SD] age: 26.5[±5.1] years, 11F) in the hippocampus (F(1,36)=8.2,pFDR=0.004) and across its subfields (allpFDR<0.001). Following diazepam, rCBF in the hippocampus (and subfields, allpFDR<0.001) was significantly reduced (t(69)=-5.1,pFDR<0.001) and normalised to HC levels (F(1,41)=0.3,pFDR=0.225).

Conclusions

Diazepam can normalise hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in the pathophysiology of psychosis.
Modelling the within-host dynamics ofPlasmodium vivaxhypnozoite activation: an analysis of the SPf66 vaccine trial
Authors: Mehra Somya , Nosten Francois , Luxemburger Christine , White Nicholas J , Watson James A
Published: January 2024

Plasmodium vivaxparasites can lie dormant in the liver as hypnozoites, activating weeks to months after sporozoite inoculation to cause relapsing malarial illness. It is not known what biological processes govern hypnozoite activation. We use longitudinal data from the most detailed cohort study ever conducted in an area where bothPlasmodium falciparumandP. vivaxwere endemic to fit a simple within-host mathematical model ofP. vivaxhypnozoite activation. 1344 children living on the Thailand-Myanmar border were followed each day for 21 months. There were 2504 vivax and 1164 falciparum malaria symptomatic episodes recorded over 1988 person-years. The model assumes that hypnozoites activate independently at a constant rate (‘exponential clock model’). When this model was embedded in a stochastic framework for repeated infectious mosquito bites, with seasonality inferred from the incidence of clinical falciparum malaria episodes, it explained the observed temporal patterns of multiple (up to 13) recurrent vivax malaria episodes. Under this model we estimate the mean dormancy period for a single hypnozoite to be 6 months (i.e. a half-life of 4 months). We use the calibrated within-host model to characterise population level overdispersion in the risk of relapse, and assess the potential utility of a serological test for radical cure in low transmission settings. We show that mefloquine treatment of falciparum malaria eliminates early vivax relapses; and that there are substantially moreP. vivaxrecurrences than expected under the model following artesunate monotherapy treatment for falciparum malaria. These results suggest that hypnozoites can be activated by symptomatic malarial illness.
Spatiotemporal Forecasting of Opioid-related Fatal Overdoses: Towards Best Practices for Modeling and Evaluation
Authors: Heuton Kyle , Kapoor Jyontika , Shrestha Shikhar , Stopka Thomas J. , Hughes Michael C.
Published: January 2024

To inform public health interventions, researchers have developed models to forecast opioid-related overdose mortality. However, these efforts often have limited overlap in the models and datasets employed, presenting challenges to assessing progress in this field. Furthermore, common error-based performance metrics, such as root mean squared error, are not directly suitable to assess a key modeling purpose: the identification of priority areas for public health interventions. We recommend a new intervention-aware performance metric and establish a set of baseline models with competitive performance. To show how model and metric choice vary across locations, we explore two distinct geographies: Cook County, Illinois and the state of Massachusetts. We introduce a new, intervention-aware evaluation metric: the Percentage of Best Possible Reach (%BPR). The top-performing models based on error-based metrics recommend fixed-budget interventions in areas that do not always reach the most possible overdose events. In Massachusetts the top models, as ranked by our proposed %BPR metric, could have reached 18 additional fatal overdoses per year in our 2020-2021 test period compared to models favored by error-based metrics, assuming the ability to intervene in 100 census tracts out of the 1620 in Massachusetts. We release open code and data for others to build upon.

Repository for code and data:https://github.com/tufts-ml/opioid-overdose-models
The Molecular Signature of Neuropathic Pain in a Human Model System
Authors: Sandy-Hindmarch Oliver P , Chang Pao-Sheng , Scheuren Paulina Simonne , De Schoenmacker Iara , Hubli Michèle , Loizou Constantinou , Wirth Stephan , Mahadevan Devendra , Wiberg Akira , Furniss Dominic , Denk Franziska , Baskozos Georgios , Schmid Annina
Published: January 2024

Peripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. In this multicentre cohort study, we describe the local molecular signature of neuropathic pain at the lesion site, using peripheral nerves of patients with Morton’s neuroma as a human model system of neuropathic pain.

Plantar tibial nerves were collected from 22 patients with Morton’s neuroma (18 female, median age 60.0 [IQR 16.0] years) and control nerves from 11 participants (4 females, 58.0 [21.0] years) without a nerve injury. Pre-surgery, we collected data on pain severity, duration and nature (e.g., neuropathic pain inventory, NPSI).

RNA bulk sequencing of peripheral nerves identified 3349 genes to be differentially expressed between Morton’s neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses (WGCNA) revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed that the densities of macrophages as well as B-cells were higher in Morton’s neuroma than control samples. The findings for T-cells were inconclusive. Modules associated with defence response, neurogenesis and muscle system development correlated with paroxysmal and evoked pain in people with Morton’s neuroma. Macrophage cell populations identified by deconvolution analysis as well as single differentially expressed genes (MARCO, CD163, STAB1;indicating the presence of a specific M(GC) subset of macrophages) correlated with paroxysmal pain.

Immunofluorescent analyses confirmed the presence of demyelination, higher densities of intraneural T-cells and CD163+MARCO+macrophage subsets in Morton’s neuroma compared to control nerves. Histological CD68+macrophage density correlated with burning pain. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+subset implicated.
Redefining Clinical Hyperprogression: the Incidence, Clinical Implications, and Risk Factors of Hyperprogression in Non-Small Cell Lung Cancer Treated with Immunotherapy
Authors: Djunadi Trie Arni , Oh Youjin , Lee Jeeyeon , Yu Jisang , Chung Liam Il-Young , Lee Yeunho , Kim Leeseul , Hong Timothy , Lee Soowon , Shah Zunairah , Park Joo Hee , Yoon Sung Mi , Chae Young Kwang
Published: January 2024

Introduction

Immune checkpoint inhibitors (ICIs) may be associated with hyperprogressive disease (HPD). However, there is currently no standardized definition of HPD, with its risk factors and clinical implications remaining unclear. We investigated HPD in lung cancer patients undergoing immunotherapy, aiming to redefine HPD, identify risk factors, and assess its impact on survival.

Methods

Clinical and radiologic data from 121 non-small cell lung cancer (NSCLC) patients with 136 immunotherapy cases were reviewed retrospectively. Three HPD definitions (Champiat et al., HPDc; Saâda-Bouzid et al., HPDs; and Ferrara et al., HPDf) were employed. Additionally, all new measurable lesions on the post-treatment CT scan were incorporated in measuring the sum of longest diameters (SLD) to define modified HPD (mHPD).

Results

Among the 121 patients, 4 (3.3%) had HPDc, 11 (9.1%) had HPDs, and none had HPDf. Adding all new measurable lesions increased HPD incidence by 5%–10% across definitions. Multivariate analysis revealed significantly lower progression-free survival (PFS) and overall survival (OS) for patients with HPDc (HR 5.25, p=0.001; HR 3.75, p=0.015) and HPDs (HR 3.74, p<0.001; HR 3.46, p<0.001) compared to those without. Patients with mHPD showed similarly poor survival outcomes as HPD patients. Liver metastasis at diagnosis was associated with HPDs, and a high tumor burden correlated with HPDc.

Conclusions

The incidence and risk factors of HPD varied with different definitions, but mHPD identified more cases with poor outcomes. This comprehensive approach may enhance the identification of at-risk patients and lead to a better understanding of HPD in lung cancer during immunotherapy.
GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study
Authors: D’Souza Precilla , Farmer Cristan , Johnston Jean , Han Sangwoo T , Adams David , Hartman Adam L. , Zein Wadih , Huryn Laryssa A. , Solomon Beth , King Kelly , Jordan Christopher , Myles Jennifer , Nicoli Elena-Raluca , Rothermel Caroline E , Mojica Algarin Yoliann , Huang Reyna , Quimby Rachel , Zainab Mosufa , Bowden Sarah , Crowell Anna , Buckley Ashura , Brewer Carmen , Regier Deborah , Brooks Brian , Baker Eva , Vézina Gilbert , Thurm Audrey , Tifft Cynthia J
Published: January 2024

Purpose

GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 (GLB1; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637,NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials.

Methods

Forty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments.

Results

Classification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit ofN-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease.

Conclusion

The comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials.
Characterising and differentiating cognitive and motor speed in older adults: a longitudinal birth cohort study
Authors: Bundil Indra , Baltruschat Sabina , Zhang Jiaxiang
Published: January 2024

Objectives

Information processing speed (IPS) has been proposed to be a key component in healthy ageing and cognitive functioning. Yet, current studies lack a consistent definition and specific influential characteristics. This study aimed at investigating IPS as a multifaceted concept by differentiating cognitive and motor IPS.

Design, setting and participants

A retrospective data analysis using data from the Medical Research Council National Survey of Health and Development (MRC NSHD; a population-based cohort of UK adults born in 1946) at childhood (ages 8, 11, and 15) and adulthood (ages 60-64 and 68-70). Using structural equation modelling, we constructed two models of IPS with 2124 and 1776 participants, respectively.

Outcome measures

Measures of interest included IPS (i.e., letter cancellation, simple and choice reaction time), intelligence (i.e., childhood intelligence and NART), verbal memory, socio-economic status (SES) and cognitive functions measured by the Addenbrooke’s Cognitive Examination III, as well as a variety of health indexes.

Results

We found distinct predictors for cognitive and motor IPS and how they relate to other cognitive functions in old age. In our first model, SES and anti-psychotic medication usage emerged as significant predictors for cognitive IPS, intelligence and smoking as predictors for motor IPS, while both share sex, memory, and anti-epileptic medication usage as common predictors. Notably, all differences between both IPS types ran in the same direction except for sex differences, with women performing better than men in cognitive IPS and vice versa in motor IPS. The second model showed that both IPS measures, as well as intelligence, memory, anti-psychotic and sedative medication usage explain cognitive functions later in life.

Conclusion

Taken together, these results shed further light on IPS as a whole by showing there are distinct types and that these measures directly relate to other cognitive functions.

STRENGTH & LIMITATIONS

A large longitudinal cohort data set with different measurements of information processing speed that are widely used

Information processing speed is not only related to variables measured at the same time but also to childhood and premorbid intelligence and cognitive functions in later life

Limitations of the cohort dataset include different response rates between waves, thus some variables were not available for all individuals at certain time points, and IPS scores were derived from a small number of trials

The study involved self-reported measures which might have increased the proportion of misclassification
The Post-Septic Peripheral Myeloid Compartment Reveals Unexpected Diversity in Myeloid-Derived Suppressor Cells
Authors: Barrios Evan L. , Leary John , Darden Dijoia B. , Rincon Jaimar C. , Willis Micah , Polcz Valerie E. , Gillies Gwendolyn S. , Munley Jennifer A. , Dirain Marvin L. , Ungaro Ricardo , Nacionales Dina C. , Gauthier Marie-Pierre L. , Larson Shawn D. , Morel Laurence , Loftus Tyler J. , Mohr Alicia M. , Maile Robert , Kladde Michael P. , Mathews Clayton E. , Brusko Maigan A. , Brusko Todd M. , Moldawer Lyle L. , Bacher Rhonda , Efron Philip A.
Published: January 2024

Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing followed by transcriptomic analysis, we identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome.
Unveiling the oncogenic significance of thymidylate synthase in human cancers
Authors: Geng Yibo , Xie Luyang , Wang Yang , Wang Yan
Published: January 2024

Background

Thymidylate synthase (TYMS) constitutes a pivotal and potent target in the context of chemoresistance. However, the oncogenic role of TYMS has received insufficient attention.

Methods

Leveraging data from the Cancer Genome Atlas and various public databases, we conducted an extensive investigation into the oncogenic role of TYMS across 33 cancer types.

Results

TYMS exhibited pronounced expression across a spectrum of cancers and demonstrated associations with clinical outcomes in diverse cancer patient cohorts. Furthermore, genetic alterations were identified as potential influencers of overall survival in specific tumor types. Notably, the expression of thymidylate synthase correlated with tumor-infiltrating CD4+ cells in select cancers. Additionally, the functional mechanism of TYMS encompassed nucleotidase activity, chromosome segregation, and DNA replication progress.

Conclusions

This study furnishes a comprehensive understanding of the oncogenic role played by TYMS in human tumors.
Atherogenic sdLDL-cholesterol and resistin association with vitamin B12 in relation to Body Mass Index
Authors: Ashfaq Fauzia , Haji Alhaji Jwaher , Alharbi Mohammed Salem , Khatoon Fahmida , Alhatlani Nayef Hamad E , Mari Alkhamisi Fahad Ayash , Alshuwaier Ghareeb O. , Khan Mohammad Idreesh , Beg Mirza Masroor Ali
Published: January 2024

Introduction

Obesity is a known risk factor for many chronic diseases and is a growing global health concern and poor health outcomes have consistently been linked to body mass index (BMI). Small dense low-density lipoprotein (sdLDL) changes brought on by obesity may increase the likelihood of endothelium penetration and subsequent atherogenesis. Numerous tissues’ metabolic and secretory functions are altered by obesity, which may also increase the serum resistin level.

Methods

Present study included 300 participants with diffent BMI among them sdLDL and resistin was evaluated. HbA1c was analysed by whole blood of EDTA and the serum were thawed sample was used for lipid parameters (TG, cholesterol, HDL, LDL, VLDL and sdLDL) and vitamin B12 analysis as well as resistin level was analysed by ELISA.

Results

Study observed higher HbA1c (%, p=0.0004), LDL (mg/dl) (<0.0001), TG (mg/dl) (<0.0001), Cholesterol (mg/dl) (<0.0001), VLDL (mg/dl) (<0.0001) in obese compared to overweight, normal BMI, except HDL. Smokers and hypertensive participants had higher sdLDL (p=0.03, p=0.0001) and resistin level (p=0.03, p<0.0001). Obese participants had high amount of sdLDL (p<0.0001, p<0.0001) and resistin level (p<0.0001, p<0.0001) compared to overweight and normal BMI. SdLDL and resistin were found to be positively correlated as well as correlation analysis of sdLDL and resistin level was observed to be significantly correlated with BMI, systolic, TG, cholesterol, VLDL, LDL while negative correlation with HDL level. ROC analysis showed that sdLDL and resistin could be used as prognostic factor for overweight/obesity at cutoff value of 18.55 mg/dl (sdLDL) and 750 pg/ml (resistin). It was also observed that the participant with normal BMI had 389.6 pmol/L while overweight participant had 300.6 pmol/L (p<0.0001) and obese had 291.0 pmol/L (p<0.0001).

Conclusion

Study concluded that the obese participants had higher TG, cholesterol, VLDL, LDL and lower HDL level. The most importantly, higher sdLDL level and resistin level was observed in obese participants as well as higher sdLDL and resistin could influence the higher lipid parameters (TG, cholesterol, VLDL, LDL) and lower HDL level. It was also observed that obese participants had lower vitamin B12 level and could lead to other metabolic error.
An internally controlled system to study microtubule network diversification links tubulin evolution to the use of distinct microtubule regulators
Authors: Kennard Andrew S. , Velle Katrina B. , Ranjan Ravi , Schulz Danae , Fritz-Laylin Lillian K.
Published: January 2024

Diverse eukaryotic cells assemble microtubule networks that vary in structure and composition. While we understand how cells build microtubule networks with specialized functions, we do not know how microtubule networks diversify across deep evolutionary timescales. This problem has remained unresolved because most organisms use shared pools of tubulins for multiple networks, making it impossible to trace the evolution of any single network. In contrast, the amoeboflagellateNaegleriauses distinct tubulin genes to build distinct microtubule networks: whileNaegleriabuilds flagella from conserved tubulins during differentiation, it uses divergent tubulins to build its mitotic spindle. This genetic separation makes for an internally controlled system to study independent microtubule networks in a single organismal and genomic context. To explore the evolution of these microtubule networks, we identified conserved microtubule binding proteins and used transcriptional profiling of mitosis and differentiation to determine which are upregulated during the assembly of each network. Surprisingly, most microtubule binding proteins are upregulated during only one process, suggesting thatNaegleriauses distinct component pools to specialize its microtubule networks. Furthermore, the divergent residues of mitotic tubulins tend to fall within the binding sites of differentiation-specific microtubule regulators, suggesting that interactions between microtubules and their binding proteins constrain tubulin sequence diversification. We therefore propose a model for cytoskeletal evolution in which pools of microtubule network components constrain and guide the diversification of the entire network, so that the evolution of tubulin is inextricably linked to that of its binding partners.