bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Dose Short-Term Scheduled Ketorolac Reduces Opioid Use and Pain in Orthopaedic Polytrauma Patients: A Randomized Clinical Trial
Authors: Foster Jeffrey A. , Kavolus Matthew W. , Landy David C. , Pectol Richard W. , Sneed Chandler R. , Kinchelow Daria L. , Griffin Jarod T. , Hawk Gregory S. , Aneja Arun
Published: September 2023

Objective:

To determine whether scheduled low-dose, short-term ketorolac is associated with reduced length of stay, opioid use, and pain in orthopaedic polytrauma patients.

Design:

Double-blinded, randomized controlled trial

Setting:

One Level 1 trauma center

Patients:

From August 2018 to October 2022, 70 orthopaedic polytrauma patients between 18-75 years-old with a New Injury Severity Score (NISS) > 9 were randomized. 70 participants were enrolled, with 35 randomized to the ketorolac group and 35 to the placebo group.

Intervention:

15 mg of intravenous (IV) ketorolac every 6 hours for up to 5 inpatient days or 2 mL of IV saline in a similar fashion

Main Outcome Measurements:

Length of Stay (LOS), Morphine Milligram Equivalents (MME), Visual Analogue Scale (VAS), and Complications

Results:

Study groups were not significantly different with respect to age, BMI, and NISS (p>0.05). Median LOS was 8 days (interquartile range [IQR], 4.5 to 11.5) in the ketorolac group compared to 7 days (IQR, 3 to 10) in the placebo group (p = 0.275). Over the 5-day treatment period, the ketorolac group experienced a 32% reduction in average MME (p = 0.013) and a 12-point reduction in baseline-adjusted mean VAS (p = 0.037) compared to the placebo group. There were no apparent short-term adverse effects in either group.

Conclusion:

Scheduled low-dose, short-term IV ketorolac was associated with significantly reduced inpatient opioid use and pain in orthopaedic polytrauma patients with no significant difference in LOS and no apparent short-term adverse effects. The results support the use of scheduled low-dose, short-term IV ketorolac for acute pain control among orthopaedic polytrauma patients. Further studies are needed to delineate lasting clinical effects and potential long-term effects, such as fracture healing.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
RESOLUTION OF CHOROIDAL METASTASIS AND ASSOCIATED SUBRETINAL EXUDATION OF METASTATIC CUTANEOUS MELANOMA 15 DAYS AFTER TREATMENT WITH COMBINED TARGETED THERAPY
Authors: Wanten Victor , Vanhonsebrouck Eva , Jacob Julie
Published: September 2023

Purpose:

The purpose of this study was to report a case of metastatic cutaneous melanoma to the choroid with rapid and complete resolution of associated choroidal elevation and subretinal fluid after the initiation of combined targeted therapy.

Methods:

We describe a case of a 41-year-old man diagnosed with a metastatic cutaneous melanoma to the choroid of his right eye, for which treatment with dabrafenib/trametinib was initiated.

Results:

A 41-year-old man with a medical history of a BRAF V600E/V600E2/V600D-mutated invasive superficial spreading cutaneous melanoma presented with acute metamorphopsia and blurred vision in his right eye. Examination revealed a best-corrected visual acuity (BCVA) of 20/22 and two elevated choroidal lesions temporal to the fovea with subretinal exudation to the fovea on fundoscopy. On repeat examination 3 days later, his vision had further decreased to 20/50 with an increase of subretinal fluid. Treatment with BRAF/MEK inhibitor dabrafenib/trametinib was initiated, with complete resolution of the choroidal masses and subretinal exudation and improvement of the BCVA to 20/22 after only 15 days. An 8-week follow-up after the start of therapy showed stable fundoscopic and tomographic findings, with further improvement of BCVA to 20/17 and no ocular side effects.

Conclusion:

A case of metastatic cutaneous melanoma to the choroid with choroidal elevation and subretinal exudation to the fovea, for which treatment with dabrafenib/trametinib was initiated. Rapid and complete resolution of choroidal metastasis and the associated subretinal exudation after the initiation of combined targeted therapy was seen, without any ocular side effects.
Moyamoya disease mimicking primary central nervous system vasculitis: A case report
Authors: Morikawa Ryo , Suzuki Junichiro , Nakai Noriyoshi , Takasu Syuntaro , Itoh Takayuki , Ito Yasuhiro
Published: September 2023

Rationale:

Both Moyamoya disease (MMD) and primary central nervous system vasculitis (PCNSV) cause cerebrovascular stenosis resulting in similar ischemic neurological events, although therapeutic approaches are distinct from each other. High-resonance vascular wall imaging (HRVWI) with contrast-enhanced magnetic resonance imaging (MRI) is believed to be useful to differentiate PCNSV from MMD by detecting enhancement of cerebral vascular walls. However, recent studies have reported that the vascular walls of major arteries and superficial cerebral arteries are also enhanced by HRVWI in some MMD cases.

Patient concerns:

A 40-year-old Chinese woman admitted to our hospital with transient weakness of the right hand for a week. A cerebral infarction of the left frontal lobe was detected by diffusion-weighted brain MRI. Magnetic resonance angiography demonstrated severe stenosis of the left middle cerebral artery (MCA) and extensive vascular narrowing. Magnetic resonance angiography incidentally taken 3 years before admission showed only a mild stenosis at the proximal portion of right MCA with intact left internal carotid artery (ICA) and MCA. Moreover, on HRVWI with contrast-enhanced MRI after admission, the wall of ICA was strongly enhanced, and the superficial cerebral arteries were also highly enhanced, which initially suggested PCNSV. Despite these findings, reticular blood vessels were confirmed by digital subtraction angiography, and p.R4810K polymorphism in the ring finger protein 213 gene was detected.

Diagnosis:

Based on these result, the patient was diagnosed with MMD.

Interventions:

Bypass surgery was performed.

Outcomes:

Ischemic events have never been experienced since surgery.

Lessons:

Our MMD case demonstrated marked asymmetrical progression of cerebral artery stenosis, and enhanced vascular walls of ICA and superficial cerebral arteries by HRVWI, which made differential diagnosis from PCNSV difficult. Genetic analysis of SNP in the ring finger protein 213 gene should be performed to rule out MMD to avoid misdiagnosis of PCNSV particularly in Asian population.
Propiverine induced pure visual hallucinations without cognitive impairment: A case report
Authors: Selçuk Mahmut
Published: September 2023

Rationale:

Propiverine is believed to have fewer adverse effects on the central nervous system than other anticholinergic medications since it penetrates the blood–brain barrier less deeply. In daily practice, no evidence links propiverine use to neuropsychiatric adverse effects. To our knowledge, this is the first report of psychotic symptoms being linked to propiverine use.

Patient concerns:

A urologist prescribed 30 mg/day of propiverine capsules to a 62-year-old male patient who complained of urine incontinence and visited the urology outpatient clinic. The patient returned to the urology outpatient clinic a week later because he was experiencing visual hallucinations.

Interventions:

In the psychiatry outpatient clinic, the patient was conscious, cooperative, and oriented during the mental state examination. He spoke about daylong visual hallucinations that included visions of numerous animals and geometric forms. His mood was somewhat anxious as a result of these images, which started appearing 3 days after taking the propiverine capsule and persisted for 4 days. His cognitive functions were normal. Physical examination, blood chemistry, endocrinology, and brain exams using cranial tomography and electroencephalogram revealed no abnormalities. We advised stopping the medication since visual hallucinations started soon after taking propiverine capsules.

Outcomes:

After discontinuation of propiverine capsules, the patient’s visual hallucinations disappeared.

Lessons:

Health practitioners should be aware that adverse effects like visual hallucinations can happen even with anticholinergic medications like propiverine that have a low level of penetration into the blood–brain barrier.
Regional Social Vulnerability is Associated with Geographic Disparity in Waitlist Outcomes for Patients with Non-HCC MELD Exceptions in the United States
Authors: Cannon Robert M. , Goldberg David S. , Sheikh Saulat S. , Anderson Douglas J. , Pozo Marcos , Rabbani Umaid , Locke Jayme E.
Published: September 2023

Background:

This study was undertaken to evaluate the role of regional social vulnerability in geographic disparity for patients listed for liver transplant with non-HCC MELD exceptions.

Methods:

Adults listed at a single center for a first time liver only transplant without HCC after June 18, 2013 in the SRTR database as of March 2021 were examined. Candidates were mapped to hospital referral regions (HRRs). Adjusted likelihood of mortality and liver transplant were modeled. Advantaged HRRs were defined as those where exception patients were more likely to be transplanted, yet no more likely to die in adjusted analysis. The Centers for Disease Control’s Social Vulnerability Index (SVI) was used as the measure for community health. Higher SVIs indicate poorer community health.

Results:

There were 49,494 candidates in the cohort, of whom 4,337 (8.8%) had MELD exceptions. Among continental US HRRs, 27.3% (n=78) were identified as advantaged. The mean SVI of advantaged HRRs was 0.42 vs. 0.53 in non-advantaged HRRs (P=0.002), indicating better community health in these areas. Only 25.3% of advantaged HRRs were in spatial clusters of high SVI vs. 40.7% of non-advantaged HRRs, while 44.6% of advantaged HRRs were in spatial clusters of low SVI vs.38.0% of non-advantaged HRRs (P=0.037).

Conclusion:

Advantage for non-HCC MELD exception patients is associated with lower social vulnerability on a population level. These findings suggest assigning similar waitlist priority to all non-HCC exception candidates without considering geographic differences in social determinants of health may actually exacerbate rather than ameliorate disparity.
Logic + probabilistic programming + causal laws
Authors: Belle Vaishak
Published: September 2023

Probabilistic planning attempts to incorporate stochastic models directly into the planning process, which is the problem of synthesizing a sequence of actions that achieves some objective for a putative agent. Probabilistic programming has rapidly emerged as a key paradigm to integrate probabilistic concepts with programming languages, which allows one to specify complex probabilistic models using programming primitives like recursion and loops. Probabilistic logic programming aims to further ease the specification of structured probability distributions using first-order logical artefacts. In this article, we briefly discuss the modelling of probabilistic planning through the lens of probabilistic (logic) programming. Although many flavours for such an integration are possible, we focus on two representative examples. The first is an extension to the popular probabilistic logic programming language PROBLOG, which permits the decoration of probabilities on Horn clauses—that is, prolog programs. The second is an extension to the popular agent programming language GOLOG, which permits the logical specification of dynamical systems via actions, effects and observations. The probabilistic extensions thereof emphasize different strengths of probabilistic programming that are particularly useful for non-trivial modelling issues raised in probabilistic planning. Among other things, one can instantiate planning problems with growing and shrinking state spaces, discrete and continuous probability distributions, and non-unique prior distributions in a first-order setting.
Profitable entanglement for channel discrimination
Authors: Oskouei Samad Khabbazi , Mancini Stefano , Rexiti Milajiguli
Published: September 2023

We investigate the usefulness of side entanglement in discriminating between two generic qubit channels, up to unitary pre- and post-processing, and determine exact conditions under which it does enhance (as well as conditions under which it does not) the success probability. This is done in a constructive way by first analysing the problem for channels that are extremal in the set of completely positive and trace-preserving qubit linear maps and then for channels that are inside such a set.
Gravity-induced dispersion in a chiral waveguide: transient regimes and imperfect temporal interfaces
Authors: Jones I. S. , Movchan N. V. , Movchan A. B.
Published: September 2023

The paper includes analysis of an elastic chiral waveguide, subjected to gravity, where a coupling between different displacement components is assumed owing to gyroscopic action. The importance of gravity and chirality on the dispersion of waves is demonstrated and behaviour in all regimes, including asymptotic ones, is addressed and linked to the value of the chirality parameter. In the transient regimes, we analyse chiral imperfect temporal interfaces in the waveguide subjected to gravity.
Education in the Anthropocene: assessing planetary health science standards in the USA
Authors: Capel Samantha L. R. , Allan Brian F. , Favela Alonso , Clem C. Scott , Ooi Sean Khan , Virrueta Herrera Stephany , Wilson Loralee J. , Strickland Lynette R.
Published: September 2023

The environmental crises defining the Anthropocene demand ubiquitous mitigation efforts, met with collective support. Yet, disengagement and disbelief surrounding planetary health threats are pervasive, especially in the USA. This scepticism may be influenced by inadequate education addressing the scope and urgency of the planetary health crisis. We analysed current K-12 science standards related to planetary health throughout the USA, assessing their quality and potential predictors of variation. While planetary health education varies widely across the USA with respect to the presence and depth of terms, most science standards neglected to convey these concepts with a sense of urgency. Furthermore, state/territory dominant political party and primary gross domestic product (GDP) contributor were each predictive of the quality of planetary health education. We propose that a nation-wide science standard could fully address the urgency of the planetary health crisis and prevent political bias from influencing the breadth and depth of concepts covered.
Hufsiella ginkgonis gen. nov., sp. nov. and Hufsiella arboris sp. nov., isolated from tree barks
Authors: Kang Heeyoung , Bae Seokhyeon , Kim Haneul , Joh Kiseong
Published: September 2023

Two Gram-staining-negative, aerobic, rod-shaped, bacteria that formed pale-pinkish colonies, designated HMF7056T and HMF7647T were isolated from Ginkgo (Ginkgo biloba) and Korean cornel dogwood (Cornus offcinalis), respectively. Phylogenetic analyses based on sequences of 16S rRNA genes and 92 core genes indicated that two strains represent novel species within the family

Sphingobacteriaceae

. HMF7056T and HMF7647T showed high 16S rRNA sequence similarities to

Daejeonella lutea

N7d-4T (93.9 % and 95.7 %, respectively). The genomes of HMF7056T and HMF7647T were 5.2 and 4.8 Mbp in size with 50.5 and 42.5 % DNA G+C contents, respectively. Menaquinone-7 was the main respiratory quinone. The predominant fatty acids of HMF7056T and HMF7647T were iso-C15 : 0 and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The major polar lipid of both strains was phosphatidylethanolamine. The average nucleotide identity and digital DNA–DNA hybridization values of HMF7056T, HMF7647T and related species were well below the threshold limit for species delineation (<68.9 and <20.8 %, respectively). The average amino acid identity values of HMF7056T, HMF7647T with related type strains were below 67.8 and 68.3 %, respectively. On the basis of the results of phenotypic and phylogenetic characterizations, the two strains are considered to represent members of a novel genus of the family

Sphingobacteriaceae

, for which the names Hufsiella ginkgonis gen. nov., sp. nov. and Hufsiella arboris sp. nov. are proposed. The type strains are HMF7056T (=KCTC 72282T =NBRC 113964T) and HMF7647T (=KCTC 72283T =NBRC 113965T), respectively.
Digital thErapy For Improved tiNnitus carE Study (DEFINE): Protocol for a Randomised Controlled Trial
Authors: Smith Matthew E , Sharma Dhiraj , Rivero-Arias Oliver , Rand Kim , Barrack Lucy , Ogburn Emma , Young Michael , Field Polly , Multmeier Jan , Muzaffar Jameel
Published: September 2023

Tinnitus is a common health condition, affecting approximately 15% of the UK population. The tinnitus treatment with the strongest evidence base is Cognitive Behavioural Therapy (CBT), with standard tinnitus therapy typically augmented with education, relaxation and other techniques. Availability of CBT and conventional tinnitus therapy more broadly is limited for tinnitus sufferers.

The DEFINE trial aims to assess whether smartphone-delivered tinnitus therapy, the Oto app, is as effective as current standard care, one-to-one therapist-delivered tinnitus treatment for the treatment of tinnitus in adults. The trial is registered in the ISRCTN Registry:ISRCTN99577932.

DEFINE is an open-label, non-inferiority, prospective, parallel design, randomised-controlled trial. Recruitment, interventions and assessments will be remote, enabling UK-wide participant involvement.

198 participants aged 18 years or more will be recruited via social media advertisement or via primary care physicians. A screening process will identify those with tinnitus that impacts health-related quality of life, and following consent smartphone-based audiometry will be performed. Randomisation 1:1 to the Oto app or one-to-one therapist-led tinnitus therapy will be performed centrally by computer, matching groups for age, sex and hearing level. Following participant allocation, the Oto app will be provided for immediate use, or a one-to-one remote therapy appointment booked to occur within approximately 1 week, with up to 6 sessions delivered.

Participant outcomes will be collected at 4,12, 26 and 52 weeks via questionnaire and phone call. The primary outcome is the change in Tinnitus Functional Index (TFI) total score measured at 26 weeks following allocation. Adverse events will be recorded. A health economic evaluation in the form of a cost-utility analysis will be performed using data from participant submitted EuroQol 5D-5L and Health Utilities Index Mark 3 scores and resource use data.

Trial results will be made publicly available, including a plain English summary.
Determinants of anti-retroviral therapy adherence among adolescents living with HIV in the Kingdom of Eswatini
Authors: Hlophe Londiwe D. , Shumba Constance S. , Bedada Diribsa T. , Nyasulu Peter S.
Published: September 2023

Background

The success of antiretroviral therapy (ART) depends on a high level of adherence to the life-long therapy of 95% and above. However, in Eswatini, adolescents and young people aged 15 to 24 years, have poor ART adherence as evidenced by low viral load (VL) suppression rates (76% and 63% among female and males respectively) compared to the general population (96%). The wide age-band of 15 to 24 years in reporting viral suppression rates means that adolescent specific data is limited, and younger adolescents aged 10-14 years are excluded. This study explored the level of ART adherence and associated factors among adolescents living with HIV (ALHIV) aged 10 to 19 years on ART in Eswatini.

Methods

We performed a retrospective analysis of 911 medical records of ALHIV aged 10 to 19 years on ART for at least a month in Eswatini for the period 1stJanuary 2017 to 30thSeptember 2022. Bivariate logistic regression was fitted for each predictor variable. Missing values were imputed using multiple imputation by chained equation (MICE). Statistically significant (p-value ≤0.2) predictor variables were included in a multivariable logistic regression model. P-value ≤0.05 was used to declare statistical significance in the final regression model.

Results

ART adherence of 88.5% was recorded with higher adherence among males (88.9%) than females (87.8%). Hhohho region had highest adherence (90.7%) while Shiselweni region had lowest adherence (82%). Adherence was low among ALHIV with a non-suppressed baseline VL result (65.3%) and those assigned to multi-month ART model of care at ART initiation (66.7%). The Shiselweni region (OR 0.47; 95%CI 0.26-2.78), suppressed baseline VL result (OR 5.49; 95%CI 3.36-8,96) and assigned to the main-stream ART care model (OR 0.22; 95%CI 0.05-0.95) were statistically associated with ART adherence. In the multivariable regression analysis, only Shiselweni region and suppressed baseline VL result were statistically associated with ART adherence.

Conclusion

Eswatini ALHIV have a low ART adherence compared to general population. Shiselweni region is negatively associated with ART adherence among ALHIV while a suppressed baseline VL is positively associated with improved ART adherence. There is therefore a need to intensify interventions aimed at early ART initiation and intensive follow-up and support among ALHIV especially in the Shiselweni region.
A new cell culture resource for investigations of reptilian gene function
Authors: Samudra Sukhada P. , Park Sungdae , Esser Elizabeth A. , McDonald Tryggvi P. , Borges Arianna M. , Eggenschwiler Jonathan , Menke Douglas B.
Published: September 2023

The recent establishment of CRISPR/Cas9 gene editing inA. sagreilizards makes it a powerful model system for studies of reptilian gene function. To enhance the versatility of this model, we developed an immortalized lizard fibroblast cell line (ASEC-1) for the exploration of reptilian gene function in cellular processes. We demonstrate the use of thisin vitrosystem by scrutinizing the role of primary cilia in lizard Hedgehog (Hh) signaling. Through CRISPR/Cas9 mutagenesis we disrupted theift88gene, which is required for ciliogenesis in diverse organisms. We find that the loss ofitf88from lizard cells results in an absence of primary cilia, a partial derepression ofgli1transcription, and an inability of the cells to respond to the Smoothened agonist, SAG. Through a cross-species analysis of SAG-induced transcriptional responses in cultured limb bud cells, we further determined that ∼46% of genes induced as a response to Hh pathway activation inA. sagrei,are also SAG-responsive inM. musculuslimb bud cells. Our results highlight conserved and diverged aspects of Hh signaling in anoles and establish a new resource for investigations of reptilian gene function.
Using a function-first ‘scout fragment’-based approach to develop allosteric covalent inhibitors of conformationally dynamic helicase mechanoenzymes
Authors: Ramsey Jared R. , Shelton Patrick M.M , Heiss Tyler K. , Olinares Paul Dominic B. , Vostal Lauren E. , Soileau Heather , Grasso Michael , Warrington Sara , Adaniya Stephanie , Miller Michael , Sun Shan , Huggins David J. , Myers Robert W. , Chait Brian T. , Vinogradova Ekaterina V. , Kapoor Tarun M.
Published: September 2023

Helicases, classified into six superfamilies, are mechanoenzymes that utilize energy derived from ATP hydrolysis to remodel DNA and RNA substrates. These enzymes have key roles in diverse cellular processes, such as genome replication and maintenance, ribosome assembly and translation. Helicases with essential functions only in certain cancer cells have been identified and helicases expressed by certain viruses are required for their pathogenicity. As a result, helicases are important targets for chemical probes and therapeutics. However, it has been very challenging to develop selective chemical inhibitors for helicases, enzymes with highly dynamic conformations. We envisioned that electrophilic ‘scout fragments’, which have been used for chemical proteomic based profiling, could be leveraged to develop covalent inhibitors of helicases. We adopted a function-first approach, combining enzymatic assays with enantiomeric probe pairs and mass spectrometry, to develop a covalent inhibitor that selectively targets an allosteric site in SARS-CoV-2 nsp13, a superfamily-1 helicase. Further, we demonstrate that scout fragments inhibit the activity of two human superfamily-2 helicases, BLM and WRN, involved in genome maintenance. Together, our findings suggest a covalent inhibitor discovery approach to target helicases and potentially other conformationally dynamic mechanoenzymes.
AccessPD - a ‘next generation’ registry to accelerate Parkinson’s disease research
Authors: Chang Yun-Hsuan , Periñan Maria Teresa , Wilson Matt , Noyce Alastair J
Published: September 2023

Objective

To create a registry of patients with Parkinson’s disease (PD) and a rich database of PD-relevant information that can be used to stratify participants for precision opportunities.

Background

Recruitment to studies and trials is a major rate-limiting factor in PD research. Participants from lower socioeconomic backgrounds or geographically remote areas often have restricted access to clinical research opportunities. AccessPD is a novel platform that aims to accelerate progress of PD research.

Design/Methods

Potential participants are identified using electronic health records (EHRs) held by their primary care providers. They are contacted via a text message with an individualized link to the study portal. Electronic patient-reported outcomes (ePRO) are collected via regular online questionnaires and integrated with existing EHR.

Results

200 participants were recruited within the first 6 months, with an average age of 70.8 years at the time of enrollment. When re-engaged, 191 participants answered the follow-up questionnaire. Here, to showcase the potential of AccessPD, we described the most common diagnoses before and after the diagnosis of PD, the most commonly prescribed drugs, and we used a case study to demonstrate how precision opportunities for research can be created by identifying participants who could benefit from device-aided therapies using consensus criteria.

Conclusions

AccessPD will enroll a minimum of 2000 patients. Early-stage analysis using ePROs and EHR data demonstrated AccessPD’s unique ability to link different data sources that could be used to stratify patients for longitudinal observational studies or recruit patients into clinical trials most suited to them.
Discovery of Urinary Metabolite Biomarkers of Psychiatric Disorders Using Two-Sample Mendelian Randomization
Authors: Zaki Jihan K. , Tomasik Jakub , McCune Jade , Scherman Oren A. , Bahn Sabine
Published: September 2023

Background

Psychiatric disorders cause substantial patient suffering world-wide, which could be alleviated through the discovery of early diagnostic biomarkers. Urinary markers have promising practical applications; however, no robust urine biomarkers exist currently for psychiatric disorders. While the traditional biomarker discovery process is costly and time-consuming, genetic methods utilizing existing data from large-scale studies, such as Mendelian randomization, may provide an alternative, cost-effective approach to identifying such biomarkers.

Methods

A two-sample Mendelian randomization analysis was conducted in R using GWAS data for seven psychiatric disorders from the Psychiatrics Genomics Consortium, as well as a meta-analysis of urinary metabolite GWAS studies and the GWAS Catalog. Mendelian randomization assumptions were assessed using the MR-Egger intercept, P-values, and genetic associations from the PhenoScanner database.

Outcomes

The Mendelian randomization analysis revealed 67 analyte-disorder associations, of which 21 were exclusive to a single disorder. Most notable associations were observed between tyrosine and schizophrenia (β=−0.041, SE=0.013, Q=0.027), and creatine and bipolar disorder (β=−0.077, SE=0.019, Q=0.002), which validated across multiple studies, as well as that of pyridoxal (β=0.10, SE=0.03, Q=0.042) and ferulic acid 4-sulfate (β=0.077, SE=0.025, Q=0.037) to anorexia nervosa, and N,N-dimethylglycine to attention deficit hyperactivity disorder (β=−0.39, SE=0.11, Q=0.008).

Interpretation

These results indicate an association between bipolar disorder, schizophrenia, anorexia nervosa, and attention deficit hyperactivity disorder with urinary metabolite marker alterations. Most of the findings were supported by previous literature. The results provide a roadmap for future experimental and clinical validation of the identified biomarker candidates and demonstrate the utility of using genetic instruments for urinary biomarker discovery.
A novel ultrasensitive assay for plasma p-tau217: performance in individuals with subjective cognitive decline and early Alzheimer’s disease
Authors: Gonzalez-Ortiz Fernando , Ferreira Pamela C L , Gonzalez Armand , Montoliu-Gaya Laia , Ortiz-Romero Paula , Kac Przemyslaw R. , Turton Michael , Kvartsberg Hlin , Ashton Nicholas J. , Zetterberg Henrik , Harrison Peter , Bellaver Bruna , Povala Guilherme , Villemagne Victor L. , Pascoal Tharick A. , Ganguli Mary , Cohen Anne D. , Miguillon Carolina , Contador Jose , Suarez-Calvet Marc , Karikari Thomas K. , Blennow Kaj
Published: September 2023

INTRODUCTION

Detection of Alzheimer’s disease (AD) pathophysiology among cognitively unimpaired individuals and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma p-tau217 is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.

METHODS

We employed a novel p-tau217 immunoassay (UGOT p-tau217) in four independent cohorts (n=308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (β-AARC).

RESULTS

UGOT p-tau217 showed high accuracy (AUC= 0.80-0.91) identifying Aβ pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC= 0.91).

DISCUSSION

UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
A Retrospective Case Study of Successful Translational Research: Cardiovascular Disease Risk Assessment, Experiences in Community Engagement
Authors: Bales Michael E. , Zhu Jifeng , Ganzer Christine A. , Aboharb Farid , Keeler Allegra , Ryon Krista A. , Ehrmann Brett J. , Imperato-McGinley Julianne ,   the H2H Consortium
Published: September 2023

In underserved communities in New York City, uninsured adults encounter a greater risk of cardiovascular disease and diabetes. The Heart-to-Heart Community Outreach Program (H2H) is addressing these disparities by providing screenings for diabetes and other cardiovascular disease risk factors, fostering community engagement in translational research at our CTSC. Screening events are hosted in partnership with community faith-based institutions. Participants provide medical history, complete a survey, and receive individualized counseling by clinicians with referrals for follow-up care. The population served is disproportionately non-white, uninsured, with low-income, and underserved. The program empowers participants to make beneficial lifestyle changes using myriad strategies to reach those most in need. This required strong foundational program leadership, effective inter-institutional collaboration, and maintaining of community trust. Leveraging partnerships with faith-based institutions and community centers in at-risk NYC neighborhoods, H2H addresses the increasing burden of diabetes and cardiovascular disease risk factors in vulnerable individuals and provides a model for similar initiatives.
Autostent: A Semi-Automated Approach to Designing Customized 3D-Printed Oral Radiation Stents for Patients with Head and Neck Cancer
Authors: Agrawal Anshuman , Zaid Mohamed M. , Roach Millicent A. , Xiao Lianchun , Chambers Mark S. , Koay Eugene J.
Published: September 2023

Oral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Although customized 3D-printed oral stents are more quickly fabricated and non-inferior (in terms of patient reported outcomes) compared to conventionally-fabricated stents, the design process is still relatively time-consuming, unstandardized, and requires experienced technicians. We hypothesized that semi-automating the 3D-printed stent design process can reduce design time and standardize the workflow. Using oral stent design principles established over decades by oral oncologists, we developed a customized computer program (Autostent) using MATLAB to semi-automate the design process. We then compared a previously described method utilizing non-automated computer-aided design with Autostent. Three users designed stents for four patients with HNC enrolled on a prospective observational study. These patients were selected based on differing dental anatomies, and each user designed stents for each patient thrice, using both the non- and semi-automated methods. The design time and stent volumes for the two methods were statistically analyzed. Semi-automation was found to significantly reduce the average design time by 23.6 minutes (51.2%, p=0.001), independent of user, dental anatomy, and trial number. Additionally, semi-automation reduced the average stent volume by 4.33 mL (12.9%, p=0.016, univariate analysis). While this was not statistically significant after accounting for the other experimental variables (p=0.40, multivariate analysis), semi-automation did reduce the variability in the stent volume across users (overall standard error of the mean reduced by 40%). Thus, the semi-automated workflow significantly reduced the design time and the variability in the stent volume across users compared to the non-automated workflow. This may lead to potential cost benefits, standardization of the device, and increased population-wide access to a device that could help reduce toxicities for HNC.
Quinoclamine inhibits Shiga toxin production in enterohemorrhagicEscherichia coli
Authors: Kar Oiti , Feng Hsiao-Cheng , Hirano Hiroyuki , Teng Ching-Hao , Osada Hiroyuki , Hashimoto Masayuki
Published: September 2023

Objectives

EnterohemorrhagicEscherichia coli(EHEC) is responsible for the most severe symptoms ofE. coliinfections, including hemorrhagic colitis and hemorrhagic uremic syndrome. Shiga toxin 2 (Stx2) plays a significant role as a major virulence factor. The genes encoding Stx2 locate in lambda-like prophage on the EHEC genome. Consequently, Stx2 is expressed when production of the phage is induced by the SOS response. Antibiotic treatment is not recommended for curing the bacterial infection, because it is associated with severe hemorrhagic uremic syndrome. If Stx2 production is prevented, EHEC pathogenicity significantly decreases, and antibiotics may be available to treat the infection.

Methods

We conducted two independent screenings to identify Stx2 production inhibitors for libraries from the RIKEN Natural Product Depository (NPDepo); namely, screening of the Authentic Library, and two-round screening of the Pilot and Analog Libraries.

Results

The screening of Authentic Library identified niclosamide as a Stx2 production inhibitor. Besides, two naphthoquinoids were identified after the two-round of screening of the Pilot and Analog Libraries. Niclosamide, and quinoclamine, which has structure shared in the two naphthoquinoids, prevented cell lysis via the phage production and ceased Stx2 production in EHEC. The SOS reporter assay indicated that quinoclamine prevented the SOS response inE. coli, whereas niclosamide did not.

Conclusions

These findings suggest that quinoclamine inhibited Stx2 production by preventing the SOS response, whereas niclosamide was involved in phage propagation following the SOS response. These compounds can be a potential therapeutic option to treat EHEC infections.
Characterising the Protein-Protein Interaction Between MDM2 and 14-3-3σ; Proof of Concept for Small Molecule Stabilisation
Authors: Ward Jake A. , Romartinez-Alonso Beatriz , Kay Danielle F. , Bellamy-Carter Jeddidiah , Thurairajah Bethany , Basran Jaswir , Kwon Hanna , Leney Aneika C. , Macip Salvador , Roversi Pietro , Muskett Frederick W. , Doveston Richard G.
Published: September 2023

Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumour suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of wild type p53. The 14-3-3 family of adaptor proteins are known to bind to MDM2 and the 14-3-3σ isoform controls MDM2 cellular localisation and stability to inhibit its activity. Therefore, small molecule stabilisation of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. In this work we provide a detailed biophysical and structural characterisation of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. Each of the two phosphorylated stretches of MDM2 occupies one of the two binding grooves of a 14-3-3σ dimer, a novel model for binding of di-phosphorylated peptides to 14-3-3 proteins. In addition, we show that the 14-3-3σ/MDM2 interaction is amenable to small molecule stabilisation. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in stablisation of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilisers.
Prolonged delays in human microbiota transmission after a controlled antibiotic perturbation
Authors: Xue Katherine S. , Walton Sophie Jean , Goldman Doran A. , Morrison Maike L. , Verster Adrian J. , Parrott Autumn B. , Yu Feiqiao Brian , Neff Norma F. , Rosenberg Noah A. , Ross Benjamin D. , Petrov Dmitri A. , Huang Kerwyn Casey , Good Benjamin H. , Relman David A.
Published: September 2023

Humans constantly encounter new microbes, but few become long-term residents of the adult gut microbiome. Classical theories predict that colonization is determined by the availability of open niches, but it remains unclear whether other ecological barriers limit commensal colonization in natural settings. To disentangle these effects, we used a controlled perturbation with the antibiotic ciprofloxacin to investigate the dynamics of gut microbiome transmission in 22 households of healthy, cohabiting adults. Colonization was rare in three-quarters of antibiotic-taking subjects, whose resident strains rapidly recovered in the week after antibiotics ended. In contrast, the remaining antibiotic-taking subjects exhibited lasting responses, with extensive species losses and transient expansions of potential opportunistic pathogens. These subjects experienced elevated rates of commensal colonization, but only after long delays: many new colonizers underwent sudden, correlated expansions months after the antibiotic perturbation. Furthermore, strains that had previously transmitted between cohabiting partners rarely recolonized after antibiotic disruptions, showing that colonization displays substantial historical contingency. This work demonstrates that there remain substantial ecological barriers to colonization even after major microbiome disruptions, suggesting that dispersal interactions and priority effects limit the pace of community change.
Nanoconnectivity: a quantitative approach to examine the structural complexity of the brain
Authors: Turégano-Lopez Marta , de las Pozas Félix , Santuy Andrea , Rodríguez José-Rodrigo , DeFelipe Javier , Merchán-Pérez Angel
Published: September 2023

Unraveling the highly complex connectivity at the synaptic level is critical for the understanding of brain function. However, investigating the structure of the brain is time consuming and technically demanding. We have developed and applied a tracing method that allows us to obtain a simplified or skeletonized version of all nerve fibers present within a given brain sample, without the need for full 3D reconstructions. Every tracing or “skeleton” is linked to its corresponding synaptic contacts, so the result is an intricate meshwork of axons and dendrites interconnected by a cloud of synaptic junctions. The tissue sample is obtained by volume electron microscopy (FIB-SEM) and tracing is performed by dedicated software. In addition, the software provides the length of each skeleton as well as the number and positions of its corresponding synapses. With this approach, we have identified clear as well as subtle quantitative differences between three brain regions (the stratum radiatum of the hippocampus and layers 1 and 3 of the somatosensory cortex). For example, we have found that axons and dendrites are densely packed in the neuropil of these three regions, reaching close to 8 kilometers of nerve fibers per cubic mm in layer 1. In all cases, the predominant fibers were excitatory axons, followed by spiny dendrites, inhibitory axons and smooth dendrites. Other examples include the fact that the excitatory axons in the stratum radiatum establish many more synapses per micron than the axons of the other regions, or the lack of correlation between the number of synapses established on the spines of a given dendrite and the number of synapses established on the dendritic shaft. Using this methodology, we obtain a set of quantitative parameters including the number and proportions of excitatory and inhibitory synapses; the numbers of dendrites and axons; the proportion of excitatory and inhibitory axons; the linear densities of synapses established on dendritic spines and dendritic shafts; the linear densities of synapses established by excitatory and inhibitory axons; and the lengths of the different types of dendrites and axons. Taken together, these data characterize each region, allowing us to compare them on a quantitative basis and to identify subtle traits and differences that would have escaped a qualitative analysis. With this strategy, we can achieve a better understanding of the structure and dynamics of the brain, and we are better equipped to explore how they change during both normal and pathological conditions.
Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
Authors: López-Ayllón Blanca D. , Marín Silvia , Fernández Marco Fariñas , García-García Tránsito , Fernández-Rodríguez Raúl , Lucas-Rius Ana de , Redondo Natalia , Mendoza-García Laura , Foguet Carles , Grigas Juozas , Calvet Alba , Villalba José Manuel , Rodríguez Gómez María Josefa , Megías Diego , Mandracchia Biagio , Luque Daniel , Lozano Juan José , Calvo Cristina , Thomson Timothy M. , Garrido Juan J. , Cascante Marta , Montoya María
Published: September 2023

Antiviral signaling, immune response and cell metabolism in human body are dysregulated by SARS-CoV-2, the causative agent of the COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While all four ORFs caused mitochondrial fragmentation and altered mitochondrial function, only ORF3a and ORF9c induced a marked structural alteration in mitochondrial cristae. ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes. In contrast, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes for proteins with critical mitochondrial functions and morphology. Genome-Scale Metabolic Models predicted common and private metabolic flux reprogramming, notably a depressed amino acid metabolism, and an enhanced metabolism of specific lipids distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

One-Sentence Summary

Mitochondria and metabolic alterations induced by SARS- CoV-2 accessory proteins ORF3a, ORF9b, ORF9c, ORF10 in pulmonary cells unravel new targets of intervention.
Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition
Authors: Vollger Mitchell R. , Korlach Jonas , Eldred Kiara C. , Swanson Elliott , Underwood Jason G. , Cheng Yong-Han H. , Ranchalis Jane , Mao Yizi , Blue Elizabeth E. , Schwarze Ulrike , Munson Katherine M. , Saunders Christopher T. , Wenger Aaron M. , Allworth Aimee , Chanprasert Sirisak , Duerden Brittney L. , Glass Ian , Horike-Pyne Martha , Kim Michelle , Leppig Kathleen A. , McLaughlin Ian J. , Ogawa Jessica , Rosenthal Elisabeth A. , Sheppeard Sam , Sherman Stephanie M. , Strohbehn Samuel , Yuen Amy L. ,   University of Washington Center for Mendelian Genomics (UW-CMG),   Undiagnosed Diseases Network (UDN), Reh Thomas A. , Byers Peter H. , Bamshad Michael J. , Hisama Fuki M. , Jarvik Gail P. , Sancak Yasemin , Dipple Katrina M. , Stergachis Andrew B.
Published: September 2023

Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploidde novogenome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA,PDK3,MAB21L1, andRB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four ‘omes’ to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.