bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between trough levels of infliximab and postoperative endoscopic recurrence in Crohn’s disease patients submitted to ileocolonic resections
Authors: Baraúna Fernanda S.B. , Magro Daniela O. , Miranda Eron F. , Marçal Gustavo N. , Nones Rodrigo B. , Kotze Paulo G.
Published: October 2023

Objectives

The aim of this study was to evaluate serum levels of Infliximab (IFX) in patients with Crohn’s disease (CD) who underwent an ileocolonic resection and to correlate them with the presence or absence of endoscopic disease recurrence.

Methods

An observational and cross-sectional study was carried out in patients from 2 treatment centers in Curitiba-PR, with CD, who underwent ileocaecal resection and used IFX after surgery. Drug serum levels were measured, and colonoscopy was performed 30 days before or after collection. Patients were then divided into two groups: with or without endoscopic recurrence (defined as a Rutgeerts score greater than or equal to 2), and mean serum IFX levels were identified and compared. The primary objective was the correlation between recurrence and the median levels of IFX, performed comparatively between groups.

Results

Of the 21 patients included in the study, 14 had no endoscopic recurrence and 7 had it. There was no difference between groups in terms of baseline patient characteristics, mono or combo therapy treatment, serum albumin, and the time elapsed between collection of serum levels and diagnosis, surgery, and beginning of therapy. Patients with endoscopic recurrence used more biologics previously (P = 0.027). There was no difference between the median values of serum IFX levels between the groups: (4.71 [0.03–14.4]) in patients without recurrence versus (2.18 [0.88–14]) in those with recurrence (P = 0.601).

Conclusion

Low serum IFX levels were not correlated with postoperative endoscopic recurrence. Studies with a larger number of patients are needed to better test the proposed hypothesis.
Prevalence and genotypic diversity of Human papillomavirus infection among male and female sex workers in Thailand
Authors: Supindham Taweewat , Tangmunkongvorakul Arunrat , Aurpibul Linda , Sripan Patumrat , Utaipat Utaiwan , Hongjaisee Sayamon , Srithanaviboonchai Kriengkrai
Published: October 2023

Background

Human papillomavirus (HPV) is associated with cancer. Female sex workers (FSW) are known to be at risk for HPV, but little is known about male sex workers (MSW).

Methods

We examined HPV prevalence and associated risk factors in both populations. During 2022, HPV testing using vaginal or penile samples, HIV testing, and interviews were performed among 100 MSW and 100 FSW in Chiang Mai, Thailand.

Results

The prevalence of all HPV types was 63.5% (66% in MSW, 61% in FSW), HPV16 prevalence was 14%, HPV52 was 13%, and HPV18 was 4%. There was no difference between MSW and FSW for these subtypes. The prevalence of HPV16 or HPV18 was 17%, and for HPV16, HPV18, or HPV52 it was 26%. HIV-positive participants had higher prevalence of all HPV types (94% vs. 60%, p = 0.004), HPV16 or 18 (39% vs. 15%, p = 0.018), and HPV16, 18, or 52 (50% vs. 23%, p = 0.017).

Conclusion

We demonstrated an equally high HPV prevalence across the sexes. Further studies are needed to determine if this indicates an equal risk for cancer. Increased HPV awareness, screening, and vaccination should be considered, regardless of gender.
Optimal strategies for assessing and managing pain, agitation, and delirium in the critically ill surgical patient: What you need to know
Authors: Evans Susan L. , Olney William J. , Bernard Andrew C. , Gesin Gail
Published: October 2023

Pain, agitation, and delirium (PAD) are primary drivers of outcome in the ICU, and expertise in managing these entities successfully is crucial to the intensivist's toolbox. In addition, there are unique aspects of surgical patients that impact assessment and management of PAD. In this review, we address the continuous spectrum of assessment, and management of critically ill surgical patients, with a focus on limiting PAD, particularly incorporating mobility as an anchor to ICU liberation. Finally, we touch on the impact of PAD in specific populations, including opioid use disorder, traumatic brain injury, pregnancy, obesity, alcohol withdrawal, and geriatric patients. The goal of the review is to provide rapid access to information regarding PAD and tools to assess and manage these important elements of critical care of surgical patients.
Poor Visual Outcome After First Attack in a Cohort of Patients With Myelin Oligodendrocyte Glycoprotein-Related Optic Neuritis
Authors: Handzic Armin , Naidu Sumana , Brossard-Barbosa Natalie , Margolin Edward
Published: October 2023

Background:

Myelin oligodendrocyte glycoprotein-associated optic neuritis (MOG-ON) is typically a highly treatable condition that responds quickly to treatment with high doses of corticosteroids. We reviewed the cohort of patients with MOG-ON to identify patients who had poor visual outcome after the first attack despite rapid initiation of treatment.

Methods:

Records of all patients diagnosed with MOG-ON seen in a tertiary neuro-ophthalmology practice were reviewed to identify and describe those with poor visual recovery (final visual acuity of 20/200 or worse in at least one eye) after the first attack despite initiation of treatment within 1 week of symptoms onset.

Results:

Two patients of 36 fulfilled inclusion criteria: both had bilateral severe optic neuritis at presentation, and both were seen within 7 days of symptoms onset and treated immediately with pulse doses of intravenous corticosteroids followed by very-slow oral taper. Plasma exchange (PLEX) was performed 2 weeks after symptoms onset in both patients because of poor response to steroids, followed by monthly intravenous immunoglobulin infusions. Despite the use of all available treatment modalities, final visual outcome was poor in both patients. In both patients, there was enhancement of intracanalicular portion of optic nerve in the worse-seeing eye.

Conclusions:

In this cohort of patients with MOG-ON, 2 (5.6%) had very poor visual outcome after the first attack despite immediate initiation of treatment with pulse doses of corticosteroids and subsequent treatment with PLEX. These cases highlight that despite immediate initiation and escalation of treatment, some patients with MOG-ON can have very poor visual outcomes after the initial attack that may be because of the involvement of the intracanalicular portion of the optic nerves.
Handwritten prescription practices in a public hospital in Uasin Gishu County, Kenya: a best practice implementation project
Authors: Amdany Henry , Kiprop Jedidah W.
Published: October 2023

Background:

Prescription writing error is a common phenomenon in the health sector. Appropriate handwritten prescription practices minimize medical errors during medical drug dispensing.

Objectives:

This project aimed to identify the extent to which clinicians adhere to handwritten drug prescription best practices and implement evidence-based strategies to improve compliance with handwritten prescription best practices in an outpatient department.

Methods:

The project was conceptually informed by the JBI Model of Evidence-Based Health care and the JBI Evidence Implementation Framework. Baseline and follow-up audit data were collected and analyzed using JBI's Practical Application of Clinical Evidence System (PACES) software. The JBI Getting Research into Practice (GRiP) program was used to identify potential barriers and design intervention strategies. The project was conducted in a public hospital outpatient department in Uasin Gishu County, Kenya.

Results:

There was a 100% improvement in compliance with the number of prescribers who had received education on essential features of a handwritten drug prescription. High compliance was observed in prescriptions that indicated the patient name (99%) and date of prescription (98%) in the follow-up audit. Approximately half of the prescriptions included a diagnosis of the disease in both the baseline and the follow-up audit. However, in the follow-up audit, only 21% of the prescriptions had legible handwriting and 27% prescribed drugs using the generic drug name.

Conclusion:

Regular audits and dissemination of audit findings through continuous medical education, hospital communication forums, and notices improved compliance with the number of prescriptions that contained the patient identifier and the date of prescription.
ICTV Virus Taxonomy Profile: Qinviridae 2023
Authors: Wolf Yuri I. , Koonin Eugene V. , Krupovic Mart , Kuhn Jens H.
Published: October 2023

Qinviridae is a family of negative-sense RNA viruses with genomes of 7.3–8.2 kb that have been associated with crustaceans, insects, gastropods, and nematodes. The qinvirid genome consists of two segments, each with at least one open reading frame (ORF). The large (L) segment ORF encodes a large protein containing an RNA-directed RNA polymerase (RdRP) domain. The small (S) segment ORF encodes a nucleocapsid protein. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Qinviridae, which is available at ictv.global/report/qinviridae.
Comparing the effectiveness of the NHS Health Check and the Polypill Prevention Programmes in the primary prevention of heart attacks and strokes
Authors: Wald Nicholas J. , Hingorani Aroon D. , Vale Stephen , Bestwick Jonathan P , Morris Joan
Published: October 2023

Objective

To compare the NHS Health Check Programme with the Polypill Prevention Programme in the primary prevention of heart attacks and strokes.

Design

Use of published data and methodology to produce flow charts of the two programmes to determine screening performance and heart attacks and strokes prevented.

Setting

The UK population.

Intervention

The NHS Health Check Programme using a QRisk score on people aged 40-74 to select those eligible for a statin is compared with the Polypill Prevention programme in people aged 50 or more to select people for a combination of a statin and 3 low dose blood pressure lowering agents. In both programmes people had no history of heart attack or stroke.

Main outcome measures

In 1000 people the number of heart attacks and strokes prevented in the two programmes.

Results

Assuming 100% uptake and adherence to the screening protocol, in every 1000 persons, the NHS Health Check Programme would prevent 287 cases of a heart attack or stroke in individuals who would gain on average about 4 years of life without a heart attack or stroke, the precise gain depending on the extent of treatment for those with raised blood pressure, and 136 would be prescribed statins with no benefit. The corresponding figures for the Polypill Prevention Programme are 316 individuals who would, on average, gain 8 years of life without a heart attack or stroke with 260 prescribed the polypill with no benefit. Based on published estimates of uptake and adherence to of the NHS Health Check programme, only 24 cases per 1000 are currently benefitting instead of 287. This result could be achieved in the Polypill Prevention Programme with just 8% (24/316) of the eligible population taking part.

Conclusions

The Polypill Prevention Programme is by design simpler with the potential of preventing many more heart attacks and strokes; even an uptake of 40% would represent a 5-fold greater preventive effect than the NHS Health Check Programme.
Generation of CRISPR-edited birch Plants without DNA integration using Agrobacterium-mediated Transformation Technology
Authors: Sun Shilin , Han Xue , Jin Ruoxuan , Jiao Junbo , Wang Jingwen , Niu Siyuan , Yang Ziyao , Wu Di , Wang Yucheng
Published: October 2023

CRISPR/Cas9 system has emerged as a powerful tool in genome editing; however, generation of CRISPR-edited DNA-free plants is still challenging. In this study,Betula platyphylla(birch) was used to build a method to generate CRISPR-edited plant without foreign DNA integration using Agrobacterium-mediated transformation (CPDAT method). This technique utilizes transient genetic transformation to introduce T-DNA coding gRNA and Cas9 into birch cells, and T-DNA will express to synthesize gRNA and Cas9 protein, which will form a complex to cleave the target DNA site. The genome may be mutated due to DNA repair, and these mutations will be preserved and accumulated not dependent on whether T-DNA is integrated into the genome or not. After transient transformation, birch plants were cut into explants to induce adventitious buds without antibiotic selection pressure. Each adventitious bud can be considered as an independent potentially CRISPR-edited line for mutation detection. CRISPR-edited birch plants without foreign DNA integration are further selected by screening CRISPR-edited lines without T-DNA integration. Among 65 randomly chosen independent lines, the mutation rate was 80.00% including 40.00% of lines with both alleles mutated. In addition, 5 lines out of 65 studied lines (7.69%) were CRISPR-edited birch plants without DNA integration. In conclusion, this innovative method presents a novel strategy for generating CRISPR-edited birch plants, thereby significantly enhancing the efficiency of generating common CRISPR-edited plants. These findings offer considerable potential to develop plant genome editing techniques further.
Factors associated with SARS-CoV-2 among persons living with HIV in Zambia: Analysis of three concurrent SARS-CoV-2 prevalence surveys conducted in July 2020 in six districts of Zambia
Authors: Chanda Stephen Longa , Sialubanje Cephas , Nawa Mukumbuta , Sinyange Nyambe , Malambo Warren , Zulu James , Banda Dabwitso , Zulu Paul , Hines Jonas
Published: October 2023

People living with HIV (PLHIV) are a unique population because of their altered immune systems and taking antiretroviral therapy (ART) that may modify risk of SARS-CoV-2. Evidence from sub-Saharan African countries suggests that, despite not having higher SARS-CoV-2 infection prevalence than HIV-negative persons, PLHIV suffer worse COVID-19 outcomes. We assessed the prevalence of SARS-COV-2 infection by HIV status in Zambia in July 2020.

We analyzed data from three different concurrent SARS-CoV-2 prevalence surveys (household, outpatient-department, and health-worker) conducted in six districts of Zambia in July 2020. Information on demographics and medical history was collected. Nasopharyngeal swabs were used to screen for SARS-CoV-2 RNA using polymerase-chain-reaction (PCR) and blood specimens were screened for SARS-CoV-2 virus-specific antibodies using an enzyme-linked-immunosorbent-assay (ELISA). Test-specific SARS-CoV-2 prevalence was calculated. Multilevel logistic regression models were used to measure test-specific adjusted odd ratios (aORs) of SARS-CoV-2 positivity by HIV status, controlling for demographic and medical history.

We analysed the outcomes of the two different tests separately. Among 7,092 participants, 4,717 (66.5%) consented to blood-draw and 4,642 (65.5%) consented to nasopharyngeal swab. Overall SARS-CoV-2 positivity was 9.4% by PCR and 3.8% by ELISA. SARS-CoV-2 prevalence detected by PCR was higher among PLHIV than HIV-negative respondents (12.4% vs 9.1%, respectively, OR: 1.4, 95% confidence intervals [CI]: 1.0-1.9) and lower by ELISA (1.9% vs 3.9%, respectively, OR: 0.5, 95%CI: 0.2-0.9). Among PLHIV, not being on ART was an independent predictor of SARS-CoV-2 PCR positivity (aOR: 5.24,95% CI: 1.19-22.22) but did not have a significant effect on ELISA results.

During the first COVID-19 wave in Zambia, PLHIV were more likely to be acutely infected with SARS-CoV-2 but less likely to be seropositive than participants without HIV. Intervention programs could focus on early access to COVID-19 vaccinations, testing and ART might reduce COVID-19 morbidity among PLHIV.
Fin elaboration via anterior-posterior regulation by Hedgehog signaling in teleosts
Authors: Tanaka Yoshitaka , Okayama Shun , Ansai Satoshi , Abe Gembu , Tamura Koji
Published: October 2023

Fins in fishes are appendages that serve to facilitate maneuvering in water. Compared to their ancestral state, teleosts have reduced radial bones in their paired fin skeletons and have acquired elaborated, agile paired fins. We found that mutation ofHedgehog interacting protein(Hhip), encoding an antagonist of Hedgehog signaling, leads to an increase of radial bones in a localized region and replicates the ancestral state. Interestingly, the caudal fin, which has undergone a reduction of skeleton structure in teleosts, as well as the paired fins, exhibit a regional-specific branching of the 2nd hypural inhhip-/-mutant zebrafish. These results imply that Hedgehog signaling is repressed during fin development in teleosts compared to the ancestral state. Molecular genetic analyses show thatshhb, one of theSonic hedgehog(Shh) genes, encoding one of the Hedgehog ligands in teleosts, is expressed during subdivision of endochondral components in paired fin skeletal development, and that mutation ofshhbleads to hypoplasia of the paired fin skeletons. Therefore, we suggest that paired and caudal fins in fishes possess a specific region susceptible to Hedgehog signaling. The reduction of radial bones by repressive regulation of Hedgehog signaling may induce fin elaboration in teleosts.
p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Authors: Serra François , Nieto-Aliseda Andrea , Fanlo Lucía , Rovirosa Llorenç , Cabrera-Pasadas Mónica , Lazarenkov Aleksey , Urmeneta Blanca , Alcalde Álvaro , Nola Emanuele M. , Okorokov Andrei L. , Fraser Peter , Graupera Mariona , Castillo Sandra D. , Sardina Jose Luis , Valencia Alfonso , Javierre Biola M.
Published: October 2023

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, using a multi-omics integration framework, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains and DNA loops within minutes of its activation, which escort the p53 transcriptional program along time. Focused on p53-bound enhancers, we report a core transcriptional program of 340 genes directly regulated by p53 over distance, most of these not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Taken together, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help future designs of p53-based cancer therapies.
Harnessing Generative AI to Decode Enzyme Catalysis and Evolution for Enhanced Engineering
Authors: Xie Wen Jun , Warshel Arieh
Published: October 2023

Enzymes, as paramount protein catalysts, occupy a central role in fostering remarkable progress across numerous fields. However, the intricacy of sequence-function relationships continues to obscure our grasp of enzyme behaviors and curtails our capabilities in rational enzyme engineering. Generative artificial intelligence (AI), known for its proficiency in handling intricate data distributions, holds the potential to offer novel perspectives in enzyme research. By applying generative models, we could discern elusive patterns within the vast sequence space and uncover new functional enzyme sequences. This review highlights the recent advancements in employing generative AI for enzyme sequence analysis. We delve into the impact of generative AI in predicting mutation effects on enzyme fitness, activity, and stability, rationalizing the laboratory evolution ofde novoenzymes, decoding protein sequence semantics, and its applications in enzyme engineering. Notably, the prediction of enzyme activity and stability using natural enzyme sequences serves as a vital link, indicating how enzyme catalysis shapes enzyme evolution. Overall, we foresee that the integration of generative AI into enzyme studies will remarkably enhance our knowledge of enzymes and expedite the creation of superior biocatalysts.
GABRDpromotes the progression of breast cancer through CDK1-dependent cell cycle regulation
Authors: Shang Qingyao , Ren Fei , Feng Kexin , Yang Chenxuan , Zhao Shuangtao , Liu Jiaxiang , Kang Xiyu , Yue Jiaxian , Zhang Ruixuan , Meng Xiangzhi , Wang Xiang , Wang Xin
Published: October 2023

Purpose

Y-aminobutyric acid (GABA) is an important inhibitory amino acid neurotransmitter that exerts its biological function by binding to GABA receptors, which not only play an important role in neuromodulation, but also involved in regulating the development of tumors. Gamma-aminobutyric acid type A receptor subunit delta (GABRD) encodes the δ subunit of GABAAreceptor, its impact on breast cancer has not been clearly studied. This study is aiming to reveal the relationship betweenGABRDand breast cancer development.

Methods

We performed a tissue microarray to quantifyGABRDexpression levels in tumor tissue and paracarcinoma tissue. The regulation ofGABRDin the proliferation, migration, and apoptosis of breast cancer was examined by a loss-of-function study. A GeneChip microarray was used to probe GABRD for potential downstream molecules. The interaction between GABRD and CDK1 was verified by a set of functional tests and rescue experiments as well as coimmunoprecipitation.

Results

GABRDwas expressed at significantly higher levels in tumor tissues and was associated with advanced tumor progression. SilencingGABRDresulted in a significant decrease in proliferation and migration and an increase in apoptosis of breast cancer.GABRDregulated the cell cycle by directly interacting with CDK1, which was identified as an important downstream target.

Conclusion

GABRDis the breast cancer-related gene and highlights the importance of the GABRD–CDK1 axis in regulating breast cancer proliferation, which provides potential for the development of novel therapeutics.
Identifying Incarceration Status in the Electronic Health Record Using Natural Language Processing in Emergency Department Settings
Authors: Huang Thomas , Socrates Vimig , Gilson Aidan , Safranek Conrad , Chi Ling , Wang Emily A. , Puglisi Lisa B. , Brandt Cynthia , Taylor R. Andrew , Wang Karen
Published: October 2023

Background

Incarceration is a highly prevalent social determinant of health associated with high rates of morbidity and mortality and racialized health inequities. Despite this, incarceration status is largely invisible to health services research due to poor electronic health record capture within clinical settings. Our primary objective is to develop and assess natural language processing (NLP) techniques for identifying incarceration status from clinical notes to improve clinical sciences and delivery of care for millions of individuals impacted by incarceration.

Methods

We annotated 1,000 unstructured clinical notes randomly selected from the emergency department for incarceration history. Of these annotated notes, 80% were used to train the Longformer-based and RoBERTa NLP models. The remaining 20% served as the test set. Model performance was evaluated using accuracy, sensitivity, specificity, precision, F1 score and Shapley values.

Results

Of annotated notes, 55.9% contained evidence for incarceration history by manual annotation. ICD-10 code identification demonstrated accuracy of 46.1%, sensitivity of 4.8%, specificity of 99.1%, precision of 87.1%, and F1 score of 0.09. RoBERTa NLP demonstrated an accuracy of 77.0%, sensitivity of 78.6%, specificity of 73.3%, precision of 80.0%, and F1 score of 0.79. Longformer NLP demonstrated an accuracy of 91.5%, sensitivity of 94.6%, specificity of 87.5%, precision of 90.6%, and F1 score of 0.93.

Conclusion

The Longformer-based NLP model was effective in identifying patients’ exposure to incarceration and has potential to help address health disparities by enabling use of electronic health records to study quality of care for this patient population and identify potential areas for improvement.
Health Systems Reforms in Bangladesh: An Analysis of the Last Three Decades
Authors: Udechukwu Treasure , Fofana Thierno Oumar , Carnapete Louise , Haider Shams Shabab , Hanif Suhi , Clech Lucie , Ridde Valéry
Published: October 2023

Objective

We reviewed the evidence regarding the health sector reforms implemented in Bangladesh within the past 30 years to understand their impact on the health system and healthcare outcomes.

Method

We completed a scoping review of the most recent and relevant publications on health system reforms in Bangladesh from 1990 through 2023. Studies were included if they identified health sector reforms implemented in the last 30 years in Bangladesh, if they focused on health sector reforms impacting health system dimensions, if they were published between 1991 and 2023 in English or French and were full-text peer-reviewed articles, literature reviews, book chapters, grey literature, or reports.

Results

Twenty-four studies met the inclusion criteria. The primary health sector reform shifted from a project-based approach to financing the health sector to a sector-wide approach. Studies found that implementing reform initiatives such as expanding community clinics and a voucher scheme improved healthcare access, especially for rural districts. Despite government efforts, there is a significant shortage of formally qualified health professionals, especially nurses and technologists, low public financing, a relatively high percentage of out-of-pocket payments, and significant barriers to healthcare access.

Conclusion

Evidence suggests that health sector reforms implemented within the last 30 years had a limited impact on health systems. More emphasis should be placed on addressing critical issues such as human resources management and health financing, which may contribute to capacity building to cope with emerging threats, such as climate change.
The neurostructural consequences of glaucoma and their overlap with disorders exhibiting emotional dysregulations: a voxel-based meta-analysis and tripartite system model
Authors: Klugah-Brown Benjamin , Bore Mercy C. , Liu Xiqin , Gan Xianyang , Biswal Bharat B. , Kendrick Keith M. , Chang Dorita , Zhou Bo , Becker Benjamin
Published: October 2023

Glaucoma is a neurodegenerative disorder characterized by progressive optic nerve damage and the most common cause for irreversible blindness. Emotional dysregulations are common in glaucoma patients, with high rates of generalized anxiety and depression. Glaucoma leads to pathological changes in the visual pathways of the brain, yet accumulating evidence suggests that the brain changes may reach beyond the visual system. To robustly determine brain morphological alterations in glaucoma and determine a potential overlap with changes observed in anxiety and depression we performed a pre-registered comparative meta-analysis of case control studies examining brain structural integrity in patients with glaucoma, and further determined whether the identified regions are nodes of distinct overarching large-scale networks and overlap with meta-analytic brain structural maps of generalized anxiety disorder (GAD) and major depressive disorder (MDD). Glaucoma patients exhibited robust reductions in gray matter volume in regions contributing to visual processing (lingual gyrus, thalamus), but volumetric reductions extended beyond systems involved in visual processing and also affected the left putamen and insula. Behavioral and functional network level decoding demonstrated distinct large-scale networks and involvement in visual, motivational or affective domains, respectively. Reductions in the insular region involved in pain and affective processes overlapped with alterations previously observed in GAD. Our findings may suggest a tripartite brain model of glaucoma, with changes in visual processing regions such as the lingual gyrus as well as additional alterations in putamen and insular regions meta-analytically associated with motivational or emotional functions, respectively. Together the findings indicate broad neuroanatomical alterations in glaucoma that extend beyond the visual system and may gate further pathological developments.
Delay in Clearance of Labeled Protons Post-Acute Head Trauma Utilizing 3D ASL MRI (Arterial Spin Labeling) a Pilot Study
Authors: Joseph Charles R , Kang Jubin , Grohol Bryce N , Zivcevska Marija , Lenke Joshua , Rich Ethan Dean , Arrasmith Connor James , Dorman Ian Shepherd , Clark Bradley Waman , Love Kim , Ferry Ben , Rolfs Mark E
Published: October 2023

Background

The study aims were to correlate acute head injury cognitive changes with ASL-MRI reduced glymphatic clearance rate (GCRs) and determine GC improvement with recovery. Concussive-brain injury disrupts the blood brain barrier (BBB) and reduces cMTT (capillary mean transit time) and GCRs. Concussion is clinically diagnosed utilizing history and exam findings. ASL-MRI assesses brain perfusion ingress and outflow.

Methods

3D TGSE (turbo-gradient and spin echo) PASL (pulsed arterial spin labeling) 3T MRI with 7 long TI’s (time to inversion) assessed the GCRs (slope of the linear decay of signal vs. time) of labeled protons 2800-4000 ms post-labeling in bifrontal, bitemporal, and biparietal regions within 7 days of mild acute traumatic brain injury and after clinically cleared to return to usual activities. The Sport Concussion Assessment Tool Version 5 (SKAT5) and Brief Oculomotor/Vestibular Assessment (administered by sports physicians) evaluated injured student athletes’ cognitive function prior to ASL MRIs.

Results

Pilot study demonstrated significant GCRs improvement (95% [CI] -0.06 to -0.03 acute phase; to [CI] - recovery [CI] 0.0772 to -0.0497 ; P <0.001 in Frontal lobes; and Parietal lobes (95% [CI] -0.0584 to -0.0251 acute; [CI] -0.0727 to - 0.0392 recovery; P = 0.024) in 9 head injured athletes (8 female 1 male mean age 20). 6 age/activity matched normal controls (4 female 2 male mean age 22) were also compared.

Conclusion

Acute head trauma disrupts the BBB reducing GCR measured using this 3D ASL MRI technique. ASL MRI is a potential noninvasive biomarker of acute brain injury and subsequent recovery.

Key Message

Objective measure of post mild TBI recovery has remained elusive as conventional anatomic imaging techniques and biomarkers are not sensitive. This pilot study demonstrates the potential of leveraging alterations in brain perfusion in the late phase capturing both delayed capillary perfusion and retained free fluid clearance from the brain, both the result of blood brain barrier leak from the acute trauma. Our noninvasive ASL MRI technique identified both anatomic site-specific delay in clearance acutely as well as restoration of normal flow post recovery. This time and cost-efficient noninvasive technique may, with additional validation, provide a needed objective measure for identifying physiologic changes post-acute injury and upon clinical recovery.
Perceptual formant discrimination during speech movement planning
Authors: Wang Hantao , Ali Yusuf , Max Ludo
Published: October 2023

Evoked potential studies have shown that speech planning modulates auditory cortical responses. The phenomenon’s functional relevance is unknown. We tested whether, during this time window of cortical auditory modulation, there is an effect on speakers’ perceptual sensitivity for vowel formant discrimination. Participants made same/different judgments for pairs of stimuli consisting of a pre-recorded, self-produced vowel and a formant-shifted version of the same production. Stimuli were presented prior to a “go” signal for speaking, prior to passive listening, and during silent reading. The formant discrimination stimulus /uh/ was tested with a congruent productions list (words with /uh/) and an incongruent productions list (words without /uh/). Logistic curves were fitted to participants’ responses, and the just-noticeable difference (JND) served as a measure of discrimination sensitivity. We found a statistically significant effect of condition (worst discrimination before speaking) without congruency effect. Post-hoc pairwise comparisons revealed that JND was significantly greater before speaking than during silent reading. Thus, formant discrimination sensitivity was reduced during speech planning regardless of the congruence between discrimination stimulus and predicted acoustic consequences of the planned speech movements. This finding may inform ongoing efforts to determine the functional relevance of the previously reported modulation of auditory processing during speech planning.
A Subcortical Feeding Circuit Linking Interoception to Jaw movement
Authors: Kosse Christin , Ivanov Jessica , Knight Zachary , Pellegrino Kyle , Friedman Jeffrey
Published: October 2023

The brain processes an array of stimuli enabling the selection of an appropriate behavioural response but the neural pathways linking interoceptive inputs to outputs for feeding are poorly understood. Here we delineate a subcortical circuit in which brain-derived neurotrophic factor (BDNF) expressing neurons in the ventromedial hypothalamus (VMH) directly connect interoceptive inputs to motor centers controlling food consumption and jaw movements. VMHBDNFneuron inhibition increases food intake by gating motor sequences of feeding through projections to premotor areas of the jaw. When food is unavailable, VMHBDNFinhibition elicits consummatory behaviors directed at inanimate objects such as a wooden block and inhibition of mesencephalic trigeminal area (Me5) projections evokes rhythmic jaw movements. The activity of these neurons is decreased during food consumption and increases when food is in proximity but not consumed. Activity is also increased in obese animals and after leptin treatment. VMHBDNFneurons receive monosynaptic inputs from both agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus (Arc) and constitutive VMHBDNFactivation blocks the orexigenic effect of AgRP activation. These data delineate an Arc→VMHBDNF→Me5 circuit that senses the energy state of an animal and regulates consummatory behaviors in a state dependent manner.
A novel subgroup of light-driven sodium pumps with an additional Schiff base counterion
Authors: Podoliak E. , Lamm G. H. U. , Alekseev A. , Marin E. , Schellbach A. V. , Fedotov D. A. , Stetsenko A. , Maliar N. , Bourenkov G. , Balandin T. , Baeken C. , Astashkin R. , Schneider T. R. , Bateman A. , Wachtveitl J. , Schapiro I. , Busskamp V. , Guskov A. , Gordeliy V. , Kovalev K.
Published: October 2023

Light-driven sodium pumps (NaRs) are unique ion-transporting microbial rhodopsins. The major group of NaRs is characterized by an NDQ motif and has two aspartic acid residues in the central region essential for sodium transport. Here we identified a new subgroup of the NDQ rhodopsins bearing an additional glutamic acid residue in the close vicinity to the retinal Schiff base. We thoroughly characterized a member of this subgroup, namely the proteinErNaR fromErythrobacter sp. HL-111and showed that the additional glutamic acid results in almost complete loss of pH sensitivity for sodium-pumping activity, which is in contrast to previously studied NaRs.ErNaR is capable of transporting sodium efficiently even at acidic pH levels. X-ray crystallography and single particle cryo-electron microscopy reveal that the additional glutamic acid residue mediates the connection between the other two Schiff base counterions and strongly interacts with the aspartic acid of the characteristic NDQ motif. Hence, it reduces its pKa. Our findings shed light on a new subgroup of NaRs and might serve as a basis for their rational optimization for optogenetics.
Association between movement patterns, microbiome diversity, and potential pathogen presence in free-ranging feral pigeons foraging in dairy farms
Authors: Crafton Miranda , Cahani Shai , Lublin Avishai , Rauer Luise , Spiegel Orr
Published: October 2023

The feedback between host behavior and disease transmission is well acknowledged, but empirical studies demonstrating associations between individual’s pathogens or microbiota composition and their movement are rare. We investigated these associations in feral pigeons (Columba livia domestica), a synanthrope species known to host a plethora of zoonotic pathogens. We captured pigeons in three dairy farms along an urbanization gradient in central Israel. We combined GPS-tracking with Next Generation Sequencing to characterize pigeons’ movement and microbiota, respectively. We found that pigeons roosted primarily in human settlements, with frequent visits to dairy farms and other agricultural sites. Microbiota diversity and composition varied between sites and the individuals within them, and several pathogens relevant to poultry, cattle, and human-health were frequently detected. Pigeons in the urban site covered shorter distances and carried a greater diversity of bacteria compared to those in rural sites. Intriguingly, beyond these among-site differences, exploratory individuals (measured by the number of unique locations they visited) had more diverse microbiota. We conclude that pigeons can potentially serve as transmission vectors among wildlife, livestock, and humans . Further, the associations between host behavior and microbiota diversity emphasize the relevance of wildlife movement analyses for disease ecology and One Health.
A methoxylated flavone fromArtemisia afrakillsMycobacterium tuberculosis
Authors: Kellogg Joshua J. , Alonso Maria Natalia , Jordan R. Teal , Xiao Junpei , Cafiero Juan Hilario , Bush Trevor , Towler Melissa , Weathers Pamela , Shell Scarlet S.
Published: October 2023

Tuberculosis, caused by Mycobacteriumtuberculosis(Mtb), is a deadly and debilitating disease globally affecting millions annually. Emerging drug-resistant Mtb strains endanger the efficacy of the current combination therapies employed to treat tuberculosis; therefore, there is an urgent need to develop novel drugs to combat this disease.Artemisia afrais used traditionally in southern Africa to treat malaria and recently has shown anti tuberculosis activity. This genus synthesizes a prodigious number of phytochemicals, many of which have demonstrated human health effects. Transcriptomic analysis revealed thatA. afraexerts different effects on Mtb compared toA. annuaor the well-known antimalarial artemisinin, suggesting other phytochemicals present inA. afrawith unique modes of action. A biochemometric study ofA. afraresulted in the isolation of a methoxylated flavone (1), which displayed considerable activity against Mtb strain mc26230. Compound1had an MIC of 312.5 μg/mL and yielded no viable colonies after 6 days of treatment. In addition,1was effective in killing hypoxic Mtb cultures, with no viable cultures after 2 days of treatment. This suggested thatA. afrais a source of potentially powerful anti-Mtb phytochemicals with novel mechanisms of action.
Optimising Spectronaut search parameters to improve data quality with minimal proteome coverage reductions in DIA analyses of heterogeneous samples
Authors: Baker Christa P. , Bruderer Roland , Abbott James , Arthur J. Simon C. , Brenes Alejandro J.
Published: October 2023

Data independent acquisition has seen breakthroughs that enable comprehensive proteome profiling using short gradients. As the proteome coverage continues to increase, the quality of the data generated becomes much more relevant. Using Spectronaut, we show that the default search parameters can be easily optimised to minimise the occurrence of false positives across different samples. Using an immunological infection model system to demonstrate the impact of adjusting search settings we analysed mouse macrophages and compared their proteome to macrophages spiked withCandida albicans. This experimental system enabled the identification of ‘false positives’ sinceCandida albicanspeptides and proteins should not be present in the mouse only samples. We show that adjusting the search parameters reduced ‘false positive’ identifications by 89% at the peptide and protein level, thereby considerably increasing the quality of the data. We also show that these optimised parameters incur a moderate cost, only reducing the overall number of ‘true positive’ identifications across each biological replicate by <6.7% at both the peptide and protein level. We believe the value of our updated search parameters extends beyond a two-organism analysis and would be of great value to any DIA experiment analysing heterogenous populations of cell types or tissues.
Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma
Authors: Thomas Nicholas J. , Luck Cuyler , Shlimon Nicole , Ponce Rovingaile Kriska , Kosibaty Zeinab , Okimoto Ross A.
Published: October 2023

CIC-DUX4 is a rare and understudied transcription factor fusion oncoprotein. CIC-DUX4 co-opts native gene targets to drive a lethal form of human sarcoma. The molecular underpinnings that lead to oncogenic reprograming and CIC-DUX4 sarcomagenesis remain largely undefined. Through an integrative ChIP and RNA-Seq analysis using patient-derived CIC-DUX4 cells, we define CIC-DUX4 mediated chromatin states and function. We show that CIC-DUX4 primarily localizes to proximal and distal cis-regulatory elements where it associates with active histone marks. Our findings nominate key signaling pathways and molecular targets that enable CIC-DUX4 to mediate tumor cell survival. Collectively, our data demonstrate how the CIC-DUX4 fusion oncoprotein impacts chromatin state and transcriptional responses to drive an oncogenic program in undifferentiated sarcoma.

Significance

CIC-DUX4 sarcoma is a rare and lethal sarcoma that affects children, adolescent young adults, and adults. CIC-DUX4 sarcoma is associated with rapid metastatic dissemination and relative insensitivity to chemotherapy. There are no current standard-of-care therapies for CIC-DUX4 sarcoma leading to universally poor outcomes for patients. Through a deep mechanistic understanding of how the CIC-DUX4 fusion oncoprotein reprograms chromatin state and function, we aim to improve outcomes for CIC-DUX4 patients.
Importin-7-dependent nuclear localization of theFlaviviruscore protein is required for infectious virus production
Authors: Itoh Yumi , Tokunaga Makoto , Miyamoto Yoichi , Suzuki Tatsuya , Takada Akira , Ninomiya Akinori , Matsuda Mami , Yoneda Yoshihiro , Oka Masahiro , Suzuki Ryosuke , Matsuura Yoshiharu , Okamoto Toru
Published: October 2023

Flaviviridaeis a family of positive-stranded RNA viruses, including human pathogens such as Japanese encephalitis virus (JEV), dengue virus (DENV), zika virus (ZIKV), and West Nile virus (WNV). Nuclear localization of the viral core protein is conserved amongFlaviviridae, and this feature may be targeted for developing broad-ranging anti-flavivirus drugs. However, the mechanism of core protein translocation to the nucleus and the importance of nuclear localization in the viral life cycle remain unknown. We aimed to identify the molecular mechanism underlying core protein nuclear translocation. We identified importin-7 (IPO7), an importin-β family protein, as a nuclear carrier forFlaviviridaecore proteins. Nuclear import assays revealed that core protein was transported into the nucleus via IPO7, whereasIPO7deletion by CRISPR/Cas9 impaired their nuclear localization. To understand the importance of core protein nuclear localization, we evaluated the production of infectious virus or single-round-infectious-particles in wild-type or IPO7-deficient cells; both processes were significantly impaired in IPO7-deficient cells, whereas intracellular infectious virus levels were equivalent in wild-type and IPO7-deficient cells. These data suggested that IPO7-mediated nuclear localization of core proteins plays a role in the release of infectious virus particles of flaviviruses.
Mixed Methods Evaluation of the ‘Caring for Providers to Improve Patient Experience’ intervention
Authors: Afulani Patience A. , Getahun Monica , Okiring Jaffer , Ogolla Beryl A. , Oboke Edwina N. , Kinyua Joyceline , Oluoch Iscar , Odiase Osamuedeme , Ochiel Dan , Mendes Wendy Berry , Ongeri Linnet
Published: October 2023

Objective

To assess the impact of the “Caring for Providers to Improve Patient Experience (CPIPE)” intervention, which sought to improve person-centered maternal care (PCMC) by addressing two key drivers—provider stress and bias.

Methods

CPIPE was successfully piloted over 6-months in two health facilities in Migori County, Kenya in 2022. The evaluation employed a mixed-methods pretest-posttest-non-equivalent-control-group design. Data are from surveys with 80 providers (40 intervention; 40 control) at baseline and endline, and in-depth-interviews with 20 intervention providers. We conducted bivariate, multivariate, and difference-in-difference analysis of quantitative data and thematic analysis of qualitative data.

Results

In the intervention group, average knowledge scores increased from 7.8(SD=2.4) at baseline to 9.5(SD=1.8) at endline for stress(p=0.001), and from 8.9(SD=1.9) to 10.7(SD=1.7) for bias(p=0.001); perceived stress scores decreased from 20.9(SD=3.9) to 18.6(SD=5.3)(p=0.019), and burnout from 3.6(SD=1.0) to 3.0(SD=1.0)(p=0.001); with no significant change in the control group. Qualitative data indicated CPIPE had impact at multiple levels. At the individual level, it improved provider knowledge, skills, self-efficacy, attitudes, behaviors, and experiences. At the interpersonal level, it improved provider-provider and patient-provider relationships leading to a supportive work environment and improved PCMC. At the institutional level, it created a system of accountability for providing PCMC and nondiscriminatory care; and collective action and advocacy to address sources of stress.

Conclusion

CPIPE impacted multiple outcomes in the theory of change leading to improvements in both provider and patient experience, including for the most vulnerable patients. These findings will contribute to global efforts to prevent burnout and promote PCMC and equity.

Clinical trial registration

ClinicalTrials.gov Identifier:NCT05019131https://www.clinicaltrials.gov/study/NCT05019131?term=Afulani&checkSpell=false&rank=1
Remote Photoplethysmography (rPPG): A State-of-the-Art Review
Authors: Pirzada Pireh , Wilde Adriana , Doherty Gayle , Harris-Birtill David
Published: October 2023

Peripheral oxygen saturation (SpO2) and heart rate (HR) are critical physiological measures that clinicians need to observe to decide on an emergency intervention. These measures are typically determined using a contact-based pulse oximeter. This approach may pose difficulties in many cases, such as with young children, patients with burnt or sensitive skin, cognitive impairments, and those undergoing certain medical procedures or severe illnesses. Remote Photoplethysmography (rPPG) allows for unobtrusive sensing of these vital signs in a variety of settings for health monitoring systems. Several research studies have been conducted to use rPPG for this purpose; however, there is still not a commercially available, clinically validated system that overcomes the concerns highlighted in this paper. We present a state-of-the-art review of rPPG-related research conducted including related processes and techniques, such as regions of interest (ROI) selection, extracting the raw signal, pre-processing data, applying noise reduction algorithms, Fast Fourier transforms (FFT), filtering and extracting these vital signs. Further, we present a detailed, critical evaluation of available rPPG systems. Limitations and future directions have also been identified to aid rPPG researchers in further advancing this field.