bluuebunny/crossref_metadata_2025 huggingface dataset:
Dihydropyrimidinase enzyme deficiency and congenital isolated adrenocorticotrophin deficiency: dual genetic diagnosis in a Sri Lankan boy
Authors: Mohideen Shifaniya Banu , Fernando Pitipanage Mihika Samindi , Beetz Christian , Schroder Sabine , Pereira Catarina , Gunatilleke Senaka , Rathnayake Pyara , Jasinge Eresha
Published: August 2024

We report on a male patient who was investigated for frequent apneic episodes, feeding problems, hypotonia, and left-sided middle cerebral artery infarction in the magnetic resonance imaging at 2 weeks of age. Primary diagnosis of dihydropyrimidinase (DPYS) deficiency was suspected following the analysis of urine for organic acid; DPYS deficiency was strongly suggested by the presence of dihydrouracil, thymine, and uracil. Subsequent genetic evaluation by whole exome sequencing revealed 2 separate mutations, homozygous pathogenic variant c.1010T>C p.Leu337Pro of the DPYS gene, resulting in DPYS deficiency, and homozygous pathogenic variant c.535C>T p.Arg179* of TBX19 gene, which is associated with autosomal recessive congenital isolated adrenocorticotrophic hormone deficiency. Currently, the patient is 2 years old, and he has gross motor retardation and seizure disorder. We suggest that the clinical phenotype of the proband can be a result of mixed expression of both mutations.
Beyond the Rotational Deathline: Radio Emission from Ultra-long Period Magnetars
Authors: Cooper A J , Wadiasingh Z
Published: August 2024

Motivated by the recent detection of ultralong-period radio transients, we investigate new models of coherent radio emission via low-altitude electron–positron pair production in neutron stars (NSs) beyond rotationally powered curvature radiation deathlines. We find that plastic motion (akin to ‘continental drift’) and qualitatively similar thermoelectric action by temperature gradients in the crusts of slowly rotating, highly magnetized NSs could impart mild local magnetospheric twists. Regardless of which mechanism drives twists, we find that particle acceleration initiates pair cascades across charge-starved gaps above a mild critical twist. Cascades are initiated via resonant inverse-Compton scattered photons or curvature radiation, and may produce broad-band coherent radio emission. We compute the pair luminosity (maximum allowed radio luminosity) for these two channels, and derive deathlines and ‘active zones’ in $P-\dot{P}$ space from a variety of considerations. We find these twist-initiated pair cascades only occur for magnetar-like field strengths $B \gtrsim 10^{14}$ G and long periods: $P_{\rm RICS} \gtrsim 120 \,\, (T/10^{6.5} {\rm K})^{-5} \, {\rm s}$ and $P_{\rm curv} \gtrsim 150 \,\, ({\rm v_{\rm pl}}/10^{3} {\, \rm cm \, yr^{-1}})^{-7/6} \, {\rm s}$. Using a simplified geometric model, we find that plastic motion or thermoelectrically driven twists might naturally reproduce the observed luminosities, time-scales, and timing signatures. We further derive ‘active zones’ in which rotationally powered pair creation occurs via resonantly scattered photons, beyond standard curvature deathlines for pulsars. All cascades are generically accompanied by simultaneous (non-)thermal X-ray/UV counterparts which might be detectable with current instrumentation.
Relationship between microwave and metre ranges during an impulsive solar flare
Authors: Shamsutdinova J N , Kashapova L K , Zhang J , Reid H , Zhdanov D A
Published: August 2024

An analysis of solar flares with simple temporal structures can help us to understand the features and mechanisms of energy and particle propagation. A weak impulsive solar flare that occurred on 2021 June 3 provided such opportunity. For the purposes of the study, we used microwave observations with spatial resolution from the Siberian Radioheliograph (3–6 GHz) combined with various spectral radio and X-ray data. Flare topology analysis revealed a configuration consisting of a small loop or dome-like structure associated with a compact bright source, and a long high loop system associated with the diffuse source. This indicates a compact and relatively low-lying site of acceleration and initial energy release. The radio metre and the microwave emission demonstrated a peak-to-peak correlation in three of the four bursts. The delays obtained from comparing microwave and metre radio ranges are in good agreement with the delays from the metre dynamic spectrum analysis, but the different radio bursts had different delays. We found that the electron energies derived from metre dynamic spectrum analysis are lower than those shown by hard X-ray emissions. According to the results of theoretical simulations, this can be explained by the expansion of magnetic loops with altitude. The difference in drift velocities for various radio bursts can be the result of the different size of the loop where the electron beams are propagated. This can be a feature related to the configuration type of the studied flare.
Magnesium isotope ratios in Milky Way and dwarf galaxy stars
Authors: McKenzie M , Monty S , Yong D , Kobayashi C , Karakas A I , Nissen P E , Norris J E , Rains A , Mura-Guzmán A , Wang E X , Martell S
Published: August 2024

Under the assumption of hierarchical galaxy formation, dwarf galaxies are the closest existing analogues to the high-redshift protogalaxies that merged to form the Milky Way. These low-mass systems serve as unique laboratories for studying nucleosynthetic channels given that the chemical compositions of their stars play a pivotal role in constraining their chemical enrichment history. To date, stellar abundances in dwarf galaxies have focused almost exclusively on elemental abundance ratios. While important, elemental abundances omit critical information about the isotopic composition. Here, we compute the Mg isotopic ratios of six accreted dwarf galaxy stars (low $\alpha$) and seven Milky Way stars (high $\alpha$) using a set of high-resolution (65 000 < R < 160 000) and high signal-to-noise ratio ($\rm {S/N} \gt 250$) optical spectra. We show, for the first time, that at a given [Fe/H] stars born in a dwarf galaxy differ in their Mg isotopic ratios from stars born in the Milky Way. However, when comparing isotopic ratios at a given [Mg/H] rather than [Fe/H], a powerful diagnostic emerges that suggests nucleosynthesis processes are consistent across different stellar environments. This universality of Mg isotopic abundances provides additional dimensionality for chemical evolution models and helps to constrain massive star nucleosynthesis across cosmic time.
SegVir: Reconstruction of Complete Segmented RNA Viral Genomes from Metatranscriptomes
Authors: Tang Xubo , Shang Jiayu , Chen Guowei , Chan Kei Hang Katie , Shi Mang , Sun Yanni
Published: August 2024

Segmented RNA viruses are a complex group of RNA viruses with multisegment genomes. Reconstructing complete segmented viruses is crucial for advancing our understanding of viral diversity, evolution, and public health impact. Using metatranscriptomic data to identify known and novel segmented viruses has sped up the survey of segmented viruses in various ecosystems. However, the high genetic diversity and the difficulty in binning complete segmented genomes present significant challenges in segmented virus reconstruction. Current virus detection tools are primarily used to identify nonsegmented viral genomes. This study presents SegVir, a novel tool designed to identify segmented RNA viruses and reconstruct their complete genomes from complex metatranscriptomes. SegVir leverages both close and remote homology searches to accurately detect conserved and divergent viral segments. Additionally, we introduce a new method that can evaluate the genome completeness and conservation based on gene content. Our evaluations on simulated datasets demonstrate SegVir’s superior sensitivity and precision compared to existing tools. Moreover, in experiments using real data, we identified some virus segments missing in the NCBI database, underscoring SegVir’s potential to enhance viral metagenome analysis. The source code and supporting data of SegVir are available via https://github.com/HubertTang/SegVir.
Possible usefulness of fluorodeoxyglucose positron emission tomography in diagnosing polyarteritis nodosa: A case report and literature review
Authors: Yukishima Toshitaka , Ohmura Shin-ichiro , Yonezawa Haruka , Katayama Motoyuki , Otsuki Yoshiro , Miyamoto Toshiaki , Ogawa Noriyoshi
Published: August 2024

Polyarteritis nodosa (PAN) is a systemic rheumatic disease that affects medium-sized arteries. PAN is typically not associated with anti-neutrophil cytoplasmic antibodies and has no serological surrogate markers. Therefore, its diagnosis requires pathological findings. However, the positive rate of biopsy in diagnosing PAN is not high, and the biopsy area is often limited. Several investigators have reported the usefulness of imaging findings in diagnosing PAN, independent of pathological findings. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET)/CT has recently been approved for the diagnosis of large-vessel vasculitis in Japan. Several studies have also demonstrated the usefulness of FDG-PET/CT in diagnosing medium-vessel vasculitis. However, no studies have evaluated the usefulness of FDG-PET/CT for diagnosing PAN compared to other modalities, and it is not clear whether FDG-PET/CT is superior to other modalities for diagnosing PAN. Herein, we report a case of PAN and compare the usefulness of FDG-PET/CT with other modalities in diagnosing PAN.
DNA damage-induced phosphorylation of a replicative DNA helicase results in inhibition of DNA replication through attenuation of helicase function
Authors: Homiski Caleb , Dey-Rao Rama , Shen Shichen , Qu Jun , Melendy Thomas
Published: August 2024

A major function of the DNA damage responses (DDRs) that act during the replicative phase of the cell cycle is to inhibit initiation and elongation of DNA replication. It has been shown that DNA replication of the polyomavirus, SV40, is inhibited and its replication fork is slowed by cellular DDR responses. The inhibition of SV40 DNA replication is associated with enhanced DDR kinase phosphorylation of SV40 Large T-antigen (LT), the viral DNA helicase. Mass spectroscopy was used to identify a novel highly conserved DDR kinase site, T518, on LT. In cell-based assays expression of a phosphomimetic form of LT at T518 (T518D) resulted in dramatically decreased levels of SV40 DNA replication, but LT-dependent transcriptional activation was unaffected. Purified WT and LT T518D were analyzed in vitro. In concordance with the cell-based data, reactions using SV40 LT-T518D, but not T518A, showed dramatic inhibition of SV40 DNA replication. A myriad of LT protein-protein interactions and LT’s biochemical functions were unaffected by the LT T518D mutation; however, LT’s DNA helicase activity was dramatically decreased on long, but not very short, DNA templates. These results suggest that DDR phosphorylation at T518 inhibits SV40 DNA replication by suppressing LT helicase activity.
Clinical Features and Outcomes of Pediatric and Adult Patients Hospitalized for Coronavirus Disease 2019: A Comparison Across Age Strata
Authors: Li Grace X , Gopchandani Komal , Brazer Noah , Tippett Ashley , Choi Chris , Hsiao Hui-Mien , Oseguera Miriam , Foresythe Abiodun , Bhattacharya Sanchita , Servellita Venice , Sotomayor Gonzalez Alicia , Spinler Jennifer K , Gonzalez Mark D , Gulick Dalia , Kraft Colleen , Kasinathan Vyjayanti , Wang Yun F (Wayne) , Dien Bard Jennifer , Chen Pei Ying , Flores-Vazquez Jessica , Odom John Audrey R , Planet Paul J , Devaraj Sridevi , Annapragada Ananth V , Luna Ruth Ann , Chiu Charles Y , Rostad Christina A
Published: August 2024

Background

Coronavirus disease 2019 (COVID-19) continues to cause hospitalizations and severe disease in children and adults.

Methods

This study compared the risk factors, symptoms, and outcomes of children and adults hospitalized for COVID-19 from March 2020 to May 2023 across age strata at 5 US sites participating in the Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence consortium. Eligible patients had an upper respiratory swab that tested positive for severe acute respiratory syndrome coronavirus 2 by nucleic acid amplification. Adjusted odds ratios (aOR) of clinical outcomes were determined for children versus adults, for pediatric age strata compared to adolescents (12–17 years), and for adult age strata compared to young adults (22–49 years).

Results

Of 9101 patients in the Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence cohort, 1560 were hospitalized for COVID-19 as the primary reason. Compared to adults (22–105 years, n = 675), children (0–21 years, n = 885) were less commonly vaccinated (14.3% vs 34.5%), more commonly infected with the Omicron variant (49.5% vs 26.1%) and had fewer comorbidities (P < .001 for most comparisons), except for lung disease (P = .24). After adjusting for confounding variables, children had significantly lower odds of receiving supplemental oxygen (aOR, 0.57; 95% confidence interval, .35–.92) and death (aOR, 0.011; 95% confidence interval, <.01–.58) compa­­red to adults. Among pediatric age strata, adolescents 12–17 years had the highest odds of receiving supplemental oxygen, high-flow oxygen, and ICU admission. Among adults, those 50–64 years had the highest odds of mechanical ventilation and ICU admission.

Conclusions

Clinical outcomes of COVID-19 differed across pediatric and adult age strata. Adolescents experienced the most severe disease among children, whereas adults 50–64 years experienced the most severe disease among adults.
Opportunities for Enhanced Public Health Surveillance via Molecular Detection and Sequencing of Diverse Respiratory Viruses From Self-collected SARS-CoV-2 Antigen Test Swabs
Authors: Schmidt Kat , Pollett Simon D , Richard Stephanie A , Hogan Vivian , Hone Emily , Rothenberg Jennifer , Tant Rezalina , Wayman Michele , Friend Chantele , Thapa Kamala , Ulomi Lola , Davies Julian , Michel Amber , Burgess Timothy H , O’Connell Robert J , Simons Mark P , Tilley Drake H , Fries Anthony C , Colombo Rhonda E
Published: August 2024

We sequenced and genotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, adenovirus, and respiratory syncytial virus, among other pathogens, from residual anterior nasal swabs self-collected for rapid SARS-CoV-2 antigen testing at the US Naval Academy. This is a key proof-of-concept for an acute respiratory infection surveillance approach, which could leverage prevalent SARS-CoV-2 antigen self-testing.
Unique brain injury patterns after proton vs photon radiotherapy for WHO grade 2-3 gliomas
Authors: Winter Sebastian F , Gardner Melissa M , Karschnia Philipp , Vaios Eugene J , Grassberger Clemens , Bussière Marc R , Nikolic Katarina , Pongpitakmetha Thanakit , Ehret Felix , Kaul David , Boehmerle Wolfgang , Endres Matthias , Shih Helen A , Parsons Michael W , Dietrich Jorg
Published: August 2024

Background

Central nervous system (CNS) injury following brain-directed radiotherapy remains a major challenge. Proton radiotherapy (PRT) minimizes radiation to healthy brain, potentially limiting sequelae. We characterized CNS radiotoxicity, including radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), in glioma patients treated with PRT or photons (XRT).

Patients and Methods

Thirty-four patients (19 male; median age 39.6 years) with WHO grade 2-3 gliomas treated with partial cranial radiotherapy (XRT [n = 17] vs PRT[n = 17]) were identified and matched by demographic/clinical criteria. Radiotoxicity was assessed longitudinally for 3 years post-radiotherapy via serial analysis of T2/FLAIR- (for RIL), contrast-enhanced T1- (for TN), and susceptibility (for CMB)-weighted MRI sequences. RIL was rated at whole-brain and hemispheric levels using a novel Fazekas scale-informed scoring system.

Results

The scoring system proved reliable (ICC > 0.85). Both groups developed moderate-to-severe RIL (62%[XRT]; 71%[PRT]) within 3 years; however, XRT was associated with persistent RIL increases in the contralesional hemisphere, whereas contralesional hemispheric RIL plateaued with PRT at 1-year post-radiotherapy (t = 2.180; P = .037). TN rates were greater with PRT (6%[XRT] vs 18%[PRT]; P = ns). CMB prevalence (76%[XRT]; 71%[PRT]) and burden (mean #CMB: 4.0[XRT]; 4.2[PRT]) were similar; however, XRT correlated with greater contralesional hemispheric CMB burden (27%[XRT]; 17%[PRT]; X2 = 4.986; P = .026), whereas PRT-specific CMB clustered at the radiation field margin (X2 = 14.7; P = .002).

Conclusions

CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality-specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting underlying dosimetric and radiobiological differences. Familiarity with such injury patterns is essential to improve patient management. Prospective studies are needed to validate these findings and assess their impacts on neurocognitive function.
A one-way ticket: Wheat roots do not functionally refill xylem emboli following rehydration
Authors: Harrison Day Beatrice L , Johnson Kate M , Tonet Vanessa , Bourbia Ibrahim , Blackman Chris J , Brodribb Timothy J
Published: August 2024

Understanding xylem embolism spread in roots is essential for predicting the loss of function across root systems during drought. However, the lasting relevance of root embolism to plant recovery depends on whether roots can refill xylem emboli and resume function after rehydration. Using MicroCT and optical and dye staining methods, we investigated embolism repair in rehydrated intact roots of wheat (Triticum aestivum L. ‘Krichauff’) exposed to a severe water deficit of −3.5 MPa, known to cause approximately 30% total root network embolism in this species. Air emboli in the xylem vessels of intact roots remained clearly observable using MicroCT after overnight rehydration. This result was verified by xylem staining of the root system and optical quantification of emboli, both of which indicated a lack of functional root xylem recovery 60 h following soil re-saturation. The absence of root xylem refilling in wheat has substantial implications for how we understand plant recovery after drought. Our findings suggest that xylem embolism causes irreversible damage to the soil–root hydraulic connection in affected parts of the root network.
Understanding policy integration through an integrative capacity framework
Authors: Vince Joanna , Fudge Maree , Fullbrook Liam , Haward Marcus
Published: August 2024

An important aspect of policy integration is the need for policymakers to establish integrative capacity. However, very few scholars who refer to this concept have explained what integrative capacity is and what aspects of the policy process policymakers need to focus on to establish that capacity. In this paper, we define integrative capacity and introduce an “integrative capacity framework” that outlines key components required by public agencies to progress policy integration. Drawing on existing literature, we apply three dimensions of policy—the policy process, program, and politics—to identify where integrative capacity can occur. Within those dimensions, we identify four conditions that can impact integration: coordination and coherence; accountability, transparency, and legitimacy; resourcing and adequate institutional architecture. We argue that by unpacking the integrative capacity concept, scholars and policymakers can utilize the framework to identify what elements of the policy process need to be addressed to increase the likelihood of integrative policy success.
Reincarnation and anti-essentialism: An argument against the essentiality of material origins
Authors: Deshmukh Ajinkya , Janssen-Lauret Frederique
Published: August 2024

We argue that Indian speakers’ discourse about reincarnation represents a counterexample to the ordinary-language evidence for the Kripkean thesis of material-origin essentialism. Advocates of the essentiality of origins contend not only that persons have the property of coming from the two particular gametes they actually came from essentially, but also that competent ordinary-language speakers find this view intuitively compelling. We adduce evidence from Indian speakers’ discourse, both ordinary-language remarks and published literature about reincarnation, to disconfirm that contention. We argue that the view that persons are mental entities is clearly coherent, intuitive, and not obviously necessarily false. We consider mental essentialism as an alternative, according to which persons are only accidentally embodied or biological. But we argue against it in favour of a modally relative anti-essentialism: what properties count as essential to an object and what properties count as accidental is not fixed but varies according to pragmatic utility.
Factors Associated With Physical Activity and Sedentary Behavior in People With Parkinson Disease: A Systematic Review and Meta-Analysis
Authors: Domingues Vitoria L , Makhoul Marina P , de Freitas Tatiana B , Polese Janaine C , Silva-Batista Carla , Barbieri Fabio A , Torriani-Pasin Camila
Published: August 2024

Objective

The goal of this review was to investigate factors associated with physical activity and sedentary behavior in people with Parkinson disease (PD). The magnitude of these associations was investigated in line with the International Classification of Functioning, Disability and Health components.

Methods

A systematic literature review was conducted until February 2023, searching four databases (PubMed, EMBASE, Web of Science, and Scopus) for original articles investigating associations with physical activity or sedentary behavior in people with PD. Two independent researchers performed data extraction, and the risk of bias in the included studies was assessed using the Quality in Prognosis Studies tool. Meta-analyses were conducted to determine the magnitude of the associations, and significant regression models from the included studies were described.

Results

Forty-two studies were included. Twenty-one factors associated with overall physical activity were identified. Higher levels of physical activity had a small association with cognition and body mass index and a fair association with 17 factors related to self-efficacy, physical function, mobility, quality of life, age, PD symptoms, and more. Better manual dexterity and functional gait had moderate to good associations with higher levels of physical activity. The regression model with the higher magnitude was composed mostly of contextual factors, except for the body max index. The magnitude of factors associated with physical activity intensity or sedentary behavior could not be identified.

Conclusion

Functional gait and manual dexterity were the strongest factors related to physical activity in people with PD. Further investigation is needed to understand the factors associated with physical activity intensity and sedentary behavior.

Impact

This study emphasizes the significance of considering contextual factors alongside body function and structure, activity and participation, and the health condition to enhance physical activity improvement during the rehabilitation process. By adopting such a holistic approach, rehabilitation professionals can optimize the overall health and well-being of individuals with Parkinson disease.
Socioeconomic impacts of land restoration in agriculture: A systematic review
Authors: Malan Mandy , Berkhout Ezra , Duchoslav Jan , Voors Maarten , Van Der Esch Stefan
Published: August 2024

Land restoration programmes are an increasingly popular tool to reduce degradation and increase livelihoods. This study aims to summarize the available evidence on the socioeconomic impacts of interventions aiming to promote land restoration or prevent land degradation, including agroforestry, conservation agriculture, integrated soil fertility management, and soil and water conservation. Using a systematic approach to selecting and assessing the quality of relevant studies, this review reveals a paucity of evidence. We identify twenty-nine causal studies, of which just six assess socioeconomic outcomes, only three studies were conducted outside of Africa, and none assessed agroforestry. The twenty-nine studies provide insights into thirty-five intervention–outcome combinations, of which 71 per cent reveal a positive impact on the outcome studies. We discuss the implications for policy and research.
The Unidroit Principles on International Commercial Contracts and sustainable development
Authors: Mouttotos Nicholas
Published: August 2024

A number of motivations currently drive multinational corporations to the inclusion, monitoring, and enforcement of contract requirements for sustainability. These can be either as a result of investor demand for environment, social, and governance policies; regulatory requirements for inclusion of such contract stipulations; or the increasing litigation for conduct leading to environmental harm, but they can also be a result of reputational risk linked to the failure of adoption of such policies. This article examines the role of contract law in enforcing such requirements, which have traditionally been viewed with suspicion due to their unilateral nature. The article poses the features of the International Institute for the Unification of Private Law’s Principles on International Commercial Contracts as a beneficial regime to further the goals of sustainability through the use of contextual interpretation enabled through the good faith principle, the recognition of the importance of trade usages, and the limitations placed on party autonomy. The article posits that a major shift in the ideological orientation of contract law through the imposition of limitations on the pacta sunt servanda principle in order to protect the public interest is not warranted. Rather, tools such as contractual interpretation and the establishment of contractual standards of sustainability are better placed to ensure enforcement and compliance with the widely established practice of inclusion of sustainability standards and codes of conduct.
System analysis based on weighted gene co‐expression analysis identifies SOX7 as a novel regulator of hepatic stellate cell activation and liver fibrosis
Authors: Liu Yuwei , Wang Xiaomei , Wang Zhongfeng , Gao Xiuzhu , Xu Hongqin , Gao Yanhang , Niu Junqi
Published: August 2024

Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY‐related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF‐β1 stimulated LX‐2 cells. SOX7 knockdown promoted activation and proliferation of LX‐2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β‐catenin and phosphorylation of Smad2 and Smad3 induced by TGF‐β1. Furthermore, overexpression of SOX7 using AAV8‐SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
FTY720/Fingolimod mitigates paclitaxel‐induced Sparcl1‐driven neuropathic pain and breast cancer progression
Authors: Singh Sandeep K. , Weigel Cynthia , Brown Ryan D. R. , Green Christopher D. , Tuck Connor , Salvemini Daniela , Spiegel Sarah
Published: August 2024

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor‐bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine‐1‐phosphate receptor 1 (S1PR1), alleviated paclitaxel‐induced neuropathic pain. FTY720 also significantly attenuated paclitaxel‐stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte‐secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti‐tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.
An Intervention to Improve Evidence-based Nicotine Prescribing by Primary Care Physicians
Authors: Martinez Alaina , Sazegar Payam
Published: August 2024

Objectives

Nearly 70% of people who use tobacco want to quit. Combination nicotine replacement therapy (cNRT), a long-acting controller plus short-acting reliever, is the most effective way to prescribe nicotine but is infrequently prescribed by primary care physicians (PCPs). We tested the feasibility and effectiveness of a brief, educational intervention to increase cNRT prescribing by PCPs in a large integrated health system.

Methods

We conducted a pre-post study from 2022–2023 at a large integrated health system in California where specific NRT products are covered with a prescription. PCPs were offered a 30-minute virtual training about cNRT during a required monthly meeting (n = 267; 202 attended). The training was interactive, included simple “asks” and a 6-week follow-up communication. Chi-square analysis was used to test for changes in cNRT prescribing behaviors in the 6 months before and after training.

Results

Among physicians who completed a posttraining questionnaire (180/202), 93% reported increased confidence, 91% reported favorable attitudes, and 88% reported intention to prescribe cNRT. According to data obtained from the integrated pharmacy database, the total number of patients who received a cNRT prescription increased from the 6-month pre- to 6-month postintervention from 135 (9%) to 380 (23%), P < 0.001. The total number of physicians who prescribed cNRT increased pre- to posttraining from 78 (23%) to 124 (37%), P < 0.001.

Conclusion

cNRT is an underutilized form of tobacco cessation therapy by PCPs. This may reflect a gap in prescriber knowledge. A brief, virtual training delivered to PCPs was associated with increased cNRT prescribing.
International Classification of Diseases, Tenth Revision Diagnosis Codes Are Overutilized in the Diagnosis of Chronic Pancreatitis
Authors: Ladna Michael , Madhok Ishaan , Bhat Adnan , Ruiz Nicole , Brown Jackson , Wilson Jake , Jiang Peter , Taylor Robert , Radetic Mark , George John , Forsmark Christopher
Published: August 2024

Background

Retrospective studies and large databases, such as the OneFlorida Clinical Research Consortium, rely on International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes to identify patients with specificity. This study aimed to determine if ICD-10 codes for CP are overutilized.

Materials and Methods

Retrospective analysis was conducted for patients with ICD-10 codes K86.0 (alcohol-induced CP) and K86.1 (other CP) from February 2018 to February 2020. Data were extracted from the integrated electronic data repository. This study was approved by the institutional review board. The diagnosis of CP was defined as either being made by a gastroenterologist, proven by biopsy, or having characteristic findings on cross-sectional imaging with appropriate symptoms.

Results

Five hundred four (37%) out of the 1360 patients had no evidence of CP. When broken down by diagnosis code, 41 of 176 charts (23.3%) with K86.0 and 461 of 1184 charts (38.6%) with K86.1 had no evidence of CP. Two hundred ninety-nine of these patients had either a single episode of acute pancreatitis, recurrent acute pancreatitis, or episode of acute necrotizing pancreatitis. Of note, 81 patients had no identifiable abdominal pathology.

Conclusions

Although the OneFlorida database makes multicenter research more accessible, it does not replace labor-intensive chart review given the propensity for overdiagnosis.
Validating ICD-10-CM Diagnostic Codes With Laboratory Test Results for Use in Identifying Chlamydial and Gonococcal Infections Among American Indians and Alaska Natives: Indian Health Service, 2016–2021
Authors: Haberling Dana L. , Mauk Kerry , Bornstein Ethan , Nuorti J. Pekka , Apostolou Andria
Published: August 2024

Background

National case rates of chlamydia and gonorrhea (CT/GC) among American Indian and Alaska Native (AI/AN) persons are disproportionately high. The Indian Health Service (IHS), which provides health care to members of federally recognized tribes, does not currently have a dedicated CT/GC surveillance system. The purpose of this study was to validate the use of CT/GC diagnostic codes for estimating diagnosed CT/GC infections among AI/AN persons who use IHS services.

Methods

We conducted a retrospective study using IHS medical records from all persons 15 years and older from 2016 to 2021. We linked records with CT (A56, A74) and GC (A54, O98.2) International Classification of Diseases, 10th Revision, Clinical Modification diagnostic codes to laboratory results within 30 days for each person. We calculated the sensitivity, specificity, and positive and negative predictive values of CT/GC diagnostic codes using laboratory test results as the reference standard.

Results

We identified more than 1.6 million CT/GC laboratory tests, and 52,815 CT and 19,971 GC diagnostic codes. Diagnostic code sensitivity was slightly higher for CT (54%) than GC (50%). Specificity, positive predictive value, and negative predictive value were high for CT and GC (range, 83.3%–99.8%). About one-third of CT/GC diagnostic codes could not be linked to a test result.

Conclusions

The validation indicates that diagnostic codes align well with linked laboratory test results. However, because of the relatively large number of diagnostic codes and positive test results that could not be linked, combining the 2 would inform more reliable estimates of diagnosed CT/GC infections among AI/AN persons who use IHS for health care.
Firearm Fatalities in the Pediatric Population
Authors: Cina Alexandra , Tarozzi Ilaria , Arunkumar Ponni , Gitto Lorenzo
Published: August 2024

Gunshot injuries are one of the leading causes of death from trauma in the United States. In recent years, the US has experienced an increasing number of fatal pediatric cases related to firearms.

A search of the database of the Cook County Medical Examiner's Office over the period January 2016–December 2021 revealed 418 deaths by gunshot wounds (GSWs) among people aged between 0 and 18 years old. Subjects were subcategorized in infants (0 to 1 year), toddlers (≥1 to 3 years), preschool (≥3 to 6 years), preadolescents (≥6 to 12 years), and adolescents (≥12 to 18 years).

Most victims were males (n = 374) and adolescents (357 males and 30 females). Homicide (n = 373) was the most common manner of death. Only 2 deaths were accidental. Single GSWs deaths (n = 232) were more common than multiple GSWs (n = 186) and preferentially directed to the head in both homicides and suicides. Gang or robbery related events in areas of readily available firearms explained 4.5% of homicides (17 out of 373 cases). Among deaths by self-inflicted GSWs (n = 36), 7 cases were linked to psychiatric disorders, 3 to family difficulties, 2 to history of playing Russian roulette, and 2 to bullying at school.

Pediatric gunshot injuries and deaths are an important public health problem. Understanding and addressing individual and societal risk factors should be the first step toward prevention.
Ruptured Aortic Valve Aneurysm Caused by Infective Endocarditis in a SARS-CoV-2–Positive Autopsy Case
Authors: Takasu Shojiro , Matsumoto Sari , Kanto Yuko , Iwadate Kimiharu
Published: August 2024

Aortic valve aneurysm, an extremely rare complication secondary to infective endocarditis (IE), may cause heart failure due to rupture of the aneurysm. Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications and alter susceptibility to secondary infections such as IE. Herein, we report a case of IE with a fatal outcome caused by rupture of an aortic valve aneurysm in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–positive autopsy case. The patient was a 67-year-old male diagnosed with heart failure after presenting with edema and weight gain. He was found dead in bed 2 weeks after initial symptom presentation. Autopsy revealed an aneurysmal sac in the center of the noncoronary cusp of the aortic valve with an opening of approximately 1 cm in the center of the aneurysmal wall. Histologically, aortic valve vegetation, destruction of the aortic valve cusp, rupture of the aneurysmal wall, and an abscess under the aortic intima were observed. Gram staining of the aneurysmal wall showed a gram-positive coccus. The reverse transcription quantitative polymerase chain reaction assay was positive for SARS-CoV-2. Because no defined risk factors for IE other than SARS-CoV-2 infection were observed, the association between IE and COVID-19 was highly likely.
Multicenter Observational Study of Electroconvulsive Therapy in Japan
Authors: Sakayori Takeshi , Wada Ken , Takebayashi Minoru , Ueda Satoshi , Machino Akihiko , Yoshimura Atsushi , Sawayama Enami , Maruyama Fumi , Tanabe Haruka , Takahashi Hidehiko , Azuma Hideki , Koishikawa Hiraki , Ozawa Hiroki , Okuhira Kazuya , Yasuda Kazuyuki , Miyakawa Koichi , Yoshimura Reiji , Ozaki Shigeru , Yokoyama Shin , Eto Shinkichi , Tomonaga Shoko , Isomura Shuichi , Nonomura Tsukasa , Okubo Yoshiro
Published: August 2024

Objectives

The present study is the first large-scale, multicenter survey on modified electroconvulsive therapy (ECT) in Japan. We aimed to comprehend the current implementation status of ECT based on the annual reports of 2016 from 21 facilities that were certified by the Japanese Society of General Hospital Psychiatry as ECT certified facilities and participated in this multicenter observational study.

Methods

We investigated the distributions of diagnosis, gender, and age of patients receiving acute-phase ECT, and the efficacy, safety, and adverse events.

Results

The number of patients receiving acute-phase ECT was 524. According to International Classification of Diseases, 10th Revision, 344 patients (65.6%) were diagnosed with mood disorders (F3), 156 patients (29.8%) were diagnosed with schizophrenia and with schizotypal and delusional disorders (F2), and 151 subjects were male and 334 subjects were female. The mean age of patients was 60.4 years (SD 15.9), and patients 60 years or older accounted for 57.9%. Efficacy did not significantly differ between diagnoses, nor between genders. However, the efficacy rate was significantly higher in elderly patients. In acute-phase ECT, 4 severe adverse events occurred.

Conclusions

Our multicenter study confirmed that F3 (mood disorders) was the most common indication for ECT at 66%, followed by F2 (schizophrenia, schizotypal, and delusional disorders) at 30%, with no difference in efficacy, indicating that ECT is still performed as 1 of the treatment options for schizophrenia in Japan. The present results suggested that accumulation of annual data from multiple centers can be useful for more effective and safer ECT practices.
Analytical Validation of MyProstateScore 2.0
Authors: Meyers Jacob I , Schatz Tabea M , Seitz Cameron J , Botbyl Rachel , Moore Bradley S , Crafts Bill G , Heaton Spencer , Kitchen John R
Published: August 2024

Prostate cancer (PCa) remains the most common cancer and the second leading cause of cancer-related deaths among men in the United States. Early detection is critical, yet routine prostate-specific antigen (PSA) screening has shown limited benefits, often leading to unnecessary biopsies. MyProstateScore 2.0 (MPS2), a novel urinary 18-biomarker test, aims to improve the detection of clinically significant prostate cancer (csPCa) while minimizing the risk of unnecessary procedures. This study aims to validate the analytical performance of MPS2, including analytical detection limits, reproducibility, and robustness across various potential interfering substances. The limit of detection (LoD) and lower limit of quantitation (LLOQ) for the 18 MPS2 biomarkers ranged from 40 to 160 copies/reaction and 80 to 320 copies/reaction, respectively. The upper limit of quantitation (ULOQ) was determined to be up to 10^7 copies/reaction for most analytes. The linear amplification of MPS2 biomarker amplification was confirmed between the defined LLOQ and ULOQ. Eleven of 12 potential interfering substances tested had minimal impact on the assay. The exception was whole blood, which delayed biomarker detection. In conclusion, MPS2 exhibits robust analytical performance, with reliable detection and quantitation limits. This validation supports the clinical use of MPS2 for accurately predicting clinically-significant PCa, potentially reducing unnecessary biopsies and associated complications.
The Evolving Epidemiology of Infective Endocarditis: An Observational Study from Western India
Authors: Madan Surabhi , Vyas Aditya , Ramar Dharshni , Rana Manish
Published: August 2024

Background

Over the last few decades, the epidemiology and the management of infective endocarditis (IE) is undergoing significant evolution and advancements respectively. Many studies from the developed world and some from India have brought this to light.

Objective

To study demography, risk factors, microbiological spectrum, clinical profile, management, and outcome of IE in a tertiary care setup in western India.

Materials and Methods: This is a retrospective observational study of 90 patients diagnosed with definite as well as possible IE and admitted to the intensive care units (ICU) and wards in our institute from April 2015 to May 2022. Demographics, signs and symptoms, laboratory results, echocardiography, radiological findings, treatment, and outcomes were studied.

Results

73 (81.1%) were definite and 17 (18.9%) were possible cases of IE. 93.3% cases were community-acquired, 6.7% were hospital acquired. Mean age of the patients was 43.3 + or - 18.8 years. Male: female ratio was 4.3:1. 62.2% had an underlying cardiac illness, with congenital heart disease (CHD) being the most common (18.9%) followed by rheumatic heart disease (RHD) (16.5%). Fever, weight loss, dyspnea, and cough were the common presenting symptoms. 69 (76.7 %) patients had native valve IE, 13 (14.4%) had prosthetic valve IE, 6 (6.7%) had vegetations on the endothelium without involvement of the valves, 2 (2.2%) patients had vegetations on the prosthetic material used for repair of congenital heart defects. About 48% of patients had a history of prior receipt of antibiotics. Blood cultures were positive in 48 (53.3%) patients. Most common valve infected was the mitral valve (MV) and the most common organisms isolated were the viridans group of streptococci (VGS), with penicillin (Pn) MIC <0.5 mcg/ml of all but one isolate. Transesophageal echocardiography (TEE), done in 17 patients, improved the pick-up of abnormal echo findings from 83.3% to 91.1%. Ceftriaxone was the most common antibiotic used. Surgery was done in 22 (24.4%) patients. 67 (74.4%) patients were cured, 14 (15.6%) patients died and 9 (10%) patients were lost to follow-up.

Conclusion

The increasing age of patients, absence of any underlying cardiac ailment, the importance of TEE in patients with high suspicion of IE, and the trend towards early surgery were the important aspects highlighted with respect to the changes happening in the field of IE. Almost all the strains of VGS, the most common isolated organisms, retained their sensitivity to Pn and ceftriaxone, making the treatment possible with once-a-day dosing of ceftriaxone monotherapy, highlighting the utilization of outpatient antibiotic therapy (OPAT).
JMJD3 mediated senescence is required to overcome stress induced hematopoietic defects
Authors: Nakata Yuichiro , Ueda Takeshi , Sera Yasuyuki , Kanai Akinori , Ikeda Ken-ichiro , Yamasaki Norimasa , Nagamachi Akiko , Kobatake Kohei , Taguchi Masataka , Sotomaru Yusuke , Ichinohe Tatsuo , Honda Zen-ichiro , Manabe Ichiro , Suda Toshio , Takubo Keiyo , Kaminuma Osamu , Honda Hiroaki
Published: August 2024

Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence viap16Ink4aupregulation in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. JMJD3 deficiency impaired stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress conditions. These impaired phenotypes were rescued through exogenous and retroviral introduction ofp16Ink4a. This JMJD3-p16INK4aaxis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a JMJD3 selective inhibitor attenuated leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4amediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress conditions, suggesting a new link for aging and anti-cancer therapies.
Coevolution of phenological traits shapes plant-pollinator coexistence
Authors: Duchenne François , Dominguez-García Virginia , Molina Francisco P. , Bartomeus Ignasi
Published: August 2024

Previous research has revealed how species traits determine species interactions, and how species interactions influence species coexistence. However, this hierarchical view ignores the coevolutionary feedback from species interactions to species traits and its consequences for species coexistence. Here, we developed a theoretical model to explore how the coevolution of morphological and phenological traits shape the structure and stability of mutualistic interaction networks. We found phenological traits lead to distinctive coevolutionary opportunities for species and to different emergent properties at community level than morphological traits, because they decouple mutualism and competition. Morphological coevolution led to modular and specialized interaction networks with a low structural stability, while phenological coevolution was required to achieve nested interaction networks with a higher structural stability. This suggested that phenological coevolution is key in the emergence of stable communities. Our theoretical prediction was consistent with empirical observations: across 17 empirical pollination networks we found a high proportion of phenological motifs promoting facilitation over competition, suggesting an important role of phenological coevolution in community assembly. In addition, the phenological structure of the empirical communities was a major determinant of their structural stability. Our results highlight the importance of phenological coevolution in the emergence of diverse and stable communities.