bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue culture-independent approaches to revolutionizing plant transformation and gene editing
Authors: Quiroz Luis Felipe , Khan Moman , Gondalia Nikita , Lai Linyi , McKeown Peter C , Brychkova Galina , Spillane Charles
Published: October 2024

Despite the transformative power of gene editing for crop improvement, its widespread application across species and varieties is limited by the transformation bottleneck that exists for many crops. The genetic transformation of plants is hindered by a general reliance on in vitro regeneration through plant tissue culture. Tissue culture requires empirically determined conditions and aseptic techniques, and cannot easily be translated to recalcitrant species and genotypes. Both Agrobacterium-mediated and alternative transformation protocols are limited by a dependency on in vitro regeneration, which also limits their use by non-experts and hinders research into non-model species such as those of possible novel biopharmaceutical or nutraceutical use, as well as novel ornamental varieties. Hence, there is significant interest in developing tissue culture-independent plant transformation and gene editing approaches that can circumvent the bottlenecks associated with in vitro plant regeneration recalcitrance. Compared to tissue culture-based transformations, tissue culture-independent approaches offer advantages such as avoidance of somaclonal variation effects, with more streamlined and expeditious methodological processes. The ease of use, dependability, and accessibility of tissue culture-independent procedures can make them attractive to non-experts, outperforming classic tissue culture-dependent systems. This review explores the diversity of tissue culture-independent transformation approaches and compares them to traditional tissue culture-dependent transformation strategies. We highlight their simplicity and provide examples of recent successful transformations accomplished using these systems. Our review also addresses current limitations and explores future perspectives, highlighting the significance of these techniques for advancing plant research and crop improvement.
CsNAC17 enhances resistance to Colletotrichum gloeosporioides by interacting with CsbHLH62 in Camellia sinensis
Authors: Han Rui , Mei Huiling , Huang Qiwei , Ma Cunqiang , Zhao Yuxin , Jeyaraj Anburaj , Zhuang Jing , Wang Yuhua , Chen Xuan , Liu Shujing , Li Xinghui
Published: October 2024

The pathogen Colletotrichum gloeosporioides causes anthracnose, a serious threat to tea trees around the world, particularly in warm and humid regions. RNA-Seq data have previously indicated NAC transcription factors are involved in anthracnose resistance, but underlying mechanisms remain unclear. The BiFC, Split-LUC, and Co-IP assays validated the interaction between CsbHLH62 and CsNAC17 identified through yeast two-hybrid (Y2H) screening. CsNAC17 or CsbHLH62 overexpression enhanced anthracnose resistance, as well as enhanced levels of H2O2, hypersensitivity, and cell death in Nicotiana benthamiana. The NBS-LRR gene CsRPM1 is regulated by CsNAC17 by binding directly to its promoter (i.e. CACG, CATGTG), while CsbHLH62 facilitates CsNAC17’s binding and increases transcriptional activity of CsRPM1. Additionally, transient silencing of CsNAC17 and CsbHLH62 in tea plant leaves using the virus-induced gene silencing (VIGS) system resulted in decreased resistance to anthracnose. Conversely, transient overexpression of CsNAC17 and CsbHLH62 in tea leaves significantly enhanced the resistance against anthracnose. Based on these results, it appears that CsbHLH62 facilitates the activity of CsNAC17 on CsRPM1, contributing to increased anthracnose resistance.
Nausea and vomiting in pregnancy: a cross-sectional study of community pharmacists in the UK
Authors: Payne Bradley , Righton Olivia , Nana Melanie , Chapman Sarah , Williamson Catherine , Lakhani Shivali , Alter Marsha , Bell Zoe , Flynn Angela C
Published: October 2024

Objectives

To assess the content and frequency of advice community pharmacists (CPs) provide to pregnant women with nausea and vomiting, their confidence in providing advice, and their knowledge of the safety of medication used to manage the condition.

Methods

An online questionnaire of closed- and open-ended questions was distributed to CPs in the UK in May 2023. Closed-ended questions were analysed quantitatively, and conventional content analysis was utilised for open-ended responses.

Key findings

One hundred and eighty-one respondents completed the questionnaire, 24 responses were excluded, leaving data from 157 available for analysis. The majority (90.4%) of participants reported having experience in providing advice on nausea and vomiting with varying levels of confidence. Advice provided included using over-the-counter products, lifestyle modifications, reassurance, medication advice, and referring to other healthcare professionals. Knowledge of first-line antiemetics considered safe in pregnancy varied; cyclizine was correctly identified as safe during pregnancy by 57.3%, followed by 37.6% for promethazine and 31.2% for prochlorperazine. Self-reported confidence and having experience providing advice were related to higher medication safety identification rates. Five percent of participants reported previous training on the condition, while 70% reported wanting further education, preferably delivered via an online medium.

Conclusions

This study showed that although 90% of CPs provide advice on nausea and vomiting in pregnancy, their medication safety knowledge varied. The majority of CPs reported wanting further education that would ensure women could access reliable information and evidence-based advice to optimise management of the condition.
Health disparities in the risk of severe acidosis: real-world evidence from the All of Us cohort
Authors: Gatz Allison E , Xiong Chenxi , Chen Yao , Jiang Shihui , Nguyen Chi Mai , Song Qianqian , Li Xiaochun , Zhang Pengyue , Eadon Michael T , Su Jing
Published: October 2024

Objective

To assess the health disparities across social determinants of health (SDoH) domains for the risk of severe acidosis independent of demographical and clinical factors.

Materials and Methods

A retrospective case-control study (n = 13 310, 1:4 matching) is performed using electronic health records (EHRs), SDoH surveys, and genomics data from the All of Us participants. The propensity score matching controls confounding effects due to EHR data availability. Conditional logistic regressions are used to estimate odds ratios describing associations between SDoHs and the risk of acidosis events, adjusted for demographic features, and clinical conditions.

Results

Those with employer-provided insurance and those with Medicaid plans show dramatically different risks [adjusted odds ratio (AOR): 0.761 vs 1.41]. Low-income groups demonstrate higher risk (household income less than $25k, AOR: 1.3-1.57) than high-income groups ($100-$200k, AOR: 0.597-0.867). Other high-risk factors include impaired mobility (AOR: 1.32), unemployment (AOR: 1.32), renters (AOR: 1.41), other non-house-owners (AOR: 1.7), and house instability (AOR: 1.25). Education was negatively associated with acidosis risk.

Discussion

Our work provides real-world evidence of the comprehensive health disparities due to socioeconomic and behavioral contributors in a cohort enriched in minority groups or underrepresented populations.

Conclusions

SDoHs are strongly associated with systematic health disparities in the risk of severe metabolic acidosis. Types of health insurance, household income levels, housing status and stability, employment status, educational level, and mobility disability play significant roles after being adjusted for demographic features and clinical conditions. Comprehensive solutions are needed to improve equity in healthcare and reduce the risk of severe acidosis.
University of North Carolina adolescent and young adult cancer program: reach and characteristics of care
Authors: Stein Jacob , Wardell Alexis , Ritzwoller Dawn M , Swift Catherine , Matson Melissa , Winslow Hannah C , Muthukrishnan Hrishika , Waters Austin R , Haines Emily R , Lux Lauren , Smitherman Andrew B
Published: October 2024

Cancer care organizations often struggle to adequately address the unique needs of adolescent and young adult cancer patients, resulting in poorer outcomes compared with other age groups. Creation of adolescent and young adult cancer programs serves to bridge this gap and improve quality of care for this population. We aimed to describe the evolution and impact of the University of North Carolina at Chapel Hill’s Adolescent and Young Adult Cancer Program. To do so, we conducted a retrospective cohort study utilizing electronic health record data matched with North Carolina Cancer Registry data from 2014 to 2022. Between 2014 and 2022, a total of 4016 adolescents and young adults (aged 13-39 years) received cancer care at the University of North Carolina Medical Center, with 670 having contact with the Adolescent and Young Adult Cancer Program. Program-contacted patients were younger, more likely to be non-Hispanic Black race, and more likely to have metastatic disease or hematologic malignancies. We saw a steady increase in patient volume over the study period, corresponding with program growth.
Nonhomogeneous hidden semi-Markov models for toroidal data
Authors: Lagona Francesco , Mingione Marco
Published: October 2024

A nonhomogeneous hidden semi-Markov model is proposed to segment bivariate time series of wind and wave directions according to a finite number of latent regimes and, simultaneously, estimate the influence of time-varying covariates on the process’ survival under each regime. The model is a mixture of toroidal densities, whose parameters depend on the evolution of a semi-Markov chain, which is in turn modulated by time-varying covariates. It includes nonhomogeneous hidden Markov models and hidden semi-Markov models as special cases. Parameter estimates are obtained using an Expectation-Maximization algorithm that relies on an efficient augmentation of the latent process. Fitted on a time series of wind and wave directions recorded in the Adriatic Sea, the model offers a clear-cut description of sea state dynamics in terms of latent regimes and captures the influence of time-varying weather conditions on the duration of such regimes.
Pooled safety evaluation for a new single-shot live-attenuated chikungunya vaccine
Authors: Maurer Gabriele , Buerger Vera , Larcher-Senn Julian , Erlsbacher Florian , Dubischar Katrin , Eder-Lingelbach Susanne , Jaramillo Juan Carlos
Published: October 2024

Background

Chikungunya disease, caused by chikungunya virus (CHIKV), is associated with substantial morbidity, including debilitating CHIKV-related arthralgia.

Methods

Three clinical trials of a CHIKV vaccine (VLA1553, IXCHIQ®) were conducted in the USA: a Phase 1 dose-finding trial, a pivotal Phase 3 trial and a Phase 3 lot-to-lot consistency trial. Participants were healthy adults (≥18 years) and received a single intramuscular dose of VLA1553 (3520 participants) or placebo (1033 participants). Solicited injection site and systemic adverse events (AEs) (10–14 days post-vaccination), unsolicited AEs (28 and 180 days post-vaccination), AEs of special interest (AESIs) (28 days post-vaccination), medically attended AEs (MAAEs), serious AEs (SAEs) (180 days post-vaccination) and pregnancies were evaluated. Safety data were pooled, and analyses were descriptive.

Results

Overall, 63.7% of participants receiving VLA1553 experienced AEs (44.7% for placebo) that were generally mild. Solicited injection-site AEs, solicited systemic AEs and unsolicited (Day 29) AEs were reported by 15.5, 50.9 and 22.7% of participants who received VLA1553 and 11.1, 26.9 and 13.4% who received placebo. Arthralgia was reported by 16.7% of participants who received VLA1553 and 4.8% of participants who received placebo; none required medical attention. MAAEs, AESIs and SAEs were reported by 12.4, 0.3 and 1.5% of participants who received VLA1553 and 11.3, 0.1 and 0.8% of participants who received placebo. Protocol-defined AESIs were mild and short-lived, and two VLA1553-related SAEs resolved without sequelae. There were no clinically important differences in AE incidence based on age or medical history and no VLA1553-related adverse pregnancy outcomes. There were three deaths (two in the VLA1553 group and one in the placebo group); none was vaccine-related.

Conclusions

A single dose of VLA1553 presented with an excellent local tolerability profile and overall safety in line with that expected for a live-attenuated vaccine. The safety profile was comparable in participants aged 18–64 years and ≥65 years.
Modelling of long gamma-ray burst host galaxies at cosmic noon from damped Lyman-α absorption statistics
Authors: Krogager J -K , De Cia A , Heintz K E , Fynbo J P U , Christensen L B , Björnsson G , Jakobsson P , Jeffreson S , Ledoux C , Møller P , Noterdaeme P , Palmerio J , Vergani S D , Watson D
Published: October 2024

We study the properties of long gamma-ray burst (GRB) host galaxies using a statistical modelling framework derived to model damped Lyman-$\alpha$ absorbers (DLAs) in quasar spectra at high redshift. The distribution of $N_{\rm H\, {\small I}}$ for GRB-DLAs is $\sim$10 times higher than what is found for quasar-DLAs at similar impact parameters. We interpret this as a temporal selection effect due to the short-lived GRB progenitor probing its host at the onset of a starburst where the interstellar medium may exhibit multiple overdense regions. Owing to the larger $N_{\rm H\, {\small I}}$, the dust extinction is larger with 29 per cent of GRB-DLAs exhibiting $A(V)\gt 1$ mag in agreement with the fraction of ‘dark bursts’. Despite the differences in $N_{\rm H\, {\small I}}$ distributions, we find that high-redshift $2 \lt z \lt 3$ quasar- and GRB-DLAs trace the luminosity function of star-forming host galaxies in the same way. We propose that their differences may arise from the fact that the galaxies are sampled at different times in their star formation histories, and that the absorption sightlines probe the galaxy haloes differently. Quasar-DLAs sample the full H i cross-section, whereas GRB-DLAs sample only regions hosting cold neutral medium. Previous studies have found that GRBs avoid high-metallicity galaxies ($\sim$0.5 $Z_{\odot }$). Since at these redshifts galaxies on average have lower metallicities, our sample is only weakly sensitive to such a threshold. Lastly, we find that the modest detection rate of cold gas (H$_2$ or C i) in GRB spectra can be explained mainly by a low volume filling factor of cold gas clouds and to a lesser degree by destruction from the GRB explosion itself.
Accretion-mediated spin–eccentricity correlations in LISA massive black hole binaries
Authors: Garg Mudit , Tiede Christopher , D’Orazio Daniel J
Published: October 2024

We examine expected effective spin ($\chi _{{\rm eff},1{\rm yr}}$) and orbital eccentricity ($e_{1\rm yr}$) correlations for a population of observable equal-mass massive black hole binaries (MBHBs) with total redshifted mass $M_z\sim [10^{4.5},10^{7.5}]~{{\rm M}_{\odot }}$ embedded in a circumbinary disc (CBD) at redshifts $z=1$ and $z=2$, 1 yr before merging in the Laser Interferometer Space Antenna (LISA) band. We find a strong correlation between measurable eccentricity and negative effective spin for MBHBs that are carried to merger by retrograde accretion. This is due to the well-established eccentricity pumping of retrograde accretion and less-well-established formation of retrograde mini-discs coupled with a stable retrograde CBD throughout the binary evolution from the self-gravitating radius. Conversely, prograde accretion channels result in positive $\chi _{{\rm eff},1\rm yr}$ and non-measurable $e_{1\rm yr}$ except for almost unity Eddington ratio and $M_z\lesssim 10^{5}~{{\rm M}_{\odot }}$ MBHBs at $z=1$. This clear contrast between the two CBD orientations – and particularly the unique signature of retrograde configurations – provides a promising way to unlock the mysteries of MBHB formation channels in the LISA era.
Colour dependence of dipole in CatWISE2020 data
Authors: Panwar Mohit , Jain Pankaj , Omar Amitesh
Published: October 2024

The signal of dipole anisotropy in quasar number counts is studied using the CatWISE2020 catalogue in various colour bins. It is found that the dipole signal differs significantly in two colour bins, namely $W1-W2\lt 1.1$ and $W1-W2\gt 1.1$. While the dipole in the bin $W1-W2\lt 1.1$ points close to the direction of the cosmic microwave background dipole, the dipole in the bin $W1-W2\gt 1.1$ points in the direction $(l,b) = (194^\circ \pm 7^\circ ,19^\circ \pm 4^\circ)$, quite close to the Galactic plane. Despite the proximity to the Galactic plane, we are unable to attribute this signal to a Galactic bias. If we interpret the dipole in the bin $W1-W2\lt 1.1$ as due to our local motion, the extracted velocity turns out to be $900\pm 113$ km s$^{-1}$, which deviates from the cosmic microwave background dipole velocity with approximately 4.7σ significance. We speculate that the dipole signal in both bins is of cosmological origin and that the difference may be attributed to a redshift dependence of the dipole, representing a departure from the standard $\Lambda$CDM model.
“It’s a delicate dance”: How informal caregivers experience the role and responsibilities of supporting someone living with a lower-grade glioma
Authors: Rimmer Ben , Balla Michelle , Dutton Lizzie , Burns Richéal , Araújo-Soares Vera , Finch Tracy , Lewis Joanne , Gallagher Pamela , Williams Sophie , Menger Fiona , Sharp Linda
Published: October 2024

Background

People with lower-grade gliomas (LGG) often require long-term support with a condition that causes substantial symptom burden and is likely to progress. Partners, family, and friends often become informal caregivers (IC), but the types of support they provide, and their experiences of this, have not been well investigated. We aimed to understand how ICs experience the role and responsibilities of supporting people with LGG.

Methods

This descriptive qualitative study used semistructured interviews to explore the role and responsibilities of a purposive sample of ICs across the United Kingdom, who currently, or in the past 5 years, support(ed) someone with an LGG. Interviews were audio-recorded and transcribed, and an inductive thematic analysis was conducted.

Results

Nineteen ICs were interviewed (mean age 54.6 years; 5 males/14 females). While most participants spoke about “Being a ‘carer’,” the level of care provided varied. Participants conveyed their experiences with “Adjusting for cognitive difficulties,” “Emotional protection,” “Supporting participation in daily life,” and “Healthcare advocacy.” ICs often felt “abandoned” by healthcare services to provide required care themselves, and reported experiences with “Balancing the challenges of caregiving,” including conflict with work/childcare. Issues around “Maintaining the care recipient’s independence” were interwoven throughout.

Conclusions

ICs of people with LGG provide wide-ranging support to help manage the consequences of the illness. Consideration of ways to help ICs with the challenges of fulfilling this role, particularly, balancing support provision without inhibiting the care recipient’s independence, could help improve outcomes for ICs and people with LGG.
Immune Reconstitution Inflammatory Syndrome in a Patient With Cutaneous Leishmaniasis and HIV: A Diagnostic Challenge for Clinicians Caring for a Migrant Population in the United States
Authors: De La Hoz Alejandro , Gadi Nirupa , Lopez Christina G , Barrera-Godinez Alejandro , Miller Nancy S , Bourque Daniel L , Brem Candice , Ozluk Ekin , Seth Geetika , Kimball Sarah , Taylor Jessica L
Published: October 2024

Migration routes determine exposure to endemic infections. We present a case of complex cutaneous leishmaniasis in a man with HIV infection who migrated to the United States from Haiti, where Leishmania is uncommon, acquiring leishmaniasis while on his journey via South America and Central America. His presentation included hyperpigmented, nonulcerated plaques and nodules on his extremities, chest, back, face, palms, and soles; initially he had no mucosal lesions. Infection with Leishmania panamensis was confirmed via polymerase chain reaction. He was prescribed bictegravir/tenofovir alafenamide/emtricitabine with rapid suppression of HIV and liposomal amphotericin B for diffuse cutaneous leishmaniasis with a limited initial response. He subsequently developed mucosal lesions in the setting of immune reconstitution and was retreated with amphotericin dosed for mucocutaneous disease. A thorough migration history was critical to diagnosis. This case highlights the different presentations of leishmaniasis in people with HIV and the elevated risk for treatment failure.
Effect of Universal Masking on Non–Severe Acute Respiratory Syndrome Coronavirus 2 Healthcare-Associated Respiratory Viral Infections
Authors: Munigala Satish , Ching Patrick R , Wood Helen , Waken R J , Fox Josephine , Gasama Heather , Russell Robert , Yarbrough Melanie L , Warren David K
Published: October 2024

Background

Respiratory viral infections are common and are a major cause of morbidity and mortality. We evaluated the impact of universal masking implemented during the coronavirus disease 2019 (COVID-19) pandemic on other healthcare-associated respiratory viral infections (HA-RIs) in an academic medical center.

Methods

A retrospective cohort study was performed among all inpatients aged ≥18 years admitted between 1 May 2019 and 30 June 2022. Universal masking was implemented in May 2020 at our hospital and state-level mask mandates had been lifted by May 2021. We evaluated and compared the HA-RI rates, adjusted for monthly community-onset viral infections, during the premasking period, universal masking period, and post–community mandate period.

Results

We identified 3015 patients (median age, 58 years; 48.0% males) with a positive respiratory viral test within 14 days prior to, or during, their hospitalization; 441 (14.6%) patients had an HA-RI. Rhinovirus/enterovirus (51.0%), parainfluenza virus (14.3%), coronaviruses (229E, OC43, HKU1, and NL63; 13.2%) and influenza (10.0%) were the predominant HA-RI viruses detected. The monthly HA-RI rate decreased 34.9% (95% confidence interval, 8.8%–51.8%) after the implementation of universal masking (0.71 premasking period vs 0.19 universal masking period vs 0.35 infections per 1000 patient-days in the post–community mandate period) while accounting for a drop in the community-onset respiratory viral infections using a structural time-series model analysis (P < .001), with no significant change in HA-RI rates with the relaxation of community masking mandate.

Conclusions

Implementation of universal masking at our hospital was associated with a significantly reduced incidence of HA-RIs.
Evaluation of Primary Oral Vancomycin Prophylaxis Against Clostridioides difficile Infection During Autologous Stem Cell Transplantation
Authors: Williams Michael J , Atienza Sol , Franzen Erin , Rathod Heena , Mejaki Brittany , Graff Justin , Korman Sandra , Zouine Noah , Gul Zartash , Sana Sherjeel , Medlin Stephen , Buggy Brian P
Published: October 2024

Background

Evaluations of oral vancomycin prophylaxis (OVP) against Clostridioides difficile have been reported in stem cell transplant populations with short follow-up periods. The longest known duration of standardized follow-up post-OVP is 90 days within an allogeneic stem cell transplant population. In 2017, we implemented OVP 125 mg twice daily in autologous stem cell transplant (ASCT) recipients beginning the day of admission and continued until the day of discharge.

Methods

Patients who received an ASCT within our institution between 1 January 2012 and 31 December 2021 were included and separated into 2 groups based on the receipt of OVP. The primary study aim was to measure the incidence of C difficile infection (CDI) during the ASCT admission. A secondary aim was to evaluate for delayed CDI 180 days post-discharge. Other factors evaluated were prior history of CDI, use of systemic antimicrobials, and length of stay.

Results

Overall, 254 patients were evaluated and 58% received OVP, predominantly as primary prophylaxis (95%). Of the 18 patients who developed in-hospital CDI, 6 were in the OVP group versus 12 in the non-OVP cohort (4% vs 11%, P = .03). In the 180-day follow-up period, OVP use did not increase risk of developing CDI after discontinuation while in-hospital length of stay was identified as a significant factor.

Conclusions

The use of OVP significantly reduced the incidence of CDI during the in-hospital ASCT course without increasing CDI post-OVP use. These encouraging results should promote further research into the use of OVP in ASCT.
Opioid use and adverse health effects in breast cancer survivors
Authors: Haque Reina , Chen Lie Hong , Shi Jiaxiao , Gu Zheng , Brady-Rogers Moira , Chlebowski Rowan T , Hechter Rulin C
Published: October 2024

Background

Little information exists on adverse effects related to opioid use in breast cancer survivors following active cancer treatment, and no studies included an age-matched comparison group. Thus, we examined opioid use and risk of falls, fractures, lung problems, and cardiovascular events in breast cancer survivors in the years following active cancer treatment along with a comparison group.

Methods

We conducted a longitudinal cohort study 33 989 breast cancer survivors and 157 609 age-matched women without cancer. Rates of adverse events, and multivariable hazards ratios for association between opioid use and the adverse health effects were calculated.

Results

Women with breast cancer had greater opioid use (60% vs 48%); longer median opioid duration (18 vs 16 days); and were prescribed stronger opioids than the matched cohort over 5.6 median years of follow-up. In multivariable models, the risk of falls was 12% higher (HR, 95% CI, 1.12 [1.07-1.17]), and fracture risk was 56% (HR = 1.56 [1.48-1.65]) greater in women with breast cancer who used opioids vs the matched cohort unexposed to opioids. In an analysis restricted to women with breast cancer, opioid use was strongly associated with the risk of falls (HR = 1.74 [1.63-1.85]); fractures (HR = 2.10 [1.95-2.27]); lung problems (HR = 1.53 [1.43-1.64]); and cardiovascular events (HR = 1.70 [1.39-2.08]) than opioid non-use.

Conclusions

After active cancer treatment, opioid use and high dosage use were common in breast cancer survivors, and were associated with increased risk for falls, lung problems, fractures, and cardiovascular events. Findings underscore the need for careful monitoring of opioid use in these survivors and the exploration of alternative pain management strategies.
Therapeutic targets for gastrointestinal diseases: proteome-wide Mendelian randomization and colocalization analyses
Authors: Zhan Daqin , Yang Zhihao , Li Pengcheng , Pan Jun
Published: October 2024

Purpose

This study was aimed to identify serum proteins linked with gastrointestinal diseases by proteome-wide Mendelian randomization analysis.

Methods

We determined the casual relationship between 732 kinds of circulating proteins and the 24 kinds of gastrointestinal diseases via Mendelian randomization analysis.

Results

Four circulating proteins (FCGR3B, IL-12B, MAPKAPK2, and IL-23R) were associated with the occurrence of ulcerative colitis (UC), and IL23R was also correlated with risk of Crohn's disease (CD). Genetically predicted levels of IL23R were strongly correlated with the risk of UC and CD based on the high supporting evidence of colocalization analysis. Five circulating proteins (NOV, EFEMP1, ADGRE2, LCT, and SEMA3G) were associated with the risk of diverticulosis disease. With high supporting evidence of colocalization, genetically predicted levels of NOV and SEMA3G were inversely correlated with the risk of diverticulosis disease. Five circulating proteins (FUT3, FUT5, CRHBP, SULT2A1, and QPCTL) were associated with the occurrence of cholelithiasis. With high supporting evidence of colocalization, genetically predicted levels of FUT3 and CRHBP were inversely correlated with the risk of cholelithiasis.

Conclusions

The proteome-wide Mendelian randomization investigation identified several circulating proteins associated with the risk of UC, CD, diverticular disease and cholelithiasis, which reinforced the understanding of molecular pathogenesis and design of therapeutic targets.
Peri-operative strategy in resuscitation of unstable injured surgical patients: a primer
Authors: Abdulkhaleq Mamalchi Shahad , Matar Maher , Bass Gary Alan
Published: October 2024

Background

Trauma remains a leading cause of death, both for individuals under 40 in North America, and globally, where it contributes to ~10% of deaths annually. Thoughtful, timely, balanced resuscitation, especially in the peri-operative period for unstable injured surgical patients, is vital for optimizing outcomes. The advanced trauma life support protocol plays a pivotal role in early evaluation and management, emphasizing hemorrhage control and resuscitation strategies.

Objective

This narrative review provides a structured, evidence-based framework aimed at enhancing the educational experience of surgical trainees. It outlines key principles in peri-operative trauma resuscitation, emphasizing timely intervention, goal-directed fluid therapy, and damage control surgery (DCS) to improve patient outcomes.

Methods

A comprehensive Scale for Quality Assessment of Narrative Review Articles -guideline compliant literature search was conducted using PubMed and Google Scholar for English-language articles published between January 2000 and February 2024. The search included relevant medical subject headings terms. Additional studies were identified from reference lists. Extracted data were reviewed and organized using thematic analysis, focusing on historical perspectives, evidence-based practices, and the concept of DCS.

Results

Key findings from the 55 relevant studies selected underscore the importance of balanced fluid and blood product administration, the use of permissive hypotension in hemorrhagic shock, and the application of DCS principles. This review highlights educational strategies that foster a deeper understanding of trauma resuscitation practices, offering practical insights through case studies and technological innovations.

Conclusion

This review serves as an educational resource for surgical trainees, equipping them with a robust understanding of evidence-based trauma resuscitation. By integrating historical context, modern practices, and emerging technologies, the review aims to enhance both the theoretical knowledge and practical skills necessary for managing unstable trauma patients. Emphasis is placed on interdisciplinary teamwork, continuous education, and personalized resuscitation strategies to improve clinical outcomes.
Serial assessment of ultrasound sensitivity and scores in patients with giant cell arteritis before and 3 and 10 days after treatment
Authors: Hansen Morten , Hansen Ib Tønder , Keller Kresten Krarup , Therkildsen Philip , Hauge Ellen-Margrethe , Nielsen Berit Dalsgaard
Published: October 2024

Objectives

The objective of this study was to evaluate the sensitivity and scores of vascular US before and after initiating glucocorticoid (GC) treatment in patients with new-onset giant cell arteritis (GCA).

Methods

Treatment-naïve patients with GCA were prospectively included. 18F-fluorodeoxyglucose (18F-FDG) PET/CT, US and temporal artery (TA) biopsy were performed in all patients. US was repeated 3 and 10 days after GC commencement. Intima-media thickness and presence of halo signs were assessed. Sonographers were unblinded to the clinical data. The OMERACT GCA Ultrasonography score (OGUS) and the halo count (HC) were calculated.

Results

Forty-eight patients were included. Before GC exposure, US sensitivity was 94% (95% CI: 83–99), 73% (95% CI: 58–85), and 71% (95% CI: 56–83) when assessing all vessels, TAs, and large vessels (LVs), respectively. At day 3 and 10, the overall US sensitivity was 92% (95% CI: 78–98, P = 0.16) and 83% (95% CI: 69–92, P = 0.10), respectively. At day 10, the TA-US and LV-US sensitivity was 53% (95% CI: 38–68, P < 0.01) and 60% (95% CI: 44–74, P = 0.13), respectively. The median OGUS decreased from 1.06 (IQR 0.83–1.24) to 0.95 (IQR 0.78–1.14, P < 0.01) and 0.90 (IQR 0.73–1.01, P < 0.001) after 3 and 10 days, respectively. The median HC decreased from 3 (IQR 2–5) to 2 (IQR 1–4, P < 0.01) after 10 days.

Conclusion

The vasculitic US findings expressed by OGUS diminished after 3 days of GC treatment. TA-US sensitivity decreased after 10 days, whereas LV-US was less likely to change, highlighting the importance of LV-assessment. Consistent with the EULAR recommendations, these findings encourage prompt US assessment, preferably within 3 days, to ensure an accurate diagnosis.
Exploring the Interactions Between Psychotic Symptoms, Cognition, and Environmental Risk Factors: A Bayesian Analysis of Networks
Authors: Bosma Minke J , Marsman Maarten , Vermeulen Jentien M , Huth Karoline B S , de Haan Lieuwe , Alizadeh Behrooz Z , Simons Claudia J P , Schirmbeck Frederike
Published: October 2024

Background and Hypothesis

Psychotic disorders (PDs) have huge personal and societal impact, and efforts to improve outcomes in patients are continuously needed. Environmental risk factors (ERFs), especially modifiable risk factors, are important to study because they pose a target for intervention and prevention. No studies have investigated ERFs, cognition, and psychotic symptoms together in a network approach.

Study Design

We explored interactions between 3 important ERFs (tobacco smoking, cannabis use, and childhood trauma), 6 cognitive domains, and 3 dimensions of symptoms in psychosis. From the Genetic Risk and Outcome of Psychosis (GROUP) cohort, we used data from patients, siblings, and healthy controls to construct networks using Bayesian analyses of all 12 variables. We constructed networks of the combined sample and of patients and siblings separately.

Study Results

We found that tobacco smoking was directly associated with cognition and psychotic symptoms. The cognitive variable processing speed was the most central node, connecting clusters of psychotic symptoms and substance use through the variables of positive symptoms and tobacco smoking. Comparing the networks of patients and siblings, we found that networks were relatively similar between patients and siblings.

Conclusions

Our results support a potential central role of processing speed deficits in PDs. Findings highlight the importance of integrating tobacco smoking as potential ERFs in the context of PDs and to broaden the perspective from cannabis discontinuation to smoking cessation programs in patients or people at risk of PDs.
Reproductive safety of STING agonists MSA-2 and manganese-MSA-2
Authors: Cai Ya , He Tian , Yang Tao , Li Yating , Yi Lirong , Li Wenqing , Zhou Peng
Published: October 2024

Background

MSA-2, as an oral molecule for activating STING signaling pathway to cure the tumor entering clinical trials. The toxicity of MSA-2 has aroused wide concern, especially the reproductive toxicity can not be ignored.

Objectives

We synthesized the STING agonist (MSA-2) and its derivative manganese-MSA-2 (MSA-2-Mn) and investigated the reproductive toxicity.

Methods

We evaluated the reproductive effects of MSA-2 and MSA-2-Mn in female mice under the administration alone and on the reproductive system of male mice in the presence or absence of combined radiation.

Results

Results suggested that MSA-2 and MSA-2-Mn have negligible reproductive toxicity in healthy adults. Conclusions: This provides new ideas to enhance the efficacy of immunotherapy, as well as favorable evidence for future systemic dosing in patients of reproductive age and clinical trials of immunotherapy.
CD74+ fibroblasts proliferate upon mechanical stretching to promote angiogenesis in keloids
Authors: Zhang Jingheng , Li Shuyao , Kuang Chunmei , Shen Yunfan , Yu Haibin , Chen Fang , Tang Ruijun , Mao Song , Lv Lu , Qi Min , Zhang Jianglin , Yuan Kai
Published: October 2024

The healing of human skin wounds is susceptible to perturbation caused by excessive mechanical stretching, resulting in enlarged scars, hypertrophic scars, or even keloids in predisposed individuals. Keloids are fibro‐proliferative scar tissues that extend beyond the initial wound boundary, consisting of the actively progressing periphery and the quiescent center. The stretch‐associated outgrowth and enhanced angiogenesis are two features of the periphery of keloids. However, which cell population is responsible for transducing the mechanical stimulation to the progression of keloids remains unclear. Herein, through integrative analysis of single‐cell RNA sequencing of keloids, we identified CD74+ fibroblasts, a previously unappreciated subset of fibroblasts with pro‐angiogenic and stretch‐induced proliferative capacities, as a key player in stretch‐induced progression of keloids. Immunostaining of keloid cryosections depicted a predominant distribution of CD74+ fibroblasts in the periphery, interacting with the vasculature. In vitro tube formation assays on purified CD74+ fibroblasts ascertained their pro‐angiogenic function. BrdU assays revealed that these cells proliferate upon stretching, through PIEZO1‐mediated calcium influx and the downstream ERK and AKT signaling. Collectively, our findings propose a model wherein CD74+ fibroblasts serve as pivotal drivers of stretch‐induced keloid progression, fueled by their proliferative and pro‐angiogenic activities. Targeting the attributes of CD74+ fibroblasts holds promise as a therapeutic strategy for the management of keloids.
Brief Communication: Combination of an MIP3α-Antigen Fusion Therapeutic DNA Vaccine With Treatments of IFNα and 5-Aza-2′Deoxycytidine Enhances Activated Effector CD8+ T Cells Expressing CD11c in the B16F10 Melanoma Model
Authors: Fessler Kaitlyn , Zhang Jiaqi , Sandhu Avinaash K. , Hui Yinan , Kapoor Aakanksha R. , Ayeh Samuel K. , Karanika Styliani , Karakousis Petros C. , Markham Richard B. , Gordy James T.
Published: October 2024

Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to macrophage-inflammatory protein 3-alpha (MIP3α) with recombinant interferon alpha (IFN) and 5-Aza-2′-deoxycytidine (5Aza) treatments resulted in significantly greater antitumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in an increase in the TME of a distinct CD11c+ CD8+ T-cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared with CD11c− CD8+ T cells. In conclusion, this combination therapy results in a greater presence of highly active effector CD8+ T cells expressing CD11c in the TME, which are likely primary contributors to treatment efficacy.
Protocol of clinical population pharmacokinetics/pharmacodynamics analysis of alkaloids from the leaves of Alstonia scholaris in acute bronchitis patients
Authors: He Chunying , Cao Weiyi , Zhang Wantong , Zhao Yunli , Luo Xiaodong , Li Rui
Published: October 2024

Objective:

To validate whether orally administered capsules of alkaloids from the leaves of Alstonia scholaris (CALAS) can improve the clinical indices of acute bronchitis and to investigate the alterations in the relationship between its composition and pharmacodynamic markers, thereby providing a clinical reference for the administration of this medication.

Methods:

This is a prospectively planned, blinded, placebo-controlled, parallel-grouped clinical trial with aggregated population pharmacokinetics/pharmacodynamics (PPK/PPD) data. A total of 55 subjects will be randomly allocated into 4 arms; specifically, 10 of the 55 subjects will be selected randomly for the placebo arm, and will be orally administered placebo (Tid), and 45 subjects will be randomly assigned to CALAS treatment groups (20 mg, 40 mg, and 80 mg Tid, at 15 subjects per group). The medication, presence of cough and phlegm, as well as body temperature of every subject, will be recorded daily during treatment. About 3–4 blood samples will be collected from each subject at the following points for PPK/PPD parameters analysis: at pre-dose (0 h) and post-dose at 15 minutes, 40 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 30 hours, and 48 hours after last dosing. All the subjects will be subjected to a laboratory examination and efficacy evaluation on day 8.

Discussion:

A new integrating strategy to explore the relationship among drug components, action pathways, and clinical efficacy will be established through this study. We aim to explore the mechanism of action of CALAS in the treatment of acute bronchitis on the premise of definite active ingredients and reliable clinical efficacy. It is difficult to enroll patients in classic pharmacokinetics research because it adopts an intensive sampling method, and it cannot quantify the variability of pharmacokinetics parameters (intraindividual variation, interindividual variation, and weekly variation). Moreover, the extrapolation and prediction of dosage regimens in different species and populations cannot be achieved. Therefore, the PPK/PPD method, which takes advantage of sparse data (3–5 time points sampling per patient), is adopted to determine the measurable pathologic and physiological factors that can influence dose concentration to guide reasonable dose adjustment toward achieving optimal clinical effects.
Ocular Ultrasound, a neglected tool in the diagnosis of central retinal artery occlusion.
Authors: Sukkarieh Georges , Bonk William , Fisher Yale L , Haddock Luis J.
Published: October 2024

Purpose:

To discuss the practical utility of ocular ultrasound in central retinal artery occlusion (CRAO).

Methods:

Ocular ultrasound was obtained in 4 patients with CRAO using a 20 MHz Annular Array Probe of the ABSolu (Quantel Medical, Texas, USA) ultrasound machine.

Results:

The causative embolus occluding the central retinal artery was detected on ocular ultrasound imaging in four patients with CRAO.

Conclusion:

Ocular ultrasound, including newer generation, higher frequency ultrasound probes, aids in the detection of the “retrobulbar spot sign”, a finding that seems to be related to embolic central retinal artery occlusion. This sign will orient investigations towards finding an embolic source.
On the relation of injury to pain—an infant perspective*
Authors: Fitzgerald Maria
Published: October 2024

Forty-five years ago, Patrick Wall published his John J Bonica lecture “On the relation of injury to pain.”
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In this lecture, he argued that pain is better classified as an awareness of a need-state than as a sensation. This need state, he argued, serves more to promote healing than to avoid injury. Here I reframe Wall's prescient proposal to pain in early life and propose a set of different need states that are triggered when injury occurs in infancy. This paper, and my own accompanying Bonica lecture, is dedicated to his memory and to his unique contribution to the neuroscience of pain. The IASP definition of pain includes a key statement, “through their life experiences, individuals learn the concept of pain.”
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But the relation between injury and pain is not fixed from birth. In early life, the links between nociception (the sense) and pain (the need state) are very different from those of adults, although no less important. I propose that injury evokes three pain need states in infancy, all of which depend on the state of maturity of the central nervous system: (1) the need to attract maternal help; (2) the need to learn the concept of pain; and (3) the need to maintain healthy activity dependent brain development.
Severe acquired Factor VII deficiency complicating an aplastic anemia, successfully treated with corticosteroids
Authors: Batton Romain , Pierre Chamouni , Carrette Marion , Gaëtan Sauvêtre , Barbay Virginie
Published: October 2024

Factor VII deficiency is a rare hemostatic disorder that can lead to severe clinical outcomes. Due to the scarcity of reported cases, treatment guidelines for this condition remain unclear. In this report, we present a case of acquired factor VII deficiency (aFVII) in an elderly female with medullary aplasia. The initial clinical manifestation was hemarthrosis, accompanied by a rapid increase in prothrombin time. Prompt intervention involved supplementation to address the deficiency. Subsequent laboratory testing failed to detect any specific factor VII inhibitor. Considering the patient's frailty, immunosuppressive therapy comprising only corticosteroids was administered. The potential triggering mechanisms may include recurrent episodes of sepsis or an underlying autoimmune condition. Further research is necessary to better understand the etiology and optimal management of aFVII deficiency.
The role of factor XIII in patient blood management
Authors: Žunić Miodrag , Vreča Nino , Bevc Sebastjan
Published: October 2024

Factor XIII (FXIII), a plasma transglutaminase, is a coagulation factor that plays a crucial role in blood clotting and patient blood management. The studies have demonstrated that FXIII targets a wide range of additional substrates that have an important role in hemostasis, especially in posttraumatic patients, patients undergoing surgery or obstetrics, being involved in wound healing and tissue repair. Morover, FXIII deficiency has also been described and an extensive research has shown that FXIII deficiency is a rare coagulopathy that leads to longer bleeding time, perioperative and postoperative complications and slower wound healing.

Present article aims to overview the diverse functions of FXIII and to highlight its role in patient blood management.
Cervical myelopathy mistaken for complex regional pain syndrome: A case report
Authors: Bak Jiwon , Hwang Byeongmun
Published: October 2024

Rationale:

Degenerative cervical myelopathy (DCM) is characterized by spastic gait impairment, upper limb dysfunction, and sphincter disturbances. The pathological mechanism involves a combination of mechanical compression and ischemic processes, which are most commonly associated with the narrowing of the vertebral canal. However, DCM requires differential diagnosis from diseases of the central nervous system that cause neuropathic pain, such as complex regional pain syndrome (CRPS) and postherpetic neuralgia.

Patient concerns:

This report presents a case of DCM misdiagnosed as CRPS. Delayed diagnosis can lead to residual symptoms and functional disability.

Diagnoses:

Definitive diagnosis requires a correlation between physical findings and imaging results. Magnetic resonance imaging is the modality of choice, and spinal cord compression is the hallmark finding.

Interventions:

Anterior cervical discectomy and fusion.

Outcomes:

At the 8-week postoperative follow-up, the patient reported reduced pain. Arm function was almost normal, and although the gait was unstable, he was able to walk without assistance.

Lessons:

DCM can be easily confused with CRPS or postherpetic neuralgia. Therefore, physicians should consider the presence of different neuropathic pain syndromes when neuropathic pain develops. Patients with prior conditions affecting the cervical spine should be aware of the potential development of cervical myelopathy.