bluuebunny/crossref_metadata_2025 huggingface dataset:
Night-time sleep duration and postpartum weight retention in primiparous women
Authors: Ryan Jeanna T , Day Heather , Egger Marlene J , Wu Jiqiang , Depner Christopher M , Shaw Janet M
Published: December 2023

Objectives

Approximately 75% of women weigh more at 1-year postpartum than pre-pregnancy. More than 47% retain >10 lbs at 1-year postpartum, which is associated with adverse health outcomes for mother and child. Disturbed sleep may contribute to risk of postpartum weight retention (PWR) as short sleep duration is associated with increased risk of obesity. Thus, we investigated whether night-time sleep duration is associated with risk for excessive PWR. We also explored night-time sleep duration and change in postpartum waist circumference.

Methods

This is an ancillary analysis from a prospective cohort study. Participants were healthy primiparous adults with a singleton birth. Excessive PWR at 1-year postpartum was defined as ≥7% of pre-pregnancy weight. Log-binomial and linear regression assessed associations between night-time sleep duration at 6 months postpartum and PWR at 1-year postpartum. Linear regression assessed the association between night-time sleep duration and change in postpartum waist circumference.

Results

Mean age of participants (N = 467) was 29.51 (SD ± 4.78) years. Night-time sleep duration by actigraphy or self-report was not associated with risk for excessive PWR (risk ratio 0.96, [95%CI 0.87–1.06]; risk ratio 0.95 [95%CI 0.83–1.07], respectively) or change in waist circumference.

Conclusion

Night-time sleep duration at 6 months postpartum was not associated with PWR at 1-year postpartum. Mixed findings among our results and previous research could be due to our focus on night-time sleep, and differences in sleep measurement methods and timeframes across studies. More comprehensively assessing sleep, including multiple sleep dimensions, may help advance our understanding of potential links between sleep and PWR.

Trial Registration

The parent study, Motherhood and Pelvic Health (MAP Study), is registered at https://clinicaltrials.gov/ct2/show/NCT02512016, NCT02512016.
Court of Cassation, Sec. II, 17 February 2023, No. 5073: foreign discretionary trusts and protection of forced heirs in Italy
Authors: Cenini Marta
Published: December 2023

The judgment under comment contains some valuable statements that may now be considered as milestones in the matter of trusts in the Italian legal system. First, the Italian Supreme Court held that a discretionary family trust which allegedly impairs the portion reserved for the forced heirs is valid and recognisable under the Hague Convention on trusts and that the only remedy available to the forced heirs is an action for reduction (“azione di riduzione”, clawback action). Although the subject matter of the dispute was not the reduction of transfers in trust, the Court also provides guidance as to who is the plaintiff and who is the defendant in an action for reduction and as to other conditions for the action. However, there are still some open questions concerning the jurisdiction and enforcement of judgments in legal systems that provide for the so-called firewall provisions.
Integrating career, health, and finance in a holistic retirement planning intervention for Australian older workers
Authors: Mooney Anna , Earl Joanne , Gerrans Paul , Wijeratne Chanaka , Mooney Carl
Published: December 2023

Inadequate retirement planning has negative consequences for individuals and society. Interventions to improve more informed planning often focus primarily on financial aspects, with the timing of workplace exit and health considerations ignored leaving retirees at risk of poor adjustment. A six-stage intervention was developed consisting of three online modules (career, health, and finance) combined with individual consultations that aimed to assist older workers (N = 829, Mage = 57.09, female = 68%) to make more considered decisions about retirement. A randomized control study using four groups (modules only, modules-plus-consultations [holistic], finance only, and a control) was employed. Holistic group participants completed three online modules, completed a general health check, and spoke to a career consultant, as well as a financial consultant. Compared with the control group, mixed-effects regressions showed improved intervention outcomes across all three experimental groups. Of these, the holistic group had the largest number of significant outcomes including increased workplace exit perceptions, financial decision-making, and career and finance goal processes. We discuss the theoretical and practical implications of integrating online modules with retirement consultations to optimize retirement decision-making.
Three-Dimensional Ultrastructure of Arabidopsis Cotyledons Infected with Colletotrichum higginsianum
Authors: Regmi Kamesh C. , Ghosh Suchismita , Koch Benjamin , Neumann Ulla , Stein Barry , O'Connell Richard J. , Innes Roger W.
Published: December 2023

We used serial block-face scanning electron microscopy (SBF-SEM) to study the host–pathogen interface between Arabidopsis cotyledons and the hemibiotrophic fungus Colletotrichum higginsianum. By combining high-pressure freezing and freeze-substitution with SBF-SEM, followed by segmentation and reconstruction of the imaging volume using the freely accessible software IMOD, we created 3D models of the series of cytological events that occur during the Colletotrichum–Arabidopsis susceptible interaction. We found that the host cell membranes underwent massive expansion to accommodate the rapidly growing intracellular hypha. As the fungal infection proceeded from the biotrophic to the necrotrophic stage, the host cell membranes went through increasing levels of disintegration culminating in host cell death. Intriguingly, we documented autophagosomes in proximity to biotrophic hyphae using transmission electron microscopy (TEM) and a concurrent increase in autophagic flux between early to mid/late biotrophic phase of the infection process. Occasionally, we observed osmiophilic bodies in the vicinity of biotrophic hyphae using TEM only and near necrotrophic hyphae under both TEM and SBF-SEM. Overall, we established a method for obtaining serial SBF-SEM images, each with a lateral ( x-y) pixel resolution of 10 nm and an axial ( z) resolution of 40 nm, that can be reconstructed into interactive 3D models using the IMOD. Application of this method to the Colletotrichum–Arabidopsis pathosystem allowed us to more fully understand the spatial arrangement and morphological architecture of the fungal hyphae after they penetrate epidermal cells of Arabidopsis cotyledons and the cytological changes the host cell undergoes as the infection progresses toward necrotrophy.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Unveiling the Slippery Secrets of Saliva: Effector Proteins of Phloem-Feeding Insects
Authors: Bleau Jade R. , Gaur Namami , Fu Yao , Bos Jorunn I. B.
Published: December 2023

Phloem-feeding insects include many important agricultural pests that cause crop damage globally, either through feeding-related damage or upon transmission of viruses and microbes that cause plant diseases. With genetic crop resistances being limited to most of these pests, control relies on insecticides, which are costly and damaging to the environment and to which insects can develop resistance. Like other plant parasites, phloem-feeding insects deliver effectors inside their host plants to promote susceptibility, most likely by a combination of suppressing immunity and promoting nutrient availability. The recent emergence of the effector paradigm in plant–insect interactions is highlighted by increasing availability of effector repertoires for a range of species and a broadening of our knowledge concerning effector functions. Here, we focus on recent progress made toward identification of effector repertoires from phloem-feeding insects and developments in effector biology that will advance functional characterization studies. Importantly, identification of effector activities from herbivorous insects promises to provide new avenues toward development of crop protection strategies.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Clarifying the Functional Role of Serotonin in Meloidogyne graminicola Host Plant Parasitism by Immunolocalization and RNA Interference
Authors: Yang Zhuhong , Zhang Zixu , Long Xiping , Shi Xuqi , Wang Di , Peng Deliang , Ye Shan , Ding Zhong
Published: December 2023

Serotonin (5-hydroxytryptamine) is an essential neurotransmitter involved in regulating various behaviors in plant-parasitic nematodes, including locomotion, egg laying, feeding, and mating. However, the functional role of serotonin in root-knot nematode invasion of host plants and the molecular mechanisms underlying feeding behavior remain poorly understood. In this study, we tested the effects of exogenous serotonin and the pharmacological compounds fluoxetine and methiothepin on the feeding behaviors of Meloidogyne graminicola. Our results suggested that M. graminicola possesses an endogenous serotonin signaling pathway and that serotonin plays a crucial role in modulating feeding behaviors in M. graminicola second-stage juveniles. We also identified and cloned the serotonin synthesis enzyme tryptophan hydroxylase ( Mg-tph-1) in M. graminicola and investigated the role of endogenous serotonin by generating RNA interference nematodes in Mg-tph-1. Silencing Mg-tph-1 substantially reduced nematode invasion, development, and reproduction. According to the immunostaining results, we speculated that these serotonin immunoreactive cells near the nerve ring in M. graminicola are likely homologous to Caenorhabditis elegans ADFs, NSMs, and RIH serotonergic neurons. Furthermore, we investigated the impact of phytoserotonin on nematode invasion and development in rice by overexpressing OsTDC-3 or supplementing rice plants with tryptamine and found that an increase in phytoserotonin increases nematode pathogenicity. Overall, our study provides insights into the essential role of serotonin in M. graminicola host plant parasitism and proposes that the serotonergic signaling pathway could be a potential target for controlling plant-parasitic nematodes.
Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti‐parasitic target
Authors: Pan Ming , Ge Ceng‐Ceng , Niu Shui‐Zhu , Duan Yin‐Yan , Fan Yi‐Min , Jin Qi‐Wang , Chen Xiang , Tao Jian‐Ping , Huang Si‐Yang
Published: December 2023

Toxoplasma gondii relies heavily on the de novo pyrimidine biosynthesis pathway for fueling the high uridine‐5′‐monophosphate (UMP) demand during parasite growth. The third step of de novo pyrimidine biosynthesis is catalyzed by dihydroorotase (DHO), a metalloenzyme that catalyzes the reversible condensation of carbamoyl aspartate to dihydroorotate. Here, functional analyses of TgDHO reveal that tachyzoites lacking DHO are impaired in overall growth due to decreased levels of UMP, and the noticeably growth restriction could be partially rescued after supplementation with uracil or high concentrations of L‐dihydroorotate in vitro. When pyrimidine salvage pathway is disrupted, both DHOH35A and DHOD284E mutant strains proliferated much slower than DHO‐expressing parasites, suggesting an essential role of both TgDHO His35 and Asp284 residues in parasite growth. Additionally, DHO deletion causes the limitation of bradyzoite growth under the condition of uracil supplementation or uracil deprivation. During the infection in mice, the DHO‐deficient parasites are avirulent, despite the generation of smaller tissue cysts. The results reveal that TgDHO contributes to parasite growth both in vitro and in vivo. The significantly differences between TgDHO and mammalian DHO reflect that DHO can be exploited to produce specific inhibitors targeting apicomplexan parasites. Moreover, potential DHO inhibitors exert beneficial effects on enzymatic activity of TgDHO and T. gondii growth in vitro. In conclusion, these data highlight the important role of TgDHO in parasite growth and reveal that it is a promising anti‐parasitic target for future control of toxoplasmosis.
Comparison of the Efficacy of HSK3486 and Propofol for Induction of General Anesthesia in Adults: A Multicenter, Randomized, Double-blind, Controlled, Phase 3 Noninferiority Trial
Authors: Gan Tong J. , Bertoch Todd , Habib Ashraf S. , Yan Pangke , Zhou Rong , Lai Yu-Ling , Liu Xiao , Essandoh Michael , Daley William L. , Gelb Adrian W.
Published: December 2023

Background

Propofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a 2,6-disubstituted phenol derivative with fast onset and quick, stable recovery. Previous studies support HSK3486 as an effective, safe anesthetic with substantially less injection-site pain than propofol. The primary objective of this study was to investigate the noninferiority of HSK3486 compared with propofol in successful general anesthesia induction.

Methods

Two hundred fifty-five participants were enrolled in HSK3486-304, a multicenter, randomized (2:1), double-blind, propofol-controlled, phase 3 study evaluating HSK3486 for general anesthesia induction in adults undergoing elective surgery with tracheal intubation. The primary endpoint was successful anesthesia induction, defined as 1 or less on the Modified Observer’s Assessment of Alertness/Sedation scale. Key secondary endpoints were proportion of participants with injection-site pain on the Numerical Rating Scale of 1 or greater and a composite endpoint, including the proportion of participants successfully induced while maintaining the desired anesthetic depth and without substantial cardiac and respiratory events. Safety endpoints included adverse events, abnormal vital signs, and injection-site pain.

Results

Two hundred fifty-one participants (HSK3486, n = 168; propofol, n = 83) were included in the analyses. General anesthesia was successfully induced in 97.0% versus 97.6% of participants with HSK3486 and propofol, respectively. The difference in success rate was −0.57% (95% CI, −5.4 to 4.2%); the noninferiority boundary of −8% was not crossed. Thirty participants (18.0%) had injection-site pain with HSK3486 versus 64 (77.1%) with propofol (P < 0.0001). Eighty-one participants (48.2%) with HSK3486 versus 42 (50.6%) with propofol (P = 0.8780) satisfied the composite endpoint. When injection-site pain was excluded, the incidence of treatment-emergent adverse events related to study drug was 17.9% for HSK3486 and 14.5% for propofol.

Conclusions

The study met its primary objective and endpoint, demonstrating noninferiority of HSK3486 compared with propofol in successful anesthetic induction. Substantially less injection-site pain was associated with HSK3486 than with propofol.

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Survival Benefit of Primary Tumor Resection Combined With Chemotherapy in Patients With Unresectable Colorectal Mucinous Adenocarcinoma With Liver Metastasis
Authors: Liao Shu-wen , Zhan Jie-qun , Liu Chu-tian , Yu Hai-tao , Wen Min-jie
Published: December 2023

Objective:

To evaluate the survival benefit of combining primary tumor resection (PTR) and chemotherapy in patients with unresectable colorectal mucinous adenocarcinoma with liver metastasis (UCR-MAC-LM).

Methods:

We obtained data from the surveillance, epidemiology, and end results database for patients with UCR-MAC-LM from 2010 to 2017. Clinicopathological characteristics were analyzed using the χ2 test. Propensity score matching was performed to balance baseline characteristics. Kaplan-Meier analysis and log-rank tests were used to estimate and compare survival outcomes. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic factors.

Results:

A total of 10,178 patients with unresectable colorectal adenocarcinoma with liver metastasis were included, of whom 6.01% (n=612) had UCR-MAC-LM. The UCR-MAC-LM group had a higher proportion of female patients, a greater number of elderly patients, an increased incidence of right colon localization, larger tumor size, and higher T and N staging than the unresectable colorectal non-mucinous adenocarcinoma with liver metastasis group (P<0.05). Multivariate analysis identified several independent prognostic factors (P<0.05). Patients with unresectable colorectal adenocarcinoma with liver metastasis who underwent PTR+C had superior survival rates compared with those who received PTR/C alone or no treatment (cancer-specific survival, P<0.05; overall survival, P<0.05). Subgroup analysis revealed that 17 of 22 groups of patients with UCR-MAC-LM who received PTR+C had significantly prolonged long-term survival compared with those who received PTR/C alone.

Conclusions:

This surveillance, epidemiology, and end results-based study indicates that PTR+C may offer a survival advantage for a specific subgroup of patients with UCR-MAC-LM compared with PTR/C alone. Nonetheless, additional clinical trials are necessary to validate these findings.
ACR-ARS Practice Parameter for Communication
Authors: Saeed Hina , Wallner Paul E. , Bates James E. , Chundury Anupama , Freedman Laura M. , Mitin Timur , Walker Gary V. , Small William , Schechter Naomi R.
Published: December 2023

Objectives:

This practice parameter was revised collaboratively by the American College of Radiology (ACR), and the American Radium Society (ARS). Timely, accurate, and effective communications are critical to quality and safety in contemporary medical practices. Radiation oncology incorporates the science and technology of complex, integrated treatment delivery and the art of providing care to individual patients. Through written physical and/or electronic reports and direct communication, radiation oncologists convey their knowledge and evaluation regarding patient care, clinical workup, and treatment provided to others in the management of the patient. Applicable practice parameters need to be revised periodically regarding medical record documentation for professional and technical components of services delivered.

Methods:

This practice parameter was developed and revised according to the process described under the heading “The Process for Developing ACR Practice Parameters and Technical Standards” on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters—Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS. Both societies have reviewed and approved the document.

Results:

This practice parameter addresses radiation oncology communications in general, including (a) medical record, (b) electronic, and (c) doctor-patient communications, as well as specific documentation for radiation oncology reports such as (a) consultation, (b) clinical treatment management notes (including inpatient communication), (c) treatment (completion) summary, and (d) follow-up visits.

Conclusions:

The radiation oncologist’s participation in the multidisciplinary management of patients is reflected in timely, medically appropriate, and informative communication with patients, caregivers, referring physician, and other members of the health care team. The ACR-ARS Practice Parameter for Communication: Radiation Oncology is an educational tool designed to assist practitioners in providing appropriate communication regarding radiation oncology care for patients.
A Prospective, Single-Arm Study to Evaluate the Safety and Efficacy of RD2-Ver.02, an Autologous Blood Clot, in the Treatment of Anal Fistula
Authors: Ram Edward , Zager Yaniv , Carter Dan , Saukhat Olga , Anteby Roi , Nachmany Ido , Horesh Nir
Published: December 2023

BACKGROUND:

Surgical treatment of complex perianal fistula is technically challenging, associated with risk of failure, and may require multiple procedures. In recent years, several biologic agents have been developed for the purpose of permanently eradicating anal fistulous disease with variable success. RD2-Ver.02 treatment is an autologous whole blood product created from the patients’ blood, which forms a provisional matrix that was found to be safe and effective in healing acute and chronic cutaneous wounds.

OBJECTIVE:

To assess the efficacy and safety of RD2-Ver.02 as a treatment for transsphincteric perianal fistulas.

DESIGN:

A prospective single-arm study.

SETTINGS:

A single tertiary medical center.

PATIENTS:

Patients with simple or complex transsphincteric fistulas confirmed by magnetic resonance imaging were included in the study. Etiology was either cryptoglandular or Crohn’s related (in the absence of active luminal bowel disease).

INTERVENTION:

The outpatient procedure was performed under general anesthesia and consisted of: 1) physical debridement and cleansing of the fistula tract; 2) suture closure of the internal opening; and 3) instillation of RD2-Ver.02 into the entire tract.

MAIN OUTCOME MEASURES:

Safety and efficacy at 6- and 12-months following surgery.

RESULTS:

Fifty-three patients (77% male) with a median age of 42 (20-72) years were included in the study. Three patients withdrew consent, and 1 patient was lost to follow-up. At the time of this interim analysis, 49 and 33 patients completed the 6 and 12 months follow-up period, respectively. Thirty-four (34) patients achieved complete healing (69%) at 6 months while 20 patients out of 33 (60%) achieved healing after 1 year. All patients who achieved healing at 6 months remained healed at the 1 year mark. In a subgroup analysis of Crohn’s patients, 7 of 9 patients completed 1-year follow-up, with 5 patients (71%) achieving clinical remission. No major side effects or postoperative complications were noted, while 2 adverse events occurred (admission for pain control and COVID-19 infection).

LIMITATIONS:

Noncomparative single-arm pilot study.

CONCLUSIONS:

Treatment with RD2-Ver.02 in perianal fistular disease was found to be feasible and safe, with an acceptable healing rate in both cryptoglandular and Crohn’s fistula in ano. Further comparative assessment is required to determine its potential role in the treatment paradigm of fistula-in-ano. See Video Abstract.
Effects of Wuzhi Capsule on Whole-Blood Tacrolimus Concentration Levels: A Systematic Review and Meta-Analysis
Authors: Zhang Chunyan , Ren Xiaolei , Liu Yi , Huang Lin , Feng Yufei , Zhang Xiaohong
Published: December 2023

Background:

Wuzhi Capsule (WZC) is a traditional Chinese medicinal herb widely used to treat drug-induced hepatitis or liver dysfunction and is usually prescribed in China to increase tacrolimus concentration. Several studies with small sample sizes have shown that WZC can increase tacrolimus concentration levels in clinical practice. This study aimed to evaluate the effect of WZC on whole-blood tacrolimus concentration levels and safety.

Methods:

We searched 7 databases for randomized clinical trials (RCTs) and observational studies (OSs) comparing whole-blood tacrolimus concentration levels between WZC and non-WZC treatments. Data analysis was performed using Review Manager version 5.3. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.

Results:

Eleven studies involving 6 RCTs and 5 OSs were included. The meta-analysis indicated that whole-blood tacrolimus concentration levels in the WZC group was significantly higher than that of the non-WZC group [weighted mean difference = 1.38, 95% CI (confidence interval), 1.21–1.56, P < 0.001], and similar results were shown in all the subgroups of follow-up time, different primary disease, and different WZC doses. In the self-control OSs, the whole-blood tacrolimus concentration levels in the WZC group was significantly higher than the non-WZC group (weighted mean difference = 1.17, 95% CI, 0.71–1.64, P < 0.001). WZC was generally well tolerated and there was no significant difference in the incidence of adverse reactions between the 2 groups.

Conclusions:

WZC can increase whole-blood tacrolimus concentration levels. This may be an economical and practical treatment choice for patients, especially those with poor oral tacrolimus absorption capabilities. Nevertheless, RCTs and OSs with large sample sizes and high quality are needed in the future to confirm these positive results.
Fluorescein Angiography Evaluation of Children Previously Treated with Anti-VEGF Monotherapy for Retinopathy of Prematurity
Authors: Karademir Fatma Poslu , Vural Aslı , Özbaş Mehmet , Demirayak Bengi
Published: December 2023

Purpose:

To determine the level of vascularization and peripheral vascular findings by fluorescence angiography (FA) in patients with aggressive retinopathy of prematurity (A-ROP) or type 1 retinopathy of prematurity (ROP) treated with a single dose of anti-vascular endothelial growth factor (VEGF).

Methods:

Data of patients referred to our clinic for FA examination between June 2016 and September 2021 were retrospectively analyzed. Patients who had their first FA examination at the age of 1 year or older were included in the study.

Results:

A total of 486 eyes of 250 patients were included. Of these, 83 eyes (17.1%) had vascular termination in zone II and 403 eyes (82.9%) in zone III. In 62.7% of eyes, the distance from the vascular terminals to the temporal ora serrata was less than 2 disc diameters (DD) and in 20.2% it was more than 2 DD. Abnormal vascular findings were noted, including circumferential vessels (41.2%), finger-like projection anomaly (36.2%), hyperfluorescence (16.9%), fine branching and blunt termination (15%), and arteriovenous shunt (9.9%).

Conclusion:

FA performed late in the course of treatment can clearly define the vascular termini and detect abnormalities that cannot be detected by indirect ophthalmoscopy. Follow-up with FA can help prevent complications that can lead to vision loss.
From Hai Yao, Yang Yao to Xi Yao: Sinification of Material Medical from the West
Authors: Chiu Patrick
Published: December 2023

In ancient China, Daoist philosophers developed the concepts of qi (energy), Wu Xing (five elements), and yin (feminine, dark, negative) and yang (masculine, bright, positive) opposite forces between 200 and 600 BCE. Based on these philosophies, Zhen Jiu (acupuncture), Ben Cao (materia medica), and the practice of Qi Gong (energy optimization movements) evolved as the three interrelated therapeutic regimens of Chinese medicine (Note 1). Since the time of Zhang Qian, who discovered China’s western regions in the 1st century BCE, Hai Yao (the exotic elements of materia medica from the maritime Silk Road countries), had been transmitted from the ancient land and maritime routes of the Silk Road to China in the past two millennia (Note 2). Since the late 17th century, the English East India Company, later called the British East India Company, introduced Yang Yao (opium) to the Manchu Qing Empire to balance a growing trade deficit for tea export from China to the British Empire. After the First Opium War ended in 1842, enterprising expatriate chemists and druggists in the treaty ports imported Xi Yao (modern medicines from the Western world) for sale to the merchant navy and the local market. From the second half of the 19th century onwards, both Hai Yao and Xi Yao have become a fully integrated part of modern China’s armamentarium for the Chinese medicine and Western hospitals and retail pharmacy sectors. This paper articulates the journey of adoption of exotic elements of materia medica from the ancient land and sea routes of the Silk Road, including the western regions and the rest of the world in the past two millennia. Opium traders, ship surgeons, medical and pharmaceutical missionaries, enterprising traders, and policymakers together transformed Ben Cao into Xi Yao during the late Manchu Qing dynasty and the early Nationalist Era.
TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas
Authors: Libert Diane , Zhao Shuchun , Younes Sheren , Mosquera Alicia P. , Bharadwaj Sushma , Ferreira Cristiane , Natkunam Yasodha
Published: December 2023

Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival (P=0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.
Neighborhood Perceptions Are Associated With Intrinsic Amygdala Activity and Resting-State Connectivity With Salience Network Nodes Among Older Adults
Authors: Ortiz-Whittingham Lola R. , Zhan Liang , Ortiz-Chaparro Erika N. , Baumer Yvonne , Zenk Shannon , Lamar Melissa , Powell-Wiley Tiffany M.
Published: December 2023

Objective

Neighborhood perceptions are associated with physical and mental health outcomes; however, the biological associates of this relationship remain to be fully understood. Here, we evaluate the relationship between neighborhood perceptions and amygdala activity and connectivity with salience network (i.e., insula, anterior cingulate, thalamus) nodes.

Methods

Forty-eight older adults (mean age = 68 [7] years, 52% female, 47% non-Hispanic Black, 2% Hispanic) without dementia or depression completed the Perceptions of Neighborhood Environment Scale. Lower scores indicated less favorable perceptions of aesthetic quality, walking environment, availability of healthy food, safety, violence (i.e., more perceived violence), social cohesion, and participation in activities with neighbors. Participants separately underwent resting-state functional magnetic resonance imaging.

Results

Less favorable perceived safety (β = −0.33, p
FDR = .04) and participation in activities with neighbors (β = −0.35, p
FDR = .02) were associated with higher left amygdala activity, independent of covariates including psychosocial factors. Less favorable safety perceptions were also associated with enhanced left amygdala functional connectivity with the bilateral insular cortices and the left anterior insula (β = −0.34, p
FDR = .04). Less favorable perceived social cohesion was associated with enhanced left amygdala functional connectivity with the right thalamus (β = −0.42, p
FDR = .04), and less favorable perceptions about healthy food availability were associated with enhanced left amygdala functional connectivity with the bilateral anterior insula (right: β = −0.39, p
FDR = .04; left: β = −0.42, p
FDR = .02) and anterior cingulate gyrus (β = −0.37, p
FDR = .04).

Conclusions

Taken together, our findings document relationships between select neighborhood perceptions and amygdala activity as well as connectivity with salience network nodes; if confirmed, targeted community-level interventions and existing community strengths may promote brain-behavior relationships.
ENDOCANNABINOID SYSTEM IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS MODULATES AUTONOMIC AND CARDIOVASCULAR CHANGES BUT NOT VASOPRESSIN RESPONSE IN A RAT HEMORRHAGIC SHOCK MODEL
Authors: Busnardo Cristiane , Fassini Aline , Lopes-Azevedo Silvana , Omena-Giatti Luana , Goulart Melissa T. , Antunes-Rodrigues José , Alves Fernando H.F. , Corrêa Fernando M.A. , Crestani Carlos C.
Published: December 2023

We evaluated the participation of the endocannabinoid system in the paraventricular nucleus of the hypothalamus (PVN) on the cardiovascular, autonomic, and plasma vasopressin (AVP) responses evoked by hemorrhagic shock in rats. For this, the PVN was bilaterally treated with either vehicle, the selective cannabinoid receptor type 1 antagonist AM251, the selective fatty acid amide hydrolase amide enzyme inhibitor URB597, the selective monoacylglycerol-lipase enzyme inhibitor JZL184, or the selective transient receptor potential vanilloid type 1 antagonist capsazepine. We evaluated changes on arterial pressure, heart rate, tail skin temperature (ST), and plasma AVP responses induced by bleeding, which started 10 min after PVN treatment. We observed that bilateral microinjection of AM251 into the PVN reduced the hypotension during the hemorrhage and prevented the return of blood pressure to baseline values in the posthemorrhagic period. Inhibition of local 2-arachidonoylglycerol metabolism by PVN treatment with JZL184 induced similar effects in relation to those observed in AM251-treated animals. Inhibition of local anandamide metabolism via PVN treatment with URB597 decreased the depressor effect and ST drop induced by the hemorrhagic stimulus. Bilateral microinjection of capsazepine mitigated the fall in blood pressure and ST. None of the PVN treatments altered the increased plasma concentration of AVP and tachycardia induced by hemorrhage. Taken together, present results suggest that endocannabinoid neurotransmission within the PVN plays a prominent role in cardiovascular and autonomic, but not neuroendocrine, responses evoked by hemorrhage.
REVIEWING THE DYSREGULATION OF ADAMTS13 AND VWF IN SEPSIS
Authors: Madarati Hasam , Singh Kanwal , Sparring Taylor , Andrisani Peter , Liaw Patricia C. , Fox-Robichaud Alison E. , Kretz Colin A.
Published: December 2023

Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the intensive care unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation, which is characterized by microvascular thrombosis. Von Willebrand factor (VWF) and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of VWF and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their use as markers of severe illness, and potential targets for new therapeutic development.
Role of microglia in sepsis-associated encephalopathy pathogenesis: an update
Authors: Yu Zhijie , Shi Hui , Zhang Jingjing , Ma Chunhan , He Chen , Yang Fei , Zhao Lina
Published: December 2023

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, which is characterized by cognitive dysfunction, a poor prognosis, and high incidences of morbidity and mortality. Substantial levels of systemic inflammatory factors induce neuroinflammatory responses during sepsis, ultimately disrupting the central nervous system's (CNS) homeostasis. This disruption results in brain dysfunction through various underlying mechanisms, contributing further to SAE’s development. Microglia, the most important macrophage in the CNS, can induce neuroinflammatory responses, brain tissue injury, and neuronal dysregulation, resulting in brain dysfunction. They serve an important regulatory role in CNS homeostasis and can be activated through multiple pathways. Consequently, activated microglia are involved in several pathogenic mechanisms related to SAE and play a crucial role in its development. This article discusses the role of microglia in neuroinflammation, dysfunction of neurotransmitters, disruption of the blood-brain barrier (BBB), abnormal control of cerebral blood flow, mitochondrial dysfunction, and reduction in the number of good bacteria in the gut as main pathogenic mechanisms of SAE, and focuses on studies targeting microglia to ameliorate SAE to provide a theoretical basis for targeted microglial therapy for SAE.
Progressive Reduction in Preventable Mortality in a State Trauma System Using Continuous Preventable Mortality Review to Drive Provider Education: Results of Analyzing 1,979 Trauma Deaths from 2015 to 2022
Authors: Mabry Charles D , Davis Benjamin , Sutherland Michael , Robertson Ronald , Carger Jennifer , Wyrick Deidre , Collins Terry , Porter Austin , Kalkwarf Kyle
Published: December 2023

BACKGROUND:

The state legislature codified and funded the Arkansas Trauma System (ATS) in 2009. Quarterly preventable mortality reviews (PMRs) by the ATS began in 2015 and were used to guide state-wide targeted education to reduce preventable or potentially preventable (P/PP) deaths. We present the results of this PMR-education initiative from 2015 to 2022.

STUDY DESIGN:

The ATS uses a statistical sampling model of the Arkansas Trauma Registry to select ~40% of the deaths for quarterly review, reflecting the overall the Arkansas Trauma Registry mortality population. A multispecialty PMR committee reviews the medical records from prehospital care to death, and hospital and regional advisory council reviews for each death. The PMR committee assigns opportunities for improvement (OFIs), cause(s) of death, and the likelihood of preventability for each case. Education to improve trauma care includes annual state-wide trauma meetings, novel classes targeted at level III/IV trauma center hospital providers, trauma evidence–based guidelines, and PMR “pearls.”

RESULTS:

We reviewed 1,979 deaths with 211 (10.6%) deaths judged to be P/PP deaths. There was a progressive decrease in P/PP deaths and OFIs for P/PP deaths. Five OFI types targeted by education accounted for 72% of the 24 possible OFI types in the P/PP cases, and 94% of the “contributory OFIs.” Reductions in “delay in treatment” resulted in the most rapid decrease in P/PP deaths.

CONCLUSIONS:

Using ongoing PMR studies to target provider education led to a reduction in P/PP deaths and OFIs for P/PP deaths. Focusing on education designed to improve preventable mortality can result in a substantial decrease in P/PP deaths by 43% (14% to 8%) for trauma systems.
Association between the oral microbiome and brain resting state connectivity in schizophrenia
Authors: Lin Dongdong , Fu Zening , Liu Jingyu , Perrone-Bizzozero Nora , Hutchison Kent E. , Bustillo Juan , Du Yuhui , Pearlson Godfrey , Calhoun Vince D.
Published: December 2023

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N=213 SZ and healthy control (HC) subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p= 6×10−3; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H2S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8% of brain functional network connectivity from each component also showed significant differences between SZ and HC with strong performance in classifying SZ from HC, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.
SEAD: an augmented reference panel with 22,134 haplotypes boosts the rare variants imputation and GWAS analysis in Asian population
Authors: Yang Meng-Yuan , Zhong Jia-Dong , Li Xin , Tian Geng , Bai Wei-Yang , Fang Yi-Hu , Qiu Mo-Chang , Yuan Cheng-Da , Yu Chun-Fu , Li Nan , Yang Ji-Jian , Liu Yu-Heng , Yu Shi-Hui , Zhao Wei-Wei , Liu Jun-Quan , Sun Yi , Cong Pei-Kuan , Khederzadeh Saber , Zhao Pian-Pian , Qian Yu , Guan Peng-Lin , Gu Jia-Xuan , Gai Si-Rui , Yi Xiang-Jiao , Tao Jian-Guo , Chen Xiang , Miao Mao-Mao , Lei Lan-Xin , Xu Lin , Xie Shu-Yang , Li Jin-Chen , Guo Ji-Feng , Karasik David , Yang Liu , Tang Bei-Sha , Huang Fei , Zheng Hou-Feng
Published: December 2023

Here, we present theSouth andEastAsian referenceDatabase (SEAD) panel (https://imputationserver.westlake.edu.cn/), which comprises whole genome sequencing data from 11,067 individuals across 17 countries in Asia. The SEAD panel, which excludes singleton variants, consists of 22,134 haplotypes and 88,294,957 variants. The SEAD panel demonstrated higher accuracy compared to 1kGP, TOPMed and ChinaMAP in South Asian population. And as the proportion of South Asian ancestry increased, the proportion of low-frequency and rare well-imputed variants imputed using the SEAD panel progressively increased, whereas those imputed with TOPMed panel significantly decreased. Additionally, when imputing the East Asian population, the SEAD showed comparable concordance in imputation with ChinaMAP panel, while the TOPMed panel was inferior. Finally, we applied the augmented SEAD panel to conduct a discovery and replication genome-wide association study (GWAS) for hip and femoral neck (FN) bone mineral density (BMD) traits within the 5,369 Westlake BioBank for Chinese (WBBC) genotyped samples. The single-variant test suggests that rare variants nearSNTG1gene are associated with hip BMD (rs60103302, MAF=0.0092,P=1.67×10−7). The variant-set analysis also suggests the association of this gene (Pslide_window=9.08×10−9,Pgene_centric=5.27×10−8). The gene and variants achieved a suggestive level for FN BMD. This gene was not reported previously and can only be detected by using Asian reference panel. The preliminary experiment in-vitro demonstrated that the identified rare variant could upregulate theSNTG1expression, which in turn inhibits the proliferation and differentiation of preosteoblast.
Evaluating HIV-1 Infectivity and Virion Maturation Across Varied Producer Cells with a Novel FRET-Based Detection and Quantification Assay
Authors: McGraw Aidan , Hillmer Grace , Choi Jeongpill , Narayan Kedhar , Marquez Dacia , Tibebe Hasset , Izumi Taisuke
Published: December 2023

The maturation of HIV-1 virions is a crucial process in viral replication. Although T cells are a primary source of virus production, much of our understanding of virion maturation comes from studies using the HEK293T human embryonic kidney cell line. Notably, there is a lack of comparative analyses between T cells and HEK293T cells in terms of virion maturation efficiency in existing literature. We previously developed an advanced virion visualization system based on the FRET principle, enabling the effective distinction between immature and mature virions via fluorescence microscopy. In this study, we utilized pseudotyped, single-round infectious viruses tagged with FRET labels (HIV-1 Gag-iFRETΔEnv) derived from Jurkat (a human T lymphocyte cell line) and HEK293T cells to evaluate their virion maturation rates. HEK293T-derived virions demonstrated a maturity rate of 81.79%, consistent with other studies and our previous findings. However, virions originating from Jurkat cells demonstrated a significantly reduced maturation rate of 68.67% (p < 0.0001). Correspondingly, viruses produced from Jurkat cells exhibited significantly reduced infectivity compared to those derived from HEK293T cells, with the relative infectivity measured at 65.3%. This finding is consistent with the observed relative maturation rate of viruses produced by Jurkat cells. These findings suggest that initiation of virion maturation directly correlates with viral infectivity. Our observation highlights the dynamic nature of virus-host interactions and their implications for virion production and infectivity.
TMEM41B is an endoplasmic reticulum Ca2+release channel maintaining T cell metabolic quiescence and responsiveness
Authors: Ma Yuying , Wang Yi , Zhao Xiaocui , Jin Gang , Xu Jing , Li Zhuoyang , Yin Na , Gao Zhaobing , Xia Bingqing , Peng Min
Published: December 2023

Naive T cells are metabolically quiescent. Here, we report an unexpected role of endoplasmic reticulum (ER) Ca2+in preserving T cell metabolic quiescence. TMEM41B, an ER-resident membrane protein previously known for its crucial roles in autophagy, lipid scrabbling and viral infections, is identified as a novel type of concentration-dependent ER Ca2+release channel. Ablation of TMEM41B induces ER Ca2+overload, triggering the upregulation of IL-2 and IL-7 receptors in naive T cells. Consequently, this leads to increased basal signaling of the JAK-STAT, AKT-mTOR, and MAPK pathways, propelling TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca2+overload also downregulates CD5, a suppressor of TCR signaling, thereby reducing the activation threshold of TMEM41B-deficient T cells, resulting in attenuated tolerance and heightened T cell responses during infections. In summary, TMEM41B-mediated ER Ca2+release is a pivotal determinant governing metabolic quiescence and responsiveness of naive T cells.