bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of the Dobbs v Jackson Women's Health Organization Decision on Obstetrics and Gynecology Graduating Residents' Practice Plans
Authors: Woodcock Alexandra L. , Carter Gentry , Baayd Jami , Turok David K. , Turk Jema , Sanders Jessica N. , Pangasa Misha , Gawron Lori M. , Kaiser Jennifer E.
Published: September 2023

OBJECTIVE:

To explore the association of the Dobbs v Jackson Women's Health Organization (Dobbs) decision on future practice locations of graduating obstetrics and gynecology residents.

METHODS:

This is a mixed-methods survey study of obstetrics and gynecology residents graduating from sites with Ryan Program abortion training programs (109 sites) between March 8, 2023, and April 25, 2023. We conducted both univariate and multivariable logistic regression analyses to identify factors that were associated with post-Dobbs change in career plans, particularly location. We also performed a thematic analysis using responses to the survey's optional, open-ended prompt, “Please describe how the Dobbs v Jackson Women's Health Organization decision impacted your professional plans.”

RESULTS:

Of an estimated 724 residents graduating from residencies with Ryan Program abortion training programs, 349 participated in the survey (48.2% response rate); 17.6% of residents indicated that the Dobbs decision changed the location of intended future practice or fellowship plans. Residents who before the Dobbs decision intended to practice in abortion-restrictive states were eight times more likely to change their practice plans than those who planned to practice in protected states before the Dobbs decision (odds ratio 8.52, 95% CI 3.81–21.0). In a thematic analysis of open-ended responses, 90 residents wrote responses related to “not living in a state with abortion restrictions.” Of residents pursuing fellowship, 36 indicated that they did not rank or ranked lower programs in restrictive states.

CONCLUSION:

These findings demonstrate reduced desire of residents in obstetrics and gynecology to practice or pursue fellowship in restrictive states after residency. This reduction in obstetrics and gynecology workforce could significantly exacerbate maternity care deserts.
Neighborhood Socioeconomic Disadvantage and Abnormal Birth Weight
Authors: Venkatesh Kartik K. , Yee Lynn M. , Johnson Jasmine , Wu Jiqiang , McNeil Becky , Mercer Brian , Simhan Hyagriv , Reddy Uma M. , Silver Robert M. , Parry Samuel , Saade George , Chung Judith , Wapner Ronald , Lynch Courtney D. , Grobman William A.
Published: September 2023

OBJECTIVE:

To examine whether exposure to community or neighborhood socioeconomic disadvantage as measured by the ADI (Area Deprivation Index) is associated with risk of abnormal birth weight among nulliparous individuals with singleton gestations.

METHODS:

This was a secondary analysis from the prospective cohort NuMoM2b study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be). Participant addresses at cohort enrollment between 6 and 13 weeks of gestation were geocoded at the Census tract level and linked to the 2015 ADI. The ADI, which incorporates the domains of income, education, employment, and housing quality into a composite national ranking of neighborhood socioeconomic disadvantage, was categorized by quartiles (quartile 1, least disadvantaged, reference; quartile 4, most disadvantaged). Outcomes were large for gestational age (LGA; birth weight at or above the 90th percentile) and small for gestational age (SGA; birth weight below the 10th percentile) compared with appropriate for gestational age (AGA; birth weight 10th–90th percentile) as determined with the 2017 U.S. natality reference data, standardized for fetal sex. Multinomial logistic regression models were adjusted for potential confounding variables.

RESULTS:

Of 8,983 assessed deliveries in the analytic population, 12.7% (n=1,143) were SGA, 8.2% (n=738) were LGA, and 79.1% (n=7,102) were AGA. Pregnant individuals living in the highest ADI quartile (quartile 4, 17.8%) had an increased odds of delivering an SGA neonate compared with those in the lowest referent quartile (quartile 1, 12.4%) (adjusted odds ratio [aOR] 1.32, 95% CI 1.09–1.55). Pregnant individuals living in higher ADI quartiles (quartile 2, 10.3%; quartile 3, 10.7%; quartile 4, 9.2%) had an increased odds of delivering an LGA neonate compared with those in the lowest referent quartile (quartile 1, 8.2%) (aOR: quartile 2, 1.40, 95% CI 1.19–1.61; quartile 3, 1.35, 95% CI 1.09–1.61; quartile 4, 1.47, 95% CI 1.20–1.74).

CONCLUSION:

Neonates of nulliparous pregnant individuals living in U.S. neighborhoods with higher area deprivation were more likely to have abnormal birth weights at both extremes.
DISAPPEARING CHOROIDAL SPOTS ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY PRECEDING RECURRENCE OF MULTIFOCAL CHOROIDITIS WITH CHORIORETINAL ATROPHY
Authors: Marchese Alessandro , Bar-Meir Avram , Jampol Lee M. , Mirza Rukhsana G.
Published: September 2023

Purpose:

To describe idiopathic multifocal choroiditis with chorioretinal atrophy developing choroidal flow voids on optical coherence tomography angiography that preceded a recurrence of the disease.

Methods:

Case report.

Results:

A 24-year-old woman presented with visual field changes and occasional photopsias. Systemic workup for syphilis, tuberculosis, and sarcoidosis was negative. Clinical findings and multimodal imaging were consistent with idiopathic multifocal choroiditis with chorioretinal atrophy, complicated by inactive choroidal neovascularization in her right eye. She was treated with systemic corticosteroids with a taper over 3 months without change in her examination. She was then stable for 2 years. At that point, the patient experienced increased photopsias, but her examination result was unchanged. Optical coherence tomography angiography showed multiple flow voids in the choroid that were not present 6 months ago. No lesions were seen on other imaging modalities. Structural optical coherence tomography showed some subtle hyperreflectivity throughout the choroid that was previously absent. Given the unknown significance of these flow voids, the patient was asked to return for follow-up in 1 month. Her photopsias improved, and her vision remained normal. On repeat examination after 1 month, the patient had developed a few subtle yellow lesions in the superonasal quadrant of the left eye. There were no macular lesions. The repeat optical coherence tomography angiography revealed that the flow voids were fading.

Conclusion:

Imaging findings using optical coherence tomography angiography in our patient with idiopathic multifocal choroiditis showed choroidal flow voids that preceded clinical recurrence, not detected by other imaging modalities. Future studies should determine whether optical coherence tomography angiography can be used to detect subclinical lesions preceding clinical recurrences of idiopathic multifocal choroiditis.
Combination therapy with kidney protective therapies: optimizing the benefits?
Authors: Kotwal Sradha , Perkovic Evan , Perkovic Vlado
Published: September 2023

Purpose of review

Recent advances in the treatment of chronic kidney disease (CKD) have led to the development of several new agents that are kidney protective, particularly in people with diabetes. These agents include sodium/glucose cotransporter-2 inhibitors (SGLT-2 inhibitors), mineralocorticoid receptor antagonists (MRAs), and glucagon-like peptide-1 receptor agonists (GLP-1RAs). This review summarizes the available data regarding the effects of using these therapies in combination.

Recent findings

There is convincing evidence that SGLT-2 inhibitors and MRAs individually improve kidney function and reduce the risk of cardiovascular events in people with CKD, especially diabetic CKD. There is some evidence that GLP-1RAs may be beneficial, but further studies are needed.

The available data support an additive kidney and cardiovascular benefit using combination therapy with SGLT-2 inhibitors and MRAs, and possibly with SGLT2 inhibitors and GLP-1RAs, but more long-term data are needed. The currently available data suggest that combining these agents would likely be beneficial and may be an appropriate long-term strategy.

Several new agents are useful in slowing the progress of CKD. Further research to identify which combinations of agents work best together and which combinations are most effective for people with different characteristics, in order to personalize treatment and improve outcomes for people with CKD, should be a priority.
Sensitivities evaluation of five radiopharmaceuticals in four common medullary thyroid carcinoma metastatic sites on PET/CT: a network meta-analysis and systematic review
Authors: Li Pengyu , Zhang Yujie , Xu Tianfeng , Zhu Jingqiang , Wei Tao , Zhao Wanjun
Published: September 2023

Objectives

Detecting medullary thyroid carcinoma (MTC) metastatic lesions accurately is still a challenge for clinicians. PET/computed tomography (PET/CT) seems to be the most effective method in recent years. However, the sensitivity of each radiopharmaceutical varies greatly in different metastatic sites. We aim to investigate and compare five novel and common PET or PET/CT radiopharmaceutical sensitivities at the four most frequent metastatic sites by network meta-analysis.

Methods

We searched for studies evaluating PET/CT radiopharmaceutical sensitivities at different metastatic sites in PubMed, Web of Science, Embase, and Cochrane Library. The risk bias was analyzed, and publication bias was accessed by funnel plot asymmetry tests. We performed both global inconsistency and local inconsistency tests by evaluating the agreement between direct and indirect comparisons. Then, we made pairwise meta-analyses and network meta-analyses for each metastatic site. Finally, we performed the surface under the cumulative ranking curves (SUCRA) and calculated the SUCRA values to rank the probability of each radiopharmaceutical being the most sensitive method.

Results

In our results, 243 patients from 9 clinical studies which accessed sensitivities of different radiopharmaceuticals in MTC metastatic sites were included. For lymph nodes and liver, TF2/68Ga-SSM288 showed the highest SUCRA values (0.974 in lymph nodes, 0.979 in liver). The SUCRA values for 18F-DOPA and 68Ga-SSA for bone metastatic lesions were nearly identical (0.301 and 0.319, respectively) and were higher than the other three radiopharmaceuticals. For lung lesions, 11C-methionine had the highest SUCRA value (0.412).

Conclusion

TF2/68Ga-SSM288 had the best sensitivity in lymph nodes and liver lesions. 11C-methionine was most sensitive in lung lesions. While 18F-DOPA and 68Ga-SSA had familiar sensitivities to be the best two radiopharmaceuticals.
Predictors of cardiovascular risk in familial hypercholesterolemia
Authors: Romero-Jiménez Manuel Jesús , Mansilla-Rodríguez María Elena , Gutiérrez-Cortizo Eva Nadiejda
Published: September 2023

Purpose of review

Familial hypercholesterolemia is associated with an increased risk of cardiovascular disease. The current international guidelines of the main scientific societies consider that, all people with Familial Hypercholesterolemia have a high or very high cardiovascular risk. However, the occurrence of atherosclerotic cardiovascular disease is very heterogeneous in this population. Stratifying risk within people with familial hypercholesterolemia is essential to identify individuals who require intensive cholesterol-lowering therapies.

Recent findings

In the last year, several studies have been published focusing on the contribution of diabetes to Familial Hypercholesterolemia, the role of stroke, as a manifestation of atherosclerotic disease, and the external validation of the SAFEHEART risk equation in the English population diagnosed with Familial Hypercholesterolemia.

It is necessary the development of a tool that allows us to identify, in a simple, reproducible, and universal way, patients who may have a high risk of suffering a cardiovascular event and who are susceptible to more intensive treatments to reduce cholesterol levels.
The history of ethical principles in liver transplant organ allocation in the united states: how historical and proposed allocations system fare in balancing utility vs. urgency and justice vs. pragmatism
Authors: Ahearn Aaron
Published: September 2023

Purpose of review

The United States (US) liver transplant community is processing changes to the allocation system and developing a new proposal that will result in even greater change. This review evaluates the ethical implications of these decisions, focusing on two sets of competing ethical principles (Urgency vs. Utility and Justice vs. Pragmatism).

Recent findings

About four years ago, the Organ Procurement and Transplantation Network (OPTN) implemented the Acuity Circle Model to replace the geographic boundaries of organ procurement organizations (OPOs). Here, we review how effectively this model reduced regional variation in access and improved waitlist survival. Likewise, the OPTN is planning to transition to a continuous distribution model which will redefine the scoring systems for allocation. We will discuss how the ethical priorities discussed above should be considered while developing the new system.

Every change in organ allocation policy must balance competing ethical imperatives. Although our community's emphasis on urgency over utility is appropriate, we should study the potential benefits of considering utility in the system. Meanwhile, our push for more Justice in the system should remain our imperative and Pragmatism should only be considered to minimize the costs of these changes.
Quality Tool School: Improving the Delivery of Quality Improvement Education in a Children’s Hospital
Authors: Gallup James , Buckingham Don , Dolan Kevin , Macias Charlie
Published: September 2023

Background:

In 2013, Nationwide Children’s Hospital’s (NCH) Quality Tool School (QTS) was created as an initial Quality Improvement educational series, composed of three separate classes, totaling 5.5 hours of hands-on QI training. QTS complemented the NCH 40-hour Quality Improvement Essentials course.

Methods:

Over 10 years, the series went through three phases of aims: Phase 1: develop and implement three core courses (Project Tools, Excel, and Control Charts); Phase 2: have participants complete the entire series of all three classes; Phase 3: have participants who complete the entire series of all three classes demonstrate the application of learning through involvement in a quality improvement project.

Results:

Since initiation, QTS has provided an educational entry point for 1428 NCH employees to participate in QI projects and teams. QTS has shown statistically significant improvement in 2 of the 3 principal aims. The Phase 1 metric of average monthly one-class participation completion percentage showed a statistically significant centerline shift from 9 to 16 students in October 2018. The Phase 3 metric Percentage of QTS participants completing the QTS series of classes and then participating in a QI team began in 2016 with a baseline of 42%. A centerline shift from 42% to 63% occurred in Q4 2018.

Conclusions:

QTS can provide QI education to healthcare system employees using limited resources. Organizations that strategically integrate a culture of QI into core beliefs can realize substantial improvement gains.
Current Concepts in Lower Extremity Amputation: A Primer for Plastic Surgeons
Authors: Hanwright Philip J. , Suresh Visakha , Shores Jaimie T. , Souza Jason M. , Tuffaha Sami H.
Published: September 2023

Learning Objectives:

After studying this article, the participant should be able to: 1. Understand the goals of lower extremity reconstruction and identify clinical scenarios favoring amputation. 2. Understand lower extremity amputation physiology and biomechanics. 3. Review soft-tissue considerations to achieve durable coverage. 4. Appreciate the evolving management of transected nerves. 5. Highlight emerging applications of osseointegration and strategies to improve myoelectric prosthetic control.

Plastic surgeons are well versed in lower extremity reconstruction for traumatic, oncologic, and ischemic causes. Limb amputation is an increasingly sophisticated component of the reconstructive algorithm and is indicated when the residual limb is predicted to be more functional than a salvaged limb. Although plastic surgeons have traditionally focused on limb salvage, they play an increasingly vital role in optimizing outcomes from amputation. This warrants a review of core concepts and an update on emerging reconstructive techniques in amputee care.
Long-term Course of Kidney Function in Uterus Transplant Recipients Under Treatment With Tacrolimus and After Transplantectomy: Results of the First Clinical Cohort
Authors: Ekberg Jana , Hjelmberg Marie , Norén Åsa , Brännström Mats , Herlenius Gustaf , Baid-Agrawal Seema
Published: September 2023

Background.

Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients’ kidney function.

Methods.

In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119–126) mo.

Results.

Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10–12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22–83) mo, and median trough levels (µg/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of −24 mL/min/1.73 m2, which declined further by −4 mL/min/1.73 m2 until months 10–12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at −1.9 mL/min/1.73 m2/y for the whole group.

Conclusions.

Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.
Sex-Related Differences in Long-term Outcomes across the Spectrum of Ejection Fraction in Heart Failure Patients
Authors: Kawai Akane , Nagatomo Yuji , Yukino-Iwashita Midori , Ikegami Yukinori , Takei Makoto , Goda Ayumi , Kohno Takashi , Mizuno Atsushi , Kitamura Mitsunobu , Nakano Shintaro , Sakamoto Munehisa , Shiraishi Yasuyuki , Kohsaka Shun , Adachi Takeshi , Yoshikawa Tsutomu ,   WET-HF investigators
Published: September 2023

Background

Recently, patients with supra-normal left ventricular ejection fraction (snLVEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients.

Methods

The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3,943 patients (age 77 years; 59.8% male) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF (HFpEF). The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge.

Results

Implementation of guideline-directed medical therapy (GDMT) such as renin-angiotensin-system inhibitor (RASi), β-blocker and their combination at discharge was significantly lower in women than men in HFmrEF. Lower prescription of RASi + β-blocker combination in female HFmrEF was noted even after adjustment for covariates (p=0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint in women, but such relationship was not observed in men (pfor interaction=0.037).

Conclusions

In women, not only lower LVEF but also snLVEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for sex-specific guidelines to optimize HF management.
Patient Perception of Endoscopic and Medical Therapies for Weight Loss
Authors: Saumoy Monica , Gao Yinglin , Allison Kelly , Cronholm Peter F. , Pickett-Blakely Octavia , Kochman Michael L. , Thiruvengadam Nikhil R.
Published: September 2023

Background

For weight management, patient choice has increasingly driven therapeutic options, with less than 1% of eligible patients choosing bariatric surgery. The aim of this survey was to understand patient perceptions of endoscopic bariatric therapies (EBTs) and obesity-based pharmacotherapy.

Methods

An anonymously collected 7-question survey was distributed to gastroenterology patients undergoing screening colonoscopy.

Results

A total of 184 patients participated in the survey. Participants demonstrated a greater lack of knowledge of EBTs (78.2% unaware) compared to pharmacotherapy (35.9% unaware). 40.8% of respondents perceived that EBTs were not available in the United States. Only 15.8% of respondents recognized that pharmacotherapy requires long-term treatment to maintain weight loss. Disparities were noted in primarily Spanish-speaking patients demonstrating a lower awareness of the availability of EBTs in the US (57.6% unaware) and pharmacotherapy (62.1% unaware) compared to those with English as the primary language.

Conclusions

Patient knowledge and preference are key to engaging in weight loss therapies. Knowledge gaps regarding weight-loss options, particularly EBTs, can limit the utilization of all options for the care of patients with obesity.
Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes
Authors: Reus Lianne M. , Boltz Toni , Francia Marcelo , Bot Merel , Ramesh Naren , Koromina Maria , Pijnenburg Yolande A.L. , den Braber Anouk , van der Flier Wiesje M. , Visser Pieter Jelle , van der Lee Sven J. , Tijms Betty M. , Teunissen Charlotte E. , Loohuis Loes Olde , Ophoff Roel A.
Published: September 2023

Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanismsin vivo, measuring 5,543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n=490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n=487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders, we performed a metabolome-wide association study (MWAS), identifying 40 associations between CSF metabolites and brain traits. Similarly, over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.
A Reinforcement Learning Model with Choice Traces for a Progressive Ratio Schedule
Authors: Ihara Keiko , Shikano Yu , Kato Sae , Yagishita Sho , Tanaka Kenji F. , Takata Norio
Published: September 2023

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a Simple Q- learning model, an Asymmetric model with two learning rates, a Perseverance model with choice traces, and a Perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes (MNPs), because we noticed that mice performed frequent MNPs during PR tasks. The best model was the Perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void MNPs. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of MNPs during the PR session without changing the breakpoint. The Perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the Perseverance model reveals effects of psychoactive drugs on choice behaviors during PR tasks.
Septins Enable T Cell Contact GuidanceviaAmoeboid-Mesenchymal Switch
Authors: Zhovmer Alexander S. , Manning Alexis , Smith Chynna , Wang Jian , Ma Xuefei , Tsygankov Denis , Dokholyan Nikolay V. , Cartagena-Rivera Alexander X. , Singh Rakesh K. , Tabdanov Erdem D.
Published: September 2023

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin’s GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.

SIGNIFICANCE STATEMENT

Deciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins’ GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.
DISTINCT METABOLIC STATES DIRECT RETINAL PIGMENT EPITHELIUM CELL FATE DECISIONS
Authors: Perez-Estrada J. Raúl , Tangeman Jared A. , Proto-Newton Maeve , Sanaka Harshavardhan , Smucker Byran , Del Rio-Tsonis Katia
Published: September 2023

During tissue regeneration, proliferation, dedifferentiation, and reprogramming are necessary to restore lost structures. However, it is not fully understood how metabolism intersects with these processes. Chicken embryos can regenerate their retina through retinal pigment epithelium (RPE) reprogramming when treated with fibroblast factor 2 (FGF2). Using transcriptome profiling, we uncovered extensive regulation of gene sets pertaining to proliferation, neurogenesis, and glycolysis throughout RPE-to-neural retina reprogramming. By manipulating cell media composition, we determined that glucose, glutamine, or pyruvate are sufficient to support RPE reprogramming identifying glycolysis as a requisite. Conversely, the induction of oxidative metabolism by activation of pyruvate dehydrogenase induces Epithelial-to-mesenchymal transition (EMT), while simultaneously blocking the activation of neural retina fate. We also identify that EMT is partially driven by an oxidative environment. Our findings provide evidence that metabolism controls RPE cell fate decisions and provide insights into the metabolic state of RPE cells, which are prone to fate changes in regeneration and pathologies, such as proliferative vitreoretinopathy.
Gene transfer among viruses substantially contributes to gene gain of giant viruses
Authors: Wu Junyi , Meng Lingjie , Gaïa Morgan , Hikida Hiroyuki , Okazaki Yusuke , Endo Hisashi , Ogata Hiroyuki
Published: September 2023

Horizontal gene transfers (HGTs) integrate all forms of life and viruses into a vast network of gene flow, which facilitates the transmission of genes beyond vertical inheritance and enhances genomic evolution. HGT is known to occur between closely related viruses. We hypothesized that there is frequent HGT among nucleocytoviruses, a group of diverse but evolutionarily related DNA viruses encoding hundreds to thousands of genes. However, the frequency of viral HGT (vHGT) has not been systematically investigated for nucleocytoviruses. We reconciled over 4,700 gene trees with a robust viral species tree that contains 195 reference viral genomes mainly from cultivation as a reference to infer evolutionary events, including gene gains (gene duplication, origination, and vHGT) and losses. The inferred evolutionary scenarios revealed that the genomes of these viruses have undergone numerous gene gain and loss events, with vHGT representing 28% to 42% of gene gain events in each viral order. By integrating the evolutionary paths of multiple viruses, our data suggest that vHGT is crucial for nucleocytovirus evolution.
5-hydroxymethylcytosines regulate gene expression as a passive DNA demethylation resisting epigenetic mark in proliferative somatic cells
Authors: Wei Alex , Zhang Hongjie , Qiu Qi , Fabyanic Emily B. , Hu Peng , Wu Hao
Published: September 2023

Enzymatic erasure of DNA methylation in mammals involves iterative 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (TET) family of DNA dioxygenase proteins. As the most abundant form of oxidized 5mC, the prevailing model considers 5-hydroxymethylcytosine (5hmC) as a key nexus in active DNA demethylation that can either indirectly facilitate replication-dependent depletion of 5mC by inhibiting maintenance DNA methylation machinery (UHRF1/DNMT1), or directly be iteratively oxidized to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) and restored to cytosine (C) through thymine DNA glycosylase (TDG)-mediated 5fC/5caC excision repair. In proliferative somatic cells, to what extent TET-dependent removal of 5mC entails indirect DNA demethylation via 5hmC-induced replication-dependent dilution or direct iterative conversion of 5hmC to 5fC/5caC is unclear. Here we leverage a catalytic processivity stalling variant of human TET1 (TET1.var: T1662E) to decouple the stepwise generation of 5hmC from subsequent 5fC/5caC generation, excision and repair. By using a CRISPR/dCas9-based epigenome-editing platform, we demonstrate that 5fC/5caC excision repair (by wild-type TET1, TET1.wt), but not 5hmC generation alone (by TET1.var), is requisite for robust restoration of unmodified cytosines and reversal of somatic silencing of the methylation-sensitive, germline-specificRHOXF2Bgene promoter. Furthermore, integrated whole-genome multi-modal epigenetic sequencing reveals that hemi-hydroxymethylated CpG dyads predominantly resist replication-dependent depletion of 5mC on the opposing strand in TET1.var-expressing cells. Notably, TET1.var-mediated 5hmC generation is sufficient to induce similar levels of differential gene expression (compared to TET1.wt) without inducing major changes in unmodified cytosine profiles across the genome. Our study suggests 5hmC alone plays a limited role in driving replication-dependent DNA demethylation in the presence of functional DNMT1/UHRF1 mechanisms, but can regulate gene expression as abona fideepigenetic mark in proliferative somatic cells.
The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study
Authors: Clark Rebecca A , Portnoy Allison , Weerasuriya Chathika K , Sumner Tom , Bakker Roel , Harris Rebecca C , Rade Kirankumar , Mattoo Sanjay Kumar , Tumu Dheeraj , Menzies Nicolas A , White Richard G
Published: September 2023

Background

India has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01Eand BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies.

Methods

We applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01Eand BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025–2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds.

Results

M72/AS01Eaverted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01Ein Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01Ecould be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios.

Discussion

M72/AS01Eand BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01Eand its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.
Model-based impact evaluation of new tuberculosis vaccines in aging populations under different modeling scenarios: the case of China
Authors: Tovar Mario , Sanz Joaquín , Moreno Yamir
Published: September 2023

The slow descent in TB burden, the COVID-19 pandemic, along with the rise of multidrugresistant strains ofMycobacterium tuberculosis, seriously threaten TB control and the goals of the End TB strategy. To fight back, several vaccine candidates are under development, with some of them undergoing the phases 2B and 3 of the development pipeline. The impact of these vaccines on the general population needs to be addressed using disease-transmission models, and, in a country like China, which last year ranked third in number of cases worldwide, and where the population is undergoing a fast process of demographic aging, the impact of TB vaccination campaigns may depend heavily upon the age of targeted populations and with the mechanistic descriptions of the TB vaccines. For these reasons, transmission models need to capture the coupling between TB dynamics and demographic evolution, as well as to be able to accommodate different mechanistic descriptions of TB vaccine protection. In this work, we studied the potential impact of a new TB vaccine in China targeting adolescents (15-19 y.o.) or elderly people (60-64 y.o.), according to varying vaccine descriptions that represent reasonable mechanisms of action leading to prevention of disease (PoD), or prevention of recurrence (PoR), each of them targetting specific routes to TB disease. To measure the influence of the description of the coupling between transmission dynamics and aging in TB transmission models, we explored two different approaches to comptute the evolution of the contact matrices, which relate to the spreading among different age strata. Our results show that the magnitude of model-based impact estimates substantially depends upon the vaccine profile, and it is also strongly related to the modeling approach chosen to describe the time evolution of contact matrices. In spite of these sources of uncertainty, our results also show, in line with previous modeling works, that elder vaccination is a suitable option in China to reduce the incidence of TB.
A Window into Mammalian Basement Membrane Development: Insights from themTurq2-Col4a1Mouse Model
Authors: Jones Rebecca A. , Trejo Brandon , Sil Parijat , Little Katherine A. , Pasolli H. Amalia , Joyce Bradley , Posfai Eszter , Devenport Danelle
Published: September 2023

Basement membranes (BMs) are specialized sheets of extracellular matrix that underlie epithelial and endothelial tissues. BMs regulate traffic of cells and molecules between compartments, and participate in signaling, cell migration and organogenesis. The dynamics of mammalian BMs, however, are poorly understood, largely due to a lack of models in which core BM components are endogenously labelled. Here, we describe themTurquoise2-Col4a1mouse, in which we fluorescently tag collagen IV, the main component of BMs. Using an innovative Planar-Sagittal live imaging technique to visualize the BM of developing skin, we directly observe BM deformation during hair follicle budding and basal progenitor cell divisions. The BM’s inherent pliability enables dividing cells to remain attached to and deform the BM, rather than lose adhesion as generally thought. Using FRAP, we show BM collagen IV is extremely stable, even during periods of rapid epidermal growth. These findings demonstrate the utility of themTurq2-Col4a1mouse to shed new light on mammalian BM developmental dynamics.
p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein
Authors: Mittal Priyasi , Khandelwal Nitin , Chander Yogesh , Verma Assim , Kumar Ram , Putatunda Chayanika , Barua Sanjay , Gulati Baldev Raj , Kumar Naveen
Published: September 2023

The inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38-α knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38α, suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In addition, we demonstrated that long-term culture of SARS-CoV-2 in the presence of p38 inhibitor SB203580 does not easily select resistant viral mutants. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK.
Comparative Analysis of SARS-CoV-2 Antigenicity across Assays and in Human and Animal Model Sera
Authors: Mühlemann Barbara , Wilks Samuel H , Baracco Lauren , Bekliz Meriem , Carreño Juan Manuel , Corman Victor M , Davis-Gardner Meredith E. , Dejnirattisai Wanwisa , Diamond Michael S , Douek Daniel C. , Drosten Christian , Eckerle Isabella , Edara Venkata-Viswanadh , Ellis Madison , Fouchier Ron A M , Frieman Matthew , Godbole Sucheta , Haagmans Bart , Halfmann Peter J , Henry Amy R , Jones Terry C , Katzelnick Leah C , Kawaoka Yoshihiro , Kimpel Janine , Krammer Florian , Lai Lilin , Liu Chang , Lusvarghi Sabrina , Meyer Benjamin , Mongkolsapaya Juthathip , Montefiori David C , Mykytyn Anna , Netzl Antonia , Pollett Simon , Rössler Annika , Screaton Gavin R , Shen Xiaoying , Sigal Alex , Simon Viviana , Subramanian Rahul , Supasa Piyada , Suthar Mehul , Türeli Sina , Wang Wei , Weiss Carol D , Smith Derek J
Published: September 2023

The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.
Novel insights into phage biology of the pathogenClostridioides difficilebased on the active virome
Authors: Schüler Miriam A. , Daniel Rolf , Poehlein Anja
Published: September 2023

The global pathogenClostridioides difficileis a well-studied organism, and researchers work on unravelling its fundamental virulence mechanisms and biology. Prophages have been demonstrated to influenceC. difficiletoxin expression and contribute to the distribution of advantageous genes. All this underlines the importance of prophages inC. difficilevirulence. Although severalC. difficileprophages were sequenced and characterized, investigations on the entire active virome of a strain are still missing. Phages were mainly isolated after mitomycin C-induction, which does not resemble natural stressor forC. difficile.We examined active prophages from differentC. difficilestrains after cultivation in the absence of mitomycin C by sequencing and characterization of particle-protected DNA. Phage particles were collected after standard cultivation, or after cultivation in the presence of the secondary bile salt deoxycholate (DCA). DCA is a natural stressor forC. difficileand a potential prophage-inducing agent. We also investigated differences in prophage activity between clinical and non-clinicalC. difficilestrains. Our experiments demonstrated that spontaneous prophage release is common inC. difficile, and that DCA presence induces prophages. Fourteen different, active phages were identified by this experimental procedure. We could not identify a definitive connection between clinical background and phage activity. However, one phage exhibited distinctively higher activity upon DCA-induction in the clinical strain than in the corresponding non-clinical strain, although the phage is identical in both strains. We recorded that enveloped DNA mapped to genome regions with characteristics of mobile genetic elements other than prophages. This pointed to mechanisms of DNA mobility that are not well-studied inC. difficileso far. We also detected phage-mediated lateral transduction of bacterial DNA, which is the first described case inC. difficile. This study significantly contributes to our knowledge on prophage activity inC. difficileand revealed novel aspects onC. difficile(phage) biology.
Starch can expedite the screening for bacterial aflatoxin degraders
Authors: Sandlin Natalie , Momeni Babak
Published: September 2023

Aflatoxins (AFs) are secondary fungal metabolites that contaminate common food crops and are harmful to humans and animals. The ability to degrade or remove aflatoxins from common feed commodities will improve health standards and counter the economic drain inflicted by AF contamination. Bioremediation is a promising solution to AF contamination because of its low cost and few undesired environmental side-effects. Identifying new degrader species is highly beneficial in that it can offer alternatives to overcome the limitations of existing biodegraders, such as narrow working conditions and low degradation rates. Here, we screen several environmental isolates for their AF detoxification ability, using aflatoxin G2. We use different carbon sources (glucose and starch) as isolation and culturing media to examine the effect of the environment on degradation ability. Strains isolated in media with starch as the primary carbon source showed a higher percentage of good AF degraders, 16% compared to 2% when glucose was the primary carbon source. Additionally, the majority of species isolated in glucose medium exhibited improved degradation efficiency when moved into starch medium, with one isolate improving degradation levels from 30% to 70%. Our starch screen also revealed three previously unidentified AF degrader bacterial species. Good aflatoxin G2degraders also appear to perform well against aflatoxin B1. Overall, for AF degradation, starch medium expedites the screening process and generally improves the performance of isolates. We thus propose that using starch as the carbon source is a promising means to identify new AF degraders in the environment.