bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis
Authors: Shang Yiyang , Wang Cai’e , Lu Huiyuan , Chai Lu , Xu Wentao , Bernardi Mauro , Qi Xingshun
Published: September 2024

Background:

Terlipressin has been widely used for various cirrhosis-related complications, but its safety profile remains controversial. Herein, this issue was systematically evaluated.

Methods:

All studies reporting adverse events (AEs) of terlipressin in cirrhosis were screened. Incidences were pooled using a random-effects model. Subgroup analyses were performed according to the patient’s characteristics and treatment regimens. Interaction among subgroups was evaluated.

Results:

Seventy-eight studies with 7257 patients with cirrhosis were included. The pooled incidences of any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs were 31%, 22%, 5%, 5%, 4%, and 4% in patients with cirrhosis receiving terlipressin, respectively. Patients with hepatorenal syndrome had higher incidences of any SAEs (29% vs. 0% vs. 0%, p
interaction = 0.01) and treatment-related SAEs (8% vs. 1% vs. 7%, p
interaction = 0.02) than those with variceal bleeding or ascites. Patients who received terlipressin with human albumin had higher incidences of any SAEs (18% vs. 1%, p
interaction = 0.04) and treatment-related SAEs (7% vs. 0%, p
interaction = 0.09) than those without albumin. Patients with total bilirubin level >4.3 mg/dL had higher incidences of any AEs (69% vs. 24%, p
interaction = 0.02), any SAEs (64% vs. 0%, p
interaction < 0.01), and treatment-related SAEs (8% vs. 1%, p
interaction = 0.04) than those ≤4.3 mg/dL.

Conclusions:

AEs are common in patients with cirrhosis receiving terlipressin and influenced by clinical scenarios, combination with albumin, and bilirubin levels.
Effect of maneuvers, diuresis, and fluid administration on ultrasound-measured liver stiffness after Fontan
Authors: Debnath Pradipta , Morin Cara E. , Bonn Julie , Thapaliya Samjhana , Smith Clayton A. , Dillman Jonathan R. , Trout Andrew T.
Published: September 2024

Background:

To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls.

Methods:

In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis.

Results:

Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (−0.05 m/s, −3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (−0.79 m/s, −26.5%, p = 0.004) and 60 minutes (−0.78 m/s, −26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (−0.12 m/s, −8.70%, p = 0.002), 30 minutes (−0.15 m/s, −10.9%, p = 0.003), and 60 minutes (−0.1 m/s, −10.9%, p = 0.005).

Conclusions:

LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients.
Prevalence of subclinical hypothyroidism and longitudinal thyroid-stimulating hormone changes in youth with metabolic dysfunction–associated steatotic liver disease: An observational study
Authors: Untalan Matthew , A. Crimmins Nancy , Yates Katherine P. , A. Mencin Ali , A. Xanthakos Stavra , Thaker Vidhu V.
Published: September 2024

Background:

Studies on adults have shown an association between overt or subclinical hypothyroidism and metabolic dysfunction–associated steatotic liver disease (MASLD). The goal of this study was to assess the relationship between thyroid-stimulating hormone (TSH) levels and the histological characteristics of MASLD in youth.

Methods:

This observational study used prospectively collected liver biopsy and clinical data from youth enrolled in 2 pediatric clinical trials in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Thyroid assays were compared between youth with MASLD and population-based controls aged ≤18 years from the National Health and Nutrition Examination Survey. Individuals with overt hypothyroidism, abnormal antithyroid antibodies, or thyroid-related medications were excluded. Subclinical hypothyroidism was defined as TSH between 4.5 and 10.0 uIU/L. Multinomial logistic regression was used to test the association between TSH and MASLD histological changes at baseline, adjusting for age, sex, race/ethnicity, and body mass index. Mixed-effect models, including treatment and time, were used for the longitudinal analysis.

Results:

Mean TSH, total thyroxine (T4), total triiodothyronine (T3), and free T4 levels were higher (p < 0.001) in the NASH CRN cohort (n = 218; 421 observations) than in the National Health and Nutrition Examination Survey cohort (n = 2198). TSH levels were positively associated with increased steatosis over time (p = 0.03). Subclinical hypothyroidism was associated with borderline or definite metabolic-associated steatohepatitis on histology at baseline (p = 0.03) and with changes in fibrosis over time (p = 0.01).

Conclusions:

The association between TSH and steatosis severity in individuals with normal thyroid hormone concentrations suggests an independent role of TSH in MASLD.
Neighborhood Deprivation and Recovery Following Traumatic Brain Injury Among Older Adults
Authors: Albrecht Jennifer S. , Kirk Jennifer , Ryan Kathleen A. , Falvey Jason R.
Published: September 2024

Objective:

Understanding the extent to which neighborhood impacts recovery following traumatic brain injury (TBI) among older adults could spur targeting of rehabilitation and other services to those living in more disadvantaged areas. The objective of the present study was to determine the extent to which neighborhood disadvantage influences recovery following TBI among older adults.

Setting and Participants: Community-dwelling Medicare beneficiaries aged ≥65 years hospitalized with TBI 2010-2018.

Design and Main Measures:

In this retrospective cohort study, the Area Deprivation Index (ADI) was used to assess neighborhood deprivation by linking it to 9-digit beneficiary zip codes. We used national-level rankings to divide the cohort into the top 10% (highest neighborhood disadvantage), middle 11-90%, and bottom 10% (lowest neighborhood disadvantage). Recovery was operationalized as days at home, calculated by subtracting days spent in a care environment or deceased from monthly follow-up over the year post-TBI.

Results:

Among 13,747 Medicare beneficiaries with TBI, 1713 (12.7%) were in the lowest decile of ADI rankings and 1030 (7.6%) were in the highest decile of ADI rankings. Following covariate adjustment, beneficiaries in neighborhoods with greatest disadvantage [rate ratio (RtR) 0.96; 95% confidence interval (CI) 0.94, 0.98] and beneficiaries in middle ADI percentiles (RtR 0.98; 95% CI 0.97, 0.99) had fewer days at home per month compared to beneficiaries in neighborhoods with lowest disadvantage.

Conclusion:

This study provides evidence that neighborhood is associated with recovery from TBI among older adults and highlights days at home as a recovery metric that is responsive to differences in neighborhood disadvantage.
Adult Pharmacy Costs and Characteristics of Very High-Cost Prescription Drug Users in the United States, 2018–2022
Authors: Nguyen Jennifer L. , Do Duy , Swart Elizabeth C. , Lee Tiffany , Peasah Samuel K. , Patel Urvashi , Good Chester B.
Published: September 2024

Objective:

This study sought to identify: (1) the demographic and clinical characteristics of very high-cost users (defined as patients with pharmaceutical expenditures that were equal to or greater than the 99th percentile), (2) whether or not these characteristics changed over time, (3) sociodemographic and clinical correlates of being very high-cost users, (4) the average pharmaceutical costs of very-high cost users, and (5) the therapeutic classes and medications that contributed to these high costs

Background:

There are growing public concerns about rising drug costs, in part due to increased availability, greater effectiveness, and market considerations. There is a concentrated portion of patients that accounts for a disproportionately large portion of pharmaceutical expenditures.

Methods:

A large serial cross-sectional study was conducted with De-identified, member-level pharmacy claims (n = 65,739,791) from a large, national pharmacy benefits manager from January 1, 2018 to December 31, 2022. The main outcome and measures were 2018–2022 pharmaceutical expenditures; amounts were adjusted for inflation to reflect 2022-dollar values.

Results:

Across the study period, the odds of being classified as a very high-cost user were 1.31 times as high for those 45–64 years old compared with those 18–44 years old (reference category); the odds were 1.42 times as high for males compared with females; 1.13 times as high before those identifying as non-Hispanic Black compared with non-Hispanic white; 1.11 times as high for those enrolled in a health care exchange plan compared with a commercial plan. In addition, very high-cost users lived in areas with higher social needs. Human immunodeficiency virus, inflammatory conditions, multiple sclerosis, and cancer accounted for the largest share of costs among this group.

Conclusions:

This study identified the unique characteristics of very high-cost pharmaceutical users and identified the top conditions and prescription drugs that drove high pharmaceutical expenditures among this population. These findings are essential to understanding rising pharmaceutical costs in the United States and can help identify the issues and solutions of specific cost drivers within our health care policies.
Predicting invasiveness of ground-glass nodules in lung adenocarcinoma: based on preoperative 18F-fluorodeoxyglucose PET/computed tomography and high-resolution computed tomography
Authors: Wang Ximei , Yang Chunyan , Wang Xuewei , Wang Dalong
Published: September 2024

Objective

This study was conducted to explore the differential diagnostic value of PET/computed tomography (PET/CT) combined with high-resolution computed tomography (HRCT) in predicting the invasiveness of ground-glass nodules (GGNs).

Materials and methods

This retrospective analysis included 67 patients (mean age 62.5 ± 8.4, including 45 females and 22 males) with GGNs who underwent preoperative 18F-fluorodeoxyglucose (18F-FDG) PET/CT and HRCT examinations between January 2018 and October 2022. Based on the postoperative pathological results of lung adenocarcinoma, the patients were classified into two groups: invasive adenocarcinoma (IAC) and non-IAC. Besides, the clinical and imaging information of these patients was collected. HRCT signs include the existence of air bronchial signals, vascular convergence, pleural indentation, lobulation, and spiculation. Moreover, the diameter of solid components (DSolid), diameter of ground-glass nodules (DGGN), and computed tomography values of ground-glass nodules (CTGGN) were measured concurrently. Furthermore, the mean standardized uptake value, maximal standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis were assessed during PET/CT. Associations between invasiveness and these factors were evaluated using univariate and multivariate analyses.

Results

The results of logistic regression analysis demonstrated that DGGN, DSolid, consolidation tumor ratio (CTR), CTGGN, and SUVmax were independent predictors in the IAC group. The combined diagnosis based on these five predictors revealed that area under the curve was 0.825.

Conclusion

The DGGN, DSolid, CTR, CTGGN, and SUVmax in GGNs were independent predictors of IAC, and combining 18F-FDG PET/CT metabolic parameters with HRCT may improve the predictive value of pathological classification in lung adenocarcinoma.
Feasibility of self-management for amputee rehabilitation using technology and peer support for improving walking and confidence in individuals with lower limb loss
Authors: Esfandiari Elham , Miller William C. , Mortenson W. Ben , King Sheena , Underwood Heather , Ashe Maureen C.
Published: September 2024

Background:

Individuals with lower limb loss (LLL) require self-management education for amputation adaptation. eHealth technologies, like online platforms, widen access to educational resources. We developed an online self-management program for individuals with LLL called Self-Management for Amputee Rehabilitation using Technology (SMART).

Objective:

To assess the feasibility of SMART for improving walking capacity and confidence for adults with recent LLL.

Study Design:

A single-group pre-post intervention design.

Methods:

We recruited community-dwelling adults, with unilateral, transtibial, or transfemoral amputation. Self-management for amputee rehabilitation using technology included 6 weekly online educational modules, for example, pain management, diet, and sock management, and 6 weekly online meetings with a peer mentor to discuss goal setting and action planning. Outcomes were assessed at baseline (before SMART) and after 6 weeks using SMART. Feasibility indicators included process (retention rate), resource (duration of training sessions), management (participant processing), and treatment issues (effect size). The primary clinical outcome was walking capacity measured using Timed Up and Go, and secondary outcome was walking confidence measured using the Ambulatory Self-Confidence Questionnaire.

Results:

Twelve participants were recruited. The median (range) age was 56.0 (26–79) years. The retention rate was 100%. All participants were trained in less than 15 min. Four participants had an enrollment delay of more than 10 days. Two participants reported noninjurious falls because of amputation comorbidities and increased activity. The effect sizes for walking capacity and confidence were 0.51 and 0.86, respectively.

Conclusions:

Only small intervention and protocol refinements are required to SMART. These will be incorporated for a future multisite randomized controlled trial. SMART is an eHealth education program for people with LLL. Self-management for amputee rehabilitation using technology with peer support is a feasible intervention. However, adjustments to the study protocol and intervention safety are necessary before proceeding with the evaluation of SMART in a larger study.
Hypertension control and risk of age-associated dementia in people with HIV infection
Authors: Lam Jennifer O. , Hou Craig E. , Lee Catherine , Samiezade-Yazd Zahra , Levine Tory , Horberg Michael A. , Satre Derek D. , Silverberg Michael J.
Published: September 2024

Objective:

Hypertension is a major risk factor for dementia, but sustained blood pressure control is difficult to achieve. We evaluated whether inadequately controlled hypertension may contribute to excess dementia risk among people with HIV.

Design:

A retrospective cohort study.

Methods:

We studied demographically matched people with and without HIV between July 1, 2013, and December 31, 2021, who were at least 50 years old and had a hypertension diagnosis but no dementia diagnosis. Hypertension control was calculated using a disease management index (DMI), which captured degree and duration above the hypertension treatment goals of SBP less than 140 mmHg and DBP less than 90 mmHg. DMI values ranged from 0 to 100% (perfect control); hypertension was considered ‘inadequately controlled’ if DMI was less than 80% (i.e., in control for <80% of the time). Annual, time-updated DMI was calculated for SBP and DBP. Associations of SPB and DPB control with incident dementia were evaluated using extended Cox regression models.

Results:

The study included 3099 hypertensive people with HIV (mean age: 58.3 years, 90.2% men) and 66 016 people without HIV. Each year of inadequate SBP control was associated with greater dementia risk in both people with HIV (adjusted hazard ratio [aHR] = 1.26, 0.92–1.64) and people without HIV (aHR = 1.27 (1.21–1.33); P-interaction = 0.85). Similarly, inadequate DBP control was associated with greater dementia risk in both people with HIV (aHR = 1.43, 0.90–1.95) and people without HIV (aHR = 1.71, 1.50–1.93; P-interaction = 0.57).

Conclusion:

Findings suggest the association of inadequate hypertension control with greater dementia risk is similar by HIV status. Stronger associations of DBP control with dementia merit further investigation.
Immediate Breast Reconstruction After Mastectomy for Cancer Among US Military Health System Beneficiaries
Authors: Fox Justin P. , Latham Kerry P. , Darmon Sarah , Eaglehouse Yvonne L. , Bytnar Julie A. , Shriver Craig D. , Zhu Kangmin
Published: September 2024

Background

In the Military Health System (MHS), women with breast cancer may undergo surgical treatment in military hospitals (direct care) or in the civilian setting via the insurance benefit (private sector care). We conducted this study to determine immediate breast reconstruction rates among women undergoing mastectomy for cancer in the MHS by setting of care.

Methods

Using the linked Department of Defense's Central Cancer Registry and MHS Data Repository, the Department of Defense's medical claims database, we identified adult women who underwent mastectomy for breast cancer from 1998 to 2014. Patients were then subgrouped by setting of care (direct vs private sector care). The primary outcome was the rate and type of immediate breast reconstruction. Regression models were constructed to determine factors associated with receipt of immediate breast reconstruction.

Results

The final sample included 3251 women who underwent mastectomy for cancer in the direct (67.0%) or private sector care (32.6%) settings. The overall rate of immediate breast reconstruction was 29.9% with an upward trend noted throughout the study (P < 0.001). Overall, implant-based reconstruction (81.4%) was more common than tissue-based reconstruction (18.6%). Compared with direct care, the immediate breast reconstruction rate was significantly higher in the private sector care setting (49.3% vs 20.5%, P < 0.001) despite accounting for differences in clinical characteristics (adjusted odds ratio = 4.51, 95% confidence interval [3.72–5.46]).

Conclusions

Immediate breast reconstruction in the direct care setting lags that in the civilian community during the study time period. Further research is needed to ascertain current immediate reconstruction rates and understand factors contributing to any differences in rates between care settings.
Classification of Microtia With Unusable Remnant Ear and Techniques in the First Stage of Two-Stage Auricular Reconstruction
Authors: He Bei , Wang Bingqing , Zhang Qingguo
Published: September 2024

Background

The remnant ear is a very important material in auricular reconstruction surgery; its dimension, position, and shape determine how it is used. However, the local conditions of microtia patients are complex and variable. Situations may be encountered where a series of abnormal remnant ears cannot be utilized in clinical practice. Currently, there are no literature that elaborates on this type of microtia and provides systematic treatment methods. The purpose of this article is to systematically classify them and optimize the two-stage method auricular reconstruction, to provide an effective surgical method for these patients.

Methods

Based on the size, shape, and relative position of the residual ears, the unusable remnant ears were classified into three types: tiny size, abnormal shape, and relative position anomaly (over 1-cm higher than the contralateral earlobe). Fifty-three microtia patients with unusable remnant ear (54 ears) who underwent two-stage auricular reconstruction from August 2020 to August 2023 were reviewed. All patients had experienced earlobe reconstruction by using autologous rib cartilage during the first stage of surgery. Aesthetic assessments were evaluated from the naturalness of the earlobe reconstructed with autologous rib cartilage and the connection with the overall framework. The data on any complications that occurred during the follow-up period and patient satisfaction were collected.

Results

Among all patients, 31 had tiny size, 14 had abnormal shape, and 8 had excessively high positions. Patients were followed up for an average period of 9.2 months (6 to 12 months). No complex complications such as infection, skin necrosis, or cartilage exposure occurred. Fifty patients (94.3%) achieved excellent or good aesthetic outcomes. Fifty-one patients (96.2%) were satisfied with the reconstruction outcomes.

Conclusions

An accurate assessment of the residual ear preoperatively is essential. Reconstructing and splicing the earlobe with autologous rib cartilage in cases where the residual ear cannot be utilized compensate for the defect that the soft tissue cannot provide the earlobe flap. This is an effective surgical method for the ear reconstruction in such patients.
Spatial and seasonal foraging patterns drive diet differences among north Pacific resident killer whale populations
Authors: Van Cise Amy M. , Hanson M. Bradley , Emmons Candice , Olsen Dan , Matkin Craig O. , Wells Abigail H. , Parsons Kim M.
Published: September 2024

Highly social top marine predators, including many cetaceans, exhibit culturally learned ecological behaviours such as diet preference and foraging strategy that can affect their resilience to competition or anthropogenic impacts. When these species are also endangered, conservation efforts require management strategies based on a comprehensive understanding of the variability in these behaviours. In the northeast Pacific Ocean, three partially sympatric populations of resident killer whales occupy coastal ecosystems from California to Alaska. One population (southern resident killer whales) is endangered, while another (southern Alaska resident killer whales) has exhibited positive abundance trends for the last several decades. Using 185 faecal samples collected from both populations between 2011 and 2021, we compare variability in diet preference to provide insight into differences in foraging patterns that may be linked with the relative success and decline of these populations. We find broad similarities in the diet of the two populations, with differences arising from spatiotemporal and social variability in resource use patterns, especially in the timing of shifts between target prey species. The results described here highlight the importance of comprehensive longitudinal monitoring of foraging ecology to inform management strategies for endangered, highly social top marine predators.
Polymyxin combined with Ocimum gratissimum essential oil: one alternative strategy for combating polymyxin-resistant Klebsiella pneumoniae
Authors: de Melo Andressa Leite Ferraz , Rossato Luana , Velasques Jannaína , de Sousa Virginia Lopes , Pina Rodrigues Gabriel Victor , Cardoso Cláudia Andrea Lima , Arantes Julia Pimentel , Lima Bruno Fernandes , Simionatto Simone
Published: September 2024

Introduction. Multidrug-resistant infections present a critical public health due to scarce treatment options and high mortality. Ocimum gratissimum L. essential oil (O.geo) is a natural resource rich in eugenol known for its antimicrobial activity.

Hypothesis/Gap Statement. O.geo may exert effective antimicrobial activity against polymyxin-resistant Klebsiella pneumoniae and, when combined with Polymyxin B (PMB), may exhibit a synergistic effect, enhancing treatment efficacy and reducing antimicrobial resistance.

Aim. This study aims to investigate the antimicrobial activity of O.geo against polymyxin-resistant K. pneumoniae using in vitro tests and an in vivo Caenorhabditis elegans model.

Methodology. The O.geo was obtained by hydrodistillation followed by gas chromatography. The MIC and antibiofilm activity were determined using broth microdilution. Checkerboard and time-kill assays evaluated the combination of O.geo and polymyxin B (PMB), whereas a protein leakage assay verified its action.

Results. Eugenol (39.67%) was a major constituent identified. The MIC of the O.geo alone ranged from 128 to 512 µg ml−1. The fractional inhibitory concentration index (0.28) and time-kill assay showed a synergism. In addition, O.geo and PMB inhibited biofilm formation and increased protein leakage in the plasma membrane. The treatment was tested in vivo using a Caenorhabditis elegans model, and significantly increased survival without toxicity was observed.

Conclusion. O.geo could be used as a potential therapeutic alternative to combat infections caused by multidrug-resistant bacteria, especially in combination with PMB.
Integrating intraspecific variation into population dynamics reveals how interacting species persist in mutualistic communities
Authors: Arroyo-Correa Blanca , Bartomeus Ignasi , Jordano Pedro , Cagua E. Fernando , Stouffer Daniel B.
Published: September 2024

Mutualistic interactions among organisms are fundamental to the origin and maintenance of bio-diversity. Yet, the study of community dynamics often relies on species-level values, ignoring the effects of intraspecific variation. We propose a theoretical framework for evaluating the extent to which variation within populations can influence species’ persistence in mutualistic systems. Next, drawing from detailed empirical data on plant–pollinator interactions and plant fitness, we quantify intraspecific variation in the mutualistic benefits received by plants and incorporate this variation into estimations of structural stability, a robust theoretical measure of species’ likelihood of persistence. Through explicit consideration of intraspecific variation, we demonstrate that, in the absence of heterospecific plant competitors, plant populations composed of specialized individuals promote the persistence of the plant species they belong to and their associated pollinator community. However, these positive effects do not hold when plant species compete with a broader plant community. In this case, having more heterogeneous mixtures of plant individuals (i.e., both specialized and generalized) is more beneficial for a population’s persistence. By integrating the proposed framework with empirical data, we are able to explicitly account for individual-level variation, opening the door to a better understanding of the mechanisms promoting biodiversity in mutualistic communities.
Genetic diversity during selective sweeps in non-recombining populations
Authors: Kaushik Sachin , Jain Kavita , Johri Parul
Published: September 2024

Selective sweeps, resulting from the spread of beneficial, neutral, or deleterious mutations through a population, shape patterns of genetic variation at linked neutral sites. While many theoretical, computational, and statistical advances have been made in understanding the genomic signatures of selective sweeps in recombining populations, substantially less is understood in populations with little/no recombination. We present a mathematical framework based on diffusion theory for obtaining the site frequency spectrum (SFS) at linked neutral sites immediately post and during the fixation of moderately or strongly beneficial mutations. We find that when a single hard sweep occurs, the SFS decays as 1/xfor low derived allele frequencies (x), similar to the neutral SFS at equilibrium, whereas at higher derived allele frequencies, it follows a 1/x2power law. These power laws are universal in the sense that they are independent of the dominance and inbreeding coefficient, and also characterize the SFS during the sweep. Additionally, we find that the derived allele frequency where the SFS shifts from the 1/xto 1/x2law, is inversely proportional to the selection strength: thus under strong selection, the SFS follows the 1/x2dependence for most allele frequencies, resembling a rapidly expanding neutral population. When clonal interference is pervasive, the SFS immediately post-fixation becomes U-shaped and is better explained by the equilibrium SFS of selected sites. Our results will be important in developing statistical methods to infer the timing and strength of recent selective sweeps in asexual populations, genomic regions that lack recombination, and clonally propagating tumor populations.
From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling
Authors: Kasai Kazuki , Imamura Kayo , Uno Masatoshi , Sekiyama Naotaka , Miyata Tomoko , Makino Fumiaki , Yamada Ryusei , Takahashi Yoshiki , Kodera Noriyuki , Namba Keiichi , Ohnishi Hidenori , Narita Akihiro , Konno Hiroki , Tochio Hidehito
Published: September 2024

MyD88 plays a pivotal role in Toll-like receptor (TLR) and interleukin-1 family signaling through its oligomerization upon receptor activation, leading to downstream protein recruitment. The Toll/interleukin-1 receptor domain of MyD88 (TIRMyD88) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. We investigated the structure of TIRMyD88oligomers and their interactions with TLRs. Cryoelectron microscopy revealed that tandemly arrayed TIRMyD88subunits formed an antiparallel double-stranded filament that could further form rings and cylindrical filaments. Moreover, the self-assembly of TIRMyD88in vitrowas markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation stepin vivo. High-speed atomic force microscopy further captured the dynamic processes of oligomerization of TIRMyD88, in addition to its direct interaction with the receptor TIRs. Based on these results, a novel regulatory mechanism of TIRMyD88oligomerization underlying the signal initiation step was revealed.
Medin Induces Pro-Inflammatory Activation of Human Brain Vascular Smooth Muscle Cells
Authors: Karamanova Nina , Morrow Kaleb T. , Maerivoet Alana , Madine Jillian , Li Ming , Migrino Raymond Q.
Published: September 2024

Background

Medin is one of the most common amyloidogenic proteins and accumulates in the vasculature with aging. Vascular medin accumulation is associated with Alzheimer’s disease, vascular dementia and aortic aneurysms. Medin impairs smooth muscle-dependent vasodilation in isolated human brain cerebral arteries. The role of medin in vascular smooth muscle (VSMC) activation is unknown. We aim to evaluate the effects of medin on human brain VSMC activation.

Methods

VSMCs were exposed to physiologic doses of medin (0.5, 1 and 5 µM) without or with small molecule nuclear factor-κB (NFκB) inhibitor RO106-9920 (10 µM) for 20 hours. Polymerase chain reaction, Western blot/enzyme-linked immunosorbent assay were used to quantify gene and protein expressions/secretions, respectively, of pro-inflammatory factors (interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1) and structural and enzyme proteins associated with VSMC phenotypic transformation (smooth muscle actin alpha 2 (ACTA2), myosin heavy chain 11 (MYH11) and NADPH oxidase 4 (NOX4)).

Results

Medin exposure increased VSMC gene expression and protein secretion of IL-6, IL-8 and MCP-1 (protein secretion 46.0±12.8x, 20.2±4.1x and 8.7±3.1x, respectively, medin 5 µM versus vehicle, all p<0.05). There was no change in gene or protein expressions of ACTA2, MYH11 and NOX4. Co-treatment with RO106-9920 reduced medin-induced increases in IL-6 and IL-8 and a trend towards reduced MCP-1 secretion.

Conclusions

Medin induced pro-inflammatory activation of human brain VSMCs that is mediated, at least in part, by NFκB. Acute medin treatment did not alter structural proteins involved in VSMC phenotypic transformation. The findings support medin as a potential novel mediator of and therapeutic target for vascular aging pathology.
Developing a virtual Endoscopic Surgery Planning system to optimize surgical outcomes
Authors: Hittle Bradley , Odeh Ahmad , Maza Guillermo , Shen Brenda , Otto Bradley A , Stredney Don , Wiet Gregory J. , Zhao Kai
Published: September 2024

Objective

Planning and predicting functional outcomes of endoscopic sinus surgeries (e.g., nasal airflow) based solely on visualizing Computerized Tomography (CT) or endoscopy poses a challenge to produce optimal clinical outcomes.

Study design

Technology development, retrospective case report.

Methods

A virtual surgery planning (VSP) tool is developed that can load any patient’s CT data and allow surgeons to remove obstructive tissue using both visual and haptic feedback endoscopically. Pre-calculated airflow resistance, wall shear stress, pressure drop are displayed on the anatomy to identify potential sites of obstruction. After each virtual surgery, changes in nasal airflow can be computed, and the process is reiterated until an optimal result is reached.

Results

As proof-of-concept, a series of isolated or combined procedures were performed on CT of one patient, who had olfactory losses that may involve obstructions blocking the air/odor flow to the olfactory fossa (OF). For this patient, an isolated medial partial middle turbinectomy (PMT) demonstrated the best outcome, better than traditionally performed lateral PMT, while septal body reduction worsened air/odor flow to OF.

Conclusion

This proof of concept case report demonstrates the potential usefulness of VSP in preoperative planning based on objective benchmarks and could be a valuable tool for optimizing future surgical outcomes.
Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma
Authors: Sartini Sara , Omholt Lexi , Moatamed Neda A. , Soragni Alice
Published: September 2024

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.
Cortical connectivity supports motoric synchronization to both auditory and visual rhythms in a frontal-temporal network
Authors: Lu Yuhan , Yu Yanlin , Wang Xiaosha , Qin Lang , Gao Jia-Hong , Bi Yanchao , Tian Xing , Ding Nai
Published: September 2024

Synchronizing motoric responses to metrical sensory rhythms is key to social activities, e.g., group singing and dancing. It remains elusive, however, whether there is a common neural network for motoric synchronization to metrical rhythms from different sensory modalities. Here, we separate sensorimotor responses from basic sensory responses by combining a metrical sensorimotor synchronization task with frequency-domain magnetoencephalography (MEG) analysis. A common frontal-temporal network, not including visual cortex, is observed during both visual- and auditory-motor synchronization, and the network remains in congenitally deaf participants during visual-motor synchronization, suggesting the network is formed by intrinsic cortical connections instead of auditory experience. Furthermore, activation of the left and right frontal-temporal areas, as well as the ipsilateral white matter connection, separately predict the precision of auditory and visual synchronization. These results reveal a common but lateralized frontal-temporal network for visual- and auditory-motor synchronization, which is generated based on intrinsic cortical connections.
Genomic Analysis of Human-infectingLeptospira borgpeterseniiisolates in Sri Lanka: expanded PF07598 gene family repertoire, less overall genome reduction than bovine isolates
Authors: Senavirathna Indika , Jayasundara Dinesha , Warnasekara Janith , Agampodi Suneth , Putz Ellie J. , Nally Jarlath E. , Bayles Darrell O. , Chaurasia Reetika , Vinetz Joseph M.
Published: September 2024

Leptospira borgpeterseniicommonly causes human leptospirosis, including severe disease. The first published analysis ofL. borgpetersenii, performed on two strains of serovar Hardjo (L550 and JB197), concluded that theL. borgpeterseniigenome is in the process of genome decay with functional consequences leading to a more obligately host-dependent life cycle. Yet whole genome analysis has only been carried out on few strains ofL. borgpetersenii, with limited closed genomes and comprehensive analysis. Herein we report the complete, circularized genomes of seven non-HardjoLeptospira borgpeterseniiisolates from human leptospirosis patients in Sri Lanka. These isolates (all ST144) were found to be nearly identical by whole genome analysis; serotyping showed they are a novel serovar. We show that theL. borgpeterseniiisolated from humans in Sri Lanka are less genomically decayed than previously reported isolates: fewer pseudogenes (N=141) and Insertion Sequence (IS) elements (N=46) compared to N=248, N=270, and N=400 pseudogenes, and N=121 and N=116 IS elements in publishedL. borgpeterseniiHardjo genomes (L550, JB197 and TC112). Compared to previously publishedL. borgpeterseniiwhole genome analyses showing two to three VM proteins inL. borgpeterseniiisolates from cattle, rats and humans, we found that all of the humanL. borgpeterseniiisolates from Sri Lanka, including previously reported serovar Piyasena, have 4 encoded VM proteins, one ortholog ofL. interrogansCopenhageni LIC12339 and 3 orthologs of LIC12844. Our findings of fewer pseudogenes, IS elements and expansion of the LIC12844 homologs of the PF07598 family in these human isolates suggests that this newly identifiedL. borgpeterseniiserovar from Sri Lanka has unique pathogenicity. Comparative genome analysis and experimental studies of theseL. borgpeterseniiisolates will enable deeper insights into the molecular and cellular mechanisms of leptospirosis pathogenesis.

Author Summary

Leptospirosis is an emerging bacterial zoonosis worldwide.Leptospira borgpeterseniipredominates as the cause of human leptospirosis in some agricultural contexts. We address here the relatively neglected comparative genome analysis ofL. borgpetersenii. We show here thatL. borgpeterseniiisolated from humans in Sri Lanka have less genome reduction compared to available cattle isolates and have novel virulence characteristics compared to isolates from other animals including cattle and rats.
Molecular dynamics simulations of human cohesin subunits identify DNA binding sites and their potential roles in DNA loop extrusion
Authors: Gu Chenyang , Takada Shoji , Brandani Giovani B. , Terakawa Tsuyoshi
Published: September 2024

The SMC complex cohesin mediates interphase chromatin structural formation in eukaryotic cells through DNA loop extrusion. Here, we sought to investigate its mechanism using molecular dynamics simulations. To achieve this, we first constructed the amino-acid-residue-resolution structural models of the cohesin subunits, SMC1, SMC3, STAG1, and NIPBL. By simulating these subunits with double-stranded DNA molecules, we predicted DNA binding patches on each subunit and quantified the affinities of these patches to DNA using their dissociation rate constants as a proxy. Then, we constructed the structural model of the whole cohesin complex and mapped the predicted high-affinity DNA binding patches on the structure. From the spatial relations of the predicted patches, we identified that multiple patches on the SMC1, SMC3, STAG1, and NIPBL subunits form a DNA clamping patch group. The simulations of the whole complex with double-stranded DNA molecules suggest that this patch group facilitates DNA bending and helps capture a DNA segment in the cohesin ring formed by the SMC1 and SMC3 subunits. In previous studies, these have been identified as critical steps in DNA loop extrusion. Therefore, this study provides experimentally testable predictions of DNA binding sites implicated in previously proposed DNA loop extrusion mechanisms and highlights the essential roles of the accessory subunits STAG1 and NIPBL in the mechanism.
GABAergic neurons in the dorsal raphe nucleus regulate social hierarchy in mice
Authors: Lu Lidi , Fan Yanzhu , Ge Shaoxiang , Wu Yue , Wang Zhiyue , Qing Tao , Shi Suxin , Fang Guangzhan
Published: September 2024

Social hierarchy serves as a fundamental organizational mechanism within most animal societies, exerting significant influence on health, survival, and reproductive success in both humans and animals. However, the neural mechanisms by which the brain regulates dominance hierarchies remain inadequately understood. Considering that GABAergic neurons in the dorsal raphe nucleus (DRN) exert substantial inhibitory control over serotonergic firing, which may be implicated in the acquisition of dominance, we hypothesized that DRN GABAergic neurons may play a pivotal role in regulating social hierarchy. To test this hypothesis, we employed a combination of optogenetics, chemogenetics, fiber photometry recordings, and behavioral assays in mice, to elucidate the functional contributions of these neurons. Our results revealed a biphasic activity pattern of DRN GABAergic neurons, characterized by increased firing during retreats and decreased firing during push-initiation in the tube test. Furthermore, the optogenetic and chemogenetic activation of DRN GABAergic neurons led to an increase in the number of retreats and a reduction in social rank, while inhibition of these neurons produced the opposite effects. These findings elucidate the bidirectional regulatory role of DRN GABAergic neurons in social hierarchies.
Variations in human trigeminal and facial nerve branches and foramina identified by dissection and microcomputed tomography
Authors: Grimes Hannah L. , Pizzuti Valentina , Wright Maria A. , Santarius Thomas , Jones Susan
Published: September 2024

The aim of this study was to identify branches of the trigeminal and facial nerves relevant to surgical incisions and injections and the scalp block techniques in the frontotemporal region, and to determine their relationships with superficial vascular structures and bony landmarks. Half-heads from consenting embalmed donors (6 male, 2 female, mean age at death 78.4 years) were used in this study. Detailed dissection was carried out to identify the position of the auriculotemporal nerve (ATN) relative to the superior temporal artery (STA) and the facial nerve (FN) in six subjects (5 male, 1 female). The results provide a minimum safe distance of 5 mm between the STA and the frontotemporal branches of the FN at the level of the low edge of zygoma and 8mm between the low edge of zygoma and the FN trunk, providing a pre-auricular triangle of safety for incisions and injections. Variability between subjects was up to 60%. Microcomputed tomography (microCT) scans were taken from all eight subjects and the three-dimensional reconstructions were used to identify the supraorbital notch (SON), the zygomaticotemporal foramen (ZTF) and the zygomaticofacial foramen (ZFF). The volume and relative locations of these foramina were calculated for 5-8 subjects. The closest distance between ZTF and the FZS ranged from 9 to 21mm (26% variation); 3 subjects had a single ZTF while 5 subjects had two ZTF. The angle at the centre of the orbit between ZFF and the FZS ranged from 156 to 166 degrees (2.5% variation). These findings demonstrate that both traditional cadaveric dissection methods as well as contemporary microCT methods can be used to investigate the relative locations of nerves or their foramina in the human head. The findings provide anatomical considerations for fronto-temporal incisions and local anaesthesia.
Activation of 5-HT7receptors in the mouse dentate gyrus does not affect theta-burst-induced plasticity at the perforant path synapse
Authors: Siwiec Marcin , Bobula Bartosz , Kiełbiński Michał , Multan Nikola , Hess Grzegorz , Tokarski Krzysztof
Published: September 2024

Background

The study examined the effects of 5-HT7receptor activation on GABAergic transmission within the dentate gyrus and plasticity at the glutamatergic perforant path input.

Methods

Immunofluorescence imaging was performed using transverse hippocampal slices from transgenic mice expressing green fluorescent protein (GFP) under the Htr7 promoter. This was followed by whole-cell patch clamp electrophysiological recordings assessing the effects of pharmacologically activating 5-HT7receptors on spontaneous inhibitory postsynaptic currents recorded from dentate granule cells and hilar mossy cells — two glutamatergic neuron types present in the dentate gyrus. Extracellular recordings of field excitatory postsynaptic potentials were then performed to assess whether 5-HT7receptor activation influenced theta-burst stimulation-evoked plasticity of the perforant path synaptic input.

Results

It was found that parvalbumin and somatostatin interneurons in the dentate gyrus expressed GFP, which suggests they express 5-HT7receptors. However, activation of 5-HT7receptors had no effect on GABAergic transmission targeting mossy cells or granule cells. There was also no effect of 5-HT7receptor activation on perforant path plasticity either with intact or blocked GABAAreceptor signaling.

Conclusion

The presence of 5-HT7receptors in a subset of parvalbumin and somatostatin interneurons in the mouse dentate gyrus could mean that they are involved in the inhibitory control of dentate gyrus activity. However, this potential effect was not evident in slice recordings of inhibitory transmission targeting principal cells and did not affect perforant path plasticity. Further experiments are needed to fully elucidate the functional role of these receptors in the dentate gyrus.