bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower Extremity Angiosarcoma: A Life-Threatening Complication of Lymphedema
Authors: Garimella Vishal , Anand Nimay , Campbell Elliott H. , Baum Christian L. , Alavi Afsaneh
Published: April 2024

When angiosarcoma, a rare and aggressive tumor of the soft tissue, develops in the setting of chronic lymphedema, it is referred to as Stewart-Treves syndrome. It is usually seen in chronic lymphedema of the upper limbs postmastectomy. Angiosarcoma developing in the lower limb in the setting of chronic lymphedema is rare and has a poor outcome. The presentation of angiosarcoma can vary, ranging from a bleeding papule to a plaque or a subcutaneous mass, which can later progress to ulceration or necrosis. Treatment for Stewart-Treves syndrome is aggressive because of its poor prognosis and usually requires a multidisciplinary approach of surgery, radiation, and chemotherapy. Several theories have been put forth to explain the mechanism of Stewart-Treves syndrome, but it remains ambiguous. The current literature regarding angiosarcoma developing in the setting of chronic lymphedema in the lower limb is limited to single case reports. Herein, the authors report a series of six cases of biopsy-proven angiosarcoma in the setting of lower extremity lymphedema. Providers should include angiosarcoma in the differential diagnosis of ulcerative or vascular tumors arising in the context of lower extremity lymphedema.
Standardized In-harness Ultrasound Protocol Improves Success Rate of Brace Treatment for Dislocated Hips
Authors: Pargas-Colina Carlos D. , Allred Caleb M. , Gupta Apeksha , Blumberg Todd J.
Published: April 2024

Objective:

Infant hip dislocations benefit from early detection and treatment for optimal outcomes. Prior studies have identified that there remains wide variability in the success rate of bracing between institutions. Although there are standardized methods to screen infants for hip dysplasia, there are no clear guidelines regarding how to image a child being treated for a hip dislocation with a Pavlik harness. As a result, there is substantial variability in how treatment success or failure is monitored between and within institutions. The goal of our study is to determine whether a standardized in-harness imaging protocol improves outcomes and the likelihood of successful treatment for dislocated hips being treated with the Pavlik harness.

Methods:

All patients with hip dislocations and pretreatment ultrasound (US) were included from July 2018 to July 2022. A new institutional US protocol was implemented in July 2020, during which standardized in-harness imaging was obtained for patients with hip dislocations. Patients treated before the implementation of standardized in-harness imaging were categorized as nonstandardized and after implementation as a standardized group. Outcomes were compared between standardized and nonstandardized groups. P <0.05 determined the statistical significance.

Results:

One hundred twenty-eight hips met the inclusion criteria (n = 97 patients). The mean age at diagnosis was 41.6 ± 23.4 days and was predominantly female (85.6%). There was no significant difference between the patients' demographics and baseline clinical characteristics between the standardized and nonstandardized groups. Pavlik harness success rate was significantly higher in the standardized group (85% vs 60%, P = 0.0024). Twenty-eight hips in the nonstandardized group remained dislocated and were indicated for surgical treatment, whereas only 8 hips remained dislocated in the standardized group and necessitated closed or open reduction.

Conclusions:

Standardization of in-harness imaging for patients undergoing treatment for developmental hip dislocations can significantly improve the Pavlik harness success rate. These findings emphasize the importance of obtaining images with the hip in flexion and abduction to prevent inadvertent stress during US evaluation for hips that have not yet stabilized, which may lead to premature cessation of the Pavlik harness.

Level of Evidence:

Level III.
Science of Learning Strategy Series: Article 5, Incentivizing Sleep in Continuing Professional Development
Authors: Van Hoof Thomas J. , Madan Christopher R. , Sumeracki Megan A. , Meehan Thomas P.
Published: April 2024

The science of learning (learning science) is an interprofessional field that concerns itself with how the brain learns and remembers important information. Learning science has compiled a set of evidence-based strategies, such as distributed practice, retrieval practice, and interleaving, which are quite relevant to continuing professional development (CPD). Spreading out study and practice separated by cognitive breaks (distributed practice), testing oneself to check mastery and memory of previously learned information (retrieval practice), and mixing the learning of distinct but related material (interleaving) represent strategies that are underutilized in CPD. Participants and planners alike can benefit from learning science recommendations to inform their decisions. Sleep, the subject of this article and critical to distributed practice, is the ideal circumstance for the brain to process priority information. The authors make the case for sleep as a legitimate part of a learning activity and worthy of consideration in the award of CPD credits.
Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach
Authors: Chang Anne Lynn S. , Brown Ryanne , Li Shufeng , Betancourt Nicolas , Teng Joyce
Published: April 2024

Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 (P
adjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: P
adjusted < 0.0001; cytoplasmic: P
adjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.
Clinical analysis of patients with deep sternal wound infection-induced sepsis: a retrospective cohort study
Authors: Song Bin , Cui Zhentian , Ju Hongyan , Sun Yue , Liu Dandan , Li Guanggang
Published: April 2024

Background

This study aimed to summarize the clinical characteristics of patients with deep sternal wound infection-induced sepsis after median sternotomy and improve the treatment outcomes of infection-related sepsis.

Methods

A retrospective cohort study was conducted on 21 patients with deep sternal wound infection-induced sepsis after median sternotomy who were admitted to the Department of Critical Care. The clinical manifestations, laboratory test results, infection control, and organ and nutritional support of the patients were summarized, and the follow-up data were obtained.

Results

The primary symptoms of deep sternal wound infection-induced sepsis included dyspnea, high fever, chills, and altered state of consciousness. Laboratory test results revealed increased inflammatory markers and decreased oxygenation index. Renal and liver function injury were observed in 8 and 4 patients, respectively; 18 and 12 patients demonstrated elevated D-dimer and N-terminal Pro B type natriuretic peptide levels, respectively. Of the 8 patients whose wound secretions tested positive for bacteria,Acinetobacter baumanniiandStaphylococcus aureusinfections were present in 6 and 2 patients, respectively. One of the 6 patients whose blood cultures tested positive for bacteria demonstratedCandida albicansinfection. Fifteen patients received ventilator-assisted ventilation and 2 patients received renal replacement therapy. Of all the 21 patients, 17 were cured, 2 died, and 2 were discharged.

Conclusion

Postmedian sternotomy sepsis attributed to a deep sternal wound infection usually results from a preexisting condition. The most prominent clinical manifestation is dyspnea, which is sometimes accompanied by the impairment of organ function. Infection prevention, proper nutrition support, and maintenance of healthy organ function are the cornerstones for successful treatment outcomes.
Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory
Authors: Keating Paula Elizabeth , Hock Barry D. , Chin Paul K. L. , O'Donnell John Liston , Barclay Murray Lindsay
Published: April 2024

Background:

Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated.

Methods:

Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA.

Results:

Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA.

Conclusions:

Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.
Tacrolimus Monitoring in Liver Transplant Recipients, Posttransplant Cholestasis: A Comparative Between 2 Commercial Immunoassays and a Liquid Chromatography-Tandem Mass Spectrometry Method
Authors: Parant François , Delignette Marie-Charlotte , Charpiat Bruno , Lacaille Louis , Lebosse Fanny , Monneret Guillaume , Mohkam Kayvan , Mabrut Jean-Yves , Aubrun Frederic , Heyer Laurent , Antonini Teresa
Published: April 2024

Background:

Cholestasis commonly occurs after orthotopic liver transplantation. It can be extrahepatic because of mechanical obstruction or intrahepatic because of various causes. During cholestasis episodes, blood concentrations of tacrolimus (TAC) metabolites may increase, potentially affecting TAC concentrations measured by immunoassays. This study aimed to simultaneously evaluate the analytical performance of 2 TAC immunoassays, a quantitative microsphere system (QMS) immunoassay, and chemiluminescence microparticle immunoassay, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a reference method in liver transplant recipients.

Methods:

This single-center study included 265 patients who underwent orthotopic liver transplantation. In total, 942 blood samples were collected. TAC trough concentrations were measured using LC-MS/MS and 2 immunoassays in parallel. The plasma concentrations of conjugated bilirubin were measured in all samples. The results were analyzed using Bland–Altman plots and Passing–Bablok regressions.

Results:

The Bland–Altman plot analysis showed that the TAC QMS immunoassay has a significant bias (+37%) compared with LC-MS/MS, and this bias was higher in patients with cholestasis with hyperbilirubinemia (≤+70% in patients with conjugated bilirubin >150 µmol/L). In comparison, the chemiluminescence microparticle immunoassay showed acceptable analytical performance in patients with hyperbilirubinemia (bias <10%).

Conclusions:

In agreement with previous findings, the TAC QMS immunoassay showed a positive bias compared with LC-MS/MS. This bias is remarkably high in patients with cholestasis and hyperbilirubinemia, suggesting the cross-reactivity of TAC metabolites with the monoclonal antibody used in the QMS immunoassay.
Analyzing the trend of mortality due to traffic and nontraffic accidents: a study in the north of Iran
Authors: Nikbakht Hossein-Ali , Farajpour Fatemeh , Farhadi Zeynab , Hashemi Seyedeh N. , Jahani Mohammad-Ali
Published: April 2024

Background:

Examining the raw and standardized mortality rates is the primary strategy for improving life expectancy and human health in society through identifying risk factors and dealing with the factors that cause them.

Objectives:

This study examined the trend of mortalities due to traffic and nontraffic accidents.

Methods:

This cross-sectional study examines the registered mortalities during the years 2016–2022 in the form of a census in the health department’s death registration and classification system. Mortality was analyzed as raw and standardized mortality in each 100 000 population.

Results:

Out of 18 265 deaths during 2016–2022, 1305 (7.15%) were related to accidents and incidents. The age-standardized total mortality rate in the first year was 32.9, and in the final year of the study, it was 33.3 per 100 000 people; although there are fluctuations, this trend is upward (P.trend=0.021). Also, the age-standardized traffic death rate in the first year is 19, and in the final year is 12 per 100 000 people; this decreasing trend was not statistically significant (P.trend=0.061). The incidence of age-standardized intentional nontraffic deaths was 1.7 in the first year of the study interval and 9.8 in the last year in 100 000 people, which showed an upward trend (P.trend<0.001).

Conclusion:

In light of the generally increasing trend of accidents, especially nontraffic accidents, universal and well-rounded measures are necessary for safety matters and reducing mortality.
Association of detrusor wall thickness (DWT) with lower urinary tract symptom severity in benign prostatic hyperplasia: a cross-sectional study
Authors: Bhattarai Kishor , Khadka Hensan , Thapa Bikash Raj , Katwal Shailendra
Published: April 2024

Background and objective:

Benign prostatic hyperplasia manifests as lower urinary tract symptoms (LUTS) and prostate gland enlargement, leading to bladder outlet obstruction with consequent structural and functional impacts on the bladder. Urodynamic studies are resource-intensive and invasive. Detrusor wall thickness (DWT) assessment offers a cost-effective, reproducible alternative for evaluating LUTS severity in males with bladder outlet obstruction, utilizing ultrasonographic examination.

Methods:

This prospective cross-sectional study, conducted at a tertiary care center from May 2023 to January 2024, included 171 patients with LUTS who underwent transabdominal ultrasound for DWT measurements. LUTS severity, assessed using International Prostate Symptom Scores (IPSS) classified participants into mild and moderate-to-severe symptom groups. Pearson’s correlation coefficient assessed the association between DWT and IPSS, and an independent sample t-test compared means, using a significance level of 5% (P-value ≤0.05).

Results:

This study involved participants aged 65.01±11.55 years with an IPSS score ranging from 1 to 35, with a mean for mild and moderate-to-severe symptom groups were 4±2.12 and 15.93±6.74, respectively. DWT mean of 1.64±0.38 mm for mild, and 2.4±0.43 mm for moderate to severe symptoms. Pearson’s correlation (r=0.697, n=171, P<0.001) indicated a strong DWT-LUTS correlation and a significant DWT mean difference between mild and moderate-to-severe symptom groups was found via an independent t-test (P<0.001, 95% CI: −0.8970 to −0.6414).

Conclusion:

The study establishes the value of transabdominal ultrasound-detected DWT as a cost-effective, noninvasive, and reproducible tool for assessing LUTS severity in males with benign prostatic hyperplasia.
Estimates of the Lifetime Productivity Costs of Chlamydia, Gonorrhea, and Syphilis in the United States
Authors: Chesson Harrell , Spicknall Ian H. , Kreisel Kristen M. , Gift Thomas L.
Published: April 2024

Background

Productivity costs of sexually transmitted infections (STIs) reflect the value of lost time due to STI morbidity and mortality, including time spent traveling to, waiting for, and receiving STI treatment. The purpose of this study was to provide updated estimates of the average lifetime productivity cost for chlamydia, gonorrhea, and syphilis, per incident infection.

Methods

We adapted published decision tree models from recent studies of the lifetime medical costs of chlamydia, gonorrhea, and syphilis in the United States. For each possible outcome of infection, we applied productivity costs that we obtained based on published health economic studies. Productivity costs included the value of patient time spent to receive treatment for STIs and for related sequelae such as pelvic inflammatory disease in women. We used a human capital approach and included losses in market (paid) and nonmarket (unpaid) productivity. We conducted 1-way sensitivity analyses and probabilistic sensitivity analyses.

Results

The average lifetime productivity cost per infection was $28 for chlamydia in men, $205 for chlamydia in women, $37 for gonorrhea in men, $212 for gonorrhea in women, and $411 for syphilis regardless of sex, in 2023 US dollars. The estimated lifetime productivity cost of these STIs acquired in the United States in 2018 was $795 million.

Conclusions

These estimates of the lifetime productivity costs can help in quantifying the overall economic burden of STIs in the United States beyond just the medical cost burden and can inform cost-effectiveness analyses of STI prevention activities.
Breakthrough Mpox Outbreak Investigation, the Delicate Balance Between Host Immune Response and Viral Immune Escape
Authors: Moretti Marco , Meuwissen Annelies , Rezende Antonio M. , Zange Sabine , Van Nedervelde Els , de Block Tessa , Vercauteren Koen , Demuyser Thomas , Allard Sabine D.
Published: April 2024

Background

Limited data are available on Mpox breakthrough infections.

Purpose

The purpose of this study is to investigate a Mpox breakthrough outbreak in 3 vaccinated individuals.

Methods

Study participants provided informed consent. Serology testing was performed in one involved individual (ID-1) using an in-house assay detecting anti-orthopoxvirus IgG. Whole genome sequencing (WGS) was carried out and compared with the reference sequence ON563414.3 (https://www.ncbi.nlm.nih.gov/nuccore/ON563414.3/).

Results

Three individuals vaccinated with modified vaccinia Ankara–Bavaria Nordic contracted Mpox following one sexual intercourse event. One of them (ID-1) had received only one vaccine dose, while the other two were fully vaccinated. ID-1 presented to the sexual health clinic of the Universitair Ziekenhuis Brussel with proctitis related to Mpox. Despite one vaccination, serology testing Three months post vaccine showed absence of Mpox virus (MPXV) specific antibodies in ID-1. In contrast, 2 weeks after the sexual intercourse, seroconversion occurred. Whole genome sequencing of the isolated MPXV showed, compared with the reference sequence, a total of seven single nucleotide variants with four of them indicating protein amino-acid changes.

Conclusion

Incomplete MPXV vaccination as well as MPXV variants might result in breakthrough infections. Preventive measures, such as MPVX vaccination, could maintain immunity in individuals with higher risk of MPXV infection, and might lower disease severity.
JYNNEOS Vaccine Safety Surveillance During the 2022 Mpox Outbreak Using the Vaccine Adverse Event Reporting System and V-safe, United States, 2022 to 2023
Authors: Duffy Jonathan , Myers Tanya R. , Marquez Paige , Rouse Douglas , Brown Hannah , Zhang Bicheng , Shay David K. , Moro Pedro L.
Published: April 2024

Background

In response to the 2022 mpox outbreak in the United States, people with higher potential for exposure to mpox were recommended to receive 2 doses of the JYNNEOS vaccine. Vaccine safety was monitored using 2 complementary systems.

Methods

The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system that accepts reports of adverse events after vaccination. VAERS is capable of rapidly identifying rare adverse events and unusual reporting patterns. Medical records were requested and reviewed for adverse events of special interest, including myocarditis. Adverse event reporting rates were calculated as the number of verified adverse event cases divided by the number of JYNNEOS doses administered. V-safe for mpox was a voluntary smartphone-based vaccine safety surveillance system that sent enrolled persons text messages linked to health surveys asking about reactions and health impact events occurring after vaccination.

Results

There were 1,207,056 JYNNEOS doses administered in the United States. VAERS received 1927 reports for JYNNEOS. The myocarditis reporting rate per million doses was 2.69 after dose 1 and 8.64 after dose 2. V-safe had 213 participants complete at least one health survey. Rates of injection site and systemic reactions were similar in the first week after dose 1 and dose 2.

Conclusions

JYNNEOS vaccine safety surveillance findings from VAERS and v-safe did not identify any unexpected safety concerns. The VAERS reporting rate for myocarditis was similar to previously published population background rates.
Opt-Out Syphilis Screening at an Urgent Care Center in Atlanta: Evaluation of a Pilot Program
Authors: Sweitzer Stephanie , Sharp Joseph , Baker Dylan , Lynch Alexis , Stauch Meredith A. , Wheatley Matthew , Lora Meredith , Cantos Valeria D. , Gruen Judah
Published: April 2024

Background

Human immunodeficiency virus (HIV) and syphilis disproportionately impact communities with low access to primary care, who often utilize urgent care centers (UCCs) for sexual health care. UCC visits represent an opportunity for identification and treatment of syphilis and linkage to HIV testing and prevention services. We describe a universal, opt-out syphilis screening program pilot at an Atlanta UCC.

Methods

A chart review was performed on patients 18 years and older who were offered opt-out syphilis screening and had a rapid plasma reagin (RPR) test collected from September 1, 2021 to December 31, 2021. Demographic data, syphilis stage and treatment, and HIV testing and serostatus were abstracted from the electronic health record. Patients with reactive RPRs were contacted by a study physician for syphilis staging and treatment, counseling, and referral for HIV preexposure prophylaxis (PrEP) or treatment.

Results

From September 1, 2021 to December 31, 2021, 5794 patients were triaged and 1381 underwent RPR screening (23.8%). Eighty (5.8%) had reactive RPRs, and 42 (52.5%) had active syphilis. Of those with active syphilis, 39 (92.9%) received any treatment, and 35 (83.3%) completed treatment. Patients with late syphilis were less likely to complete syphilis treatment (adjusted odds ratio, 0.03; P = 0.009; 95% confidence interval, 0.002–0.42). Among 955 offered PrEP, 41 (4.3%) expressed interest in PrEP, and 7 (0.7%) completed PrEP clinic intake. Univariate analysis did not identify any factors associated with interest in PrEP.

Conclusions

In a UCC setting, routine, opt-out syphilis testing resulted in increased syphilis identification and treatment. It also provided an opportunity for PrEP counseling and referral, although few patients completed PrEP clinic intake.
Exercise Training for Women With Fibromyalgia Syndrome
Authors: Silva Lais Carneiro , Dittgen Michelle , Meroni Roberto , Sanchez-Romero Eleuterio A. , Rossettini Giacomo , Villafañe Jorge Hugo , Corbellini Camilo
Published: April 2024

Background:

To identify in the literature the exercise training therapies for females with fibromyalgia that may improve pain management and quality of life (QOL).

Methods:

A literature search was conducted in MEDLINE and PEDro databases for human studies up to June 2021. We considered studies if they investigated exercise therapies and their impact on pain, QOL, physical function, and mental health in female patients with fibromyalgia.

Results:

We identified 112 clinical trials. After posterior analyses, 15 articles were selected, and 8 were considered eligible.

Conclusions:

Selected studies demonstrated that high-intensity and moderate-intensity aerobic training combined or not with muscle strength anaerobic exercise reduces pain and improves QOL in females with fibromyalgia.
Suppressive Role of Pigment Epithelium-derived Factor in a Rat Model of Corneal Allograft Rejection
Authors: Chu Xiaoran , Yin Yilan , Chen Sijing , Chen Fu , Liu Hui , Zhao Shaozhen
Published: April 2024

Background.

Immunological rejection is the most common reason for corneal transplantation failure. The importance of T cells in corneal allograft rejection is well demonstrated. Recent studies highlight that pigment epithelium-derived factor (PEDF) plays an immunoregulatory role in ocular diseases by enhancing the suppressive phenotype of regulatory T cells besides its other functions in neurotrophy and antiangiogenesis.

Methods.

The effects of PEDF on immune rejection were examined in rat models of corneal transplantation using slit-lamp microscope observation, immunohistochemistry, flow cytometry, and Western blot. In vitro, we demonstrated PEDF reduced alloreactive T-cell activation using real-time polymerase chain reaction, flow cytometry, and Western blot.

Results.

Topical administration of PEDF provided corneal transplantation rats with an improved graft survival rate of corneal allografts, reduced hemangiogenesis, and infiltration of immune cells in corneas, in particular, type 17 T helper cells while increased regulatory T cells. Moreover, nerve reinnervation within grafts was promoted in PEDF-treated recipient rats. In vitro, PEDF inhibited alloreactive T-cell activation via the c-Jun N-terminal kinase/c-Jun signaling pathway and upregulated the expressions of interleukin-10 and transforming growth factor-β, emphasizing the suppressive role of PEDF on immune responses.

Conclusions.

Our results underscore the feasibility of PEDF in alleviating corneal allograft rejection and further illustrate its potential in managing immune-related diseases.
Uncontrolled hypertension is associated with an increased risk of end-stage renal disease in patients with type 2 diabetes who underwent postpercutaneous coronary intervention: A nationwide population-based study
Authors: Kim Hyunglae , Park Yong-Moon , Ko Seung-Hyun , Cho Yun-Jung , Kim Hyung Wook , Kim Yong Kyun , Han Kyung-Do , Yun Jae-Seung , Kim Kyuho , Moon Donggyu
Published: April 2024

Background

Little is known about the use of hypertension to predict end-stage renal disease (ESRD) in patients with type 2 diabetes mellitus (T2DM) and established coronary artery disease who underwent percutaneous coronary intervention (PCI). Here, we evaluated the effect of differential blood pressure (BP) levels on future ESRD in this population.

Methods

Using nationwide health check-up data from the Korean National Health Insurance Service between 2015 and 2016, we obtained data for 80,187 patients with T2DM who underwent previous PCI. Patients were classified into four groups according to BP level measured within at least 2 years after PCI: systolic BP <120 (reference), <130, <140, <160, and ≥160 mm Hg; diastolic BP <80 (reference), <90, <100, and ≥100 mm Hg. The primary outcome was incident ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. Multivariate Cox proportional hazard regression analysis was used to estimate the adjusted hazard ratio (HR) (95% CI) according to BP group.

Results

The mean age was 67.7 years, and 80.9% of the participants were treated with antihypertensive medication. ESRD occurred in 1,362 (1.70%) patients during the 4.7-year follow-up. After adjustment for confounding factors, the HR of ESRD patients significantly and sequentially increased in the higher BP groups. Similar findings were noted regarding the relationship between incident ESRD and pulse pressure (PP). According to the subgroup analysis, this relationship was more significant for SBP in those aged <65 years than in those who were aged 65 years or older (Pfor interaction=0.0498). ESRD risk was linearly associated with systolic BP and had a J-shaped association with diastolic BP in patients with baseline values of 70 and 68 mm Hg.

Conclusions

In this nationwide population-based study, elevated systolic and diastolic BP and PP were associated with the risk of developing ESRD in a dose‒response manner among T2DM patients who underwent PCI. To prevent ESRD, more strict BP control is needed in T2DM patients who underwent PCI.
The Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin Inhibits Long QT 3 Late Sodium Currents in a Mutation Specific Manner
Authors: Lunsonga Lynn C. , Fatehi Mohammad , Long Wentong , Barr Amy J. , Gruber Brittany , Chattopadhyay Arkapravo , Barakat Khaled , Edwards Andrew G. , Light Peter E.
Published: April 2024

Background

Sodium/glucose cotransporter 2 inhibitors (SGLT2is) such as empagliflozin have demonstrated substantial cardioprotective effects in patients with or without diabetes. The SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INais also the primary mechanism involved in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene that encodes the major cardiac sodium channel isoform Nav1.5. Therefore, we investigated the effect of empagliflozin on late INain thirteen known LQT3 mutations located in distinct regions of the channel structure.

Methods

The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin (10 µM) on late INain recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation contraction coupling.

Results

Empagliflozin selectively inhibited late INain LQT3 mutations residing in the inactivation gate region of Nav1.5, with no effect on either peak current or channel kinetics. In contrast, empagliflozin caused inhibition of both peak and late INain mutations in the S4 voltage-sensing regions as well as changes in activation and inactivation kinetics and a slowing of recovery from inactivation. Empagliflozin had no effect on late/peak INaor channel kinetics in channels containing LQT3 mutations located in the putative empagliflozin binding region. Simulation of our experimental findings in a mathematical model of human ventricular myocytes predicts that empagliflozin may have a desirable therapeutic effect in LQT3 mutations located in the inactivation gate region.

Conclusions

Our results show that empagliflozin selectively inhibits late INa, without affecting gating kinetics, in LQT3 mutations residing in the inactivation gate region. Patients with mutations in voltage-sensing regions are less suitable candidates as empagliflozin may prevent action potential firing. The SGLT2is may therefore be a promising novel precision medicine approach for patients with certain LQT3 mutations.
The evaluation of the clinical effect of primary insomnia treated with the manual acupuncture therapy: a study protocol for a parallel, randomized controlled trial
Authors: Zhu Kean , Zhou Chuanlong , Zhang Quanai , Han Dexiong , Chen Weiji , Wang Wenfang , Wu Bin , Lin Xianming , Liu Yingjun
Published: April 2024

Background

Clinically, primary insomnia (PI) manifests as difficulty falling asleep, difficulty maintaining sleep, or early waking up. The occurrence of PI is closely related to emotional disorders, social stress and environmental stress. According to current studies, acupuncture offers significant advantages in treating PI. The manual acupuncture has been used for the treatment of insomnia for decades. Different acupuncture strategies, including electroacupuncture, manual acupuncture, and multiple acupuncture, have been reported to treat insomnia. However, there are few standardized clinical reports to investigate the effect of the manual acupuncture and its mechanism.

Methods

This study was a parallel, randomized controlled trial designed to investigate the clinical efficacy of the manual acupuncture in treating PI, and to clarify the mechanism. The study included a 4-week treatment period and a 4-week follow-up period. All eligible 74 patients diagnosed with PI will be evaluated using scales before treatment, and then be randomly assigned to the acupuncture group and the placebo acupuncture group at a ratio of 1:1. Both groups choose the same acupoints. The patients will be evaluated at 4 weeks before treatment, after 4 weeks of treatment and 4 weeks after treatment respectively. The patients in the acupuncture group were treated with manual acupuncture and placebo acupuncture group received the tube of Park sham devices. All 12 sessions of treatment will last over 4 weeks (3 sessions per week). The main outcome measure will be the change in Pittsburgh sleep quality index before and after treatment, and the secondary outcome measures include Chalder-14 fatigue scale, Epworth sleepiness scale, self-rating depression scale, self-rating anxiety scale, polysomnography and heart rate variability.

Discussion

This study will evaluate the efficacy and safety of the manual acupuncture, and the results will provide a scientific theoretical basis for the clinical promotion.

Trail registration

ClinicalTrails.govIdentifier:NCT05830887. Registered 23 March 2023.
Lesion Volume as a Predictor for Return to Work After Endovascular Therapy - a Four-year Prospective Cohort Study
Authors: Berg Helland Gisle , Beyer Mona K , Enriquez Brian Anthony , Ihle-Hansen Hege , Ihle-Hansen Håkon , Andersson Stein , Leonardssen Esten Høyland , Stangeland Helle , Ùjhelyi Bettina , Hagberg Guri , Harbo Hanne Flinstad , Aamodt Anne Hege , Høgestøl Einar August
Published: April 2024

Background: There are no known objective biomarkers for predicting Return to Work (RTW) in ischemic stroke survivors. This study aims to explore the predictive utility and define a cut-off value of lesion volume on RTW after endovascular treatment (EVT). Methods: We included patients <65 years undergoing EVT at Oslo University Hospital (OUS) between January 2017 and May 2019. Employment status was obtained at both baseline and a four-year follow-up. Stroke lesion volumes were segmented using magnetic resonance imaging (MRI) scans 24 hours post EVT. Logistic regression models were conducted to assess the impact of lesion volume on RTW-status at follow-up, adjusted for patients? characteristics, stroke related factors and treatment. We calculated the Receiver Operating Characteristic curve to determine the optimal lesion volume cut-off. Machine learning (ML) regression models were employed to assess the predictive abilities of baseline clinical and imaging variables for RTW. Results: Of the 109 individuals treated, 81 (74%) were employed at baseline. Among these, 60 completed four-year follow-up with MRI available for stroke lesion segmentation and were included in the analyses. Mean age at stroke onset was 51.8 years (range 23.5?64.9), 50% were female. Median lesion volume was 18 ml (IQR 45-7). After four years, 34 (57%) had successfully RTW. The odds for not RTW increased by 5% for every 1 ml increase in lesion volume (adjusted odds ratio [aOR], 95% CI, 1.02?1.11], P=0.02). A lesion volume cut-off value of 29 cm3 yielded a sensitivity of 0.91 and specificity of 0.65 for predicting RTW. Notably, the most influential feature in the ML model for predicting RTW was lesion volume. Conclusion: Lesion volume was the most robust predictor of RTW four years after EVT. Our findings suggest that a cut-off of 29 cm3 is suitable to distinguish between those with high and low chance of RTW.
Integrating molecular and clinical variables to predict myocardial recovery
Authors: Visker Joseph R. , Brintz Ben J. , Kyriakopoulos Christos P. , Hillas Yanni , Taleb Iosif , Badolia Rachit , Shankar Thirupura S. , Amrute Junedh M. , Ling Jing , Hamouche Rana , Tseliou Eleni , Navankasattusas Sutip , Wever-Pinzon Omar , Ducker Gregory S. , Holland William L. , Summers Scott A. , Koenig Steven C. , Hanff Thomas C. , Lavine Kory , Murali Srinivas , Bailey Stephen , Alharethi Rami , Selzman Craig H. , Shah Palak , Slaughter Mark S. , Kanwar Manreet , Drakos Stavros G.
Published: April 2024

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, andLRRN4CL(ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.

GRAPHICAL ABSTRACT
The entangled world of DNA quadruplex folds
Authors: Sundaresan Sruthi , Uttamrao Patil Pranita , Kovuri Purnima , Rathinavelan Thenmalarchelvi
Published: April 2024

DNA quadruplexes take part in many biological functions. It takes up a variety of folds based on the sequence and environment. Here, a meticulous analysis of experimentally determined 392 quadruplex structures (388 PDB IDs) deposited in PDB is carried out. The analysis reveals the modular representation of the quadruplex folds. 48 unique quadruplex motifs (whose diversity arises out of the propeller, bulge, diagonal, and lateral loops that connect the quartets) are identified, leading to simple to complex inter-/intra-molecular quadruplex folds. These structural two-layered motifs are further classified into 33 continuous and 15 discontinuous motifs. The discontinuous motifs cannot further be classified into parallel, antiparallel, or hybrid as one or more guanines of the adjacent quartets are not connected. While the continuous motifs can be extended to a quadruplex fold, the discontinuous motif requires additional loop(s) to complete a fold, as illustrated here with examples. Similarly, the higher-order quadruplex folds can also be represented by continuous or discontinuous motifs or their combinations. Such a modular representation of the quadruplex folds may assist in custom engineering of quadruplexes, designing motif-based drugs, and the prediction of quadruplex structure. Further, it could facilitate understanding the role of quadruplexes in biological functions and diseases.
Induction by caterpillars of stored and emitted volatiles in terpene chemotypes from populations of wild cotton (Gossypium hirsutum)
Authors: Mamin Marine , Clancy Mary V , Flückiger Galien , Quijano-Medina Teresa , Pérez-Niño Biiniza , Abdala-Roberts Luis , Turlings Ted C.J. , Bustos-Segura Carlos
Published: April 2024

Background

Upland cotton (Gossypium hirsutum) plants constitutively store volatile terpenes in their leaves, which are steadily emitted at low levels. Herbivory leads to a greater release of these stored volatiles. Additionally, damaged plants increase the accumulation of volatile terpenes in their leaves and begin to emit other terpenes and additional compounds. This has been well characterised for cultivatedG. hirsutum, but little is known about volatile production in response to herbivory in wild populations. We investigated how damage by the beet armyworm (Spodoptera exigua) affects leaf-stored and emitted volatiles in wildG. hirsutumplants. These plants were grown in a greenhouse using seeds collected from populations found along the Yucatan coast, from where this cotton species originates. We assessed whether the differences in leaf terpene profiles between two known chemotypes persisted upon herbivory, in leaves and in head-space emissions, and whether these chemotypes also differed in the production and release of herbivory-induced volatiles. In addition to chemotypic variation, we further investigated intraspecific variation in the volatile response to herbivory among genotypes, populations, and four geographic regions.

Results

The difference between the two chemotypes persisted after herbivory in the stored volatile profile of induced leaves, as well in the emissions from damaged plants. Therefore, wild cotton chemotypes may differ in their airborne interactions with their environment. The specific terpenes distinguishing these chemotypes showed a weak inducibility, raising questions about their functions. Herbivory triggered changes in stored and emitted volatiles similar to what is known for cultivated varieties ofG. hirsutum.However, we report for the first time on the emission of volatile aldoximes by cotton plants, which were only detected in the headspace upon herbivory, and displayed chemotypic and interpopulation variation. Intraspecific variation was also observed in the induced emissions of nitriles and certain terpenes. Moreover, chemotypes differed in their induction of (E)-β-ocimene stored in the leaves.

Conclusions

This comprehensive insight into herbivore-induced volatiles of wild cotton reveals variation in production and emission among populations. A full understanding of their ecological role may help in the development of future pest-management strategies for cotton crops.
Factors affecting the juvenile departure inOrientobdelloides siamensis(Oka, 1917)
Authors: Trivalairat Poramad , Trivalairat Krittiya , Raquib Tashfia , Purivirojkul Watchariya
Published: April 2024

The departure of juveniles from parental care is an important period influenced by various factors. In the laboratory, 3-5 days after copulation, ten parent individuals ofOrientobdelloides siamensisdeposited approximately 361.6±37.79 eggs on the substrate and covered them until departure. The parents incubated their single-egg cocoons for around 7-9 days until the juveniles hatched. Subsequently, the newborns turned to attach to the ventral annuli of the parent using their caudal sucker. Between seven to eleven days after hatching, when the caudal sucker of juveniles expanded over the parent’s annuli, signaling their readiness to depart, they detached from beneath the parent vent to the substrate but continued to live beneath it. Finally, to determine the timing of juvenile departure, the insufficient space availability beneath the parental vent and yolk depletion around 14-21 days after hatching were analyzed. Through these morphological characteristics and behavior, this study indicated the interactions among these factors contributing to the mechanisms influencing juvenile departure inO. siamensis.
Branched chain amino acids modulate the proteomic profile of Pro-induced differentiation for the infective stages ofTrypanosoma cruzi
Authors: de Freitas Nascimento Janaina , Damasceno Flávia Silva , Marsicobettre Sabrina , Vitorino Francisca Natália de Luna , Achijan Renan Weege , da Cunha Julia Pinheiro Chagas , Silber Ariel Mariano
Published: April 2024

Trypanosoma cruzi, the causative agent of Chagas disease, undergoes a complex life cycle involving triatomine insects as vectors and mammals. The differentiation of epimastigote forms into metacyclic trypomastigotes within the insect vector is crucial for the parasite’s life cycle progression. Factors influencing this process, including temperature, pH, and nutritional stress, along with specific metabolite availability, play a pivotal role. Amino acids like Pro, His, and Gln support cell differentiation, while branched-chain amino acids (BCAAs) inhibit it. Interestingly, combining the pro-metacyclogenic amino acid Pro with one of the anti-metacyclogenic BCAAs results in viable metacyclics with significantly reduced infectivity. To explore the characteristics of metacyclic parasites differentiated in the presence of BCAAs, proteomics analyses were conducted. Metacyclics obtained in triatomine artificial urine (TAU) supplemented with Pro alone and in combination with Leu, Ile, or Val were compared. The analyses revealed differential regulation of 40 proteins in TAU-Pro-Leu, 131 in TAU-Pro-Ile, and 179 in TAU-Pro-Val, as compared to metacyclics from TAU-Pro. Among these, 22%, 11%, and 13% of the proteins were associated with metabolic processes, respectively. Notably, enzymes related to glycolysis and the tricarboxylic acid (TCA) cycle were reduced in metacyclics with Pro-BCAAs, while enzymes involved in amino acid and purine metabolic pathways were increased. Furthermore, metacyclics with Pro-Ile and Pro-Val exhibited elevated enzymes linked to lipid and redox metabolism. These findings suggest that the presence of BCAAs can reshape the metabolism of metacyclics, contributing to the observed reduction in infectivity in these parasites.