bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expert Consideration on Regulatory Aspects for Perinatal Derivatives in Clinical Settings
Authors: Hofmann Nicola , Lafarge Xavier , Antica Mariastefania , Ferry Nicolas , Girandon Lenart , Gramignoli Roberto , Jurga Marcin , Kerdjoudj Halima , Navakauskiene Ruta , Schiavi Jessica , Shablii Volodymyr , Nicolás Francisco J , Gindraux Florelle 
Published: April 2023

Abstract
Perinatal derivatives (PnD) are drawing growing interest among the scientific community as an unrestricted source of multipotent stem cells, secretome, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options, but they require the development of regenerative approaches. With this development, the question of regulation of donation, processing, and distribution has therefore become more important. Within the European Cooperation in Science and Technology (COST) community, we compiled a group of international experts on PnD technologies, who revised and compared existing EU national regulations. Notably, despite clear European directives, each EU Country has developed their own implementation and standard levels for cell- and tissue-based therapies. To enable extended applications of PnD treatments within the EU community and worldwide, harmonization is highly recommended. This paper aims to provide an overview of the various options available to introduce PnD into clinical practice. For this purpose, the different aspects resulting from (1) the type of PnD, (2) the amount of available data, (3) the degree of manipulation, and (4) the intended application and the process toward a possible commercialization will be presented. In the future, it will be important to find a balance between regulatory requirements and the best medical quality of the PnD product.
SAA1 deficiency alleviates cardiac remodeling by inhibiting NF‐κB/p38/JNK and TGFβ/Smad pathways
Authors: Xiao Yusha , Ni Lihua , Shi Hongjie , Yang Kang , Yang Jianguo , Zhao Jinping , Liu Jinping , Luo Pengcheng 
Published: April 2023

AbstractHeart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid‐binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1‐deficient (SAA1−/−), and wild‐type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1−/− mice displayed a lower level of cardiac fibrosis than wild‐type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild‐type‐sham and knockout‐sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.
TREK-1 and TREK-2 Knockout Mice Are Not Resistant to Halothane or Isoflurane
Authors: Spencer Kira A. , Woods Christian B. , Worstman Hailey M. , Johnson Simon C. , Ramirez Jan-Marino , Morgan Philip G. , Sedensky Margaret M. 
Published: April 2023

Background
A variety of molecular targets for volatile anesthetics have been suggested, including the anesthetic-sensitive potassium leak channel, TREK-1. Knockout of TREK-1 is reported to render mice resistant to volatile anesthetics, making TREK-1 channels compelling targets for anesthetic action. Spinal cord slices from mice, either wild type or an anesthetic- hypersensitive mutant, Ndufs4, display an isoflurane-induced outward potassium leak that correlates with their minimum alveolar concentrations and is blocked by norfluoxetine. The hypothesis was that TREK-1 channels conveyed this current and contribute to the anesthetic hypersensitivity of Ndufs4. The results led to evaluation of a second TREK channel, TREK-2, in control of anesthetic sensitivity.

Methods
The anesthetic sensitivities of mice carrying knockout alleles of Trek-1 and Trek-2, the double knockout Trek-1;Trek-2, and Ndufs4;Trek-1 were measured. Neurons from spinal cord slices from each mutant were patch clamped to characterize isoflurane-sensitive currents. Norfluoxetine was used to identify TREK-dependent currents.

Results
The mean values for minimum alveolar concentrations (± SD) between wild type and two Trek-1 knockout alleles in mice (P values, Trek-1 compared to wild type) were compared. For wild type, minimum alveolar concentration of halothane was 1.30% (0.10), and minimum alveolar concentration of isoflurane was 1.40% (0.11); for Trek-1tm1Lex
, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.387), and minimum alveolar concentration of isoflurane was 1.38% (0.09; P = 0.268); and for Trek-1tm1Lzd
, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.482), and minimum alveolar concentration of isoflurane was 1.41% (0.12; P = 0.188). Neither allele was resistant for loss of righting reflex. The EC50 values of Ndufs4;Trek-1tm1Lex
did not differ from Ndufs4 (for Ndufs4, EC50 of halothane, 0.65% [0.05]; EC50 of isoflurane, 0.63% [0.05]; and for Ndufs4;Trek-1tm1Lex
, EC50 of halothane, 0.58% [0.07; P = 0.004]; and EC50 of isoflurane, 0.61% [0.06; P = 0.442]). Loss of TREK-2 did not alter anesthetic sensitivity in a wild-type or Trek-1 genetic background. Loss of TREK-1, TREK-2, or both did not alter the isoflurane-induced currents in wild-type cells but did cause them to be norfluoxetine insensitive.

Conclusions
Loss of TREK channels did not alter anesthetic sensitivity in mice, nor did it eliminate isoflurane-induced transmembrane currents. However, the isoflurane-induced currents are norfluoxetine-resistant in Trek mutants, indicating that other channels may function in this role when TREK channels are deleted.

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A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis
Authors: Bowdle T. Andrew , Haththotuwegama Kishanee J. , Jelacic Srdjan , Nguyen Sharon T. , Togashi Kei , Michaelsen Kelly E. 
Published: April 2023

Background
The dose of sugammadex recommended by the manufacturer for reversal of rocuronium is 2 mg/kg when the train-of-four count is 2 or more and 4 mg/kg when it is less than 2 but there is a posttetanic count of at least 1. The purpose of this dose-finding study was to titrate sugammadex to produce a train-of-four ratio 0.9 or greater at the conclusion of cardiac surgery, and to continue monitoring neuromuscular blockade in the intensive care unit to identify recurrent paralysis. The hypothesis was that many patients would require less than the recommended dose of sugammadex, but that some would require more, and that recurrent paralysis would not occur.

Methods
Neuromuscular blockade was monitored using electromyography during cardiac surgery. Administration of rocuronium was at the discretion of the anesthesia care team. During sternal closure, sugammadex was titrated in 50-mg increments every 5 min until a train-of-four ratio 0.9 or greater was obtained. Neuromuscular blockade was monitored with electromyography in the intensive care unit until sedation was discontinued before extubation or for a maximum of 7 h.

Results
Ninety-seven patients were evaluated. The dose of sugammadex required to achieve a train-of-four ratio of 0.9 or greater varied from 0.43 to 5.6 mg/kg. There was a statistically significant relationship between the depth of neuromuscular blockade and the sugammadex dose required for reversal, but there was a large variation in dose required at any depth of neuromuscular blockade. Eighty-four of 97 patients (87%) required less than the recommended dose, and 13 (13%) required more. Two patients required additional sugammadex administration for recurrent paralysis.

Conclusions
When sugammadex was titrated to effect, the dose was usually less than the recommended dose, but it was more in some patients. Therefore, quantitative twitch monitoring is essential for ascertaining that adequate reversal has taken place after sugammadex administration. Recurrent paralysis was observed in two patients.

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State Variation in Severe Maternal Morbidity Among Individuals With Medicaid Insurance
Authors: Admon Lindsay K. , Auty Samantha G. , Daw Jamie R. , Kozhimannil Katy B. , Declercq Eugene R. , Wang Na , Gordon Sarah H. 
Published: April 2023

OBJECTIVE:
To measure variation in delivery-related severe maternal morbidity (SMM) among individuals with Medicaid insurance by state and by race and ethnicity across and within states.

METHODS:
We conducted a pooled, cross-sectional analysis of the 2016–2018 TAF (Transformed Medicaid Statistical Information System Analytic Files). We measured overall and state-level rates of SMM without blood transfusion for all individuals with Medicaid insurance with live births in 49 states and Washington, DC. We also examined SMM rates among non-Hispanic Black and non-Hispanic White individuals with Medicaid insurance in a subgroup of 27 states (and Washington, DC). We generated unadjusted rates of composite SMM and the individual indicators of SMM that comprised the composite. Rate differences and rate ratios were calculated to compare SMM rates for non-Hispanic Black and non-Hispanic White individuals with Medicaid insurance.

RESULTS:
The overall rate of SMM without blood transfusion was 146.2 (95% CI 145.1–147.3) per 10,000 deliveries (N=4,807,143). Rates of SMM ranged nearly threefold, from 80.3 (95% CI 71.4–89.2) per 10,000 deliveries in Utah to 210.4 (95% CI 184.6–236.1) per 10,000 deliveries in Washington, DC. Non-Hispanic Black individuals with Medicaid insurance (n=629,774) experienced a higher overall rate of SMM (212.3, 95% CI 208.7–215.9) compared with non-Hispanic White individuals with Medicaid insurance (n=1,051,459); (125.3, 95% CI 123.2–127.4) per 10,000 deliveries (rate difference 87.0 [95% CI 82.8–91.2]/10,000 deliveries; rate ratio 1.7 [95% CI 1.7–1.7]). The leading individual indicator of SMM among all individuals with Medicaid insurance was eclampsia, although the leading indicators varied across states and by race and ethnicity. Many states were concordant in leading indicators among the overall, non-Hispanic Black, and non-Hispanic White populations (ie, in Oklahoma sepsis was the leading indicator for all three). Most states, however, were discordant in leading indicators across the three groups (ie, in Texas eclampsia was the leading indicator overall, pulmonary edema or acute heart failure was the leading indicator among the non-Hispanic Black population, and sepsis was the leading indicator among the non-Hispanic White population).

CONCLUSION:
Interventions aimed at reducing SMM and, ultimately, mortality among individuals with Medicaid insurance may benefit from the data generated from this study, which highlights states that have the greatest burden of SMM, the differences in rates among non-Hispanic Black populations compared with non-Hispanic White populations, and the leading indicators of SMM overall, by state, and by race and ethnicity.
Identification of Factors Associated With 30-day Readmissions After Posterior Lumbar Fusion Using Machine Learning and Traditional Models
Authors: Rezaii Paymon G. , Herrick Daniel , Ratliff John K. , Rusu Mirabela , Scheinker David , Desai Atman M. 
Published: April 2023

Study Design.
A retrospective cohort study.

Objective.
To identify the factors associated with readmissions after PLF using machine learning and logistic regression (LR) models.

Summary of Background Data.
Readmissions after posterior lumbar fusion (PLF) place significant health and financial burden on the patient and overall health care system.

Materials and Methods.
The Optum Clinformatics Data Mart database was used to identify patients who underwent posterior lumbar laminectomy, fusion, and instrumentation between 2004 and 2017. Four machine learning models and a multivariable LR model were used to assess factors most closely associated with 30-day readmission. These models were also evaluated in terms of ability to predict unplanned 30-day readmissions. The top-performing model (Gradient Boosting Machine; GBM) was then compared with the validated LACE index in terms of potential cost savings associated with the implementation of the model.

Results.
A total of 18,981 patients were included, of which 3080 (16.2%) were readmitted within 30 days of initial admission. Discharge status, prior admission, and geographic division were most influential for the LR model, whereas discharge status, length of stay, and prior admissions had the greatest relevance for the GBM model. GBM outperformed LR in predicting unplanned 30-day readmission (mean area under the receiver operating characteristic curve 0.865 vs. 0.850, P<0.0001). The use of GBM also achieved a projected 80% decrease in readmission-associated costs relative to those achieved by the LACE index model.

Conclusions.
The factors associated with readmission vary in terms of predictive influence based on standard LR and machine learning models used, highlighting the complementary roles these models have in identifying relevant factors for the prediction of 30-day readmissions. For PLF procedures, GBM yielded the greatest predictive ability and associated cost savings for readmission.

Level of Evidence.
3
Laminectomy With Fusion is Associated With Greater Functional Improvement Compared With Laminectomy Alone for the Treatment of Degenerative Lumbar Spondylolisthesis
Authors: Shukla Geet G. , Chilakapati Sai S. , Matur Abhijith V. , Palmisciano Paolo , Conteh Fatu , Onyewadume Louisa , Duah Henry , Griffith Azante , Tao Xu , Vorster Phillip , Gupta Sahil , Cheng Joseph , Motley Benjamin , Adogwa Owoicho 
Published: April 2023

Study Design.
Systematic review and Meta-analysis.

Objective.
To compare outcomes and complications profile of laminectomy alone versus laminectomy and fusion for the treatment of degenerative lumbar spondylolisthesis (DLS).

Summary of Background Data.
Degenerative lumbar spondylolisthesis is a common cause of back pain and functional impairment. DLS is associated with high monetary (up to $100 billion annually in the US) and nonmonetary societal and personal costs. While nonoperative management remains the first-line treatment for DLS, decompressive laminectomy with or without fusion is indicated for the treatment-resistant disease.

Methods.
We systematically searched PubMed and EMBASE for RCTs and cohort studies from inception through April 14, 2022. Data were pooled using random-effects meta-analysis. The risk of bias was assessed using the Joanna Briggs Institute risk of bias tool. We generated odds ratio and standard mean difference estimates for select parameters.

Results.
A total of 23 manuscripts were included (n=90,996 patients). Complication rates were higher in patients undergoing laminectomy and fusion compared with laminectomy alone (OR: 1.55, P<0.001). Rates of reoperation were similar between both groups (OR: 0.67, P=0.10). Laminectomy with fusion was associated with a longer duration of surgery (Standard Mean Difference: 2.60, P=0.04) and a longer hospital stay (2.16, P=0.01). Compared with laminectomy alone, the extent of functional improvement in pain and disability was superior in the laminectomy and fusion cohort. Laminectomy with fusion had a greater mean change in ODI (−0.38, P<0.01) compared with laminectomy alone. Laminectomy with fusion was associated with a greater mean change in NRS leg score (−0.11, P=0.04) and NRS back score (−0.45, P<0.01).

Conclusion.
Compared with laminectomy alone, laminectomy with fusion is associated with greater postoperative improvement in pain and disability, albeit with a longer duration of surgery and hospital stay.
Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study
Authors: Ng Pauline Yeung , Ng Andrew Kei-Yan , Ip April , Wu Mei-Zhen , Guo Ran , Yiu Kai-Hang 
Published: April 2023

OBJECTIVES:
The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined.

DESIGN:
Retrospective observational study.

SETTING:
Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System).

PATIENTS:
All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69–0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38–0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively).

CONCLUSIONS:
In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories.
IV Vitamin C in Adults With Sepsis: A Bayesian Reanalysis of a Randomized Controlled Trial*
Authors: Angriman Federico , Muttalib Fiona , Lamontagne François , Adhikari Neill K. J. ,   LOVIT Investigators
Published: April 2023

OBJECTIVES:
The Lessening Organ Dysfunction with Vitamin C trial showed a harmful effect of vitamin C on 28-day death or persistent organ dysfunction. To maximize interpretation, we present a post hoc Bayesian reanalysis.

DESIGN:
Bayesian reanalysis of a randomized placebo-controlled trial.

SETTING:
Thirty-five ICUs.

PATIENTS:
Adults with proven or suspected infection, vasopressor support, and no more than 24 hours of ICU admission.

INTERVENTIONS:
Patients were allocated to receive either vitamin C (50 mg/kg of body weight) or placebo every 6 hours for up to 96 hours.

MEASUREMENTS AND MAIN RESULTS:
The primary outcome was the composite of death or persistent organ dysfunction (i.e., vasopressor use, invasive mechanical ventilation, or new renal replacement therapy) at 28 days. We used Bayesian log-binomial models with random effects for hospital site and varying informative prior beliefs for the effect of vitamin C to estimate risk ratios (RRs) with 95% credible intervals (Crls) in the intention to treat population (vitamin C, 435 patients; placebo, 437 patients). Using weakly neutral priors, patients allocated to vitamin C had a higher risk of death or persistent organ dysfunction at 28 days (RR, 1.20; 95% Crl, 1.04–1.39; probability of harm, 99%). This effect was consistent when using optimistic (RR, 1.14; 95% Crl, 1.00–1.31; probability of harm, 98%) and empiric (RR, 1.09; 95% Crl, 0.97–1.22; probability of harm, 92%) priors. Patients allocated to vitamin C also had a higher risk of death at 28 days under weakly neutral (RR, 1.17; 95% Crl, 0.98–1.40; probability of harm, 96%), optimistic (RR, 1.10; 95% Crl, 0.94–1.30; probability of harm, 88%), and empiric (RR, 1.05; 95% Crl, 0.92–1.19; probability of harm, 76%) priors.

CONCLUSIONS:
The use of vitamin C in adult patients with proven or suspected infection and vasopressor support is associated with high probability of harm.
A robust microsatellite instability detection model for unpaired colorectal cancer tissue samples
Authors: Zhang Zili , Wan Hua , Xu Bing , He Hongyang , Shan Guangyu , Zhang Jingbo , Wu Qixi , Li Tong 
Published: April 2023

Abstract

Background:
Microsatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples.

Methods:
From January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR.

Results:
We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2).

Conclusion:
MSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.