bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal generation of IL-17A represses tumor infiltration of stem-like exhausted CD8+ T cells to demote the antitumor immunity
Authors: Zhang Ruochan , Chen Kun , Gong Caifeng , Wu Zhiyuan , Xu Chungui , Li Xing-Ning , Zhao Fei , Wang Dongmei , Cai Jianqiang , Zhou Aiping , Qu Chunfeng
Published: August 2023

Background

Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1).

Methods

Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined.

Results

Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3−, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6−Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase.

Conclusions

Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.
Border malaria: defining the problem to address the challenge of malaria elimination
Authors: Li Xiaohong , Snow Robert W. , Lindblade Kim , Noor Abdisalan M. , Steketee Richard , Rabinovich Regina , Gopinath Deyer , Gasimov Elkhan , Alonso Pedro L.
Published: August 2023

Border malaria is frequently cited as an obstacle to malaria elimination and sometimes used as a justification for the failure of elimination. Numerous border or cross-border meetings and elimination initiatives have been convened to address this bottleneck to elimination. In this Perspective, border malaria is defined as malaria transmission, or the potential for transmission, across or along shared land borders between countries where at least one of them has ongoing malaria transmission. Border malaria is distinct from malaria importation, which can occur anywhere and in any country. The authors’ analysis shows that the remaining transmission foci of malaria-eliminating countries tend to occur in the vicinity of international land borders that they share with neighbouring endemic countries. The reasons why international land borders often represent the last mile in malaria elimination are complex. The authors argue that the often higher intrinsic transmission potential, the neglect of investment and development, the constant risk of malaria importation due to cross-border movement, the challenges of implementing interventions in complex environments and uncoordinated action in a cross-border shared transmission focus all contribute to the difficulties of malaria elimination in border areas. Border malaria reflects the limitations of the current tools and interventions for malaria elimination and implies the need for social cohesion, basic health services, community economic conditions, and policy dialogue and coordination to achieve the expected impact of malaria interventions. Given the uniqueness of each border and the complex and multifaceted nature of border malaria, a situation analysis to define and characterize the determinants of transmission is essential to inform a problem-solving mindset and develop appropriate strategies to eliminate malaria in these areas.
A qualitative metasynthesis of stigma in women living with HIV in the United States
Authors: Sommer Sadie , Barroso Julie
Published: August 2023

Our goal was to synthesize qualitative studies on HIV-related stigma as experienced by women living with HIV (WLWH) in the U.S. Qualitative metasynthesis techniques as developed by Sandelowski et al. (Res Nurs Health 30(1):99–111, 2007) were used to integrate and update findings on stigma in WLWH in the U.S. in 43 reports of qualitative studies conducted between 2004 and 2023 with 1118 participants. Developed themes explored a collective narrative of women first surviving the intersectionality of multiple sources of stigma, discovering non-linear pathways to transcend their stigma, and finally experiencing resilience through their transcendence of stigma. While this metasynthesis revealed similarities to an earlier metasynthesis in the ubiquity and persistence of stigma, they differ primarily in women’s abilities to find agency in managing and opposing their stigma. This cognitive reframing of their stigma helped women to redefine stigma as ignorance and move towards a more positive assessment of the self. In doing so, they separated themselves from their stigma and the damaging effects of it. Findings from this metasynthesis may serve as a useful tool for the development of stigma reduction interventions specific to the needs and experiences of WLWH in the U.S.
A novel approach to estimate the impact of health workforce investments on health outcomes through increased coverage of HIV, TB and malaria services
Authors: Bruckner Tim A. , Lin Tracy K. , Liu Jenny , Bornemisza Olga , Ajuebor Onyema , Diallo Khassoum , Cometto Giorgio
Published: August 2023

Background

Globally, HIV, TB and malaria account for an estimated three million deaths annually. The Global Fund partnered with the World Health Organization to assist countries with health workforce planning in these areas through the development of an integrated health workforce investment impact tool. Our study illustrates the development of a user-friendly tool (with two MS Excel calculator subcomponents) that computes associations between human resources for health (HRH) investment inputs and reduced morbidity and mortality from HIV, TB, and malaria via increased coverage of effective treatment services.

Methods

We retrieved from the peer-reviewed literature quantitative estimates of the relation among HRH inputs and HRH employment and productivity. We converted these values to additional full-time-equivalent doctors, nurses and midwives (DNMs). We used log-linear regression to estimate the relation between DNMs and treatment service coverage outcomes for HIV, TB, and malaria. We then retrieved treatment effectiveness parameters from the literature to calculate lives saved due to expanded treatment coverage for HIV, TB, and malaria. After integrating these estimates into the tool, we piloted it in four countries.

Results

In most countries with a considerable burden of HIV, TB, and malaria, the health workforce investments include a mix of pre-service education, full remuneration of new hires, various forms of incentives and in-service training. These investments were associated with elevated HIV, TB and malaria treatment service coverage and additional lives saved. The country case studies we developed in addition, indicate the feasibility and utility of the tool for a variety of international and local actors interested in HRH planning.

Conclusions

The modelled estimates developed for illustrative purposes and tested through country case studies suggest that HRH investments result in lives saved across HIV, TB, and malaria. Furthermore, findings show that attainment of high targets of specific treatment coverage indicators would require a substantially greater health workforce than what is currently available in most LMICs. The open access tool can assist with future HRH planning efforts, particularly in LMICs.
Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study
Authors: Jiang Miaomiao , Yan Weiheng , Zhang Yuyanan , Lu Zhe , Lu Tianlan , Zhang Dai , Li Jun , Wang Lifang
Published: August 2023

Background

Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished.

Methods

Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran’s Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses.

Results

The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, PIVW = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, PIVW = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, PIVW = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive–compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis.

Conclusions

In this study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders.
Analysis of PERV-C superinfection resistance using HA-tagged viruses
Authors: Flecks Merle , Fischer Nicole , Krijnse Locker Jacomina , Tönjes Ralf R. , Godehardt Antonia W.
Published: August 2023

Background

Using pigs as organ donors has advanced xenotransplantation to the point that it is almost ready for clinical use. However, there is still a zoonotic risk associated with xenotransplantation, and the potential transmission of porcine endogenous retroviruses needs to be surveyed. Despite significant attempts to eliminate this risk, by the selection of PERV-C free pigs with low expression of PERV-A, -B, and by the genome-wide inactivation of PERV using CRISPR/Cas9, the impact of superinfection resistance (SIR) was not investigated. SIR is a viral trait that prevents reinfection (superinfection). For PERV, the underlying mechanism is unclear, whether and how cells, that harbor functional PERV, are protected. Using PERV-C(5683) as a reference virus, we investigated SIR in a newly developed in vitro model to pursue the mechanism and confirm its protective effect.

Results

We developed three PERV-C constructs on the basis of PERV-C(5683), each of which carries a hemagglutinin tag (HA-tag) at a different position of the envelope gene (SP-HA, HA-VRA, and RPep-HA), to distinguish between primary infection and superinfection. The newly generated PERV-C(5683)-HA viruses were characterized while quantifying the viral RNA, reverse transcriptase activity, protein expression analysis, and infection studies. It was demonstrated that SP-HA and RPep-HA were comparable to PERV-C(5683), whereas HA-VRA was not replication competent. SP-HA and RPep-HA were chosen to challenge PERV-C(5683)-positive ST-IOWA cells demonstrating that PERV-C-HA viruses are not able to superinfect those cells. They do not integrate into the genome and are not expressed.

Conclusions

The mechanism of SIR applies to PERV-C. The production of PERV-C particles serves as a defense mechanism from superinfection with exogenous PERV-C. It was demonstrated by newly generated PERV-C(5683)-HA clones that might be used as a cutting-edge tool. The HA-tagging of PERV-C is novel, providing a blueprint for the tagging of other human tropic PERV viruses. The tagged viruses are suitable for additional in vitro and in vivo infection studies and will contribute, to basic research on viral invasion and pathogenesis. It will maintain the virus safety of XTx.
Pharmacotherapeutic profile, polypharmacy and its associated factors in a cohort of people living with HIV in Brazil
Authors: da Silva Robson Pierre Nascimento , Marins Luana M. S. , Guaraldo Lusiele , Luz Paula Mendes , Cardoso Sandra W. , Moreira Ronaldo I. , Oliveira Vanessa da Gama , Veloso Valdilea G. , Grinsztejn Beatriz , Estrela Rita , Torres Thiago S.
Published: August 2023

Background

The increased survival provided by the access, development, and evolution of antiretroviral drugs (ARV) greatly increased the life expectancy of people living with HIV (PWH). This has also led to an increased occurrence of diseases or morbidities related to aging. In individuals with multiple comorbidities, the simultaneous use of multiple medications, also known as polypharmacy, is common, and rational use of medications is essential. This study aims to describe the pharmacotherapeutic profile, estimate the prevalence of polypharmacy and identify factors associated with polypharmacy in a cohort of adult PWH from a referral unit in Rio de Janeiro, Brazil.

Methods

Cross-sectional study including PWH on ARV who received at least one medical prescription (outpatient/hospitalized) in 2019. We described the proportion of prescribed medications according to ARV and Anatomical Therapeutic Chemical (ATC) classes stratified by age (< 50 vs. ≥50 years). Polypharmacy was defined as ≥ 5 medications prescribed beyond ARV. Logistic regression models assessed demographic and clinical factors associated with polypharmacy.

Results

A total of 143,306 prescriptions of 4547 PWH were analyzed. Median age was 44.4 years (IQR:35.4–54.1) and 1615 (35.6%) were ≥ 50 years. A total of 2958 (65.1%) participants self-identified as cisgender man, 1365 (30.0%) as cisgender woman, and 224 (4.9%) as transgender women. Most self-declared Black/Pardo (2582; 65.1%) and 1984 (44.0%) completed elementary education or less. Median time since HIV diagnosis was 10.9 years (IQR:6.2–17.7). Most frequently prescribed concomitant medications were nervous system (64.8%), antiinfectives for systemic use (60.0%), alimentary tract and metabolism (45.9%), cardiovascular system (40.0%) and respiratory system (37.1%). Prevalence of polypharmacy was 50.6% (95%CI: 49.2–52.1). Model results indicated that being older, self-identify as cisgender woman, having less education and longer time since HIV diagnosis increased the odds of polypharmacy.

Conclusions

We found high rates of polypharmacy and concomitant medication use in a cohort of PWH in Brazil. Targeted interventions should be prioritized to prevent interactions and improve treatment, especially among individuals using central nervous system and cardiovascular medications, as well as certain groups such as cisgender women, older individuals and those with lower education. Standardized protocols for continuous review of patients’ therapeutic regimens should be implemented.
Methods for integrating postural control into biomechanical human simulations: a systematic review
Authors: Shanbhag Julian , Wolf Alexander , Wechsler Iris , Fleischmann Sophie , Winkler Jürgen , Leyendecker Sigrid , Eskofier Bjoern M. , Koelewijn Anne D. , Wartzack Sandro , Miehling Jörg
Published: August 2023

Understanding of the human body’s internal processes to maintain balance is fundamental to simulate postural control behaviour. The body uses multiple sensory systems’ information to obtain a reliable estimate about the current body state. This information is used to control the reactive behaviour to maintain balance. To predict a certain motion behaviour with knowledge of the muscle forces, forward dynamic simulations of biomechanical human models can be utilized. We aim to use predictive postural control simulations to give therapy recommendations to patients suffering from postural disorders in the future. It is important to know which types of modelling approaches already exist to apply such predictive forward dynamic simulations. Current literature provides different models that aim to simulate human postural control. We conducted a systematic literature research to identify the different approaches of postural control models. The different approaches are discussed regarding their applied biomechanical models, sensory representation, sensory integration, and control methods in standing and gait simulations. We searched on Scopus, Web of Science and PubMed using a search string, scanned 1253 records, and found 102 studies to be eligible for inclusion. The included studies use different ways for sensory representation and integration, although underlying neural processes still remain unclear. We found that for postural control optimal control methods like linear quadratic regulators and model predictive control methods are used less, when models’ level of details is increasing, and nonlinearities become more important. Considering musculoskeletal models, reflex-based and PD controllers are mainly applied and show promising results, as they aim to create human-like motion behaviour considering physiological processes.
Prevalence and characteristics of HTLV-associated uveitis in patients from Bahia, an endemic area for HTLV − 1 in Brazil
Authors: Piai Ozores Daniele , Rathsam Pinheiro Regina , Boa-Sorte Ney , Campos e Silva Dias Maurício , Silva Lima Raianne , Hialla Almeida Araújo Thessika , Galvão-Castro Bernardo , Grassi Maria Fernanda Rios
Published: August 2023

Background

HTLV-1-associated uveitis (HAU) is an inflammatory reaction of the choroid, retina, optic nerve and vitreous that can lead to vision impairment. The worldwide prevalence of HAU varies widely.

Objective

To determine the prevalence of HAU in patients from Salvador, Bahia-Brazil, and describe uveitis type and associated symptoms.

Methods

Cross-sectional analytical study to determine the prevalence of uveitis in HTLV-1-infected patients recruited in Bahia, Brazil, a region considered endemic for HTLV-1. Patients were enrolled at a local reference center for HTLV (infected) and at an outpatient ophthalmology clinic (noninfected group). All patients were examined by the same ophthalmologist following a single protocol. Prevalence ratios (PR) were calculated.

Results

A total of 168 consecutively examined HTLV-1-infected patients and 410 noninfected patients (randomly selected) were included. Females predominated (82.1%) in the HTLV-1-infected group (versus 64.4% in the uninfected group) (p < 0.001). The mean age of infected and uninfected patients was 53.2 and 62.8 years, respectively (p < 0.001). The prevalence of uveitis in HTLV-1+ and HTLV-1− patients was 7.14% and 0.73%, respectively (PR = 9.76; 95CI%:2.79–34.15; p < 0.01). Bilateral intermediate uveitis, associated with symptoms including visual disturbances and floaters, was most commonly identified in the HTLV-1-infected patients, whereas unilateral anterior uveitis, in association with symptoms such as blurring and ocular pain, was more common in the uninfected group.

Conclusion

The prevalence of uveitis in patients with HTLV-1 was markedly higher than in uninfected subjects. HAU patients were mostly asymptomatic and exhibited bilateral presentation, with uveitis more frequently localized in the intermediate chamber.
Robotic arm-assisted total hip arthroplasty for preoperative planning and intraoperative decision-making
Authors: Lu Hanpeng , Xiao Qiang , Xu Hong , Yan Tingfang , Zhou Zongke
Published: August 2023

Aims

This article aimed to explore the efficacy of robotic arm-assisted total hip arthroplasty (THA) in improving preoperative planning and intraoperative decision-making.

Methods

In this single-center, prospective, randomized clinical controlled trial, 60 patients were randomly divided into two groups: conventional THA (cTHA) and robotic arm-assisted THA (rTHA). The rTHA underwent procedures using a robot-assisted surgical system, which generated three-dimensional models to determine the most appropriate prosthesis size and position. The standard process of replacement was executed in cTHA planned preoperatively via X-ray by experienced surgeons. Differences between predicted and actual prosthetic size, prosthetic position, and leg length were evaluated.

Results

Sixty patients were included in the study, but one patient was not allocated due to anemia. No significant preoperative baseline data difference was found between the two groups. The actual versus predicted implantation size of both groups revealed that 27/30 (90.0%) in the rTHA group and 25/29 (86.2%) in the cTHA group experienced complete coincidence. The coincidence rate for the femoral stem was higher in the rTHA group (83.3%) than that in the cTHA group (62.7%). Between the actual and predicted rTHA, the difference in anteversion/inclination degree (< 6°) was largely dispersed, while cTHA was more evenly distributed in degree (< 9°). The differences in leg length between the surgical side and contralateral side showed a significant deviation when comparing the two groups (P = 0.003), with 0.281 (− 4.17 to 3.32) mm in rTHA and 3.79 (1.45–6.42) mm in cTHA.

Conclusion

Robotic arm-assisted total hip arthroplasty can be valuable for preoperative planning and intraoperative decision-making.
TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains
Authors: Estades Ayuso Virginia , Pickles Sarah , Todd Tiffany , Yue Mei , Jansen-West Karen , Song Yuping , González Bejarano Jesús , Rawlinson Bailey , DeTure Michael , Graff-Radford Neill R. , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Dickson Dennis W. , Josephs Keith A. , Petrucelli Leonard , Prudencio Mercedes
Published: August 2023

Background

Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.

Methods

To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.

Results

We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.

Conclusions

Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.
The interaction of thrombocytopenia, hemorrhage, and platelet transfusion in venoarterial extracorporeal membrane oxygenation: a multicenter observational study
Authors: Raasveld Senta Jorinde , van den Oord Claudia , Schenk Jimmy , van den Bergh Walter M. , Oude Lansink - Hartgring Annemieke , van der Velde Franciska , Maas Jacinta J. , van de Berg Pablo , Lorusso Roberto , Delnoij Thijs S. R. , Dos Reis Miranda Dinis , Scholten Erik , Taccone Fabio Silvio , Dauwe Dieter F. , De Troy Erwin , Hermans Greet , Pappalardo Federico , Fominskiy Evgeny , Ivancan Višnja , Bojčić Robert , de Metz Jesse , van den Bogaard Bas , Donker Dirk W. , Meuwese Christiaan L. , De Bakker Martin , Reddi Benjamin , Henriques José P. S. , Broman Lars Mikael , Dongelmans Dave A. , Vlaar Alexander P. J.
Published: August 2023

Background

Thrombocytopenia, hemorrhage and platelet transfusion are common in patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO). However, current literature is limited to small single-center experiences with high degrees of heterogeneity. Therefore, we aimed to ascertain in a multicenter study the course and occurrence rate of thrombocytopenia, and to assess the association between thrombocytopenia, hemorrhage and platelet transfusion during VA ECMO.

Methods

This was a sub-study of a multicenter (N = 16) study on transfusion practices in patients on VA ECMO, in which a retrospective cohort (Jan-2018–Jul-2019) focusing on platelets was selected. The primary outcome was thrombocytopenia during VA ECMO, defined as mild (100–150·109/L), moderate (50–100·109/L) and severe (< 50·109/L). Secondary outcomes included the occurrence rate of platelet transfusion, and the association between thrombocytopenia, hemorrhage and platelet transfusion, assessed through mixed-effect models.

Results

Of the 419 patients included, median platelet count at admission was 179·109/L. During VA ECMO, almost all (N = 398, 95%) patients developed a thrombocytopenia, of which a significant part severe (N = 179, 45%). One or more platelet transfusions were administered in 226 patients (54%), whereas 207 patients (49%) suffered a hemorrhagic event during VA ECMO. In non-bleeding patients, still one in three patients received a platelet transfusion. The strongest association to receive a platelet transfusion was found in the presence of severe thrombocytopenia (adjusted OR 31.8, 95% CI 17.9–56.5). After including an interaction term of hemorrhage and thrombocytopenia, this even increased up to an OR of 110 (95% CI 34–360).

Conclusions

Thrombocytopenia has a higher occurrence than is currently recognized. Severe thrombocytopenia is strongly associated with platelet transfusion. Future studies should focus on the etiology of severe thrombocytopenia during ECMO, as well as identifying indications and platelet thresholds for transfusion in the absence of bleeding.

Trial registration: This study was registered at the Netherlands Trial Registry at February 26th, 2020 with number NL8413 and can currently be found at https://trialsearch.who.int/Trial2.aspx?TrialID=NL8413.
Electrochemically-selective electrode for quantification of dorzolamide in bulk drug substance and dosage form
Authors: Mora Mai M. , Ismail Nahla S. , Zaazaa Hala E. , Boltia Shereen A.
Published: August 2023

Three smart carbon paste electrodes were fabricated to quantify dorzolamide hydrochloride DRZ, including conventional carbon paste I, modified carbon paste embedding Silica II, and modified carbon paste embedding β-cyclodextrin III. This study is based on the insertion of DRZ with phosphomolybdic acid to create an electroactive moiety dorzolamide-phosphomolybdate ion exchanger using a solvent mediator dibutyl phthalate. The three constructed carbon paste electrodes displayed Nernstian responses and linear concentration ranges with lower detection limits. The vital performance of the created electrodes was verified in relation to various parameters. The electrodes enhance the selective determination of DRZ in the presence of inorganic ions, a co-formulated drug in the dosage form timolol maleate, and the excipient benzalkonium chloride. The modified carbon paste electrode including Silica was utilized to detect DRZ in ophthalmic eye drop form utilizing the direct calibration curve and potentiometric titration methods. Satisfactory findings were achieved by comparing them to other reported methods.
Transesophageal echocardiography (TEE)-guided transvenous pacing (TVP) in emergency department
Authors: Adi Osman , Fong Chan Pei , Tze Madeleine Kho Huei , Ahmad Azma Haryaty , Panebianco Nova , Ranga Asri
Published: August 2023

Background

Placement of a temporary pacemaker is a vital skill in the emergency setting in patients that present with life-threatening bradycardia. Transvenous pacing is the definitive method of stabilizing the arrhythmia compared to transcutaneous pacing, as it provides more comfort and better control of heart rate, until the insertion of a permanent pacemaker.

Case report

In this case report, we describe the steps using TEE to guide the insertion of transvenous pacer at the emergency department. Traditionally, the process of floating a transvenous pacer wire is performed “blindly” using landmarks and a monitoring ECG finding for capture, or under transthoracic echocardiography (TTE) ultrasound guidance. The blind procedure is associated with higher rate of failure and complications. While guidance using TTE is associated with higher success rates and fewer complications, inadequate imaging of the right side of the heart may limit the utility of this imaging modality. The use of transesophageal echocardiography (TEE) by emergency medicine and critical care physicians has gained traction in recent years due to its clear images and lack of interference with procedures being performed on the chest. In this article, we describe a protocol using TEE to guide the insertion of transvenous pacer through a case illustration.
Feasibility of chest ultrasound up to 42 m underwater
Authors: Paganini Matteo , Cantarella Giuseppe , Cialoni Danilo , Giuffrè Ezio , Bosco Gerardo
Published: August 2023

After recent advancements, ultrasound has extended its applications from bedside clinical practice to wilderness medicine. Performing ultrasound scans in extreme environments can allow direct visualization of unique pathophysiological adaptations but can be technically challenging. This paper summarizes how a portable ultrasound apparatus was marinized to let scientific divers and sonographers perform ultrasound scans of the lungs underwater up to − 42 m. A metallic case protected the ultrasound apparatus inside; a frontal transparent panel with a glove allowed visualization and operation of the ultrasound by the diving sonographer. The inner pressure was equalized with environmental pressure through a compressed air tank connected with circuits similar to those used in SCUBA diving. Finally, the ultrasound probe exited the metallic case through a sealed aperture. No technical issues were reported after the first testing step and the real experiments.
Kidney function, albuminuria, and their modification by genetic factors and risk of incident dementia in UK Biobank
Authors: Yeh Tian-Shin , Clifton Lei , Collister Jennifer A. , Liu Xiaonan , Hunter David J. , Littlejohns Thomas J.
Published: August 2023

Background

Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations.

Methods

In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (< 5 years, 5–10 years, and ≥ 10 years) to investigate potential reverse causation.

Results

Over 15 years of follow-up, 6,042 participants developed dementia. Decreased kidney function (eGFR < 60 ml/min/1.73m2) was associated with an increased risk of dementia (Hazard Ratio [HR] = 1.42, 95% Confidence Interval [CI] 1.28–1.58), compared to normal kidney function (≥ 90 ml/min/1.73m2). The strength of the association remained consistent when the models were restricted to different periods of follow-up. The HRs for incident dementia were 1.16 (95% CI 1.07–1.26) and 2.24 (95% CI 1.79–2.80) for moderate (3-30 mg/mmol) and severely increased ACR (≥ 30 mg/mmol) compared to normal ACR (< 3 mg/mmol). Dose–response associations were observed when combining eGFR and ACR, with those in the severest eGFR and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34–9.43). APOE status significantly modified the association (p = 0.04), with stronger associations observed among participants with a lower genetic risk of dementia. There was no evidence of an interaction between kidney function and non-APOE polygenic risk of dementia with dementia risk (p = 0.42).

Conclusions

Kidney dysfunction and albuminuria were individually and jointly associated with higher dementia risk. The associations were greater amongst participants with a lower genetic risk of dementia based on APOE, but not non-APOE polygenic risk.
Bacillus sp. YC7 from intestines of Lasioderma serricorne degrades nicotine due to nicotine dehydrogenase
Authors: Zhang Ke , Yin Mingshen , Lei Shengwei , Zhang Hongxin , Yin Xiaoyan , Niu Qiuhong
Published: August 2023

A large number of nicotine-containing wastes produced during the tobacco manufacturing process are seriously harmful to the environment and human health. The degradation and transformation of nicotine-containing environmental contaminants to harmless substances has become an urgent requirement. Lasioderma serricorne can grow and reproduce in nicotine-rich sources, and their intestinal microbiota show promising potential to degrade and utilize nicotine. The purpose of this study is to screen and identify nicotine-degrading bacteria from the intestines of L. serricorne and explore their degradation characteristics. A dominant strain, YC7, with significant nicotine degradation capabilities was isolated from the intestines of L. serricorne. The strain was identified as Bacillus using a polyphasic approach. The test results showed it can produce multiple enzymes that include β-glucosidase, cellulase, proteases, and amylases. The nicotine-degrading bacteria were functionally annotated using databases. Nicotine dehydrogenase (NDH) was found by combining an activity tracking test and protein mass spectrometry analysis. The YC-7 NDH in the pathway was molecularly docked and functionally verified via the gene knockdown method. The binding ability of nicotine to nicotine-degrading enzymes was investigated using molecular docking. A high-efficiency nicotine-degrading bacteria, YC-7, was isolated and screened from tobacco, and the gene functions related to degradation were verified. This investigation provides a new hypothesis for screening nicotine-degrading bacteria and increases our knowledge of potential nicotine-degrading microbial sources.
Critically ill metastatic cancer patients returning home after unplanned ICU stay: an observational, multicentre retrospective study
Authors: Gonzalez Frédéric , Starka Rémi , Ducros Laurent , Bisbal Magali , Chow-Chine Laurent , Servan Luca , de Guibert Jean-Manuel , Pastene Bruno , Faucher Marion , Sannini Antoine , Leone Marc , Mokart Djamel
Published: August 2023

Background

Data about critically ill metastatic cancer patients functional outcome after unplanned admission to the ICU are scarce. The aim of this study was to assess factors associated with 90-day return home and 1-year survival in this population.

Study design and methods

A multicenter retrospective study included all consecutive metastatic cancer patients admitted to the ICU for unplanned reason between 2017 and 2020.

Results

Among 253 included metastatic cancer patients, mainly with lung cancer, 94 patients (37.2%) could return home on day 90. One-year survival rate was 28.5%. Performance status 0 or 1 (OR, 2.18; 95% CI 1.21–3.93; P = 0.010), no malnutrition (OR, 2.90; 95% CI 1.61–5.24; P < 0.001), female gender (OR, 2.39; 95% CI 1.33–4.29; P = 0.004), recent chemotherapy (OR, 2.62; 95% CI 1.40–4.90; P = 0.003), SOFA score ≤ 5 on admission (OR, 2.62; 95% CI 1.41–4.90; P = 0.002) were significantly predictive for 90-day return home. Malnutrition (HR, 1.66; 95% CI 1.18–2.22; P = 0.003), acute respiratory failure (ARF) as reason for admission (HR, 1.40; 95% CI 1.10–1.95; P = 0.043), SAPS II on admission (HR, 1.03; 95% CI 1.02–1.05; P < 0.001) and decisions to forgo life-sustaining therapies (DFLST) (HR, 2.80; 95% CI 2.04–3.84; P < 0.001) were independently associated with 1-year mortality.

Conclusions

More than one out of three metastatic cancer patients could return home within 3 months after an unplanned admission to the ICU. Previous performance and nutritional status, ongoing specific treatment and low severity of the acute illness were found to be predictive for return home. Such encouraging findings should help change the dismal perception of critically ill metastatic cancer patients.
Synthesising results of meta-analyses to inform policy: a comparison of fast-track methods
Authors: Makowski David , Catarino Rui , Chen Mathilde , Bosco Simona , Montero-Castaño Ana , Pérez-Soba Marta , Schievano Andrea , Tamburini Giovanni
Published: August 2023

Statistical synthesis of data sets (meta-analysis, MA) has become a popular approach for providing scientific evidence to inform environmental and agricultural policy. As the number of published MAs is increasing exponentially, multiple MAs are now often available on a specific topic, delivering sometimes conflicting conclusions. To synthesise several MAs, a first approach is to extract the primary data of all the MAs and make a new MA of all data. However, this approach is not always compatible with the short period of time available to respond to a specific policy request. An alternative, and faster, approach is to synthesise the results of the MAs directly, without going back to the primary data. However, the reliability of this approach is not well known. In this paper, we evaluate three fast-track methods for synthesising the results of MAs without using the primary data. The performances of these methods are then compared to a global MA of primary data. Results show that two of the methods tested can yield similar conclusions when compared to global MA of primary data, especially when the level of redundancy between MAs is low. We show that the use of biased MAs can reduce the reliability of the conclusions derived from these methods.
Targeted delivery of isoliquiritigenin by ultrasonic microbubbles attenuate myocardial injury via suppressing inflammation and oxidative stress and activating AMPK/SIRT1/eNOS signaling pathway in rats
Authors: Liang Shuang , Zhang Lijing , Liang Shanshan
Published: August 2023

To investigate the protective efficacy of ultrasound targeted microbubble destruction (UTMD) combined with Isoliquiritigenin on myocardial injury in rats. The GK rat model of cardiomyopathy was successfully established by the induction of adriamycin. Then these rats with cardiomyopathy were randomly assigned into the model group, isoliquiritigenin microbubbles and ultrasound alone or combination group, using healthy ones as normal control. After 8-week consecutive treatment, the relevance indexes of diabetes, echocardiography as well as the hyperlipidemia, oxidative stress of model animals were examined. In addition, the fibrosis, morphological changes and inflammation response of myocardial tissues were also assessed. After further 4-week intervention, the blood biochemical indexes and the cardiac functions of model rats received the combined treatment were improved (all P < 0.05) compare to those received either monotherapy or saline. After chronic treatment, the heart/body weight ratio and serum cardiac index levels in model rats received combined treatment were significantly changed (all P < 0.05) compared with others. Furthermore, combination therapy could ameliorate excessive oxidation stress and inflammation response as well as up-regulate the expression levels of AMPK/SIRT1/eNOS signaling pathway. Targeted delivery of isoliquiritigenin by ultrasonic microbubbles can ameliorate the myocardial injury via activating AMPK/SIRT1/eNOS signaling pathways.
Current approaches to develop “off-the-shelf” chimeric antigen receptor (CAR)-T cells for cancer treatment: a systematic review
Authors: Aparicio Cristina , Acebal Carlos , González-Vallinas Margarita
Published: August 2023

Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR, which enables the recognition of the specific tumour antigen of interest. To date, CAR-T cell therapies approved for commercialisation are designed to treat haematological malignancies, showing impressive clinical efficacy in patients with relapsed or refractory advanced-stage tumours. However, since they all use the patient´s own T cells as starting material (i.e. autologous use), they have important limitations, including manufacturing delays, high production costs, difficulties in standardising the preparation process, and production failures due to patient T cell dysfunction. Therefore, many efforts are currently being devoted to contribute to the development of safe and effective therapies for allogeneic use, which should be designed to overcome the most important risks they entail: immune rejection and graft-versus-host disease (GvHD). This systematic review brings together the wide range of different approaches that have been studied to achieve the production of allogeneic CAR-T cell therapies and discuss the advantages and disadvantages of every strategy. The methods were classified in two major categories: those involving extra genetic modifications, in addition to CAR integration, and those relying on the selection of alternative cell sources/subpopulations for allogeneic CAR-T cell production (i.e. γδ T cells, induced pluripotent stem cells (iPSCs), umbilical cord blood T cells, memory T cells subpopulations, virus-specific T cells and cytokine-induced killer cells). We have observed that, although genetic modification of T cells is the most widely used approach, new approaches combining both methods have emerged. However, more preclinical and clinical research is needed to determine the most appropriate strategy to bring this promising antitumour therapy to the clinical setting.
Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer’s disease pathology in the 5xFAD mouse
Authors: Crivelli Simone M. , Quadri Zainuddin , Vekaria Hemendra J. , Zhu Zhihui , Tripathi Priyanka , Elsherbini Ahmed , Zhang Liping , Sullivan Patrick G. , Bieberich Erhard
Published: August 2023

In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.
Difference in implant design affects midflexion rotational laxity in cruciate‐retaining total knee arthroplasty: a computer navigation study
Authors: Tsuda Takashi , Hino Kazunori , Kutsuna Tatsuhiko , Watamori Kunihiko , Kinoshita Tomofumi , Takao Masaki
Published: August 2023

Purpose

This study aimed to compare midflexion rotational laxity between two different design concept models of cruciate‐retaining total knee arthroplasty: symmetrical surface design of neutral joint line obliquity and asymmetrical surface design of varus joint line obliquity.

Methods

Sixty‐three knees that underwent cruciate‐retaining total knee arthroplasty were evaluated. Manual maximum passive rotational stress without acceleration was applied to the knees under navigation monitoring. Pre‐operative and post‐operative internal and external rotational angles were measured at 30°, 45°, 60°, and 90° knee flexion.

Results

The post‐operative internal rotational laxity was significantly increased compared with pre‐operative levels at 30°, 45°, 60°, and 90° flexion among all subjects (mean 9.7° vs 11.1°, 10.6° vs 11.6°, 11.2° vs 12.9°, and 13.2° vs 14.9°; p = 0.01, 0.04, 0.001, and 0.008, respectively). The post‐operative external rotational laxity was significantly decreased compared to pre‐operative levels at 30°, 45°, 60°, and 90° flexion among all subjects (mean 10.8° vs 6.8°, 12.5° vs 9.4°, 12.8° vs 10.0°, and 11.3° vs 9.5°; p < 0.0001, < 0.0001, < 0.0001, and 0.0008, respectively). The post‐operative total rotational laxity significantly decreased, compared with pre‐operative levels, at 30° and 45° flexion among all subjects (mean 20.4° vs 17.9°, and 23.1° vs 21.1°; p = 0.002 and 0.04, respectively). The post‐operative total rotational laxity was significantly smaller in asymmetrically designed total knee arthroplasty than in symmetrically designed total knee arthroplasty at 30°, 45°, and 60° flexion (mean 19.3° vs 15.8°, 22.8° vs 18.7°, and 24.4° vs 20.8°; p = 0.03, 0.03, and 0.02, respectively), whereas no significant difference was observed at 90° flexion.

Conclusion

Compared to symmetrical surface design, asymmetrical surface design resulted in lower rotational laxity at the midflexion range in cruciate‐retaining total knee arthroplasty.

Level of evidence

III.