bluuebunny/crossref_metadata_2025 huggingface dataset:
Xylitol is prothrombotic and associated with cardiovascular risk
Authors: Witkowski Marco , Nemet Ina , Li Xinmin S , Wilcox Jennifer , Ferrell Marc , Alamri Hassan , Gupta Nilaksh , Wang Zeneng , Tang Wai Hong Wilson , Hazen Stanley L
Published: June 2024

Background and Aims

The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute.

Methods

Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10).

Results

In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12–2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects.

Conclusions

Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.
Point-of-care high-sensitivity cardiac troponin in suspected acute myocardial infarction assessed at baseline and 2 h
Authors: Cullen Louise , Greenslade Jaimi , Parsonage William , Stephensen Laura , Smith Stephen W , Sandoval Yader , Ranasinghe Isuru , Gaikwad Niranjan , Khorramshahi Bayat Maryam , Mahmoodi Ehsan , Schulz Karen , Than Martin , Apple Fred S ,   SAMIE and SEIGE investigators, Brownlee Emily , Fincher Gavin , Hall Emma , Hancock Rebecca , Gangathimmaiah Vinay , Hamilton-Craig Christian , Hobbins-King Andrew , Keijzers Gerben , McCormick Ellyse , Perez Siegfried , Staib Andrew , Zournazi Anna , Than Martin
Published: June 2024

Background and Aims

Strategies to assess patients with suspected acute myocardial infarction (AMI) using a point-of-care (POC) high-sensitivity cardiac troponin I (hs-cTnI) assay may expedite emergency care. A 2-h POC hs-cTnI strategy for emergency patients with suspected AMI was derived and validated.

Methods

In two international, multi-centre, prospective, observational studies of adult emergency patients (1486 derivation cohort and 1796 validation cohort) with suspected AMI, hs-cTnI (Siemens Atellica® VTLi) was measured at admission and 2 h later. Adjudicated final diagnoses utilized the hs-cTn assay in clinical use. A risk stratification algorithm was derived and validated. The primary diagnostic outcome was index AMI (Types 1 and 2). The primary safety outcome was 30-day major adverse cardiac events incorporating AMI and cardiac death.

Results

Overall, 81 (5.5%) and 88 (4.9%) patients in the derivation and validation cohorts, respectively, had AMI. The 2-h algorithm defined 66.1% as low risk with a sensitivity of 98.8% [95% confidence interval (CI) 89.3%–99.9%] and a negative predictive value of 99.9 (95% CI 99.2%–100%) for index AMI in the derivation cohort. In the validation cohort, 53.3% were low risk with a sensitivity of 98.9% (95% CI 92.4%–99.8%) and a negative predictive value of 99.9% (95% CI 99.3%–100%) for index AMI. The high-risk metrics identified 5.4% of patients with a specificity of 98.5% (95% CI 96.6%–99.4%) and a positive predictive value of 74.5% (95% CI 62.7%–83.6%) for index AMI.

Conclusions

A 2-h algorithm using a POC hs-cTnI concentration enables safe and efficient risk assessment of patients with suspected AMI. The short turnaround time of POC testing may support significant efficiencies in the management of the large proportion of emergency patients with suspected AMI.
A transcriptome-wide association study identified susceptibility genes for hepatocellular carcinoma in East Asia
Authors: Zhang Jingjing , Zhang Qingrong , Hu Wenyan , Liang Yuxuan , Jiang Deke , Chen Haitao
Published: June 2024

Background

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is prevalent in East Asia. Although genome-wide association studies (GWASs) of HCC have identified 23 risk regions, the susceptibility genes underlying these associations largely remain unclear. To identify novel candidate genes for HCC, we conducted liver single-tissue and cross-tissue transcriptome-wide association studies (TWASs) in two populations of East Asia.

Methods

GWAS summary statistics of 2,514 subjects (1,161 HCC cases and 1,353 controls) from the Chinese Qidong cohort and 161,323 subjects (2,122 HCC cases and 159,201 controls) from the BioBank Japan project were used to conduct TWAS analysis. The single-tissue and cross-tissue TWAS approaches were both used to detect the association between susceptible genes and the risk of HCC. TWAS identified genes were further annotated by Metascape, UALCAN, GEPIA2, and DepMap.

Results

We identified 22 novel genes at 16 independent loci significantly associated with HCC risk after Bonferroni correction. Of these, 13 genes were located in novel regions. Besides, we found 83 genes overlapped in the Chinese and Japanese cohorts with P < 0.05, of which, three genes (NUAK2, HLA-DQA1, and ATP6V1G2) were discerned by both single-tissue and cross-tissue TWAS approaches. Among the genes identified through TWAS, a significant proportion of them exhibit a credible role in HCC biology, such as FAM96B, HSPA5, POLRMT, MPHOSPH10, and RABL2A. HLA-DQA1, NUAK2, and HSPA5 associated with the process of carcinogenesis in HCC as previously reported.

Conclusions

Our findings highlight the value of leveraging the gene expression data to identify new candidate genes beyond the GWAS associations and could further provide a genetic insight for the biology of HCC.
Position Statement of the Max Planck Institute for Innovation and Competition of 6 February 2024 on the Commission’s Proposal for a Regulation of the European Parliament and of the Council on Standard Essential Patents
Authors: Drexl Josef , Harhoff Dietmar , Conde Gallego Beatriz , Slowinski Peter R
Published: June 2024

The Max Planck Institute for Innovation and Competition is a research institute within the Max Planck Society for the Advancement of Science. The Institute is committed to fundamental legal and economic research on processes of innovation and competition and their regulation. Its research focus is on the incentives, determinants and implications of innovation. The Institute informs and guides legal and economic discourse on an impartial basis. It hereby presents its position on the European Commission’s proposal of 27 April 2023 for a Regulation of the European Parliament and of the Council on standard essential patents and amending Regulation (EU) 2017/1001.
FEM-BEM coupling in fractional diffusion
Authors: Faustmann Markus , Rieder Alexander
Published: June 2024

We derive and analyze a fully computable discrete scheme for fractional partial differential equations posed on the full space ${\mathbb{R}}^{d}$. Based on a reformulation using the well-known Caffarelli–Silvestre extension, we study a modified variational formulation to obtain well-posedness. Our scheme is obtained by combining a diagonalization procedure with a reformulation using boundary integral equations and a coupling of finite elements and boundary elements. For our discrete method we present a-priori estimates as well as numerical examples.
A Robust Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)–Specific T- and B-Cell Response Is Associated With Early Viral Clearance in SARS-CoV-2 Omicron-Infected Immunocompromised Individuals
Authors: Vergouwe Magda , Biemond Jason J , van der Straten Karlijn , van Pul Lisa , Kerster Gius , Claireaux Mathieu , Burger Judith A , van Dort Karel A , Kootstra Neeltje A , Jonges Marcel , Welkers Matthijs R A , Hazenberg Mette D , Peters-Sengers Hessel , van Gils Marit J , Wiersinga W Joost , Birnie Emma , de Bree Godelieve J ,   for the TURN-COVID study group, Olijhoek Wouter , Kalmoua Zakaria , Appelman Brent , Zaaijer Hans L , van Ittersum Frans J , van der Loeff Maarten F Schim , Bomers Marije K , Kersten Marie José , Heijmans Jarom , van der Valk Marc , de Boer Mark G J , Rosendaal Frits R , Kemper E Marleen
Published: June 2024

Background

The immunological determinants of delayed viral clearance and intrahost viral evolution that drive the development of new pathogenic virus strains in immunocompromised individuals are unknown. Therefore, we longitudinally studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific immune responses in relation to viral clearance and evolution in immunocompromised individuals.

Methods

Among Omicron-infected immunocompromised individuals, we determined SARS-CoV-2–specific T- and B-cell responses, anti-spike immunoglobulin G (IgG) and IgG3 titers, neutralization titers, and monoclonal antibody (mAb) resistance–associated mutations. The 28-day post-enrollment nasopharyngeal specimen defined early (reverse-transcription polymerase chain reaction [RT-PCR] negative ≤28 days) or late (RT-PCR positive >28 days) viral clearance.

Results

Of 30 patients included (median age, 61.9 [interquartile range, 47.4–72.3] years; 50% females), 20 (66.7%) received mAb therapy. Thirteen (43.3%) demonstrated early and 17 (56.7%) late viral clearance. Patients with early viral clearance and patients without resistance-associated mutations had significantly higher baseline interferon-γ release, and patients with early viral clearance had a higher frequency of SARS-CoV-2–specific B cells at baseline. In non-mAb-treated patients, day 7 IgG and neutralization titers were significantly higher in those with early versus late viral clearance.

Conclusions

An early robust adaptive immune response is vital for efficient viral clearance and associated with less emergence of mAb resistance–associated mutations in Omicron-infected immunocompromised patients. This emphasizes the importance of early SARS-CoV-2–specific T- and B-cell responses and thereby provides a rationale for development of novel therapeutic approaches.
Current practices and challenges of outpatient parenteral antimicrobial therapy: a narrative review
Authors: Wolie Zenaw T , Roberts Jason A , Gilchrist Mark , McCarthy Kate , Sime Fekade B
Published: June 2024

Extended hospitalization for infection management increases inpatient care costs and the risk of healthcare-associated adverse events, including infections. The growing global demand for healthcare, the diminishing availability of hospital beds and an increasing patient preference for care within their own home have been the primary drivers of the expansion of hospital-in-the-home programmes. Such programmes include the use of IV antimicrobials in outpatient settings, known as outpatient parenteral antimicrobial therapy (OPAT). However, OPAT practices vary globally. This review article aims to describe the current OPAT practices and challenges worldwide. OPAT practice begins with patient evaluation and selection using eligibility criteria, which requires collaboration between the interdisciplinary OPAT team, patients and caregivers. Depending on care requirements, eligible patients may be enrolled to various models of care, receiving medication by healthcare professionals at outpatient infusion centres, hospital clinics, home visits or through self-administration. OPAT can be used for the management of many infections where an effective oral treatment option is lacking. Various classes of parenteral antimicrobials, including β-lactams, aminoglycosides, glycopeptides, fluoroquinolones and antifungals such as echinocandins, are used globally in OPAT practice. Despite its benefits, OPAT has numerous challenges, including complications from medication administration devices, antimicrobial side effects, monitoring requirements, antimicrobial instability, patient non-adherence, patient OPAT rejection, and challenges related to OPAT team structure and administration, all of which impact its outcome. A negative outcome could include unplanned hospital readmission. Future research should focus on mitigating these challenges to enable optimization of the OPAT service and thereby maximize the documented benefits for the healthcare system, patients and healthcare providers.
Temperature dependence of the mutation rate towards antibiotic resistance
Authors: Van Eldijk Timo J B , Sheridan Eleanor A , Martin Guillaume , Weissing Franz J , Kuipers Oscar P , Van Doorn G Sander
Published: June 2024

Objectives

Environmental conditions can influence mutation rates in bacteria. Fever is a common response to infection that alters the growth conditions of infecting bacteria. Here we examine how a temperature change, such as is associated with fever, affects the mutation rate towards antibiotic resistance.

Methods

We used a fluctuation test to assess the mutation rate towards antibiotic resistance in Escherichia coli at two different temperatures: 37°C (normal temperature) and 40°C (fever temperature). We performed this measurement for three different antibiotics with different modes of action: ciprofloxacin, rifampicin and ampicillin.

Results

In all cases, the mutation rate towards antibiotic resistance turned out to be temperature dependent, but in different ways. Fever temperatures led to a reduced mutation rate towards ampicillin resistance and an elevated mutation rate towards ciprofloxacin and rifampicin resistance.

Conclusions

This study shows that the mutation rate towards antibiotic resistance is impacted by a small change in temperature, such as associated with fever. This opens a new avenue to mitigate the emergence of antibiotic resistance by coordinating the choice of an antibiotic with the decision of whether or not to suppress fever when treating a patient. Hence, optimized combinations of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.
Activity of cefepime, carbapenems and new β-lactam/β-lactamase inhibitor combinations on Enterobacter cloacae complex and Klebsiella aerogenes in Spain (SMART 2016–2022)
Authors: Rodríguez-Villodres Ángel , Lepe-Balsalobre Esperanza , Ortiz De La Rosa José Manuel , Giner Almaraz Salvador , González De Herrero Elisa , Cercenado Emilia , García-Fernández Sergio , Benito Rafael , Ponz Mir Ricardo , Cantón Rafael , Lepe José Antonio
Published: June 2024

Objectives

To analyse the susceptibility profile to cefepime, carbapenems and new β-lactam/β-lactamase inhibitor combinations in Enterobacter cloacae complex and Klebsiella aerogenes isolated from intra-abdominal, urinary, respiratory and bloodstream infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain.

Methods

The susceptibilities of 759 isolates (473 E. cloacae complex and 286 K. aerogenes) collected in 11 Spanish hospitals from 2016 to 2022 were analysed following the EUCAST 2023 criteria. Molecular characterization looking for β-lactamase genes was performed through PCR and DNA sequencing analysis.

Results

E. cloacae complex showed resistance to third-generation cephalosporins in 25% of the cases, whereas K. aerogenes was resistant in 35%. Regarding cefepime, resistance in E. cloacae was higher (10%) than in K. aerogenes (2%). Carbapenems showed >85% activity in both microorganisms. Ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam had good activity against these microorganisms (>95%). In contrast, the activity of ceftolozane/tazobactam was lower (80%). A high proportion of the isolates resistant to new β-lactam/β-lactamase inhibitor combinations carried a carbapenemase, mainly OXA-48-like and VIM-1.

Conclusions

Ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam show high activity against both E. cloacae complex and K. aerogenes isolates recovered in the SMART-Spain study. In contrast, differences have been found in the case of cefepime, showing more activity against K. aerogenes than E. cloacae complex. These results are useful for antimicrobial stewardship programmes and for the implementation of local and national guidelines.
Levels of Analysis and Variation in Civil War Violence and Restraint: Ideology and Contestation in Nicaragua
Authors: Thaler Kai M
Published: June 2024

How can we analyze violence against civilians in civil wars over time and with attention both to local context and international comparability? I argue that we should integrate theories across levels of analysis, applying this to testing existing theories of civil war violence and state repression in the case of the Frente Sandinista de Liberación Nacional (FSLN) in Nicaragua. Using interviews, archival evidence, and human rights reports, I argue that compared to domestic rivals and from an international perspective, the FSLN generally exhibited restraint, limiting violence against civilians due to an ideological commitment to discipline and civilian protection. Disaggregating the geographic and temporal contexts of violations at the subnational level reveals, however, that significant violence occurred where the FSLN had less territorial control, fewer civilian ties, and looser discipline, supporting contestation and command and control theories. Theories of violence may therefore explain variation at one level of analysis and not others within a given case, emphasizing the need for within-case disaggregation in explaining and comparing patterns of violence and state repression in civil wars, and the importance of unpacking violence committed by more restrained actors.
Chondroblastic osteosarcoma of the nasal cavity: an exceptional and misdiagnosed presentation
Authors: Aaboudech Taha Yassine , EL Ouazzani Hafsa , Kadiri Habiba , Benabdenbi Hanae , Rguieg Naji , EL Ouali Ibtissam , EL Kettani N Ech-cherif , Zouaidia Fouad , Cherradi Nadia
Published: June 2024

Chondroblastic osteosarcoma of the nasal cavity is a rare and aggressive tumor that presents diagnostic challenges due to its variable clinical and radiological features. Histological analysis is crucial for an accurate diagnosis, despite morphological similarities with chondrosarcoma. We present a case of primary craniofacial chondroblastic osteosarcoma originating from the nasal cavity in a 17-year-old adolescent. The tumor was characterized by cartilaginous lobules and spindle cell proliferation with osteoid matrix deposition. Immunohistochemical analysis supported the diagnosis. This case highlights the rarity of this particular presentation and emphasizes the significance of accurate diagnosis through histopathological evaluation to achieve optimal management.
WISDOM Project – XXI. Giant molecular clouds in the central region of the barred spiral galaxy NGC 613: a steep size–linewidth relation
Authors: Choi Woorak , Bureau Martin , Liu Lijie , Cappellari Michele , Davis Timothy A , Gensior Jindra , Liang Fu-Heng , Lu Anan , Moon Sanghyuk , Ruffa Ilaria , Williams Thomas G , Chung Aeree
Published: June 2024

NGC 613 is a nearby barred spiral galaxy with a nuclear ring. Exploiting high spatial resolution (≈20 pc) Atacama Large Millimetre/submillimetre Array 12CO(1–0) observations, we study the giant molecular clouds (GMCs) in the nuclear ring and its vicinity, identifying 158 spatially and spectrally resolved GMCs. The GMC sizes (Rc) are comparable to those of the clouds in the Milky Way (MW) disc, but their gas masses, observed linewidths (σobs,los), and gas mass surface densities are larger. The GMC size–linewidth relation ($\sigma _{\mathrm{obs,los}}\propto R_{\mathrm{c}}^{0.77}$) is steeper than that of the clouds of the MW disc and centre, and the GMCs are on average only marginally gravitationally bound (with a mean virial parameter 〈αobs,vir〉 ≈ 1.7). We discuss the possible origins of the steep size–linewidth relation and enhanced observed linewidths of the clouds and suggest that a combination of mechanisms such as stellar feedback, gas accretion, and cloud–cloud collisions, as well as the gas inflows driven by the large-scale bar, may play a role.
A Bayesian approach to the cosmic dipole in radio galaxy surveys: joint analysis of NVSS & RACS
Authors: Oayda Oliver T , Mittal Vasudev , Lewis Geraint F , Murphy Tara
Published: June 2024

We examine the sky distribution of radio galaxies in the NRAO VLA Sky Survey (NVSS) and the Rapid ASKAP Continuum Survey (RACS). Analyses of these samples have reported tension between their inferred dipoles and the kinematic dipole of the cosmic microwave background (CMB). This represents a challenge to the traditional assumption that the Universe is homogeneous and isotropic on large scales: the cosmological principle. We find that NVSS and RACS contain local radio sources that give a non-negligible contribution to the overall dipole signal. These need to be adequately accounted for since the aim is to probe the composition of the Universe at large scales. By appropriately considering these sources, the inferred dipole amplitude in either sample is reduced. None the less, we find support for a dipole aligning with that of the CMB but larger in amplitude, especially in the joint analysis. However, the ‘clustering dipole’ – the contribution of local sources to the net inferred dipole – appears to align with the direction of the CMB dipole, and its magnitude increases as deeper nearby sources are considered up to a comoving distance of ≈130 Mpc (h = 0.7). The significance of this observation in the context of the cosmological principle is unclear and prompts further inquiry.
Local versus global environment: the suppression of star formation in the vicinity of galaxy clusters
Authors: de Vos K , Merrifield M R , Hatch N A
Published: June 2024

In order to examine where, how and why the quenching of star formation begins in the outskirts of galaxy clusters, we investigate the de-projected radial distribution of a large sample of quenched and star-forming galaxies (SFGs) out to 30R500 around clusters. We identify the SFG sample using radio continuum emission from the Low-Frequency Array Two-metre Sky Survey. We find that the SFG fraction starts to decrease from the field fraction as far out as 10R500, well outside the virial radius of the clusters. We investigate how the SFG fraction depends on both large-scale and local environments, using radial distance from a cluster to characterise the former, and distance from fifth nearest neighbour for the latter. The fraction of SFGs in high-density local environments is consistently lower than that found in low-density local environments, indicating that galaxies’ immediate surroundings have a significant impact on star formation. However, for high-mass galaxies – and low mass galaxies to a lesser extent – high-density local environments appear to act as a protective barrier for those SFGs that survived this pre-processing, shielding them from the external quenching mechanisms of the cluster outskirts. For those galaxies that are not in a dense local environment, the global environment causes the fraction of SFGs to decrease toward the cluster centre in a manner that is independent of galaxy mass. Thus, the fraction of SFGs depends on quite a complex interplay between the galaxies’ mass, their local environment, and their more global cluster-centric distance.
Adaptation of a eukaryote-like ProRS to a prokaryote-like tRNAPro
Authors: Ivanesthi Indira Rizqita , Latifah Emi , Amrullah Luqman Fikri , Tseng Yi-Kuan , Chuang Tsung-Hsien , Pan Hung-Chuan , Yang Chih-Shiang , Liu Shih-Yang , Wang Chien-Chia
Published: June 2024

Prolyl-tRNA synthetases (ProRSs) are unique among aminoacyl-tRNA synthetases (aaRSs) in having two distinct structural architectures across different organisms: prokaryote-like (P-type) and eukaryote/archaeon-like (E-type). Interestingly, Bacillus thuringiensis harbors both types, with P-type (BtProRS1) and E-type ProRS (BtProRS2) coexisting. Despite their differences, both enzymes are constitutively expressed and functional in vivo. Similar to BtProRS1, BtProRS2 selectively charges the P-type tRNAPro and displays higher halofuginone tolerance than canonical E-type ProRS. However, these two isozymes recognize the primary identity elements of the P-type tRNAPro―G72 and A73 in the acceptor stem―through distinct mechanisms. Moreover, BtProRS2 exhibits significantly higher tolerance to stresses (such as heat, hydrogen peroxide, and dithiothreitol) than BtProRS1 does. This study underscores how an E-type ProRS adapts to a P-type tRNAPro and how it may contribute to the bacterium's survival under stress conditions.
In vivo modeling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma
Authors: Castle Jemma , Shaw Gary , Weller Dominic , Fielder Edward , Egnuni Teklu , Singh Mankaran , Skinner Roderick , von Zglinicki Thomas , Clifford Steven C , Short Susan C , Miwa Satomi , Hicks Debbie
Published: June 2024

Background

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with posterior fossa boost (PFB), underpins treatment for non-infants; however, radiotherapeutic insult to the normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated aging/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.

Methods

We have developed a clinically relevant in vivo model system that recapitulates the radiotherapy dose, targeting, and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35–37) male C57Bl/6J mice received computerized tomography image-guided CRT (human-equivalent 37.5 Gy EQD2, n = 12) ± PFB (human-equivalent 48.7 Gy EQD2, n = 12), via the small animal radiation research platform and were longitudinally assessed for > 12 months.

Results

CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n = 12), irradiated mice were significantly frailer following irradiation (frailty index; P = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; P = .026) and grip strength (P = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; P = .009) and exhibited spatial memory deficits (Barnes maze; P = .029). Receipt of PFB did not induce a more severe late-effect profile.

Conclusions

Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late effects and the development of novel interventions for their amelioration.
Harvesting information from Kaplan-Meier plots: part 1—detecting censoring
Authors: Fojo Antonio Tito , Labadie Brian
Published: June 2024

This commentary focuses on the recent article by Sherry et al on missing elements in Kaplan-Meier plots, focusing not on what is left out, but what is often ignored—information that can often call the results, interpretation, and conclusion of a clinical trial into question.
Optimizing paediatric specialist referrals for short stature in an era of multiple growth hormone indications
Authors: Krishnamoorthy Preetha , Gagné Nancy , Girgis Rose , Marks Seth , Saoudi Zoraida , Zenlea Ian , Kirsch Susan
Published: June 2024

The assessment of growth during infancy and childhood is an essential component of paediatric medicine, as atypical growth may point to the existence of an underlying health condition. To reduce morbidity, it is vital that treatment for growth disorders is provided in a timely fashion. However, although there are guidelines regarding referral criteria for short stature in Europe and the USA, there are no such guidelines in Canada. To address this, a series of consultations and workshops with paediatricians, paediatric endocrinologists, family physicians and nurses were held, with the aim of developing a consensus-based set of recommendations for children in Canada showing atypical growth and to identify red flags for children who might benefit from early referral. To achieve this, a referral algorithm and referral form for primary care providers were developed to ensure timely and appropriate referrals, and transmission of the most relevant details to the secondary care consultant.
Pattern of CYP3A5 and MDR-1 single-nucleotide polymorphism and its impact on Tacrolimus levels and clinical outcomes in living renal allograft recipient
Authors: Sangha Sukhwinder Singh , Yadav Sushma , Yadav Raj Kanwar , Kumar Asheesh , Seenu Vuthaluru , Agarwal Sanjay Kumar , Kabra Madhulika , Chowdhury Madhumita Roy , Vishwakarma Vishal Kumar , Bhowmik Dipankar
Published: June 2024

Introduction

Renal transplant is the best form of renal replacement therapy. The most favored immunosuppression includes Tacrolimus, mycophenolate mofetil, and steroids. Tacrolimus has a narrow therapeutic index and requires therapeutic drug monitoring (TDM). However, there is wide variation in tacrolimus level with weight-based fixed dosage regimens. This variability is due to polymorphism of major pathways of metabolism ie CYP3A5 and MDR1 genes. Fast metabolizers require higher dosage and slow metabolizers require lower dosage. Genotype-based dosing strategy may be useful to achieve early therapeutic level and reduce infections and rejections.

Methodology

One hundred and sixty transplant patients at tertiary care hospitals in India were included in this study from 2016 to 2018. Genetic polymorphism analysis in CYP3A5 and MDR1 genes was carried out at the time of transplant. All patients were given a fixed weight-based dosage of Tacrolimus. Data were analyzed in relation to genotype polymorphism.

Results and discussion

69.2% of wild variants of CYP 3A5 (Fast metabolizers) have low initial tacrolimus levels. 51.5% of Homo variants (Slow metabolizers) have high initial tac levels. However, all variants achieve optimum tacrolimus levels at the same time (mean 12.4 days). There were higher number of infections among slow metabolizers.

Conclusion

A fixed dosing regimen with TDM results in high and low initial tacrolimus levels in slow and fast metabolizers respectively and more infections in slow metabolizers. However, graft rejections being fewer in number, were not different. A larger sample with genotype-based dosing is required to test such a strategy.
In flagranti—functional morphology of copulatory organs of odontopygid millipedes (Diplopoda: Juliformia: Spirostreptida)
Authors: Brandt Justus , Reip Hans S , Naumann Benjamin
Published: June 2024

The copulatory organs of many animal groups exhibit a high degree of morphological complexity and diversity that is thought to have evolved on the basis of different selective mechanisms, including lock-and-key mechanism, pleiotropy, sperm competition, internal courtship, and female choice. Identifying the effects of these different selective mechanisms on the copulatory organs is one of the central topics of the study of sexual selection. To tackle this challenge, knowledge of the functions of all parts of the copulatory organs is indispensable. Here we study the functional morphology of the gonopods (male copulatory organs) and vulvae (female copulatory organs) in the odontopygid millipede Spinotarsus sp. (Diplopoda: Spirostreptida: Odontopygidae). While the vulvae of female odontopygids are rather simple, male gonopods are complex, walking leg-derived copulatory organs that exhibit many movable sub-parts. Using X-ray microscopy-based 3D reconstruction, confocal laser scanning microscopy, and mating observations, we revise the functional morphology of odontopygid gonopods, propose biological roles, and evaluate the possible involvement of different selective mechanisms underlying their evolution.
Remimazolam: its clinical pharmacology and evolving role in anesthesia and sedation practice
Authors: Masui Kenichi
Published: June 2024

Purpose of review

Remimazolam is a novel benzodiazepine anesthetic/sedative, designed as a rapidly metabolized carboxylic acid. Since its recent launch, the role of remimazolam in modern anesthesia and sedation practice is still evolving. This review aims to outline the clinical pharmacology and clinical utility of remimazolam to elucidate its potential advantages and limitations.

Recent findings

Remimazolam is “short-acting” but not ultra-short-acting compared with propofol based on context-sensitive decrement times. But compared to propofol, the availability of the benzodiazepine antagonist, flumazenil, is considered an advantage, particularly in certain emergency situations such as in patients with difficult airways. However, because flumazenil is shorter acting than remimazolam when remimazolam accumulates or is present in a high concentration, the reappearance of remimazolam sedation may occur after the initial reversal of anesthesia/sedation from flumazenil administration. Although it is beneficial that remimazolam causes less respiratory depression and hypotension than propofol, serious respiratory depression and hypotension can still occur. Remimazolam administration causes minimal or no pain on injection. Remimazolam is associated with less postoperative nausea and vomiting than inhaled anesthetics, but propofol is clearly superior in this regard. The anesthetic/sedative effects may be prolonged by severe hepatic impairment; remimazolam tolerance can occur in long-term benzodiazepine users.

Remimazolam may be beneficial to use in procedural sedation and general anesthesia for patients with difficult airways or hemodynamic instability. Further clinical studies with remimazolam are warranted to identify the potential benefits in other settings and patient populations.
Postoperative pain management after abdominal transplantations
Authors: Tufegdzic Boris , Lobo Clara , Kumar Arun
Published: June 2024

Purpose of review

The aim of this review article is to present current recommendations as well as knowledge gaps and controversies pertaining to commonly utilized postoperative pain management after solid organ transplantation in the abdominal cavity.

Recent findings

Postsurgical pain has been identified as one of the major challenges in recovery and treatment after solid organ transplants. Many perioperative interventions and management strategies are available for reducing and managing postoperative pain. Management should be tailored to the individual needs, taking an interdisciplinary and holistic approach and following enhanced recovery after surgery guidelines. Many centers currently utilize peripheral and neuraxial blocks during transplantation surgery, but these techniques are far from standardized practices. The utilization of these procedures is often dependent on transplantation centers’ historical methods and perioperative cultures.

The optimal pain management regimen has not yet been definitively established, and current scientific evidence does not yet support the endorsement of a certain analgesic approach. This objective necessitates the need for high-quality randomized controlled trials.
Substance Use Disorder Care in Skilled Nursing Facilities: Characterizing Resident Experiences
Authors: Parkhideh Arianna , Beiting Kimberly J. , Yang Meredith , Landi A. Justine , Levine Stacie
Published: June 2024

Objectives

Patients with substance use disorder (SUD) may face many challenges when being cared for in skilled nursing facilities (SNFs), such as stigma and inadequate access to treatment. This study aims to learn from the perspectives of SNF residents with SUD.

Methods

Nineteen semistructured interviews were conducted at 5 SNFs in the Chicago Metropolitan Area. Additionally, Likert-type responses and substance use screening tests were collected. Qualitative data were analyzed using Dedoose version 9.0.107 (Sociocultural Research Consultants, LLC, Los Angeles, CA).

Results

Qualitative analyses identified 4 themes: (1) the SNF can be a positive site for recovery, (2) barriers to recovery in SNFs are variable, (3) lived experiences with SUD care and harm reduction are heterogeneous, and (4) the needs of residents with SUD encompass multiple domains. Results highlighted the variability of access to counseling and SUD treatment, as well as the prevalence of stigma, substance use, and overdose in SNFs. Results revealed the need for access to social work support, activities, counseling services, and improved staff knowledge of treating SUD.

Conclusions

SNF residents living with SUD experience variable quality of care and may have difficulty accessing counseling and medical treatments for SUD, depending on the available resources in the facility to which they were admitted. The quality of care for residents living with SUD requires further study as more patients with SUD require SNF care.
Drug Testing Interpretation in the Peripartum Setting: Results of Clinician Survey
Authors: Kurtz Theresa , Charron Elizabeth , Shakib Julie , Smid Marcela C.
Published: June 2024

Objectives

The objectives of this study were to (1) survey obstetrical and pediatric clinicians’ experience, confidence, and training in maternal and neonatal drug testing interpretation; (2) determine their proficiency in drug test interpretation; and (3) assess predictors of correct interpretation.

Methods

We conducted a cross-sectional survey of clinicians caring for pregnant people or newborns at an urban academic center. We assessed clinicians’ demographic characteristics, experience, confidence, and prior training in interpretation of maternal and newborn drug tests. We assessed proficiency in interpreting drug tests using 11 clinical vignettes and categorized scores as poor (0–2), fair (3–5), and good (≥6) performance to facilitate data interpretation. We used descriptive statistics to summarize responses. Multinomial logistic regression was used to determine associations of clinician characteristics and score category (reference category: poor performance).

Results

In total, 103 respondents completed the survey including 60 obstetrical clinicians (58.3%), 19 family medicine physicians (18.5%), 21 pediatric clinicians (20.4%), and 3 social workers (2.9%) (response rate, ~40%). The mean correct response was 4.1 (SD, 2.17; range, 0–11). Most respondent scores were fair (n = 47.6%), followed by good (n = 28.2%) and poor (n = 24.3%). Increased frequency, confidence, and training in interpreting maternal screening and confirmatory tests were associated with higher proficiency. Increased confidence and training in interpreting neonatal screening and confirmatory tests, but not frequency, were associated with higher proficiency.

Conclusions

Most clinicians demonstrated fair proficiency in interpreting drug tests. Predictors of proficiency were confidence and prior training for drug test interpretation, suggesting that educational interventions could improve proficiency.
Validation of a Vaginal Birth After Cesarean Delivery Prediction Model Without Race and Ethnicity in Individuals With Two Prior Cesarean Deliveries
Authors: Goodman Lillian H. , Allshouse Amanda A. , Bruno Ann M. , Metz Torri D.
Published: June 2024

Previous models for prediction of vaginal birth after cesarean (VBAC) relied on race and ethnicity, raising concern for bias. In response, the Maternal-Fetal Medicine Units Network (MFMU) created a new prediction model without race and ethnicity for individuals with one prior cesarean delivery. We performed a secondary analysis of the MFMU Cesarean Registry database to evaluate whether the MFMU VBAC prediction model without race and ethnicity could accurately predict VBAC for individuals with two prior cesarean deliveries. Overall, 353 individuals were included and 252 (71%) had VBAC. An area under the curve for the receiver operating curve of 0.74 (95% CI, 0.69–0.80) was reported for the predicted probabilities for VBAC, indicating that the model can be used for prediction of VBAC in this population.
Lasers in Gynecology
Authors: Iglesia Cheryl B. , Choi Jennie Eunsook , Tadir Yona
Published: June 2024

The first published reports on the use of laser for cervical pathology date back to 1973. Technical advancements in flexible and rigid laser fibers revolutionized video laser laparoscopy in the 1990s. Fractionated lasers have been used to treat vulvovaginal symptoms associated with genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence. Review of available data suggests that fractionated lasers can improve both subjective and objective signs of vaginal atrophy and lichen sclerosus, but the evidence is weak because most of the trials are underpowered, are at risk for bias, and lack long-term follow-up. There is no strong evidence to support fractionated laser therapy for urinary incontinence or low-level laser therapy for chronic pelvic pain. Although short-term, single-arm trials suggest benefit of fractionated laser therapy for genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence, additional adequately powered, prospective, randomized, and longer-term comparative trials are needed before lasers can be recommended for these specific conditions. The purpose of this Clinical Expert Series is to review basic laser biophysics and the mechanism of action for modern fractionated lasers as relevant to the gynecologist. We also summarize safety and effectiveness data for lasers used for some of the most commonly studied gynecologic conditions: the vulvovaginal atrophy component of genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence.
Ectopic Prostatic Tissue in Female Urethral Diverticulum
Authors: Sinha Annika , Cantrell Sarah , Kozman Diana M. , Jelovsek J. Eric
Published: June 2024

BACKGROUND:

Ectopic prostatic tissue in female patients is rare. It is theorized that the presence of prostatic tissue in female patients is likely a Wolffian remnant or transformation of hormonally mediated tissue of the uterus, cervix, Skene's gland, and, rarely, periurethral tissue. Due to the increase in the use of testosterone and gender-affirming therapies, it is important to understand the role of testosterone in mediating the presence of ectopic prostatic tissue.

CASE:

We present a case of ectopic prostatic tissue in a urethral diverticulum in a female patient with exposure to testosterone hormone therapy and review the literature on this finding.

CONCLUSION:

Although rare, ectopic prostatic tissue should be considered in the differential diagnosis of anterior vaginal cysts, especially in the setting of testosterone supplementation.
Anterior Distal Femoral Hemiepiphysiodesis Using Coronally Oriented 8-plates for the Correction of Fixed Knee Flexion Deformities in Children—Preliminary Results
Authors: Hassanein Mohamed Y. , Khaled Mohamed , Hassanein Mahmoud Yahya , Abol Oyoun Nariman
Published: June 2024

Introduction:

The original technique for guided growth of the distal femur for correction of pediatric fixed knee flexion deformities (FKFDs) involves the utilization of two 8-plates inserted on either side of the trochlear groove, a technique that has been frequently linked to the development of persistent postoperative knee pain and crepitus. The present study aimed to assess the preliminary results of a novel technique where the two 8-plates are fixed in the coronal plane, one on each of the medial and lateral surfaces, so that they occupy the anterior part of the distal femur.

Methods:

Our study was a prospective case series that included cases with FKFD of >10 degrees in children with at least 12 months of predicted growth remaining. The preoperative knee flexion contracture angle was documented. The surgical procedure entailed the insertion of 2 coronally oriented 8-plates on the medial and lateral surfaces of the distal femur as anterior as possible to the axis of the femur without encroachment on the trochlear groove. The duration of time required to attain full knee extension and any complications encountered were recorded. Wilcoxon signed-rank was used to compare the preoperative and final contracture angles. The level of statistical significance was set at P<0.05.

Results:

Thirteen knees in 8 patients (6 boys and 2 girls) were included. The median age was 11 years (6 to 14). There was a significant improvement in the FKFD for the whole cohort from 25 degrees (14 to 42) to 0 degrees (−9 to 8), P<0.05. The median rate of correction was 2.0 degrees/month (0.9 to 5.8). The time till full correction was 14 months (4 to 25). Postoperative knee pain and metalware-related complications were not reported by any patient during follow-up.

Conclusions:

Guided growth of the distal femur using coronally oriented 8-plates is an effective procedure for the treatment of FKFDs in children. This modified technique may achieve faster correction while minimizing the risk of postoperative knee pain compared with the conventional technique.

Level of Evidence:

Level IV—case series.
Histopathological Confirmation of Axonal Sprouting in Regenerative Peripheral Nerve Interface
Authors: Chang Song Ho , Maenohara Yuji , Hirose Jun , Omata Yasunori , Fujiwara Sayaka , Haga Nobuhiko , Ikemura Masako , Saito Taku , Tanaka Sakae , Matsumoto Takumi
Published: June 2024

Symptomatic neuroma represents a debilitating complication after major limb amputation. The regenerative peripheral nerve interface (RPNI) has emerged as a reproducible and practical surgery aimed at mitigating the formation of painful neuroma. Although previous animal studies revealed axonal sprouting, elongation, and synaptogenesis of proximal nerve stump within the muscle graft in RPNI, there is a lack of reports confirming these physiological reactions at the histopathological level in human samples. This report presents a case of below-knee amputation with RPNI due to foot gangrene resulting from polyarteritis nodosa. Subsequently, an above-knee amputation was necessitated due to the exacerbation of polyarteritis nodosa, providing the opportunity for histopathological examination of the RPNI site. The examination revealed sprouting, elongation, and existence of neuromuscular junction of the tibial nerve within the grafted muscle. To the best of our knowledge, this is the first report demonstrating axonal sprouting, elongation, and possibility of synaptogenesis of the nerve stump within the grafted muscle in a human sample.