bluuebunny/crossref_metadata_2025 huggingface dataset:
P25 Two cases of multicentric dermatofibrosarcoma Protuberans (DFSP) and adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) in a tertiary centre
Authors: Gardner Louis , Dubois Anna , Leech Suzy , Slatter Mary , Gennery Andy , Nademi Zohreh
Published: January 2024

Dermatofibrosarcoma Protuberans (DFSP) are uncommon soft tissue sarcomas that are rarely metastatic though usually high-risk for local aggression and recurrence. DFSP is associated with t(17;22)(q22;q13) chromosomal translocation resulting in COL1A1-platelet-derived growth factorβ(PDGFB) fusion gene(Kesserwan et al. 2009). We present two patients referred to Dermatology at very different ages (patient A 12 years; patient B 6 months) with atrophic plaques and atypical nodules respectively, later demonstrated to be rare cases of multicentric DFSPs. Both were known adenosine deaminase deficient-severe combined immunodeficiency patients (ADA-SCID), associated with multiple additional pathologies(Ochs et al. 2007). Patient A had been treated aged 6 months by undergoing bone marrow transplant (BMT) from an unrelated donor, but did not present with skin lesions until ∼11 years later, whereas Patient B was referred to our centre from another country for BMT and had lesions incidentally detected whilst temporarily in the UK. Histology for both patients demonstrated a paucicellular highly infiltrative spindle cell proliferation in the deep dermis and subcutis and CD34 positivity, consistent with DFSP. Patient A’s tissue was sent to the Northern Genetics Service and the COL1A1-PDGFB fusion gene was detected. Both patients were referred to plastic surgery for multiple excisions (A-3; B-10 lesions). Patient A has since had two further plastic surgery procedures for further or wider excisions. An association between DFSP and ADA-SCID has become more widely reported, though as is highlighted by our two very different cases little is known about timing of presentations, optimal treatment and prognosis.
P26 A life threatening case of Von Zumbusch psoriasis
Authors: Moura Juliana Graciani
Published: January 2024

We report a case of a patient admitted to intensive care with a pustulating skin eruption and haemodynamic compromise with near immediate response to infliximab.

A 16-year-old male with a six-month history of mild plaque psoriasis presented to acute dermatology services with widespread annular pustular eruption, which developed days after a throat infection.

Histopathology was consistent with pustular psoriasis. After an initial partial response, the pustules spread and persisted despite 2-month treatment with topical steroids and ciclosporin (dosed to 4 mg/kg).

With raised inflammatory markers and repeated growth of Staphylococcus aureus, high dose intravenous flucloxacillin was administered. Four hours post infusion the patient became erythrodermic and haemodynamically unstable, requiring management in ICU. Repeat skin biopsy showed features of psoriasis without clear drug reaction features.

Switching classes of antimicrobials and administration of intravenous immunoglobulins led to infection resolution but no significant clinical status change. A multi-disciplinary decision was made to trial intravenous infliximab. This resulted in near-immediate 90% improvement of skin and haemodynamic status. His excellent clinical response has been maintained on adalimumab thus far. Genetic screening for possible mutations associated with pustular psoriasis, including IL36RN and CARD14, are in process.
P28 Congenital Cellular Plexiform Schwannoma Masquerading as Infantile Haemangioma – A Case Report
Authors: Oyedepo Jadesola , Slater Olga , Solman Lea
Published: January 2024

Introduction

Schwannomas are tumours of the peripheral nerve sheath that rarely metastasize but are prone to recurrence. They sometimes occur in the context of syndromes such as neurofibromatosis type 2, Carney complex, and schwannomatosis. Congenital schwannomas appear as an erythematous patch that increases in size in the first few weeks and can be easily mistaken for infantile haemangioma (IH).

Case

A 3-month-old boy was referred to us for suspected IH on the dorsum of his right hand. At birth, he had a slightly erythematous patch but was rapidly increasing in size. Initial ultrasound done locally suggested it may be an IH based on the demonstration of arterial and venous flows. He was otherwise well, and there were no concerns about his growth or development. On examination, he had a firm mass, measuring 3 cm in diameter, that was not clinically in keeping with a vascular anomaly. Our repeated ultrasound showed a solid tumour, possibly fibrosarcoma or myofibroma. Biopsy confirmed cellular plexiform schwannoma and he underwent excision. The results of whole genome sequencing are pending (SMARC-1 and NF), and he remains under the care of the oncology team.

Conclusion

Clinicians assessing infants with “haemangiomas” have a difficult task of differentiating them from other soft tissue tumours. The clinical appearance of vascularity, along with high vascular flow seen on the imaging, cannot always rule out soft tissue tumours. Assessment of firmness can be somewhat subjective, but any vascular lesion that is very firm should be investigated further.
P31 Association of atopic dermatitis with thyroid diseases: a systematic review and meta-analysis
Authors: Chi Ching-Chi , Wang Tzu-Yu
Published: January 2024

Background

Atopic dermatitis (AD) and thyroid diseases have shared immune abnormalities, but their association was largely unclear.

Objective

To systematically examine the association of AD with thyroid diseases.

Methods

A systematic review was performed and the PubMed and Embase databases were searched on 26th August 2023. The risk of bias was assessed by using the Newcastle-Ottawa Scale. A random-effects model meta-analysis was performed and a subgroup analysis based on age groups was executed.

Results

The database searches yielded 205 records after removing duplicates. Nine case-controll studies with 5,367,891 subjects were included. The risk of bias of included was generally low to unclear. AD was significantly associated with thyroid diseases (pooled odds ratio (OR) 1.50, 95% confidence interval (CI) 1.23−1.85; studies = 6; I2 = 85%), which was present in both adults and children (pooled OR being 1.46 (95% CI 1.20−1.78; studies = 2; I2 = 63%) and 3.46 (95% CI 1.15−10.45; studies = 3; I2 = 63%). AD was also associated with Hashimoto disease (pooled OR 2.00, 95% CI 0.91−4.40, I2 = 95%; studies = 2) and Graves disease (pooled OR 2.21, 95% CI 0.59−8.31 I2 = 93%; studies = 2).

Conclusions

AD is associated with an increase of thyroid diseases. AD may be associated with Hashimoto and Graves diseases, but did not reach significance due to high statistical heterogeneity and paucity of evidence. Endocrinological consultation may be considered when AD patients present with thyroid symptoms.
P33 A lichenoid eruption and severe eczema in association with IMAGe syndrome
Authors: O’Connell Garret , Bennett Mary
Published: January 2024

IMAGe syndrome is a rare genetic disorder. IMAGe is an acronym for; (1)Intrauterine restricted growthMetaphyseal dysplasiaCongenital adrenal hypoplasiaGenitourinary abnormalities in males (cryptorchidism, micropenis, and hypospadias)

Diagnosis is established by molecular genetic testing with heterozygous CDKN1C pathogenic mutation or a proband with suggestive findings in the PCNA (proliferating cell nuclear antigen)- binding domain of the maternally expressed allele.

Additional features include characteristic facies (frontal bossing), developmental delay, immunodeficiency, osteoporosis and scoliosis.

Severe, early onset eczema has been described in association with this syndrome. (2)

We present the case of a 15-year-old boy with proven IMAGe syndrome, longstanding history of atopic dermatitis, and new onset lichenoid eruption on the forearms.
What's Hot This Year in Infectious Diseases Clinical Science
Authors: Freiberg Jeffrey A , Wright Patty W
Published: January 2024

The field of infectious diseases saw numerous exciting advances in 2023. Trials of new antibiotics and treatment regimens sought to address rising rates of antimicrobial resistance. Other studies focused on the most appropriate use of currently available treatments, balancing the dual goals of providing effective treatment and impactful antimicrobial stewardship. Improvements in disease prevention were made through trials of both new vaccines and new chemoprophylaxis approaches. Concerning trends this year included increasing rates of invasive group A streptococcal infections, medical tourism-associated cases of fungal meningitis, and the return of locally acquired malaria to the United States. This review covers some of these notable trials and clinical developments in infectious diseases in the past year.
SARS-CoV-2 Antiviral Prescribing Gaps Among Nonhospitalized High-Risk Adults
Authors: Levy Matthew E , Burrows Evanette , Chilunda Vanessa , Pawloski Pamala A , Heaton Phillip R , Grzymski Joseph , Goldman Jason D , McEwen Lisa M , Wyman Dana , Dei Rossi Andrew , Dai Hang , Isaksson Magnus , Washington Nicole L , Basler Tracy , Tsan Kevin , Nguyen Jason , Ramirez Jimmy , Sandoval Efren , Lee William , Lu James , Luo Shishi
Published: January 2024

Within a multistate clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022–June 2023 among nonhospitalized patients with SARS-CoV-2 with risk factors for severe COVID-19. Among 3247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers.
Omega-3 fatty acids for cardiovascular event lowering
Authors: Kaur Gurleen , Mason R Preston , Steg Ph Gabriel , Bhatt Deepak L
Published: January 2024

Low-density lipoprotein cholesterol (LDL-C) is the main target for therapeutics aimed at reducing the risk of atherosclerotic cardiovascular disease (ASCVD) and downstream cardiovascular (CV) events. However, multiple studies have demonstrated that high-risk patient populations harbour residual risk despite effective LDL-C lowering. While data support the causal relationship between triglycerides and ASCVD risk, triglyceride-lowering therapies such as omega-3 fatty acids have shown mixed results in CV outcomes trials. Notably, icosapent ethyl, a purified formulation of eicosapentaenoic acid (EPA), has garnered compelling evidence in lowering residual CV risk in patients with hypertriglyceridaemia and treated with statins. In this review, we summarize studies that have investigated omega-3-fatty acids for CV event lowering and discuss the clinical implementation of these agents based on trial data and guidelines.
Dissecting the complex genetic basis of pre- and post-harvest traits in Vitis vinifera L. using genome-wide association studies
Authors: García-Abadillo Julian , Barba Paola , Carvalho Tiago , Sosa-Zuñiga Viviana , Lozano Roberto , Carvalho Humberto Fanelli , Garcia-Rojas Miguel , Salazar Erika , y Sánchez Julio Isidro
Published: January 2024

Addressing the pressing challenges in agriculture necessitates swift advancements in breeding programs, particularly for perennial crops like grapevines. Moving beyond the traditional biparental quantitative trait loci (QTL) mapping, we conducted a genome-wide association study (GWAS) encompassing 588 Vitis vinifera L. cultivars from a Chilean breeding program, spanning three seasons and testing 13 key yield-related traits. A strong candidate gene, Vitvi11g000454, located on chromosome 11 and related to plant response to biotic and abiotic stresses through jasmonic acid signaling, was associated with berry width and holds potential for enhancing berry size in grape breeding. We also mapped novel QTL associated with post-harvest traits across chromosomes 2, 4, 9, 11, 15, 18, and 19, broadening our grasp on the genetic intricacies dictating fruit post-harvest behavior, including decay, shriveling, and weight loss. Leveraging gene ontology annotations, we drew parallels between traits and scrutinized candidate genes, laying a robust groundwork for future trait-feature identification endeavors in plant breeding. We also highlighted the importance of carefully considering the choice of the response variable in GWAS analyses, as the use of best linear unbiased estimators (BLUEs) corrections in our study may have led to the suppression of some common QTL in grapevine traits. Our results underscore the imperative of pioneering non-destructive evaluation techniques for long-term conservation traits, offering grape breeders and cultivators insights to improve post-harvest table grape quality and minimize waste.
Divergent Acute and Enduring Changes in 50-kHz Ultrasonic Vocalizations in Rats Repeatedly Treated With Amphetamine and Dopaminergic Antagonists: New Insights on the Role of Dopamine in Calling Behavior
Authors: Serra Marcello , Costa Giulia , Onaivi Emmanuel , Simola Nicola
Published: January 2024

Background

Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to nonpharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants.

Methods

We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.) either alone or together with (1) SCH 23390 (0.1–1 mg/kg, s.c.), a dopamine D1 receptor antagonist; (2) raclopride (0.3–1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist; or (3) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation).

Results

Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors.

Conclusions

These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs.
Mapping as a Critical Making Practice in International Relations
Authors: Ragazzi Francesco
Published: January 2024

How “critical” is mapping as a method in international relations (IR)? Critical approaches have fundamentally changed the practices of mapmaking in IR. They have replaced geopolitical representations of a world divided into territorial states with notions of fields, networks, flows, rhizomes, and assemblages. This shift is both conceptual and methodological: It has led to the introduction of new methods of representation, such as multiple correspondence analysis and network analysis. These new methods have, however, been subjected to a strong critique. They are accused of reproducing the very logics of power that they aim to question, and flatten the knowledge they aim to represent. There would be, as the argument goes, an inescapable theoretical and political bias embedded in these methods. This article engages with this debate, which is ultimately about the ontological and epistemological status of mathematical methods of visual representation and, more broadly, about the role of “making” in IR. It argues that practices of mapmaking can still be designed to function as critical tools. To illustrate this argument, this article draws on ongoing research on biometric mass surveillance as part of the Security Vision project.
O03 Phenotypic antimicrobial resistance to last-resort antibiotics in carbapenemase-producing bacteria from Ukrainian patients
Authors: Verkaik Nelianne J , Wielders Cornelia C H , den Boer Hans , Langerak Diana , Vogel Marius , Witteveen Sandra , de Haan Angela , Bos Jeroen , van Westreenen Mireille , Notermans Daan W , Hendrickx Antoni P A
Published: January 2024

Background

Since March 2022, there has been an emergence of MDR microorganisms (MDRO) in Europe because of an increasing number of Ukrainian patients with MDRO. The goal was to collect large-scale phenotypic susceptibility data to assess implications for clinical practice.

Methods

For 122 MDRO (carbapenemase-producing Enterobacterales (CPE, n=96), Pseudomonas aeruginosa CPPA (n=20), carbapenem-resistant Acinetobacter baumannii-calcoaceticus (CRAB, n=6), collected from March to December 2022, broth microdilution (BMD), fosfomycin agar dilution, gradient strip ampicillin/sulbactam, sulbactam/durlobactam, ceftazidime-avibactam-aztreonam and disc diffusion (DD) cefiderocol was performed. Epidemiological data was obtained as part of mandatory reporting by Municipal Health Services (CPE), and surveillance questionnaires (CPPA/CRAB).

Results

Admission at a Ukrainian hospital in the last year was a risk factor for acquiring MDRO. Of all isolates, 65% (79/122) were blaNDM-positive. For meropenem, aminoglycosides, ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam susceptibility rates were low (0-30%). For cefiderocol, results depended on reading with or without microcolonies, applying EUCAST or CLSI breakpoints, and whether DD or BMD was used: e.g. for Klebsiella pneumoniae, 30%–97% were susceptible, depending on these variables. For colistin, 103/111 (93%) non-intrinsically resistant CPE/CPPA/CRAB isolates were susceptible. For the majority of CPE, a low MIC of <0.5 mg/L was measured for tigecycline and ceftazidime-avibactam-aztreonam. For CPPA, cefiderocol tested susceptible in 65%–100% of isolates. For CRAB, ampicillin/sulbactam MICs were ≥128 mg/L, for sulbactam/durlobactam 1–2 mg/L.

Conclusions

There is extensive phenotypic resistance to last-resort antibiotics in carbapenemase-producing bacteria from Ukrainian patients. For cefiderocol, interpretation of susceptibility results depends on a number of variables. In case of infection, treatment options are colistin, cefiderocol (CPE/CPPA/CRAB), tigecycline (CPE/CRAB), ceftazidime-avibactam-aztreonam (CPE), sulbactam/durlobactam (CRAB).
P05 Identifying novel drug targets of the ESKAPE pathogen Pseudomonas aeruginosa
Authors: Scott Ben , Wilkinson Barrie
Published: January 2024

The Gram-negative ESKAPE pathogen Pseudomonas aeruginosa is currently listed top of the priority one pathogens by the WHO that require urgent research and development of new antimicrobials. Currently, microbiologists and clinicians face an ever-growing challenge in treating MDR bacterial infections, for this, and other pathogens, using conventional antibiotics. With a limited number of antibiotics currently in clinical trials and a general stagnation in the discovery of promising antimicrobials, new drug targets are desperately needed, and recent investigations include targeting bacterial virulence factors. Targeting bacterial virulence factors should reduce the pathogenesis of an organism, slow its infection progression and prevent vital virulence processes such as biofilm formation as well as potentially increasing a strain’s susceptibility to antibiotics. However, given the incredible diversity of bacteria, virulence mechanisms vary massively, meaning that identifying a broad-spectrum virulence target presents a major challenge. This important point has brought researchers to a fascinating group of enzymes that are ubiquitous in nature, and possess a plethora of biological roles, including acting as virulence factors. The macrophage infectivity potentiators (Mips) belong to the ubiquitous FK506 binding protein (FKBPs) family of peptidyl-prolyl cis/trans isomerases (PPIases). FKBPs are found in all bacteria serving as general house-keeping proteins involved in protein folding and chaperoning. However, a small subset has been identified as virulence proteins. Mips have been characterized in several Gram-negative pathogens including Legionella pneumophila and Burkholderia pseudomallei and were shown to be essential for invasion of macrophages, both in vitro and in murine-infection models, and for other virulence determinants. Pseudomonas aeruginosa also possess three Mip virulence factors, PaMip1, PaMip2 and PaMip3, which are required for the full virulence of P. aeruginosa in in vivo and ex vivo models. Virulence can be addressed in a pharmacological manner using bacterial natural products.
P07 Antimicrobial stewardship in Ireland 2009–22: a scoping review
Authors: Barry Fiona , Smiddy Maura , Fitzgerald Tony , O’Reilly Eilis J , Murphy Olive
Published: January 2024

Objectives

The aim of this scoping review is to examine the current literature to evaluate progress related to the implementation of the Strategy for the Control of Antimicrobial Resistance in Ireland (SARI) Hospital Antimicrobial Stewardship (AMS) Working Group guidance (2009) on antimicrobial stewardship in hospitals in Ireland.

Methods

Systematic searches were carried out on four electronic databases (PubMed, CINAHL, Embase, Web of Science) and five targeted websites for grey literature sources. Titles and abstracts were screened independently by two reviewers. The remaining full-text publications were reviewed by all authors. Studies were mapped into at least one of four categories defined by recommendation headings from the SARI Hospital Antimicrobial Stewardship Working Group guidance: (A) structure and organization of AMS; (B) roles and responsibilities for prescribers; (C) antimicrobial stewardship interventions; (D) recommendations for non-acute residential healthcare institutions.

Results

The search yielded 545 peer reviewed papers for screening of which 35 were included and 327 grey reports of which 26 were included. Most articles were mapped to (C) antimicrobial stewardship interventions, with the least number mapped to (A) structure and organization of AMS. The most consistent findings in (C) were numerous implementation challenges requiring commitment by hospital leadership to provide human and financial resources, need for improved diagnostic capacity, and educational pathways for prescribers, pharmacists, nurses and patients. The findings in (A) included inadequate staffing across hospitals to implement stewardship programmes (regardless of hospital acuity) and investment required for information and communication technology resources to further support AMS and infection prevention and control.

Conclusions

There has been progress on AMS over the last 20 years and implementation remains a significant challenge. Clear identification of AMS programme management, use of data, education and communication need to be considered for the success of future implementation in all healthcare settings.
P14 Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam Real-world Analysis (SPECTRA): results from a multinational, multicentre observational study
Authors: Soriano Alejandro , Puzniak Laura , Paterson David L , Thalhalmmer Florian , Kluge Stefan , Viale Pierluigi , Watanabe Alexandre H , Obi Engels N , Kaul Sunny
Published: January 2024

Background

Ceftolozane/tazobactam (C/T) has demonstrated efficacy to treat complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and hospital acquired bacterial and ventilator-associated bacterial pneumonia. However, physicians, providers, and other stakeholders including payers want broader real-world evidence to inform clinical decisions and optimize healthcare resource use.

Methods

SPECTRA is a multinational, multicentre, retrospective, inpatient, observational study of patients treated with C/T in Australia, Austria, Germany, Italy, Mexico, Spain and the UK. Adult inpatients treated with ≥48 h of C/T were included. Demographics, clinical characteristics, treatment management patterns, and outcomes were analysed.

Results

There were 687 patients from 38 participating hospitals in 7 countries. The average age was 57.6 years (SD ±17.3), and most were male (456, 66.4%). The majority had at least one comorbidity (563, 82.0%), with the most common being heart disease (208, 30.3%), immunocompromised state (207, 30.1%) and chronic pulmonary disease (195, 28.4%). The most common indications were pneumonia (204, 29.7%), sepsis (147, 21.4%) and cIAI (106, 15.4%); 162 (23.6%) had multiple sites of infection and 245 (35.7%) were polymicrobial infections. Median C/T treatment was 12.0 days (IQR 11.0). Half of the patients were admitted to the ICU (343, 49.9%), 43.4% of which was related to the infection. Clinical success was 66.1%. All-cause in-hospital mortality was 22.0% with 8.7% being infection related. The 30 day all-cause readmission was 9.8% and 4.7% were infection related.

Conclusions

C/T was used to treat infections among critically ill patients and for multi-source, polymicrobial infections. Despite the complexity of the patients in this real-world analysis, most C/T patients had beneficial outcomes that are similar to results of controlled clinical trials.
P20 Clinical metagenomics from cell-free DNA: overview and lessons learned from 4 years as a clinical metagenomics provider
Authors: Klaften Matthias , Neder Ulrike , Becher Johannes , Holzem Rafael , Clanzett Sebastian , Mazzitelli Sonia , Hennig René , Gil-Farina Irene , Unsleber Sandra , Grumaz Silke
Published: January 2024

Background

Clinical metagenomics emerges more and more from academic research to clinical practice. Here, we share an overview of the field of clinical metagenomics on cell-free DNA found in the blood of patients with severe infections and share a few learning points regarding the implementation as a routine lab service and CE-IVD marked software running in the cloud.

Methods

We use next-generation sequencing of cell-free DNA to digitally determine relevant pathogens from patients with systemic infections in blood and other bodily fluids using our CE-IVD marked DISQVER diagnostic platform. Until now we have collected microbial data from several thousand samples within 4 years of routine service.

Results

The set up of the DISQVER test is within the regulatory framework of CE-IVD marking of software as a service (SaaS) and ISO 13485 accreditation. This brings practical implications on database quality, software lock-in/development/testing, change and risk management, technical documentation, requiring substantial resources. Also the wetlab process runs within tightly defined and controlled QM boundaries, pre-set by extensive analytical validations. We clinically validated our test for pathogen identification from blood within 8 clinical trials for intensive care medicine, haematology and coinfection in COVID-19, showing 2- to 3-fold higher identification rates for pathogens in comparison to standard of care blood culture. Furthermore, several case reports/ case series from different clinical backgrounds, frequently with difficult to diagnose pathogens, have been published. From the analysis of our routine processes with several thousand samples, we could show that the turn-around time of our mNGS process is very fast and can detect more species than blood culture. In particular, the relatively high proportion of fungi and dsDNA viruses indicates superiority of the method compared with the standard diagnostic pathway.

Conclusions

To bridge the gap between academic research and clinical implementation, many aspects of regulatory, technical and data protection requirements need to be addressed. Within the timeframe of commercial availability DISQVER from cell-free DNA found in the blood of infected patients is increasingly becoming a useful tool for infection diagnostics.
Long-Read DNA and RNA Sequencing to Streamline Clinical Genetic Testing and Reduce Barriers to Comprehensive Genetic Testing
Authors: Damaraju Nikhita , Miller Angela L , Miller Danny E
Published: January 2024

Background

Obtaining a precise molecular diagnosis through clinical genetic testing provides information about disease prognosis or progression, allows accurate counseling about recurrence risk, and empowers individuals to benefit from precision therapies or take part in N-of-1 trials. Unfortunately, more than half of individuals with a suspected Mendelian condition remain undiagnosed after a comprehensive clinical evaluation, and the results of any individual clinical genetic test ordered during a typical evaluation may take weeks or months to return. Furthermore, commonly used technologies, such as short-read sequencing, are limited in the types of disease-causing variation they can identify. New technologies, such as long-read sequencing (LRS), are poised to solve these problems.

Content

Recent technical advances have improved accuracy, increased throughput, and decreased the costs of commercially available LRS technologies. This has resolved many historical concerns about the use of LRS in the clinical environment and opened the door to widespread clinical adoption of LRS. Here, we review LRS technology, how it has been used in the research setting to clarify complex variants or identify disease-causing variation missed by prior clinical testing, and how it may be used clinically in the near future.

LRS is unique in that, as a single data source, it has the potential to replace nearly every other clinical genetic test offered today. When analyzed in a stepwise fashion, LRS will simplify laboratory processes, reduce barriers to comprehensive genetic testing, increase the rate of genetic diagnoses, and shorten the amount of time required to make a molecular diagnosis.
Aging effects on osteoclast progenitor dynamics affect variability in bone turnover via feedback regulation
Authors: Kim Young Kwan , Kameo Yoshitaka , Tanaka Sakae , Adachi Taiji
Published: January 2024

Bone turnover markers (BTMs) are commonly used in osteoporosis treatment as indicators of cell activities of bone-resorbing osteoclasts and bone-forming osteoblasts. The wide variability in their values due to multiple factors, such as aging and diseases, makes it difficult for physicians to utilize them for clinical decision-making. The progenitors of osteoclasts and osteoblasts are indispensable for a comprehensive interpretation of the variability in BTM values because these upstream progenitors strongly regulate the downstream cell activities of bone turnover. However, understanding the complex interactions among the multiple populations of bone cells is challenging. In this study, we aimed to gain a fundamental understanding of the mechanism by which the progenitor dynamics affect the variability in bone turnover through in silico experiments by exploring the cell dynamics with aging effects on osteoporosis. Negative feedback control driven by the consumptive loss of progenitors prevents rapid bone loss due to excessive bone turnover, and through feedback regulation, aging effects on osteoclast differentiation and osteoclast progenitor proliferation cause variability in the osteoclast and osteoblast activity balance and its temporal transition. By expressing the variability in the bone turnover status, our model describes the individualities of patients based on their clinical backgrounds. Therefore, our model could play a powerful role in assisting tailored treatment and has the potential to resolve the various health problems associated with osteoporosis worldwide.
The Nature and Purpose of Public Dissections in Early Modern London
Authors: Murel Jacob
Published: January 2024

Modern scholarship on the early modern European anatomy theater has long argued that public dissections were theatrical, carnivalesque affairs characterized by viewers’ fascination with the material exposure of the dissected body. This essay builds from the recent work on early modern public dissections to argue against such monolithic presentations of the early modern anatomy. To this end, the essay examines three principal source materials connected with public dissections in early modern London to more specifically argue that public dissections in sixteenth- and seventeenth-century London were solemn events focused on promoting the status of London’s barber-surgeons’ guild, the Royal College of Physicians, and the education and knowledge of their respective members. In this regard, the essay further suggests that there was no single, dominant perception of dissection and anatomy at the time, but that dissection was utilized as a tool for different individual, occupational, and institutional purposes.
Allelic reprogramming of chromatin states in human early embryos
Authors: Yuan Shenli , Gao Lei , Tao Wenrong , Zhan Jianhong , Lu Gang , Zhang Jingye , Zhang Chuanxin , Yi Lizhi , Liu Zhenbo , Hou Zhenzhen , Dai Min , Zhao Han , Chen Zi-Jiang , Liu Jiang , Wu Keliang
Published: January 2024

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here, we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse embryos. The allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early embryos. Collectively, allele-specific epigenomic reprogramming is different in humans and mice.
First-in-Human Phase I Study of Minnelide in Patients With Advanced Gastrointestinal Cancers: Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity
Authors: Borazanci Erkut , Saluja Ashok , Gockerman Jon , Velagapudi Mohana , Korn Ronald , Von Hoff Daniel , Greeno Ed
Published: January 2024

Background

Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D).

Patients and Methods

Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity.

Results

Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients.

Conclusions

This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway.
Aberrant Lipid Metabolic Signatures in Acute Myeloid Leukemia
Authors: Singh Pooja , Murali Roopak , Shanmugam Sri Gayathri , Thomas Steve , Scott Julius , Warrier Sudha , Arfuso Frank , Dharmarajan Arun , Gandhirajan Rajesh Kumar
Published: January 2024

Leukemogenesis is a complex process that involves multiple stages of mutation in either hematopoietic stem or progenitor cells, leading to cancer development over time. Acute myeloid leukemia (AML) is an aggressive malignancy that affects myeloid cells. The major disease burden is caused by immature blast cells, which are eliminated using conventional chemotherapies. Unfortunately, relapse is a leading cause of death in AML patients, with 30%-80% experiencing it within 2 years of initial treatment. The dominant cause of relapse in leukemia is the presence of therapy-resistant leukemic stem cells (LSCs). These cells express genes related to stemness that are frequently difficult to eradicate and tend to survive standard treatments. Studies have demonstrated that by targeting the metabolic pathways of LSCs, it is possible to improve outcomes and extend the survival of those afflicted by leukemia. The overwhelming evidence suggests that lipid metabolism is reprogrammed in LSCs, leading to an increase in fatty acid uptake and de novo lipogenesis. Genes regulating this process also play a crucial role in therapy evasion. In this concise review, we summarize the lipid metabolism in normal hematopoietic cells, AML blast cells, and AML LSCs. We also compare the lipid metabolic signatures in de novo versus therapy-resistant AML blast and LSCs. We further discuss the metabolic switches, cellular crosstalk, potential targets, and inhibitors of lipid metabolism that could alleviate treatment resistance and relapse.
Multisystem Inflammatory Syndrome in Children during the COVID-19 Pandemic: A Review of Clinical Manifestations, Cardiac Complications and Medical Management
Authors: Pandit Maya , Frishman William H.
Published: January 2024

The SARS-CoV-2 pandemic has led to widespread research on associated clinical syndromes. While pediatric patients were initially deemed as a low-risk population for severe COVID-related disease, an increasing number of case reports have revealed a rare but potentially life-threatening syndrome, multisystem inflammatory syndrome in children (MIS-C). MIS-C is hypothesized to be due to hyperactivation of the immune system via a cytokine storm which leads to end-organ damage via endothelial dysfunction and changes in vascular permeability. Laboratory studies have displayed increased inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate, D-dimer, tumor necrosis factor-alpha, and various interleukins. Studies have reported a wide range of clinical manifestations, including but not limited to fever, hypotension, shock, rash, coagulopathy, and gastrointestinal distress. Cardiac imaging and screening tests have revealed several complications, such as left ventricular failure, arrhythmias, and pericardial effusions. Medical management of MIS-C and cardiac sequelae have included supportive care, intravenous immunoglobulins, and corticosteroids, as well as immunomodulators, monoclonal antibodies, aspirin, and therapeutic anticoagulation, which have prevented serious outcomes in the majority of pediatric patients. Future multicenter and large-scale research is required for precise risk-stratification of MIS-C as well as long-term monitoring of sequelae. In this review, we aim to (1) outline the laboratory findings and clinical manifestations of MIS-C, and (2) describe cardiac complications and medical management of MIS-C.
Can the gut microbiome inform the effects of omega-3 fatty acid supplementation trials on cognition?
Authors: Kerman Bilal E. , Self Wade , Yassine Hussein N.
Published: January 2024

Purpose of review

Most omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation clinical trials report inconsistent or null findings on measures of cognition or Alzheimer's disease (AD) with a relatively large variability in the response to n-3 PUFA supplementation. The purpose of this review is to identify whether the gut microbiome together with the metabolome can provide critical insights to understand this heterogeneity in the response to n-3 PUFA supplementation.

Recent findings

A Western diet with high saturated fat and omega-6 fatty acid content, obesity, and lack of exercise puts strain on the gut microbiome resulting in imbalance, dysbiosis, reduced bacterial diversity, and increased abundance of the pro-inflammatory taxa. A plant-based diet has beneficial effects on the gut microbiota even when deficient in n-3 PUFAs. Human and animal studies show that increased intake of the n-3 PUFAs correlates with increased beneficial intestinal bacteria when compared to a Western diet.

The composition of the gut microbiota can help define the effects of n-3 PUFA supplementation on the brain and lead to more personalized nutritional interventions.
Tick-borne infections in children in North America
Authors: Taylor-Salmon Emma , Shapiro Eugene D.
Published: January 2024

Purpose of review

Because both incidence and awareness of tick-borne infections is increasing, review of major infections and recent advances related to their diagnosis and management is important.

Recent findings

A new algorithm, termed modified two-tier testing, for testing for antibodies to Borrelia burgdorferi, the cause of Lyme disease, has been approved and may replace traditional two-tier testing. In addition, doxycycline is now acceptable to use for treatment of and/or prophylaxis for Lyme disease for up to 21 days in children of any age. Borrelia miyamotoi, a bacterium in the relapsing fever type of Borrelia, is the first of this type of Borrelia that is transmitted by hard-bodied ticks such as Ixodes scapularis.

Awareness of these infections and advances in their diagnosis and treatment is important to assure the best outcomes for affected patients. Table 1 contains a summary of infections discussed.
Investigation of the effects of thymoquinone (TQ) and polyvinylpyrrolidone (PVP) on the motility, viability, and chromatin status of sperm in normozoospermic semen samples
Authors: Khosravi Tayebeh , Vahid Dastjerdi Amir Reza , Eftekhari Sayed Amin , Golshan Iranpour Farhad
Published: January 2024

Objective:

Adverse effects of polyvinylpyrrolidone (PVP) on sperm membrane and chromatin have been proven in many studies. Among the natural products proposed as an alternative for PVP, thymoquinone (TQ)-a major constituent of Nigella sativa plant- has been suggested as a potential natural spermostasis. Therefore, this study aimed to compare the effects of TQ with PVP for sperms motility, survival, DNA denaturation, and DNA fragmentation in normozoospermic men (men with a normal or healthy sperm profile).

Methods:

An experimental trial was carried out on 30 normozoospermic men of the Andrology Unit of (Shahid Beheshti Hospital, Isfahan, Iran). Each washed semen samples were divided into four fractions and was randomly treated with TQ (50 μg/ml), %5 PVP, and %10 PVP (M/V) which was compared to untreated fraction (control).

Results:

There was a significant difference between the four groups in terms of motility, viability, DNA denaturation, and fragmentation (P <0.05). TQ caused sperm immobility, while 5% PVP and 10% PVP decreased (98 and 99%, respectively) sperm motility compared to control. TQ did not affect sperm viability compared to the control group, but PVP decreased it. Besides, TQ did not affect DNA denaturation and fragmentation, but PVP increased it.

Conclusion:

TQ could be used as an alternative natural spermostasis with less adverse effects rather than PVP which causes more efficient immobilization and isolation of individual sperm cells.
Primary hepatic angiosarcoma: a systematic review
Authors: Rojas Santiago , Rey Chaves Carlos Eduardo , Robledo Sofía , Conde Danny , Sabogal Olarte Juan Carlos
Published: January 2024

Background:

Hepatic angiosarcoma is a rare type of tumour. In adults, the diagnosis remains challenging as the clinical manifestations are generally nonspecific and are usually made too late when complications or metastases are already present, associated with a poor prognosis. Due to the lack of agreement regarding the optimal treatment approach, a comprehensive analysis of the evidence in the literature on the surgical and survival outcomes in terms of disease-free survival time (DFS) and overall survival (OS) for patients treated for primary hepatic angiosarcoma is needed.

Study design:

A systematic review of articles published in Pubmed, EMBASE, and Scopus, from 2000 to 2023 with the search terms hepatic angiosarcoma and liver resection or hepatectomy. Pooled individual data concerning the prognosis following various therapies was analyzed.

Results:

A total of 15 articles involving 886 patients were eligible for inclusion. The male population represents 66.2% (n=586) of the population, with a median age of 57 years (41–66). The median survival rate was 7 months. The median OS after surgical resection was 17.18 months (SD 12.6) vs. 3.72 months (SD 4.6) for patients treated without a surgical approach. The median DFS was 15.2 months (SD 11).

Conclusion:

Primary liver angiosarcoma remains a surgical challenge with a poor prognosis even with complete surgical resection and adjuvant therapy. Surgical management shows increased overall survival in comparison with non-surgical management. Early diagnosis could change the natural history of the disease. The literature available is scarce, and further studies are required to create standardized diagnostic and treatment protocols.
Effects of online education on prosthetics orthotics education during COVID-19
Authors: Uysal Halil Hakan , Yildirim Sahan Tezel , Keklicek Hilal , Anaforoglu Kulunkoglu Bahar
Published: January 2024

Background:

It is obvious that educational activities were affected globally due to the pandemic.

Objective:

This study was planned to examine the effects of online education on undergraduate degree (UD) and associate degree (AD) Orthotics and Prosthesis education in the COVID-19 pandemic.

Study Design:

A crossectional online survey.

Method:

The Google Forms questionnaire was delivered to students of Orthotics and Prosthesis in the level of undergraduate degree and AD and academicians conducted in the study. Next, the participants were reviewed regarding their knowledge about devices used for online education and related technical problems. A 5-point Likert-type questionnaire with 18 questions that was developed specifically for this study was applied to examine their views on online education.

Results:

The study included 472 participants who had a mean age of 21.30 ± 0.22 years. Among the participants, 262 were AD students (55.5%). Approximately 82% of the participants were used their mobile phones for connection. The connection problems, and inappropriateness of online education in applied course, preference of online education for theoretical courses, insufficiency of digital course materials, failure to access education easily, insufficiency of online examinations for measurement and evaluation, and preference of homework over online education were stated by 79%, 88.3%, 41.9%, 54.5%, 70.1%, 41.7%, and 42.8% of the participants, respectively.

Conclusion:

Both academicians and students experienced connection problems, and applied courses were not suitable for online education. Motivation to attend the courses was low in online education, relevant workload increased, online examinations were not sufficient for measurement and evaluation, and studies were more unplanned. It is necessary to switch to formal education after the pandemic.