SDRC is implicated in the pathogenesis of Staphylococcus aureus osteomyelitis. However, the precise mechanism by which SDRC contributes to the progression of this infection remains unclear. To explore SDRC’s role in osteomyelitis, experiments were conducted on mouse models infected with Staphylococcus aureus strains containing either the wild type SDRC sequence or a knockout (KO-SDRC) sequence. Levels of inflammatory factors like IL-6 and TNF-α were measured using Elisa. Furthermore, changes in osteogenic indicators such as ALP, OST, and Runx2 were detected using qPCR and Western blot analysis. Additionally, transcriptome sequencing was employed to gain deeper insights into the potential molecular mechanisms underlying SDRC’s promotion of Staphylococcus aureus-induced osteomyelitis. The study revealed that the ability of Staphylococcus aureus to form biofilms was significantly weakened in strains where the SDRC protein was knocked out. Moreover, mice infected with the KO-SDRC strain exhibited enhanced ossification processes. Transcriptome sequencing demonstrated significant overexpression of the Myh7 gene in the SDRC knockout osteomyelitis mouse. Subsequent knockout of the Myh7 gene led to notable reductions in mRNA and protein expressions of osteogenic indicators including Runx2, ALP, OSX, and Osteocalcin. Overall, these findings suggest that SDRC plays a crucial role in promoting the malignant progression of osteomyelitis caused by Staphylococcus aureus. Its main mechanism involves enhancing the formation of Staphylococcus aureus biofilms. Conversely, Myh7 may exert an inhibitory effect on the SDRC protein, reducing biofilm formation and mitigating the severity of osteomyelitis. These findings offer novel insights into potential therapeutic targets for the treatment of osteomyelitis.

Introduction: The efficacy and safety of fibroblast growth factor 21 (FGF21) analogs in patients with nonalcoholic steatohepatitis (NASH) remains unclear. Therefore, we aimed to compare the use of FGF21 analogs with placebo in patients with NASH. Methods: We searched Medline, Embase, and Cochrane databases from inception to December 2023. The primary outcomes were: triglycerides levels, high-density lipoprotein (HDL) levels, low-density lipoprotein (LDL) levels, NASH resolution, N-terminal type III collagen propeptide (PRO-C3) levels, and adverse events. Subgroup analyses were performed according to drug dosages. We used Review Manager 5.4 to pool the data, assessing heterogeneity with I2. Results: Eight studies reporting data of 967 patients were included in this review. Follow-up ranged from 16 to 121 weeks and dosage ranged from 3 to 70mg a day. When compared to placebo, FGF21 analogs were significantly associated with a reduction in triglycerides (MD -22.07; 95% CI -36.67 to -7.47) and PRO-C3 (MD -6.12; 95% CI -8.05 to -4.20). There were no significant differences in the resolution of NASH (RR 3.57; 95% CI 0.91 to 13.94). Higher rates of adverse events (RR 1.08; 95% CI 1.01 to 1.14) were observed in patients who received the intervention. Conclusion: Despite a higher incidence of adverse events for FGF21 analogs, they showed positive effects on the lipid profile and biomarker for the formation of fibrotic tissue. However, no improvement in NASH resolution was observed. Keywords: FGF21 analog; pegozafermin; efruxifermin; pegbelfermin; fibrosis; NASH.

Modern machine learning methods, and their use alongside established paradigms such as Quality by Design, have the potential to fundamentally change the way bioprocesses are developed. In particular, horizontal knowledge transfer methods, which seek to exploit data from historical processes to facilitate process development for a new product, provide an opportunity to rethink process development workflows. In this work, we firstly assess the potential of two knowledge transfer approaches, meta learning and one-hot encoding, in combination with Gaussian process (GP) models. We compare their performance to GPs developed only on data of the new process. Using simulated mammalian cell cultivation data, we observe that both knowledge transfer approaches outperform the individual-product approach. In the second part, we address the question whether experiments for a new product could be designed more effectively by exploiting existing knowledge. In particular, we suggest to specifically design few runs for the novel product to calibrate knowledge transfer models, a task that we coin calibration design. We propose a novel, customised metric to identify a set of calibration design runs, which exploits differences in process evolutions of historical products. In two simulated case studies, we observed that training with calibration designs yields similar test set errors compared to common approaches of Design of Experiments. However, much fewer experiments are needed for the former, suggesting an interesting alternative for future bioprocess development. Overall, the results suggest that process development could be significantly streamlined when systematically carrying knowledge from one product to the next.

Mesophyll conductance ( g m ) describes the efficiency with which CO 2 moves from substomatal cavities to chloroplasts. Despite the stipulated importance of leaf architecture in affecting g m , there remains a considerable ambiguity about how and whether anatomy influences g m . This is, in part, because studies exploring the relationship between leaf architecture and g m have often relied on simple linear or exponential models to identify correlations. Here, we employed non-linear machine learning models to more comprehensively assess the relationship between ten leaf architecture traits and g m . These models achieved excellent predictability of g m , which depended on the leaf architecture traits considered as predictors. Dissection of the importance of leaf architecture traits in the models indicated that cell wall thickness and chloroplast area exposed to internal airspace have a large impact on interspecific variation in g m . Additionally, other leaf architecture traits, such as: leaf thickness, leaf density, and chloroplast thickness emerged as important predictors of g m . We found significant differences in the predictability between models trained on different plant functional types (PFTs): those trained on woody species could predict g m by anatomical traits on other woody PFTs, ferns, and C 3 herbaceous plants, whereas the converse did not hold in general. By moving beyond simple linear and exponential models, our analyses demonstrated that a larger suite of leaf architecture traits drive differences in g m than has been previously acknowledged. These findings pave the way for modulating g m by strategies that modify its leaf architecture determinants.

Title: Radical Total Pelvic Exenteration with Concomitant Right Nephrectomy in the Management of Recurrent Endometrioid Ovarian Adenocarcinoma: A Case Report and Literature ReviewAuthors: Raghavskandhan Ramachandran1, Sabina Nistor2, William Gietzmann3, Nicholas Symons4, Hooman Soleymani Majd2, 5Word Count: 2220Authors:Medical Sciences Division, University of Oxford, Oxford, United KingdomDepartment of Gynaecology Oncology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomDepartment of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomDepartment of Colorectal Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomNuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United KingdomCorresponding Author Details:Hooman Soleymani Majd, MDAddress: Department of Gynaecology Oncology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Rd, Headington, Oxford, United Kingdom, OX3 7LETelephone: 07958285604Email: hooman.soleymanimajd@msd.ox.ac.ukORCID: 0000-0003-3293-5321There are no conflicts of interest.No funding was received for this case report.The patient has given consent for the writing of this case report and the inclusion of surgical images.

Physiological stress parameters have the potential to serve as valuable early warning indicators for the conservation of animal populations. However, measuring stress in wildlife is often challenging, due to the lack of knowledge about baseline levels, and intrinsic differences between individuals across species. This study is aimed at filling this gap by investigating the influence of intrinsic factors, including sex, age, body condition, and reproductive status on the physiological stress of a forest bird community. For measuring stress levels, we used the heterophil to lymphocyte (H/L) ratio of the bird community which was assessed using a novel deep learning approach based on Convolutional Neural Networks applied to whole blood smear scans. Using phylogenetically controlled analyses across the bird species, we found higher H/L ratios in adult birds than in juveniles and observed higher stress levels in females than in males. While body condition had no effect on the H/L ratio, reproductive birds tended to have higher H/L ratios than non-reproductive birds, regardless of their sex. Furthermore, we found a robust phylogenetic signal of the H/L ratio in the studied bird community. Our results emphasize the importance of considering intrinsic factors when using stress physiology for assessing the condition of bird populations and communities.

Aim: The management of type 2 diabetes patients poses challenges for non-diabetologists healthcare professionals and may result in potentially inappropriate prescriptions of antidiabetic drugs which can be limited using screening tools. The aim was to set up nominal groups of healthcare professionals from several disciplines and develop a list of explicit definition of potentially inappropriate prescriptions of antidiabetic drugs. Methods: In a qualitative, nominal-groups approach, expert diabetologists, general practitioners, and pharmacists in France developed explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs in patients with type 2 diabetes. The study was overseen by a steering committee and complied with the Consolidated Criteria for Reporting Qualitative Research. Results: Three nominal groups comprised a total of 30 participants (14 pharmacists, 10 diabetologists, and 6 general practitioners) and generated 89 explicit definitions. These definitions were subsequently merged and validated by the steering committee and nominal group participants, resulting in 38 validated explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs. The definitions encompassed four contexts: (i) the temporary discontinuation of a medication during acute illness (n=9; 24%), (ii) dose level adjustments (n=23; 60%), (iii) inappropriate treatment initiation (n=3; 8%), and (iv) the need for further monitoring in the management of type 2 diabetes (n=3; 8%). Conclusion: This qualitative study is the first to have produced a specific tool of explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs. Although the new list provides valuable insights, it must be validated by expert consensus (e.g. in a Delphi survey) before implementation in practice

DRESS Syndrome Without Eosinophilia Presented with Extensive Skin Rash and Acute Respiratory FailureNattanicha Chaisrimaneepan, MD1, Corley Pruneda MD2, Marwan Elmassry MD1, and Mahmoud Abdelnabi, MD, MSc11 Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas2 Dermatology Department, Texas Tech University Health Sciences Center, Lubbock, TexasCorresponding author: Nattanicha Chaisrimaneepan, MD Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th St., Lubbock, TX 79430 (e-mail: nattanicha.chaisrimaneepan@ttuhsc.edu)

This paper has designed a bandpass filter using a coplanar stripline stub (CPS) resonator consisting of open and short-ended strip lines connected to the PIN Diode switches. The use of spurline stub resonators inside CPS results in bandpass and bandstop filters, depending on the PIN diode switch configurations. The work presents a novel circuit architecture aimed at reducing parasitic resonance of the spurline resonators and acquire the necessary series stub characteristics. The proposed filter resonates at 6.9-9 GHz and 1.7-4.7 GHz, and 8.4 GHz when the PIN diodes are forward and reverse-biased, respectively. It also resonates at 1-2.1 GHz, 4.8-5.3 GHz, and 6.9-9 GHz when one diode is reverse-biased, and the other is connected in forward bias. An insertion loss below -0.55 dB and a return loss less than 10dB have been obtained during simulation and measurement. The designed filter can find different applications for the 1.8 GHz GSM band, 2.4/5.8GHz (WLAN), 3.6 GHz (WiMAX), Long Term Evolution (LTE), and WIFI. The filter can be used in various multi-frequency systems owing to its compact size. The measured and simulated findings of the proposed CPS spurline stub resonator wideband bandpass filters are substantially consistent.

Aminoxyl-mediated electrocatalysis offers a sustainable approach for the oxidation of alcohols to carboxylic acids. However, the high dosage of aminoxyl radicals and the limiting current density hinder the practicality of industrial application. Herein, a nickel-based electrocatalyst (Ni-tpdc) was synthesized on a three-dimensional porous graphite felt substrate. Taking advantage of the synergistic effect of the electrochemically activated Ni-tpdc/GF electrocatalyst with 4-acetamido-TEMPO, the yield of 4-pyridinecarboxylic acid was up to 99% with only 1 mol% ACT. A series of in situ measurements showed that NiOOH enhanced the activity of the intrinsic electrocatalyst. Additionally, the synergistic system was extended to the oxidation of various heterocyclic alcohols. The scale-up synthesis of chiral acid (LEV-CO 2H) was achieved in an improved electrolyzer with a yield of 95.4%, enantiomeric retention of 99.2%, and space-time yield of 34.12 kg/(m 3·h). The practicality and effectiveness of this synergistic electrocatalytic strategy in practical electrosynthesis was further demonstrated.

The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Atherosclerotic Plaque: Cytokine Profile in Diabetic Individuals Marcin Hachuła1, Michał Kosowski1, Marcin Basiak*1, Bogusław Okopień11.Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, PolandCorrespondence to: Marcin Basiak M.D., Ph.D., Assoc. Prof.: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland, phone: +48-32-208-85-10,mbasiak@sum.edu.pl.Conflicts of Interest: The authors declare no conflict of interest.

Interferon-induced helicase C domain-containing protein 1 (IFIH1) is one of the main pattern recognition receptors that sense viral RNA and activate host cells to mount an effective antiviral immunity. Therefore, a case-control study (90 patients with mild/moderate COVID-19 and 90 matched controls) was performed to explore the association of two variants of the IFIH1 gene with COVID-19 risk using the tetra-primer amplification refractory mutation system-polymerase-chain-reaction method. The first is a missense variant, rs1990760 C/T, and the second is an intergenic variant, rs2111485 A/G. In addition, serum IFIH1 levels were assessed using an ELISA kit. Results revealed that mutant alleles ( T and G, respectively) and corresponding homozygous genotypes (TT and GG, respectively) of both variants were significantly associated with increased risk of COVID-19. IFIH1 levels were significantly higher in patients compared to controls and were favorably affected by the rs1990760 and rs2111485 mutant-type genotypes. In conclusion, IFIH1 protein showed up-regulated levels in the serum of patients with mild/moderate COVID-19. In addition, the IFIH1 gene variants rs1990760 C/T and rs2111485 A/G were associated with susceptibility to COVID-19, and the study suggests that their mutant-type genotypes are not only associated with increased risk of COVID-19 but also contributed to higher serum IFIH1 levels.

1. Recognition of favourable environmental conditions for seed germination and seedling survival in different types of forest sites is crucial both for effective regeneration of introduced tree and for control of its spontaneous spread. Studies on the encroachment of North American northern red oak Quercus rubra into European Scots pine forests revealed high abundances of seedlings and saplings under shrubs, with lower abundances in open areas or in clumps of bilberry Vaccinium myrtillus. It was unclear, does burying acorns by seed-hoarders in moss or soil in different microhabitats impact survival of red oak seeds and seedlings, and does acorn size matter? 2. Results of previous (observational) studies were verified in a 3-year experimental study: a pool of 900 sown acorns was monitored in natural conditions. 3. Study revealed that ~80% of sown acorns were lost due to pilferage, lack of germination, fungal infection, and death of sprouting acorns and leafed-out seedlings. The fate of acorns and seedlings depended largely on acorn size and differed among microsite types. Viable seedlings were twice as likely to develop from large- and medium-sized, than from small acorns. Surviving seedlings grew mainly from acorns sown under moss cover within bilberry clumps or in open area, confirming a positive ‘burial effect’. Less than 10% of acorns sown under shrubs developed into viable seedlings, contradicting former conclusions on their ‘nurse effect’. 4. The occurrence of extensive bilberry clumps and small clusters of shrubs in pine forests favours Q. rubra regeneration, but severe fluctuations of the warming climate limit the viability of red oak seeds and seedlings. Prognosed range shifts of native tree species and expected dramatic loss of V. myrtillus climatic optima will impact Q. rubra distribution in European forests. Meanwhile, to prevent red oak spread (if necessary), it is recommended to remove shrubs from pine stand.

Relations among territoriality, abundance, and habitat suitability are fundamental to the ecology of many animal populations. Theory suggests two classes of possible responses to increasing abundance in territorial species: 1) the ideal free distribution (IFD) predicts smaller territory sizes and decreased fitness as individuals adaptively pack into suitable habitats, and 2) the ideal despotic distribution (IDD) predicts stable territory sizes and fitness in preferred habitats for dominant individuals and increased use of marginal habitats and reduced fitness for subordinate individuals. We analyzed the territory sizes and locations of seven migratory songbird species occupying a 10-hectare plot in the Hubbard Brook Experimental Forest, New Hampshire, USA over a 52-year period. All species varied in abundance during the study, some dramatically, and all species displayed clear patterns of habitat preferences within the study plot. Consistent with IFD, and contrary to IDD, territory sizes decreased with local abundance for all species, irrespective of spatial patterns. There was surprisingly high variation in territory size within years. Conformity of territory size to predictions of the ideal free distribution has general consequences for population dynamics and argues for the efficacy of territorial signaling in songbirds.

Understanding indirect interspecific effects (IIEs) on population dynamics is key for predicting community dynamics. Yet, empirically teasing apart IIEs from other interactions and population drivers is data-demanding. We used stochastic population models parameterized with long-term vital rate time series to simulate population trajectories and examine IIEs in a high-arctic vertebrate trophic chain: Svalbard reindeer, its scavenger (Arctic fox), and a migratory fox prey (barnacle goose). Reindeer carcass supply shaped fox abundance fluctuations, subsequently affecting goose fluctuations. Yet reindeer and goose population growth rates were only weakly correlated, probably due to stochasticity, density dependence and life history traits. However, by isolating the effects of individual processes within our simulation model, we demonstrate the presence of strong IIEs on goose population fluctuations and extinction probability. Thus, we highlight the long-term impact of species interactions, including IIEs, on species coexistence and communities, beyond immediate effects and short-term fluctuations.

We hypothesized that cell energy metabolic profiles correlate with normal, dysplastic, and tumor cell/tissue statuses and may be indicators of aggressiveness in oral squamous cell carcinoma (OSCC) cells.The energy-related proteins that were differentially expressed in human OSCC fragments (n=3) and their adjacent epithelial tissue (TAE) were verified using mass spectrometry. Immunohistochemistry for 4-hydroxynonenal (4-HNE) was performed to evaluate the oxidative stress patternsin OSCC (n=10), epithelial dysplasia (n=9), and normal epithelial (n=4) biopsies. The metabolic modulation of OSCC aggressiveness was investigated in human OSCC cell lines with different levels of epithelial–mesenchymal transition proteins. All OSCC fragments exhibited an increase in glycolysis-related proteins and a decrease in mitochondrial activity compared to the TAE region (p<0.05), probably due to the downregulation of pyruvate dehydrogenase and antioxidant proteins. Additionally, the OSCC cell line with a mesenchymal profile (SCC25) had a lower mitochondrial mass and membrane potential and generated lower levels of reactive oxygen and nitrogen species than the TAE region. When we analyzed 4-HNE, the reactive species levels were increased in the epithelial regions of OSCC and potentially malignant lesions. A decrease in the levels of 4-HNE/reactive species was observed in the connective tissue underlying the dysplastic regions and the OSCC invasion zone.Thus, aggressive OSCC is associated with high glycolytic and oxidative metabolism and low mitochondrial and antioxidant activities, which vary according to the differentiation level of the tumor cells and the stage of carcinogenesis.

The endophytic fungi of certain grasses and other herbaceous plants have long been known to provide plants with anti-herbivore defense compounds, but there is little information about whether the endophytes of trees also engage in such mutualisms. We investigated the influence of the endophytic fungus Cladosporium cladosporioides on the chemical defenses of black poplar (Populus nigra) trees and the consequences for feeding preference and fitness of herbivorous insects and insect community assembly. Endophyte colonization increased both constitutive- and induced poplar defenses. Generalist Lymantria dispar larvae preferred and performed better on uninfected over endophyte-infected poplar leaves, most likely due to higher concentrations of salicinoids in endophytic leaves and the endophyte-produced alkaloid stachydrine. Under field conditions, the endophytic fungus also shapes insect community assembly in young black poplar trees. Our results show that endophytic fungi can play a major role both in defending trees against herbivorous insects and in structuring insect communities.

Background: In most Low and Middle-Income Countries (LMICs), enrolment in community-based health insurance (CBHI) is still low. In Sub-Saharan Africa enrolment rate is less than 10%. There have been efforts and strategies being put in place in many countries to overcome this problem. In 1996, Tanzania introduced Community Health Fund (CHF) which was modified in 2011 whereby the government came up with the improved community health fund (iCHF). The introduction of iCHF was intended to improve service delivery to the population where an electronic integrated management information system was introduced. Objective: This study was set to explore the drivers for implementing the e-claim process of improved Community Health Funds from two districts in Central Tanzania. Methods: An exploratory case study design using a qualitative approach was adopted to explore information on the drivers of the implementation of the iCHF electronic claim process in Mkalama and Iramba districts in Singida region. In-depth interviews were used to collect data from the Eighteen (18) participants including regional health managers, district health managers, Information Technology (IT) officers, facility in charge and iCHF focal persons from dispensaries, health centres and hospitals. Data were analyzed using a thematic content analysis. Results: The drivers for implementing the iCHF e-claim process were adherence to supervision directives and government policy, resource management and client satisfaction but the e-claim system does not attract Health Community Workers (HCWs) to comply with the iCHF e-claim process Conclusion: The iCHF e-claim process is inadequately implemented and does not attract Health care workers (HCWs) due to the challenges that have been observed. These findings inform decision makers to joint efforts to improve the implementation of iCHF claim process from all levels of stakeholders.

Background: Linguistic concordance between healthcare providers and patients is critical for ensuring quality healthcare. Professional interpretation can be expensive and challenging to access. This scoping review aimed to explore the evidence on the role and education of medical students as interpreters in caring for patients with limited language proficiency (LLP), and to determine the benefits and risks associated with this practice. Methods: A scoping review using the Joanna Briggs Institute methodology was conducted. Six literature databases were searched systematically between 1946 – 02 Aug 2023. All publications discussing the use of medical students as interpreters in healthcare settings were included. Retained documents were analyzed using Covidence, with coding by two raters and regular team discussions. A thematic analysis framework was used. Results: Thirteen articles met the eligibility criteria. Multilingual medical students are frequently asked to interpret in healthcare settings. This was found to be advantageous in reducing communication barriers, improving care quality, and contributing to students’ clinical experience. Concerns were raised regarding the lack of knowledge on the professional obligations of interpreters. Interpretation training programs for medical students have been implemented at selective healthcare centres and demonstrated successful results in providing care to LLP patients. Conclusions: Medical students play an important role in addressing language barriers in healthcare institutions when serving LLP patients, by combining their unique position in the healthcare team with their medical, linguistic, and cultural competency skills. Academic institutions stand to benefit from offering interpretation training programs and integrating medical students as a resource towards delivering language-concordant care.

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2 V617F mutationShunichiro Yasuda1, Momoko Chiba1, Rie Nishitani2 and Takako Watanabe21Department of Hematology, Tokyo Kyosai Hospital, Tokyo, Japan2Department of Diabetes, Endocrinology and Metabolism, Tokyo Kyosai Hospital,Tokyo, JapanCorrespondence: Shunichiro Yasuda, M.D., Ph.D.Hematology Division Tokyo Kyosai Hospital 2-3-8 Nakameguro Meguro-ku Tokyo, 153-8934, JapanTel: +81-3-3712-3151 Fax 81-3-3793-5582E-mail:y-shunichiro@tkh.meguro.tokyo.jpMANUSCRIPT TYPE: Case reportAUTHOR CONTRIBUTIONSSY, MC, RN, TW: were involved in the patient care and management. SY, MC and RN: prepared the initial draft of the manuscript. SY, MC, TW: edited the draft and reviewed the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for any aspects related to the accuracy or integrity of the work.ACKNOWLEDGMENTSThe authors would like to thank all clinicians involved in this case and Editage (www.editage.jp) for the English language editing.FUNDING INFROMATIONThere is no funding for this article.CONFLICT OF INTEREST STATEMENTThe authors have no conflicts of interest relevant to the content of this article.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available from the corresponding author upon reasonable request.ETHICS STATEMENTThis manuscript confirms to the provisions of the Declaration of Helsinki in 1995 (as revised in Brazil 2013).CONSENTWritten informed consent was obtained from the patient to publish this report in accordance with the journal‘s patient consent policy.Key Clinical MessageHematopoietic neoplasms are considered a differential diagnosis when encountering adrenal infarction. We should recognize thatJAK2 V617F mutation can cause thrombogenicity even if there are no abnormal findings in the blood cell counts.AbstractAdrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46-year-old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U), featuring a JAK2 V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2 V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms.Key words; adrenal infarction, myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U), JAK2 V617F, CHIPINTRODUCTIONAdrenal infarction is a rare condition that occasionally develops in a hypercoagulable state 1. Antiphospholipid antibody syndrome (APS), COVID-19 infection, and heparin-induced thrombocytopenia (HITT) have been reported as underlying diseases of adrenal infarction1-3. Adrenal infarctions have also been rarely linked to myeloproliferative neoplasms (MPN), such as polycythemia vera (PV) and essential thrombocythemia (ET) 4,5.Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) is a hematological disorder that exhibits characteristics of both MDS and MPN6,7. According to the revised version of the 4th edition of the World Health Organization (WHO) classification, the categories of MDS/MPN include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (MDS/MPN-U)6-8. The diagnosis of MDS/MPN-U is based on ruling out any other subtype of MDS/MPN 7,8. Approximately 25% of cases with MDS/MPN-U have JAK2 V617F mutations8, which is a major mutation in patients with MPN9. As patients with MDS/MPN-U exhibit MPN characteristics, they may have a high risk of thrombosis. However, due to the rarity of this disease, the frequency of thrombosis in patients with MDS/MPN-U has not yet been thoroughly investigated.Herein, we present a case of JAK2 V617F-positive MDS/MPN-U with adrenal infarction. The present case had a unique clinical course in which the platelet count of the patient was almost normal at the time of adrenal infarction; however, later, the counts increased, and the characteristics of MPN became apparent. We report this case with a discussion of the thrombogenicity caused by the JAK2 V617F mutation and review previously reported cases of adrenal infarction in myeloid neoplasms.CASE HISTORY/ EXAMINATIONA 46-year-old previously healthy man presented to our emergency department with epigastric and left hypochondrial pain. He had no history of medication or family history of thrombophilia. On physical examination, his body temperature was 37.1 °C, blood pressure was 152/101 mmHg, heart rate was 118 bpm, and oxygen saturation was 97%. Electrocardiography (ECG) findings were normal, and chest radiograph showed no abnormalities. Blood tests revealed a slight increase in the platelet count (42.6×104/μL) and mild anemia (Hemoglobin: 12.9g/dL); the COVID-19 antigen test was negative. Contrast-enhanced computed tomography (CT) showed left adrenal hypertrophy and non-contrast-enhancing areas of the adrenal gland. Additionally, there was increased density of adipose tissue and fluid retention around the left adrenal gland (Fig.1A). Subsequently, he received a diagnosis of left adrenal infarction. The patient was urgently admitted to our hospital, and heparin 10000 U/day was initiated (Fig. 2). While the adrenal infarction was unilateral, there were no signs of adrenal insufficiency based on vital signs and laboratory data.DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS AND TREATMENTDue to the potential for adrenal insufficiency, we initiated the administration of hydrocortisone as a steroid cover. Endocrine examinations indicated the maintenance of the adrenal function of the patient; consequently, the hydrocortisone dose was tapered and terminated. His epigastric and left hypochondrial pain steadily relieved, and follow-up contrast-enhanced CT on day 7 revealed resolution of the left adrenal infarction (Fig.1B). Subsequently, we transitioned the antithrombotic therapy from heparin 10000U/day to edoxaban 30 mg/day, and the patient was discharged on day 16. As for the thrombotic predisposition that led to the adrenal infarction, the increase in platelet counts was not remarkable. Both protein C activity and protein S activities were within the normal range(148% and 73%, respectively). The lupus anticoagulant was negative. Hence, we could not find any causes of adrenal infarction.OUTCOME AND FOLLOW-UPSoon after discharge from our hospital, the patient suffered from a headache. Considering the possibility of edoxaban-induced headache, edoxaban treatment was discontinued on day 20. Two months later, he presented to our hospital with a persistent headache despite discontinuing edoxaban treatment. He was diagnosed with cerebral venous thrombosis (CVT) on contrast-enhanced magnetic resonance imaging (MRI), and edoxaban treatment was resumed on day 88. Simultaneously, the patient presented with right hypochondrial pain, and contrast-enhanced CT showed mild hypertrophy of the right adrenal gland (Fig.1C). He was clinically diagnosed with right adrenal infarction. Furthermore, abdominal aortic mural thrombosis was incidentally detected on contrast-enhanced CT. Regarding multiple arteriovenous thromboses in a short period, his thrombotic predisposition was examined again. Blood tests showed that various autoantibodies were all negative, and the patient did not have diabetes or dyslipidemia (Table.1). However, the platelet counts, which were almost normal at the time of the first admission, gradually increased (Fig.2). Suspecting MPN, especially ET, we examined the presence of JAK2 V617F mutation, which was found to be positive. Bone marrow aspiration showed no increase in the blasts but showed dysplastic features in granulocytes, erythroblasts, and megakaryocytes; a chromosomal abnormality with der(1;7)(q10;p10) was found in 20 out of 20 cells. Bone marrow biopsy showed no bone marrow fibrosis. WT1mRNA was slightly high (71 copies/µgRNA). Since our patient had characteristics of both MDS and MPN and the diagnostic criteria for other MDS/MPN subtypes were not fulfilled, he was diagnosed with MDS/MPN-U. At the same time, the patient was aware of a rash resembling urticaria rash and pruritus on both lower legs, with mild increase in eosinophils (8.1%). The rash and pruritus improved with the use of an antihistamine cream. Since his thrombocytosis was not remarkable (59.7×10⁴/µL) and von Willebrand Factor (vWF) ristocetin cofactor activity (vWF:RCo) did not decrease (89%), the risk of bleeding might not be high 10,11. The patient was then treated with edoxaban (30 mg/day) and aspirin (100 mg/day).On day 131, the patient was admitted to our hospital again for close examination and treatment because his platelet counts further increased (Fig.2) and the development of a new thrombosis was expected. After admission, contrast-enhanced MRI and contrast-enhanced CT were performed, which showed resolution of all arteriovenous thromboses, including the right adrenal infarction (Fig.1D). The platelet counts rose to approximately 100×10⁴/µL; therefore, hydroxyurea 500 mg/day was started on day 137 as cytoreductive therapy, which was increased to 1000 mg/day on day 140. His eosinophil count also gradually increased with a skin rash flare-up. A skin biopsy was performed, leading to the pathological diagnosis of leukocytoclastic vasculitis, which was considered closely related to MDS with der(1;7)(q10;p10)10,11. After the hydroxyurea treatment, both the platelet and eosinophil counts decreased, leading to no recurrence of new thrombosis or improvement of the skin rash. Both JAK2 V617F allele burden and the copy numbers of WT1mRNA increased in our patient, suggesting that MDS/MPN-U progressed. Furthermore, MDS with der(1;7)(p10;q10) complicated by eosinophilia has aggressive clinical features and a poor prognosis 13,14. As the prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor in patients with MDS/MPN-U who have progressive disease or severe complications 12, earlier allo-HSCT might be preferable. After obtaining adequate informed consent, including the risks and benefits of allo-HSCT, the patient was transferred to the transplantation center to receive allo-HSCT at the optimal time.DISCUSSIONIn this manuscript, we present a case of JAK2 V617F-positive MDS/MPN-U with multiple thromboses, including adrenal infarction. Although the precise mechanisms of thrombogenesis in MDS/MPN-U have not been elucidated, we speculate that MDS/MPN-U caused multiple thromboses since our patient did not have any other risk factors for thrombosis or a thrombotic predisposition. Notably, the first adrenal infarction occurred when the platelet count was only slightly elevated and MDS/MPN was not apparent. To date, various mechanisms of thrombogenesis byJAK2 V617F have been reported; 1) JAK2 V617F-positive neutrophils and monocytes release inflammatory cytokines, leading to arteriosclerosis and arterial thrombosis 13. 2)JAK2 V617F-positive neutrophils activate β1/2 integrin, promoting venous thrombosis 14,15. 3) Vascular endothelial cell expression of　JAK2 V617F promotes a prothrombotic state due to increased P-selectin expression 16. Recently, Clonal Hematopoiesis (CH) has been identified and genetic mutations associated with the disease have been detected before the development of hematological malignancies 17,18. In addition, when CH occurs and the variant allele frequency (VAF) exceeds 2%, it is called CH with indeterminate potential (CHIP) 17.JAK2 V617F-CHIP holders had a higher incidence of both arterial and venous thromboses than non-holders 17. In the present case, JAK2 V617F-CHIP may have been associated with the thrombogenicity of adrenal infarction.Previously, five cases of myeloid neoplasms that developed into adrenal infarctions have been reported (Table.2). Among these cases, two patients with ET had JAK2 V617F mutations 4,5. Indeed, one patient developed adrenal infarction before the diagnosis of ET, indicating that JAK2 V617F-CHIP was closely associated with adrenal infarction, as in our case 4. However, one patient with MDS/MPN-U did not harbor the JAK2 V617F mutation19, indicating that other gene mutations may contribute to the thrombogenesis in MDS/MPN-U. Furthermore, one case with MDS had adrenal infarction with no other thrombotic predisposition, such as MPN, suggesting that the hypercoagulable state associated with MDS may contribute to thrombogenesis 20. With reference to these case reports, other factors as well asJAK2 V617F mutation, may have caused the adrenal infarction in our case with MDS/MPN-U. A previous study suggested that SF3B1 may be a risk factor for thrombosis in MDS/MPN-RS-T, a subtype of MDS/MPN21. At present, SF3B1 mutation analysis is required for the accurate classification of MDS/MPN subtypes according to the latest 5th WHO classification. However, SF3B1 analysis can only be performed at a limited number of centers in Japan and is not available at our hospital. If SF3B1 or other gene mutation analyses become widespread and can be performed in daily practice, more accurate predictions can be made regarding the risk of thrombosis in MDS/MPN subtypes in the future.All six cases in Table.2, including the current case, developed complications such as adrenal insufficiency and thromboses at other sites. Among the six patients, five had bilateral adrenal infarction4,5,19,20,22 and four developed primary adrenal insufficiency that required steroid replacement therapies4,19,20,22. In our case, the adrenal infarction was unilateral and improved soon after edoxaban treatment. Although our patient subsequently developed adrenal infarction contralaterally, the lesions of adrenal infarction were small; therefore, the patient did not develop adrenal insufficiency.Among the six patients shown in Table.2, four developed thromboses at other sites, including one case of angina pectoris that required percutaneous coronary intervention 5. Our patient simultaneously developed CVT, abdominal aortic mural thrombosis, and adrenal infarction. In accordance with the recommendations of a previous study on the combination of antiplatelet and anticoagulant drugs for arteriovenous thrombosis in patients with MPN 23, the patient was treated with edoxaban and aspirin, and all thromboses disappeared.Although the six cases in Table.2 did not develop adrenal hemorrhagic infarction, they sometimes occurred after adrenal infarction. The mechanisms underlying adrenal infarction and adrenal hemorrhagic infarction are not fully understood; however, it is hypothesized that they are related to the unique vascular anatomy of the adrenal gland4,19,24. When treating adrenal infarction, attention should be paid to adrenal hemorrhagic infarction. In particular, patients with MPN have an increased risk of bleeding owing to a decrease in vWF activity associated with an increase in the platelet count25. Therefore, patients with adrenal infarction who have characteristics of MPN should be examined for vWF activity before starting treatment with antithrombotic agents.Patients with MDS/MPN-U generally have a poor prognosis with a median overall survival of 12.4 months, as reported by a previous study8. Although the efficacy of ruxolitinib or hypomethylating agents for MDS/MPN-U has been reported26,27, they are not curative, and the only curative treatment option is allo-HSCT 12. Since patients with severe complications before allo-HSCT have a worse prognosis, management of these complications is crucial for patients with MDS/MPN-U. Although our patient had multiple arteriovenous thromboses, they were managed with antithrombotic agents, and the patient was eventually transferred to the transplantation center without any complications.CONCLUSIONWe report a case of JAK2 V617F-positive MDS/MPN-U with adrenal infarction. Hematopoietic neoplasms are considered a differential diagnosis when encountering adrenal infarction with unknown causes. Even if there are no abnormal findings in the blood cell counts at the time of adrenal infarction, they should be carefully monitored, and when MPN is suspected, JAK2 V617F mutation should be examined. Finally, patients with adrenal infarction of hematopoietic neoplasms often have complications, and management of these complications is crucial, especially in patients eligible for allo-HSCT.REFERENCES1. Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Med (Baltim) . Mar 2003;82(2):106-18. doi:10.1097/00005792-200303000-000052. VanderVeer EA, Torbiak RP, Prebtani AP, Warkentin TE. Spontaneous heparin-induced thrombocytopenia syndrome presenting as bilateral adrenal infarction after knee arthroplasty. BMJ Case Rep . Dec 29 2019;12(12)doi:10.1136/bcr-2019-2327693. Leyendecker P, Ritter S, Riou M, et al. Acute adrenal infarction as an incidental CT finding and a potential prognosis factor in severe SARS-CoV-2 infection: a retrospective cohort analysis on 219 patients.Eur Radiol . Feb 2021;31(2):895-900. doi:10.1007/s00330-020-07226-54. Hada Y, Yamada A, Kobayashi T, et al. Bilateral Adrenal Infarction that Developed in Latent Essential Thrombocythemia. Intern Med . Jun 21 2023;doi:10.2169/internalmedicine.1947-235. Iemura T, Mano C, Oba A, et al. 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Mar 2021;3(1):134-136. doi:10.1016/j.jaccao.2021.01.00119. Hoshino Y, Manaka K, Sato J, et al. Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report. BMC Endocr Disord . Jun 5 2023;23(1):128. doi:10.1186/s12902-023-01384-520. Lockett HA, Hamilton-Wood C, Vaidya B. Addison’s disease due to bilateral adrenal infarction in a patient with myelodysplastic Syndrome.Eur J GEN Med . 2011;8:72-74.21. Nathan DI, Feld J, El Jamal SM, Mascarenhas J, Tremblay D. Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Ringing in a new future. Leuk Res . Apr 2022;115:106820. doi:10.1016/j.leukres.2022.10682022. Hirata R, Tago M, Yamashita S, et al. Acute abdominal pain due to atypical bilateral adrenal infarction in acute myeloid leukemia with alterations related to myelodysplasia: A case report. Clin Case Rep . Oct 2023;11(10):e7925. doi:10.1002/ccr3.792523. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol . Dec 2020;95(12):1599-1613. doi:10.1002/ajh.2600824. Michiels JJ, Berneman Z, Schroyens W, Krestin GP. Bilateral adrenal swelling as a cause of chest, back, and upper abdominal pain in essential thrombocythemia and polycythemia vera is due to microvascular ischemic thrombosis rather than to hemorrhage. Ann Hematol . Dec 2002;81(12):691-4. doi:10.1007/s00277-002-0500-525. Awada H, Voso MT, Guglielmelli P, Gurnari C. Essential thrombocythemia and acquired von Willebrand syndrome: The shadowlands between thrombosis and bleeding. Cancers (Basel) . Jun 30 2020;12(7)doi:10.3390/cancers1207174626. Al-Kali A, Abou Hussein AK, Patnaik M, et al. Hypomethylating agents (HMAs) effect on myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U): single institution experience. Leuk Lymphoma . Nov 2018;59(11):2737-2739. doi:10.1080/10428194.2018.143670527. Wang Q, Dai HP, Liu DD, et al. Efficacy of ruxolitinib in a patient with myelodysplastic/myeloproliferative neoplasm unclassifiable and co-mutated JAK2, SF3B1 and TP53. Leuk Res Rep . 2020;14:100229. doi:10.1016/j.lrr.2020.100229Figure legendsFigure 1. Contrast-enhanced CT showing development (A) and improvement of (B) left adrenal infarction. Contrast-enhanced CT showing development (C) and improvement (D) of right adrenal infarction.A) The arrow shows left adrenal hypertrophy and non-contrast-enhanced areas, and arrowheads show increased lipid concentrations and fluid retention around the left adrenal gland. The patient was diagnosed with left adrenal infarction. B) The left adrenal infarction improved. C) The arrow indicates mild hypertrophy of the right adrenal gland. He was diagnosed with a right adrenal infarction. D) The right adrenal infarction improved.Figure 2. Clinical course of adrenal infarction withJAK2 V617F-positive MDS/MPN-U with der(1;7)(p10;q10).Plt, platelet; Eo, eosinophil; vWF:Rco, von Willebrand Factor ristocetin cofactor activity;U, unit; Lt, left; Rt, right; AI, adrenal infarction; CVT, cerebral venous thrombosis; AMT, aortic mural thrombosis. BMA, bone marrow aspiration; BMB, bone marrow biopsy

Hemifacial spasm and blepharospasm caused by vertebral artery dolichoectasia

1 INTRODUCTIONHyper IgD Syndrome (HIDS) is a rare autosomal recessive autoinflammatory condition, determined by recurrent febrile attacks associated with lymphadenopathy, arthralgia, diarrhea, abdominal pain, and skin rash (1, 2). This disorder was first described in 1984 by Jos van der Meer(3).This disease has an early onset, generally in infancy, and febrile crises recur at varying intervals. Fever flares have a sudden onset and last approximately 4 to 6 days. An attack begins with chills, and patients often complain of weakness, headache, nausea, and diarrhea (1, 4). The hallmark characteristic of the syndrome is the presence of recurrent episodes of fever and chills, often accompanied by skin rashes (5). HIDS is caused by a mutation in the mevalonate kinase (MVK) gene, which results in a lack of mevalonate kinase enzyme activity (6, 7). Mevalonate kinase is a key enzyme in isoprenoid biosynthesis and is involved in a wide range of essential cellular processes and the synthesis of cholesterol (8).According to our current knowledge of the genetics and pathophysiology of HIDS, the diagnosis can be made in a patient with frequent episodes of fever and the usual findings associated with recording mutations in MVK or high levels of mevalonic acid, a substrate of mevalonate kinase, in the urine of patients during attacks (9). Whereas before the discovery of the MVK gene as the cause of HIDS, the presence of high serum IgD levels was necessary for the diagnosis of HIDS (10). Today, the importance of increased IgD without genetic or biochemical findings remains uncertain (9).Early diagnosis and treatment of HIDS patients is momentous, because it prevents irreversible organ damage and improves the quality of life of patients (11). Management of HIDS focuses primarily on symptomatic relief of febrile episodes and prevention of complications. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered as first-line treatment for pain and fever associated with HIDS episodes. In some patients, immunomodulatory therapy may be recommended to help control the frequency and severity of episodes (12, 13).In this case report, we presented a girl with a long history of fever episodes and skin manifestations, in whom a mutation in the MVK gene could be identified.

Mounting evidence reveals a captivating connection between oral health and cardiovascular health, prompting a surge in scientific curiosity and potential solutions for reducing global cardiovascular disease burden. This paper delves into this intricate relationship, highlighting the prevalence of oral diseases and their association with various systemic conditions. Studies exploring the potential link between poor oral hygiene, particularly periodontal disease, and cardiovascular illnesses like heart attack, stroke, and heart failure are examined. While the precise causal mechanisms remain under investigation, potential explanations involving chronic inflammation, shared risk factors, and even genetic susceptibilities are discussed. Despite the lack of definitive proof that treating gum disease directly prevents heart problems, the robust correlation necessitates prioritizing good oral hygiene practices. Regular brushing, flossing, and dental checkups are emphasized as preventive measures against periodontal disease and its potential contribution to cardiovascular risks. Addressing shared risk factors like diabetes and smoking further strengthens the protective shield against both oral and heart health concerns.The paper underscores the importance of public health initiatives promoting oral hygiene awareness, particularly among vulnerable populations facing limited access to dental care. Additionally, the crucial role of ongoing research in elucidating the exact mechanisms linking oral and cardiovascular health is highlighted, paving the way for future development of targeted interventions and personalized prevention strategies. In conclusion, while the mysteries surrounding the precise cause-and-effect relationship between oral and cardiovascular health persist, the compelling evidence presented demands a proactive approach. Prioritizing good oral hygiene, addressing shared risk factors, and advocating for accessible dental care stand as powerful tools in our collective fight against these prevalent health challenges.

Botryllus schlosseri, is a model marine invertebrate for studying immunity, regeneration, and stress-induced evolution. Conditions for validating its predicted proteome were optimized using nanoElute® 2 deep-coverage LCMS, revealing up to 4,930 protein groups and 20,984 unique peptides per sample. Spectral libraries were generated and filtered to remove interferences, low-quality transitions, and only retain proteins with >3 unique peptides. The resulting DIA assay library enabled label-free quantitation of 3,426 protein groups represented by 22,593 unique peptides. Quantitative comparisons of a laboratory-raised with two field-collected populations revealed (1) a more unique proteome in the laboratory-raised population, and (2) proteins with high/low individual variabilities in each population. DNA repair/replication, ion transport, and intracellular signaling processes were unique in laboratory-cultured colonies. Spliceosome and Wnt signaling proteins were the least variable (highly functionally constrained) in all populations. In conclusion, we present the first colonial tunicate’s deep quantitative proteome analysis, identifying functional protein clusters associated with laboratory conditions, different habitats, and strong versus relaxed abundance constraints. These results empower research on B. schlosseri with proteomics resources and enable quantitative molecular phenotyping of changes associated with transfer from in situ to ex situ and from in vivo to in vitro culture conditions.