Left Shift Research Articles

AI-based approach to enable proactive identification of early lung cancer: A retrospective population health study and economic model.

10536 Background: Approximately 48,500 new cases of lung cancer are diagnosed each year in the UK with a five-year survival rate which lags behind other European countries. Most patients are diagnosed at stage III or IV disease, which has a significantly worse prognosis. The integration of real-world data and AI techniques presents a promising avenue for improvement, using novel solutions not achievable through traditional care models. This study explores proactive patient identification at scale, aligning with the "left shift" paradigm in population health. The approach uses innovative technologies and novel data sources to identify patients with early-stage disease, enhancing both clinical and economic outcomes. Importantly, these interventions should be feasible on a large scale without overburdening already stretched clinical services. Methods: A retrospective study of real-world data for an urban population with high socioeconomic disadvantage and health needs was undertaken. Two endpoints were determined: detection potential and health economic impact. For detection potential (DP), patients aged 40 and above who underwent chest X-rays (CXR) at a large academic medical centre between 2016-2022 were included. Natural Language Processing (NLP) analysed unstructured free-text data from Electronic Health Records, combined with ICD-10 codes, for predictive model (PM) development using Machine Learning (ML) classification techniques. The PM's performance was assessed using the area under the receiver operating characteristic curve (AUCROC). Health economic impact was evaluated through a theoretical extrapolation of DP. Assuming a 9% left shift from late (stage III or IV) to early (stage I or II) disease, a health economic model (HEM) compared the impact of the current care model to a potential future state facilitated by the digital medicine care model (DMCM). Results: 75,342 patients were included, with 755 lung cancer diagnoses occurring within 6 months of CXR. The PM achieved a peak AUROC of 0.75, exceeding the performance of currently used risk prediction models (Q Cancer Risk, Risk Assessment Tools). A 9% left shift equated to 4.5 years mean increase in survival. The DMCM was associated with a net healthcare cost benefit of £6k per patient diagnosed with lung cancer, improved quality-adjusted life years of £21M for the year 1 cohort over 10 years and increased economic productivity (from additional years in workforce) of £2.4M. Conclusions: The study demonstrates the practical utility of AI-supported early lung cancer detection at population scale. Real-world evidence is needed to prospectively validate the model as cost-effective, scalable, and efficient. Future work will seek to improve the model's performance against a broader at-risk patient population and explore its applicability to other late-presenting tumours.

The endocannabinoid ARA-S acts as an endogenous rescuing factor of Kv7.1/KCNE1 carrying Long QT syndrome mutations and paves the way for drug development strategies

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation program Long QT Syndrome (LQTS) is a cardiac arrhythmia characterized by delayed ventricular repolarization. LQTS occurs when there are loss-of-function mutations in genes encoding for voltage-gated channels and their beta subunits that contribute to the cardiac action potential. Among them, the most mutated channel is Kv7.1/KCNE1, which encodes for the slowly activating component of the delayed rectifier K+ current (IKs). Families with inherited mutations in the Kv7.1/KCNE1 exhibit inconsistent correlations between genotypes and phenotypes making the clinical management of LQTS challenging. A possible strategy to help guide clinical approaches involves exploring endogenous compounds capable of modulating the Kv7.1/KCNE1 channel function, acting as potential disease modifiers. Using the two-electrode voltage clamp technique, we previously found that the endogenous endocannabinoid-like compound ARA-S, which has an arachidonic acid tail and a serine head group, facilitates activation of the wild-type Kv7.1/KCNE1 channel expressed in Xenopus oocytes. This is seen as a left shift in the voltage dependence of channel opening and an increase in conductance. Moreover, we showed that ARA-S restores a physiological QT interval in isolated guinea pig hearts suffering from drug-induced LQTS. Hence, ARA-S is an interesting endogenous Kv7.1/KCNE1 channel modulator that may influence disease severity. However, it is uncertain whether ARA-S also activates the Kv7.1/KCNE1 when it carries LQTS-associated mutations. Therefore, the current study involves studying the effect of ARA-S on mutated Kv7.1/KCNE1 channels using two-electrode voltage clamp electrophysiology. We find that ARA-S facilitates the activation of all tested LQTS mutants. However, the magnitude of the effect varies among them, suggesting that the compound´s effect is dependent on the genetic background. To understand why ARA-S has different effects, we use computational simulation approaches to study how mutations in the putative ARA-S binding sites change ARA-S efficacy. This understanding aids in developing new substances that can activate different mutations, by, for example, modifying the ARA-S tail to enhance its efficacy. We also try to understand the concentration of ARA-S required to restore a wild-type-like function of each mutant, considering the mutant's intrinsic behavior and the apparent affinity of ARA-S for the specific mutant. Altogether, this work finds ARA-S to be an efficient activator of LQTS-associated mutant Kv7.1/KCNE1 channels and is a first step towards understanding how the genetic background determines the effect of this endogenous modulator.

Feline Calicivirosis in the catteries

Cat breeding has become very popular nowadays. The presence of these animals in catteries, especially in conditions of imperfect compliance with sanitary and hygienic requirements, often causes outbreaks of viral diseases, the causative agents of which are transmitted mainly by the aerogenic transmission mechanism. Calicivirosis is the most common kennel disease; it can occur as a mono-infection and can also be associated with other viral respiratory diseases. The study aimed to evaluate the epizootic features and clinical course of feline calicivirus in catteries. It was found that the disease's stationary focus was in the experimental cattery. Depending on the year's season, the morbidity increase begins in April, peaks (40 %) in July, and gradually decreases until September. The most vulnerable age group is kittens aged 2–6 months due to imperfect immune mechanisms at this age. The disease occurs mainly manifestly in this age group, with characteristic pronounced clinical signs. Sick cats have sub febrile or pyretic fever, lack of appetite, and salivation with viscous saliva. Ulcers develop on the mucous membranes of the oral cavity. Also, erosions and ulcers are noted in the nasal mirror and on the mucous membrane of the larynx. There was conjunctivitis with serous to catarrhal-purulent exudate. Laboratory tests revealed leukopenia, acceleration of erythrocyte sedimentation rate, left shift of the nucleus, lymphocytosis, and monocytosis, which indirectly determine the viral disease and stimulation of immune functions, and the development of a systemic inflammatory response. Biochemical tests revealed the development of intoxication syndrome, hepatitis liver failure, and renal failure. The data obtained prove the systemic nature of the impact of calicivirus infection, the development of complications in the form of a systemic inflammatory response, which affects various organs and systems, particularly the liver and excretory system. The development of multiorgan pathology in feline calicivirus infection requires an integrated approach to treatment, including pathogenetic and symptomatic measures in the treatment protocol.

Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain.

Nav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain. To study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin-Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP). We show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel's maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8. Computational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain.

Neuroactive steroid hormone trajectories across the menstrual cycle in premenstrual dysphoric disorder (PMDD): the PHASE study.

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect.

Cardiac herniation post left upper lobectomy and thymectomy: a case report

BackgroundCardiac herniation occurs when there is a residual pericardial defect post thoracic surgery and is recognised as a rare but fatal complication. It confers a high mortality and requires immediate surgical correction upon recognition. We present a case of cardiac herniation occurring post thymectomy and left upper lobectomy.Case presentationInitial presentation: A 48-year-old male, hypertensive smoker presented with progressive breathlessness and was found to have a left upper zone mass confirmed on CT biopsy as carcinoid of unclear origin. PET-CT revealed avidity in a left anterior mediastinal area, left upper lobe (LUL) lung mass, mediastinal lymph nodes, and a right thymic satellite nodule. Intraoperatively: Access via left thoracotomy and sternotomy. The LUL tumour involved the left thymic lobe (LTL), left superior pulmonary vein (LSPV), left phrenic nerve and intervening mediastinal fat and pericardium, which were resected en-masse. The satellite nodule in the right thymic lobe (RTL) was adjacent to the junction between the left innominate vein and superior vena cava (SVC). The pericardium was resected from the SVC to the left atrial appendage. Clinical deterioration: Initially the patient was doing well clinically on day 1, however there was sudden bradycardia, hypotension, clamminess, and oligoanuria, with raised central venous pressures and troponins. ECG: no capture in leads V1-2, but positive deflections seen on posterior leads. Echo: no acoustic windows, but good windows seen posteriorly. CXR: left mediastinal shift. Redo operation: After initial resuscitation and stabilisation on the intensive care unit, on day 2 a redo-sternotomy revealed cardiac herniation into the left thoracic cavity with the left ventricular apex pointing towards the spine, and inferior caval kinking. After reduction and repair of the pericardial defect with a fenestrated GoreTex patch, the patient recovered well with complete resolution of the ECG and CXR.ConclusionCardiac herniation can even occur following sub-pneumonectomy lung resections and should be considered as a differential when faced with a sudden clinical deterioration, warranting early surgical correction.

203 RNA Polymerase II Meningioma Mutations Activate Forebrain Neurodevelopmental Pathways

INTRODUCTION: RNA polymerase II, which transcribes DNA into RNA, is mutated in a subset of skull base meningiomas. Patient-derived Pol II mutant meningiomas are dysregulated in pathways directing neural crest differentiation and neurodevelopment. The molecular mechanism of the Pol II driver mutation has remained elusive, and may provide novel therapeutic insight. METHODS: The POLR2A Q403K meningioma driver mutation was modeled in the mouse embryonic stem cell system using CRISPR-Cas9. Metabolic labeling of nascent RNA was performed with 4-thiouridine (SLAMseq). Pol II ChIPseq was performed to calculate the travel ratio (proportion of initiated Pol II to elongating Pol II). POLR2A Q403K and wildtype mES cells differentiated over 12 days in permissive media, RNA was harvested over multiple days, and RNAseq was performed. RESULTS: POLR2A Q403K cells had a global increase in transcription per nascent RNA sequencing, as measured by T>C conversions (p = 5.71x10-66). For active and highly-paused genes, which were enriched for neurodevelopmental pathways (FDR = 3.52x10-25), a left shift in the mean travel ratio revealed defects in pause-release as the mechanism for increased levels of nascent transcription. Recapitulating human disease, POLR2A Q403K mES cells had significant activation of Hedgehog (Padj. = 2.4x10-3) and WNT (Padj. = 5.2x10-3) signaling pathways, and by day 12 of differentiation showed significant upregulation of pathways critical for rostral cortical development including forebrain neuronal differentiation (FDR = 4.86x10-4), telencephalon development (FDR = 4.30x10-4), and neuronal differentiation (FDR = 4.39x10-4). CONCLUSIONS: Meningioma Pol II mutations drive global increases in transcription via dysregulation of pause-release. Highly-paused genes, including master regulators of neural development, are disproportionately activated by mutant Pol II. This dysregulation leads to aberrant induction of neurodevelopmental signaling, including Hedgehog and WNT, and provides a rationale for pharmacologic targeting of these pathways.

Effect of PAM on Surface Hydrophobicity of Montmorillonite and Difference of Interface Adsorption: An Experimental and Simulation Study.

How to realize efficient treatment of coal slime generated by a coal washing operation is an urgent problem to be solved in this industry. The presence of clay minerals, especially highly hydrophilic montmorillonite (MMT), is the key to the poor treatment effect of coal slime. Polyacrylamide (PAM) is very popular as a polymer agent to improve the treatment of coal slime. However, when it is used to treat coal slime with a high content of MMT, the selection of PAM type and the mechanism of action are still lacking. In this study, the effects of different types of PAM on the treatment of coal slime water containing MMT are considered by sedimentation and press filtration tests. The interaction mechanism of PAM on the MMT surface is studied by using ζ-potential, Brunauer-Emmett-Teller (BET) analysis, low-field nuclear magnetic resonance, density functional theory (DFT), and molecular dynamics (MD) simulations. The results show that the three PAM can improve the sedimentation and filtration effect of coal slime water, and the performance is CPAM > NPAM > APAM. The ζ-potential of the MMT (001) surface increases under the action of three PAM, and the effect of CPAM is the most significant. The adsorption of PAM on the MMT (001) surface has the ability to neutralize the surface charge of MMT. The flocculation of MMT particles under PAM results in an increase of particle size and a decrease of specific surface area. Meanwhile, the pore volume of MMT decreases, and the average pore size increases. In addition, PAM mainly removes vicinal water on the MMT surface. The active sites of the MMT surface and PAM are calculated by DFT. The adsorption of three PAM structural units on the MMT Na-001 surface and non-001 surface is nonbonding interaction, and the adsorption energy of CPAM is the largest. And the left shift of εp of the O atom on the MMT surface is conducive to the stable adsorption of CPAM. The MD results show that the concentration of water molecules on the surface of MMT Na-001 decreases after PAM is adsorbed on the MMT Na-001 surface, indicating that PAM can keep water molecules away from the surface of MMT, which means that the hydrophobicity of the MMT surface is enhanced. This study has guiding significance for the selection of PAM and the development of new flocculants in the treatment of coal slime with a high content of MMT.

Paraneoplastic leukocytosis in a dog following liposarcoma resection

AbstractA 10‐year‐old, female, neutered cocker spaniel presented for surgical debulking of an axillary and cranial thoracic wall liposarcoma. Pre‐surgical blood analysis demonstrated anaemia (packed cell volume 17%), leukocytosis (white blood cell count 43.95 × 109/L) and thrombocytopenia (15 × 109/L), with platelet loss secondary to chronic intra‐lesional haemorrhage or immune‐mediated destruction, and concomitant Staphylococcus pseudintermedius urinary tract infection. A blood transfusion and antibiotics were administered before surgery. Within 48 hours after surgery, an extreme leukocytosis (white blood cell count 170 × 109/L), involving a severe left shift neutrophilia (95 × 109/L) was observed; this resolved within 10 days. Serum granulocyte‐colony stimulating factor levels were similar to controls. The extreme leukocytosis was suspected to be related to a paraneoplastic leukaemoid reaction combined with an expected postoperative mild leukocytosis. Further investigation into the pathophysiology underlying similar cases is required. One month after surgery, all haematological abnormalities had normalised, and metronomic chemotherapy with chlorambucil commenced.

Aetiology, clinical profile, management and outcome of acute pancreatitis at public hospitals in Addis Ababa, Ethiopia: a prospective observational study.

Acute pancreatitis (AP) is a rare gastrointestinal pathology that has recently become increasingly common owing to lifestyle changes. Its clinical presentation ranges from mild discomfort to organ failure and death. Previous studies in Ethiopia reported that AP is rare. However, lifestyle changes have recently increased. Therefore, this study aimed to assess the aetiology, clinical profile, management, and outcomes of AP. This prospective observational study included 59 adults diagnosed with AP using the Revised Atlanta Classification between November 2021 and August 2022 at five public hospitals in Addis Ababa. The data were analyzed using SPSS 25. The mean ± standard deviation and adjusted odds ratio (AOR) at 95% CI were used. The mean age was 38.2 (SD±11.5years), mostly aged 30-44, with 67% males and 89.8% patients presenting with new-onset AP. Abdominal pain and nausea were the most common presentations in 93.2% of patients. More than 52.5% of AP cases were caused by alcohol, followed by gallstones (28.8%), and gallstones (47.1%) underwent cholecystectomy during the index admission. One patient (1.7%) died. The length of hospital stay ranges from 1-47 days and increases with the severity of AP. Patients with recurrent AP had a 2.4 folds increase in complications compared to new-onset AP (AOR=2.4, 95% CI=1.38, 15.71). Most AP cases were caused by alcohol consumption, followed by gallstones, smoking, and hypertriglyceridemia. One death in a 60-year-old male with an alcohol and smoking history was diagnosed and triaged as severe AP with persistent multiple organ failure; BISAP score 4, his Creatinine=2.55mg/dl, haematocrit 72.6%; and left shift of WBC, was associated.

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

The potential of circHIPK3 as a biomarker in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by leukocytosis and left shift. The primary molecular alteration is the BCR::ABL1, chimeric oncoprotein with tyrosine kinase activity, responsible for the initial oncogenesis of the disease. Therapy of CML was revolutionized with the advent of tyrosine kinase inhibitors, but it is still not considered curative and may present resistance and serious adverse effects. Discoveries in CML inaugurated a new era in cancer treatment and despite all the advances, a new biomarker is needed to detect resistance and adverse effects. Circular RNAs (circRNAs) are a special type of non-coding RNA formed through a process called backsplicing. The majority of circRNAs are derived from protein-coding genes. CircHIPK3 is formed from the second exon of the HIPK3 gene and has been found in various pathologies, including different types of cancer. New approaches have demonstrated the potential of circular RNAs in cancer research, and circHIPK3 has shown promising results. It is often associated with cellular regulatory pathways, suggesting an important role in the molecular dynamics of tumors. The identification of biomarkers is an important tool for therapeutic improvement; thus we review the role of circHIPK3 and its potential as a biomarker in CML.

Heterointerface engineering of rhombic Rh nanosheets confined on MXene for efficient methanol oxidation

Although metallic rhodium (Rh) is regarded as a promising platinum-alternative anode catalyst of direct methanol fuel cell (DMFC), the conventional “particle-to-face” contact model between Rh and matrix largely limits the overall electrocatalytic performance due to their insufficient cooperative effects. Herein, we report a controllable and robust heterointerface engineering strategy for the bottom-up fabrication of rhombic Rh nanosheets in situ confined on Ti3C2Tx MXene nanolamellas (Rh NS/MXene) via a convenient stereoassembly process. This unique design concept gives the resulting 2D/2D Rh NS/MXene heterostructure intriguing textural features, including large accessible surface areas, strong “face-to-face” interfacial interactions, homogeneous Rh nanosheet distribution, ameliorative electronic structure, and high electronic conductivity. As a consequence, the as-prepared Rh NS/MXene nanoarchitectures exhibit exceptional electrocatalytic methanol oxidation properties in terms of a large electrochemically active surface area of 126.2 m2 g−1Rh, a high mass activity of 1056.9 mA mg−1Rh, and a long service life, which significantly outperform those of conventional particle-shaped Rh catalysts supported by carbon black, carbon nanotubes, reduced graphene oxide, and MXene matrixes as well as the commercial Pt nanoparticle/carbon black and Pd nanoparticle/carbon black catalysts with the same noble metal loading amount. Density functional theory calculations further demonstrate that the direct electronic interaction at the well-contacted 2D/2D heterointerfaces effectively enhances the adsorption energy of Rh nanosheets and induces a left shift of the d-band center, thereby making the Rh NS/MXene configuration suffer less from CO poisoning. This work highlights the importance of rational heterointerface design in the construction of advanced noble metal/MXene electrocatalysts, which may provide new avenues for developing the next-generation DMFC devices.

Copper Intoxication in South American Camelids—Review of the Literature and First Report of a Case in a Vicuña (Vicugna vicugna)

Copper (Cu), an essential trace element in the metabolism of mammals, plays a central role in various metabolic processes. However, overdosing can lead to severe symptoms and even fatalities. Chronic Cu intoxication continues to be a problem in grazing and domestic animals, with sheep being particularly sensitive. There are few comparative studies on its impact on South American camelids (SACs). Therefore, this work presents the results of literature research combined with a case report on a 3-year-old female vicuña (Vicugna vicugna) presented to the clinic from a zoological garden in northern Germany. The animal showed reduced food intake, recumbency, bruxism, icteric mucous membranes and sclera. Auscultation revealed atony of the third compartment and the digestive tract. Similar to cases described in the literature, the animal showed rapid deterioration of its condition with unspecific symptoms of liver failure and rapid death. However, in contrast to descriptions in sheep, clinical icterus has not been previously reported in cases of other SACs. Laboratory findings from EDTA and serum samples revealed neutrophilia with a left shift, hypoproteinaemia, lymphopaenia, azotaemia, elevated levels of creatine kinase (CK), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) in the serum. Hyperbilirubinaemia and significantly elevated serum and liver Cu levels were observed. Subsequent blood samples from the remaining vicuñas and alpacas in the same enclosure showed no remarkable abnormalities. To the best of the authors’ knowledge, this case report represents the first documented case of Cu intoxication specifically in vicuñas.

Comprehensive morphologic characterization of bone marrow biopsy findings in a large cohort of patients with VEXAS syndrome: A single-institution longitudinal study of 111 bone marrow samples from 52 patients.

VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable. To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review. Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases. Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.

The shrapnel-crushed wounds in dogs: status evaluation and therapy for wound healing

Determining the clinical and laboratory status of animals with crushed wounds as a result of the traumatic effect of ammunition fragments, as well as the wound healing effect of ecologically safe drugs based on natural beekeeping products is of great importance under the conditions of the animals' stay in the war zone and territories subject to rocket-bomb and artillery fire. The aim of the research is to study the clinical condition of dogs with shrapnel-crushed wounds, observing its dynamics during systemic therapy and evaluating the therapeutic effect of wound healing using the universal biological ointment Unibiol®. During the research, various physical, hematological, biochemical, hemorheological, hemodynamic, and statistical methods were employed. Six animals with shrapnel-crushed wounds on their limbs and groin were analyzed. It was established that due to the traumatic factor, injuries in dogs are characterized by extensive tissue destruction and deconstruction. The overall condition of the animals, based on clinical signs, is described as toxemic-septic. Hematological changes such as anemia, leukocytosis, thrombocytopenia, left shift in the nucleus, monocytosis, and lymphocytosis indicate a systemic inflammatory reaction and a septic state in the dogs' bodies. Biochemical studies revealed hypoalbuminemia leading to hypoproteinemia, creatinine elevation, uremia, elevated levels of indicator transaminases, suggesting multi-organ failure. A significant decrease in circulating blood volume, increased spontaneous platelet aggregation, characterizes a moderate traumatic circulatory shock, while a 5-fold increase in the circulation of D-dimer levels indicates a significant potential for disseminated intravascular coagulation syndrome. Following infusion and antibiotic therapy, wound sanitation over 5 days led to a significant restoration of the clinical-laboratory status of the injured dogs, setting the stage for Unibiol® ointment wound-healing therapy. As a result of the treatment conducted over 21 days, the wound defect healed with the formation of complete granulation tissue and an elastic scar. The clinical trials conducted allow recommending Unibiol® ointment for effective and environmentally safe healing of severe shrapnel-crushed wounds.

Infectious Pustular Vulvovaginitis in a Buffalo: A Case Report

The present communication reports a case of infectious pustular vulvo-vaginitis in a 5 year-old Murrah buffalo. The animal had a history of abortion, retention of foetal membranes and dark, raised nodular lesions on the surface of udder with mastitis. Physical examination revealed a rectal temperature of 104 ℃ and slightly congested mucous membranes. On examination of the vaginal mucous membranes, several white, round lesions were observed. Dark circular, raised lesions were observed on the surface of the udder as well. On haematological examination it was found that there was presence of absolute neutrophilia with a mild left shift. The impression smear from vaginal mucous membrane revealed hyperplastic changes with presence of few neutrophils. The CMT score of all quarters were 2+, with pustular discharge observed from the right hindquarter. The animal was treated with Ceftiofur (1.1 mg/kg BW), gentamicin (4.4 mg/kg BW) and metronidazole (10mg/kg BW) along with b-complex vitamins and supplements containing biotin and vitamin A. The animal recovered uneventfully.

Leukemoid Reaction in an Elderly Patient with Aortic Valve Infective Endocarditis and Pancreatic Adenocarcinoma

Leukemoid reaction (LR) associated with solid tumors has been documented for many decades. LR is often associated with an unfavorable prognosis and aggressive course of the disease. However, the differential diagnosis of LR is of significant difficulty when a patient has several potential etiological factors, each of them individually may cause LR or, on the contrary, lead to a systemic reaction of the body within a single pathogenetic chain.We present a clinical observation of an elderly patient admitted to the intensive care unit due to the first-time encountered weakness in the right extremities. Clinical and instrumental examination revealed an acute cerebral ischemia with leukocytosis increase up to 60.000 cells/μL with leukocyte formula left shift and subsequent patient decompensation with lethal outcome, despite the intensive treatment.Autopsy revealed a low-differentiated adenocarcinoma of the pancreatic tail with multiple metastatic lesions in regional lymph nodes and liver, as well as a competing disease — acute infective endocarditis of the aortic valve, which was the cause of sepsis development with septicemia type and thromboembolism both in the great circulation circle with the presence of ischemic cerebral infarction, spleen infarcts, and in the small circle with the development of thromboembolism in the right segmental branches of the pulmonary artery. Given the advanced stage of pancreatic cancer and lack of direct evidence of sepsis at primary diagnosis, paraneoplastic nature of LR is more likely, but infective endocarditis and concomitant pathology also may have contributed to the development of LR.

Parallel Accelerating Number Theoretic Transform for Bootstrapping on a Graphics Processing Unit

The bootstrapping procedure has become the main bottleneck affecting the efficiency of all known fully homomorphic encryption (FHE) schemes. The state-of-the-art scheme for efficient bootstrapping, which is called fully homomorphic encryption over the torus (TFHE), accelerates polynomial multiplication by leveraging number theoretic transform (NTT) and implementing NTT in parallel on a GPU. Unfortunately, almost none of the recent advancements in NTT take full advantage of a GPU, leading to the need for more time. With this in mind, in this work, a novel faster number theoretic transform based on a GPU is proposed, in which matrix multiplication is used to implement a decomposed small-point NTT. When implementing matrix multiplication, we introduce a merging preprocessing method to merge multiple inputs of the small-point NTT, aiming to effectively minimize the count of modulo operations. Subsequently, when the merged result is multiplied by rotation factors, we use logical left shift rather than arithmetic multiplication to improve the computational efficiency. Our scheme can easily be used to realize a 1024-point NTT and the results of the experiments show that the speedup ratio of our method over the butterfly algorithm is about 2.49.

Comparative pharmacokinetic evaluation of glimepiride orodispersable and conventional tablets in rabbits

Objectives Glimepiride Orodispersable Tablets (ODT) were prepared with the goal to have rapid onset of action and higher bioavailability with ease administration to individuals with swallowing difficulty to ameliorate patient compliance. Significance Glimepiride is a contemporary hypoglycemic medication that belongs to the family of sulfonylurea derivatives. It is used in type 2 diabetes mellitus. Compliance adherence remains one of the limitations with the conventional drug delivery system especially in pediatric, geriatric, psychiatric, and traveling patients, for such population ODT provides a good alternate dosage form compared with Commercial Tablets. Method The Comparative in vivo pharmacokinetic parameters of the prepared ODT and conventional tablets (CT) were evaluated using an animal model. The plasma concentration of Glimepiride after oral administration of a single dose was determined at predetermined time intervals with HPLC. The pharmacokinetic parameters were calculated using PK Solutions 2.0 from Summit PK® software. Results The Cmax obtained with ODT (22.08 µg/ml) was significantly (p = 0.006) high, a lower tmax of 3.0 hr was achieved with the orodispersable formulation of the drug. The ODT showed 104.34% relative bioavailability as compared to CT and left shift of tmax as well. Conclusion As per findings of the in vivo investigation, the Glimepiride ODT would be beneficial in terms of patient compliance, quick onset of action, and increased bioavailability.