The global patent landscape of emerging infectious disease monkeypox.

BACKGROUND: Monkeypox is an emerging infectious disease with confirmed cases and deaths in several parts of the world. In light of this crisis, this study aims to analyze the global knowledge pattern of monkeypox-related patents and explore current trends and future technical directions in the medical development of monkeypox to inform research and policy. METHODS: A comprehensive study of 1,791 monkeypox-related patents worldwide was conducted using the Derwent patent database by descriptive statistics, social network method and linear regression analysis. RESULTS: Since the 21st century, the number of monkeypox-related patents has increased rapidly, accompanied by increases in collaboration between commercial and academic patentees. Enterprises contributed the most in patent quantity, whereas the initial milestone patent was filed by academia. The core developments of technology related to the monkeypox include biological and chemical medicine. The innovations of vaccines and virus testing lack sufficient patent support in portfolios. CONCLUSIONS: Monkeypox-related therapeutic innovation is geographically limited with strong international intellectual property right barriers though it has increased rapidly in recent years. The transparent licensing of patent knowledge is driven by the merger and acquisition model, and the venture capital, intellectual property and contract research organization model. Currently, the patent thicket phenomenon in the monkeypox field may slow the progress of efforts to combat monkeypox. Enterprises should pay more attention to the sharing of technical knowledge, make full use of drug repurposing strategies, and promote innovation of monkeypox-related technology in hotspots of antivirals (such as tecovirimat, cidofovir, brincidofovir), vaccines (JYNNEOS, ACAM2000), herbal medicine and gene therapy.

Composite Classical Hodgkin Lymphoma and Mantle Cell Lymphoma: A Case Report.

Composite lymphoma implies the presence of two or more morphological and immunophenotypical subtypes of lymphoma in a single tissue or organ. Composite lymphoma with concurrent mantle cell lymphoma (MCL) and classical Hodgkin lymphoma is extremely rare. In this case report, we present the case of a 70-year-old male who was diagnosed with a composite of MCL and classical Hodgkin lymphoma (cHL) and achieved near-complete resolution with chemoimmunotherapy. To the best of our knowledge, this is the first case of this kind demonstrating the effectiveness of a combination chemoimmunotherapy regimen leading to complete remission in composite lymphoma involving MCL and cHL. We report the history, imaging findings, and pathology and illustrate the challenges in therapeutic decision-making in managing composite lymphoma patients involving MCL and cHL. We also review the literature on this rare entity and discuss its clinical implications.

Machine learning-based evaluation of application value of pulse wave parameter model in the diagnosis of hypertensive disorder in pregnancy.

Hypertensive disorder in pregnancy (HDP) remains a major health burden, and it is associated with systemic cardiovascular adaptation. The pulse wave is an important basis for evaluating the status of the human cardiovascular system. This research aims to evaluate the application value of pulse waves in the diagnosis of hypertensive disorder in pregnancy.This research a retrospective study of pregnant women who attended prenatal care and labored at Beijing Haidian District Maternal and Child Health Hospital. We extracted maternal hemodynamic factors and measured the pulse wave of the pregnant women. We developed an HDP predictive model by using support vector machine algorithms at five-gestational-week stages.At five-gestational-week stages, the area under the receiver operating characteristic curve (AUC) of the predictive model with pulse wave parameters was higher than that of the predictive model with hemodynamic factors. The AUC values of the predictive model with pulse wave parameters were 0.77 (95% CI 0.64 to 0.9), 0.83 (95% CI 0.77 to 0.9), 0.85 (95% CI 0.81 to 0.9), 0.93 (95% CI 0.9 to 0.96) and 0.88 (95% CI 0.8 to 0.95) at five-gestational-week stages, respectively. Compared to the predictive models with hemodynamic factors, the predictive model with pulse wave parameters had better prediction effects on HDP.Pulse waves had good predictive effects for HDP and provided appropriate guidance and a basis for non-invasive detection of HDP.

SAMS-Net: Fusion of attention mechanism and multi-scale features network for tumor infiltrating lymphocytes segmentation.

Automatic segmentation of tumor-infiltrating lymphocytes (TILs) from pathological images is essential for the prognosis and treatment of cancer. Deep learning technology has achieved great success in the segmentation task. It is still a challenge to realize accurate segmentation of TILs due to the phenomenon of blurred edges and adhesion of cells. To alleviate these problems, a squeeze-and-attention and multi-scale feature fusion network (SAMS-Net) based on codec structure, namely SAMS-Net, is proposed for the segmentation of TILs. Specifically, SAMS-Net utilizes the squeeze-and-attention module with the residual structure to fuse local and global context features and boost the spatial relevance of TILs images. Besides, a multi-scale feature fusion module is designed to capture TILs with large size differences by combining context information. The residual structure module integrates feature maps from different resolutions to strengthen the spatial resolution and offset the loss of spatial details. SAMS-Net is evaluated on the public TILs dataset and achieved dice similarity coefficient (DSC) of 87.2% and Intersection of Union (IoU) of 77.5%, which improved by 2.5% and 3.8% compared with UNet. These results demonstrate the great potential of SAMS-Net in TILs analysis and can further provide important evidence for the prognosis and treatment of cancer.

Enhanced antibody-defucosylation capability of α-L-fucosidase by proximity-based protein fusion.

Up to date, the reported fucosidases generally show poor activities toward the IgG core-fucose, which limits the efficiency of ENGase-catalyzed glycoengineering process. However, EndoS or EndoS2 owns excellent activity and great selectivity towards the N-glycosylation of IgGs, and their non-catalytic domains are deduced to have specific interactions to IgG Fc domain that result in the great activity and selectivity. Herein, we constructed a series fusion protein of AlfC (an α-l-fucosidase from Lactobacillus casei BL23) with EndoS/S2 non-catalytic domain by replacing the catalytic GH (glycan hydrolase) domain of EndoS/S2 with the AlfC. We found that all these fused AlfCs showed significantly enhanced defucosylation activity toward the deglycosylated IgGs (Fucα1,6GlcNAc-IgG). We also performed the kinetic study of these fusion enzymes, and our results tend to tell that the EndoS-based fusion proteins have higher kcat values while the EndoS2-based ones possess lower Km values other than higher kcat. Conclusively, our research provides an effective approach to improve the activity of AlfC and remarkably shortened the defucosylation process within several minutes, which will significantly promote the development of glycoengineered antibodies in the future.

Eosinophilic Gastritis/Gastroenteritis.

PURPOSE OF REVIEW: Eosinophilic gastritis/gastroenteritis (EG/EGE) are rare eosinophilic infiltrative disorders in children and adults that fall under the umbrella term eosinophilic gastrointestinal disorders (EGIDs). EGIDs also include eosinophilic esophagitis (EoE) and eosinophilic colitis. In this article, we present the current literature regarding the clinical presentation, diagnostic criteria, and management of EG/EGE. RECENT FINDINGS: The underlying complex pathophysiology remains unknown, yet hypersensitivity response is a central component. Unlike EoE, standardized diagnostic criteria are lacking but, promising research employing tissue-based and blood-based methods of diagnosis have been reported. Non-EoE EGIDs are more challenging to treat than EoE. More than a third of patients may achieve spontaneous remission. Still, most will require dietary elimination and/or pharmaceutical interventions, mainly corticosteroids, but also biologics (monoclonal antibodies against IL-4, IL-5, TNFα, integrin α4ß7, and IgE), mast-cell stabilizers, leukotriene (LT)-receptor antagonists, and antihistamines. Promising research suggests the role of AK002, an anti-siglec antibody, in clinical and histological improvement. Given the rarity and underdiagnosis of EG/EGE, different natural progression compared to EoE, heterogeneous clinical manifestations, and probable normal endoscopic appearance, it is vital to maintain a high suspicion index in atopic patients, obtain at least 5-6 random biopsies from each site for gastro/duodenal eosinophilic infiltrate with the subsequent exclusion of inflammatory, allergic and infectious differential diagnoses to increase the yield of an accurate diagnosis. Corticosteroids remain the mainstay of treatment, often requiring long-term use. Steroid-sparing agents remain experimental. Goals of therapy move beyond clinical remission but lack evidence to support histological remission.

SHA-MTL: soft and hard attention multi-task learning for automated breast cancer ultrasound image segmentation and classification.

Purpose The automatic analysis of ultrasound images facilitates the diagnosis of breast cancer effectively and objectively. However, due to the characteristics of ultrasound images, it is still a challenging task to achieve analyzation automatically. We suppose that the algorithm will extract lesion regions and distinguish categories easily if it is guided to focus on the lesion regions.Method We propose a multi-task learning (SHA-MTL) model based on soft and hard attention mechanisms for breast ultrasound (BUS) image simultaneous segmentation and binary classification. The SHA-MTL model consists of a dense CNN encoder and an upsampling decoder, which are connected by attention-gated (AG) units with soft attention mechanism. Cross-validation experiments are performed on BUS datasets with category and mask labels, and multiple comprehensive analyses are performed on the two tasks.Results We assess the SHA-MTL model on a public BUS image dataset. For the segmentation task, the sensitivity and DICE of the SHA-MTL model to the lesion regions increased by 2.27% and 1.19% compared with the single task model, respectively. The classification accuracy and F1 score increased by 2.45% and 3.82%, respectively.Conclusion The results validate the effectiveness of our model and indicate that the SHA-MTL model requires less a priori knowledge to achieve better results by comparing with other recent models. Therefore, we can draw the conclusion that paying more attention to the lesion region of BUS is conducive to the discrimination of lesion types.

Research on the classification of lymphoma pathological images based on deep residual neural network.

BACKGROUND: Malignant lymphoma is a type of tumor that originated from the lymphohematopoietic system, with complex etiology, diverse pathological morphology, and classification. It takes a lot of time and energy for doctors to accurately determine the type of lymphoma by observing pathological images. OBJECTIVE: At present, an automatic classification technology is urgently needed to assist doctors in analyzing the type of lymphoma. METHODS: In this paper, by comparing the training results of the BP neural network and BP neural network optimized by genetic algorithm (GA-BP), adopts a deep residual neural network model (ResNet-50), with 374 lymphoma pathology images as the experimental data set. After preprocessing the dataset by image flipping, color transformation, and other data enhancement methods, the data set is input into the ResNet-50 network model, and finally classified by the softmax layer. RESULTS: The training results showed that the classification accuracy was 98.63%. By comparing the classification effect of GA-BP and BP neural network, the accuracy of the network model proposed in this paper is improved. CONCLUSIONS: The network model can provide an objective basis for doctors to diagnose lymphoma types.

Author Correction: A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A multi-feature image retrieval scheme for pulmonary nodule diagnosis.

Deep analysis of radiographic images can quantify the extent of intra-tumoral heterogeneity for personalized medicine.In this paper, we propose a novel content-based multi-feature image retrieval (CBMFIR) scheme to discriminate pulmonary nodules benign or malignant. Two types of features are applied to represent the pulmonary nodules. With each type of features, a single-feature distance metric model is proposed to measure the similarity of pulmonary nodules. And then, multiple single-feature distance metric models learned from different types of features are combined to a multi-feature distance metric model. Finally, the learned multi-feature distance metric is used to construct a content-based image retrieval (CBIR) scheme to assist the doctors in diagnosis of pulmonary nodules. The classification accuracy and retrieval accuracy are used to evaluate the performance of the scheme.The classification accuracy is 0.955 ±â€Š0.010, and the retrieval accuracies outperform the comparison methods.The proposed CBMFIR scheme is effective in diagnosis of pulmonary nodules. Our method can better integrate multiple types of features from pulmonary nodules.

Acute hepatitis and acute liver failure: Pathologic diagnosis and differential diagnosis.

Acute hepatitis and acute liver failure are severe medical conditions that require early clinical intervention. Histopathologic findings on a liver biopsy or a liver explant may help identify the underlying etiology or provide an important direction for further clinical, laboratory and radiographical investigation. This review is divided into two main portions. The first portion concentrates on various etiologies and discusses unique histologic features that can be associated with specific etiologies. The second portion describes the general morphologic features based on which the diagnosis of acute hepatitis and acute liver failure are made. Histopathologic distinction between collapse and cirrhosis and limitations of histopathologic assessment for underlying etiologies are addressed in this portion. Another focus of this review is non-necrotic acute liver failure, which typically features diffuse microvesicular steatosis secondary to various etiologies causing mitochondrial dysfunction. Molecular testing serves an increasingly important role in the diagnosis and management of this group of disorders.

A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 µM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease.

Goblet Cell Carcinoid/Carcinoma: An Update.

Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. The hallmark of GCC is the concentric infiltration of the appendiceal wall by small tight clusters, nests or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin. The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized as a common finding, which has been called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis. Several histologic classification/grading systems have been proposed, which correlate with overall patient survival. Treatment options are primarily based on tumor stage and the presence or absence of a high-grade adenocarcinomatous component.

Prolymphocytic transformation of lymphoplasmacytic lymphoma: an extremely unusual event.

Although rare cases of prolymphocytic transformation from splenic B-cell lymphomas and follicular lymphoma have been reported, prolymphocytic transformation from lymphoplasmacytic lymphoma has not been previously reported. We report a case of 76-year-old-male patient with a history of Waldenström macroglobulinemia diagnosed in 2010 and treated with infusion chemotherapy. He was in clinical remission for 5 years. In 2016, he presented with diffuse lymphadenopathy, and a head and neck lymph node biopsy showed lymphoplasmacytic lymphoma. MYD88 mutation was detected by polymerase chain reaction. A subsequent bone marrow biopsy showed B-cell lymphoma with increased prolymphocytes. Peripheral blood showed numerous circulating prolymphocytes. MYD88 was detected by polymerase chain reaction in the bone marrow. Cerebrospinal fluid was positive for lymphoma cells with prolymphocytic morphology. An IgM κ paraprotein was noted by immunofixation performed on the patient's serum, urine, and cerebrospinal fluid. The patient was resistant to chemotherapy, developed multiorgan failure, and died shortly thereafter.

Atypical Hemolytic Uremic Syndrome: A Brief Review.

Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab - a monoclonal antibody directed against C5 - is effective.

Identification of novel loci affecting circulating chromogranins and related peptides.

Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10-30 for rs4253311 and 1.85 × 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.

Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system.

BACKGROUND: Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder. METHODS & RESULTS: Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes. CONCLUSIONS: The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target.

Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models.

OBJECTIVE: The human prohormone chromogranin A (CHGA), an index member of the granin family is processed to generate catestatin, a peptide that is hypotensive in action and modulates catecholamine release within the sympathoadrenal system. Hypertensive patients with excess sympathetic activity have diminished catestatin. Often the study of physiological consequences of human genetic variation is confounded by elements such as other variations in obligatory linkage disequilibrium with the variant being studied. Also the phenotype of the variant may be influenced by genetic background that varies amongst individuals. This study addresses the effects of a human catestatin polymorphism (rs9658667) using humanized CHGA mouse models. METHODS: We created pertinent humanized mouse models wherein the mouse Chga gene locus was replaced by the human ortholog wild-type and the variant versions. This allowed for probing of the effects of catestatin variation in vivo with controls for other variations and global genetic background. RESULTS: Both the wild-type and variant human catestatin expressing mouse models were normotensive. The variant catestatin mouse model recapitulated physiological influence of the polymorphism on autonomic traits. These mice had diminished catecholamine, attenuated stress response and increased baroreceptor slopes that would suggest reduced risk of developing hypertension. Elevated plasma glucose, a trait observed in humans was not observed in mice expressing the variant catestatin. CONCLUSION: This functional genomics approach of creating humanized mouse models to study rs9658667 polymorphism recapitulated and validated many of the human trait associations. This approach can also be applied in the study of other human gene polymorphisms.

Molecular Mechanism for Hypertensive Renal Disease: Differential Regulation of Chromogranin A Expression at 3'-Untranslated Region Polymorphism C+87T by MicroRNA-107.

Chromogranin A (CHGA) is coreleased with catecholamines from secretory vesicles in adrenal medulla and sympathetic axons. Genetic variation in the CHGA 3'-region has been associated with autonomic control of circulation, hypertension, and hypertensive nephropathy, and the CHGA 3'-untranslated region (3'-UTR) variant C+87T (rs7610) displayed peak associations with these traits in humans. Here, we explored the molecular mechanisms underlying these associations. C+87T occurred in a microRNA-107 (miR-107) motif (match: T>C), and CHGA mRNA expression varied inversely with miR-107 abundance. In cells transfected with chimeric luciferase/CHGA 3'-UTR reporters encoding either the T allele or the C allele, changes in miR-107 expression levels had much greater effects on expression of the T allele. Cotransfection experiments with hsa-miR-107 oligonucleotides and eukaryotic CHGA plasmids produced similar results. Notably, an in vitro CHGA transcription/translation experiment revealed that changes in hsa-miR-107 expression altered expression of the T allele variant only. Mice with targeted ablation of Chga exhibited greater eGFR. Using BAC transgenesis, we created a mouse model with a humanized CHGA locus (T/T genotype at C+87T), in which treatment with a hsa-miR-107 inhibitor yielded prolonged falls in SBP/DBP compared with wild-type mice. We conclude that the CHGA 3'-UTR C+87T disrupts an miR-107 motif, with differential effects on CHGA expression, and that a cis:trans (mRNA:miR) interaction regulates the association of CHGA with BP and hypertensive nephropathy. These results indicate new strategies for probing autonomic circulatory control and ultimately, susceptibility to hypertensive renal sequelae.

Large-cell neuroendocrine carcinoma (LCNEC) without pulmonary symptoms diagnosed in a cutaneous metastasis.

PATIENT: Female, 60 FINAL DIAGNOSIS: Large-cell neuroendocrine carcinoma Symptoms: Back pain Medication: - Clinical Procedure: Vertebroplasty Specialty: Oncology. OBJECTIVE: Unusual clinical course. BACKGROUND: An atypical presentation of large-cell neuroendocrine carcinoma was diagnosed from a metastatic nodule on the chest wall. CASE REPORT: The patient was a 60-year-old female who presented with intractable back pain with an MRI showing an L3 compression fracture and multiple lesions in L3, L5, and the pelvis. The patient had a 40-pack-year smoking history. On admission, a small, non-tender nodule was noted under her left breast on the chest wall. CT and PET scan confirmed diffuse metastases in the lumbar spine, brain, lung, liver, and pancreas, without knowing the primary site. The patient underwent L3 vertebroplasty and removal of the nodule on the chest wall. The pathology report of the nodule showed large cell neuroendocrine carcinoma (LCNEC). Immunohistochemical stains were positive for cytokeratin AE 1/3, TTF-1, CD56, Synaptophysin, and chromogranin. The stains were negative for CK7, Napsin, cytokeratin 20, GATA-3, mammaglobin, and CEA. A pathology diagnosis of metastatic LCNEC was made, with the lung as the most likely original site. CONCLUSIONS: Treatment consisted of pain control through an intra-thecal pump and whole brain radiation followed by systemic chemotherapy. This case elucidates the unusual cutaneous metastatic site for LCNECs, which was biopsied to confirm the diagnosis. This is the first case of LCNEC diagnosed by a cutaneous metastasis. In conclusion, it is possible to diagnose LCNEC of the lung at a distant metastatic site with careful histological and immunohistochemical examination, which can spare patients from more harmful biopsies.