Frequency of Familial Mediterranean Fever Gene Mutation in Patients Presenting With Joint Pain and Diagnosed With Acute Rheumatic Fever.

Introduction Acute rheumatic fever (ARF) is a non-suppurative systemic inflammatory disease that manifests 1-5 weeks following a Group A beta-hemolytic streptococcal infection. On the other hand, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized as an autosomal recessive disease, with affected individuals having pathogenic mutations in the Mediterranean fever gene (MEFV) gene located on the short arm of chromosome 16. FMF and ARF have overlapping symptoms and signs, and both disorders are common in Turkey. In ARF, the target organ is the heart, while in FMF, the target organ is the kidney; both organs can benefit from prophylactic measures. Our study aims to determine the frequency of the FMF gene mutation in patients with ARF in Turkey and detect any overlapping conditions. Method Patients who were diagnosed with a first-attack ARF between May 2015 and May 2018 were retrospectively screened. Patients who underwent MEFV gene analysis considering FMF in the differential diagnosis were included in the study. Results In this study, no statistical difference was found between the presence of MEFV gene mutations, carditis, high anti-streptolysin-O antibody (ASO) levels, and the groups with monoarthritis, polyarthritis, and polyarthralgia (p >0.05). Conclusions In conclusion, patients with ARF should be evaluated for FMF to avoid irreversible complications.

Evaluation of learning and exposure in the undergraduate interventional radiology curriculum (ELIXIR).

AIM: To gauge current final year medical students' exposure to interventional radiology (IR)and assess their perceptions of IR as a prospective career option. MATERIALS AND METHODS: An online questionnaire comprising of questions that gauge final-year medical students' understanding of and exposure to IR based on the recommendations set out by the British Society of Interventional Radiology (BSIR), was sent out to final-year students across 34 UK medical schools. RESULTS: Five hundred and ten responses were collected from 33 out of 34 eligible medical schools. Sixty-four per cent of respondents rated their own IR knowledge as inadequate. On average, only 50% of all subtopics proposed in the BSIR undergraduate curriculum was covered during medical school and 32.7% of respondents were not exposed to any fundamental IR principles and techniques recommended by the BSIR during medical school. Regarding careers, 2.7% of respondents reported a definite interest in pursuing a career in IR. Most respondents (89.8%) felt that there was insufficient undergraduate teaching on IR and that they lacked information to consider pursuing a career in IR (87.5%). CONCLUSION: Insufficient exposure and teaching on IR throughout medical schools have led to a lack of awareness and consideration of IR as a future career choice amongst UK medical students. The re-evaluation of IR teaching in the medical school curricula is needed. In the long-term, such recommendations could provide the much-needed solution to the workforce shortages seen in IR.

Long-term effects of COVID-19 on lungs and the clinical relevance: a 6-month prospective cohort study.

Background: We aimed to explore the prevalence of prolonged symptoms, pulmonary impairments and residual disease on chest tomography (CT) in COVID-19 patients at 6 months after acute illness. Methods: In this prospective, single-center study, hospitalized patients with radiologically and laboratory-confirmed COVID-19 were included. Results: A high proportion of the 116 patients reported persistent symptoms (n = 54; 46.6%). On follow-up CT, 33 patients (28.4%) demonstrated residual disease. Multivariate analyses revealed that only neutrophil-to-lymphocyte ratio was an independent predictor for residual disease. Conclusion: Hospitalized patients with mild/moderate COVID-19 still had persistent symptoms and were prone to develop long-term pulmonary sequelae on chest CT. However, it did not have a significant effect on long-term pulmonary functions.

Performance of noninvasive fibrosis indices in chronic hepatitis B during pretreatment and post-treatment periods.

Background: Pretreatment and post-treatment performances of noninvasive fibrosis indices were determined in patients with chronic hepatitis B. Method: This was a retrospective, single-center study. Results: The best area under the receiver operating characteristic curve values were detected for aspartate aminotransferase-to-alanine aminotransferase ratio (0.685) for ≥F2, Fibrosis Index (FI; 0.703) for ≥F3; FI (0.872) for ≥F4 and FI (0.864) for cirrhosis. After antiviral treatment, the best area under the receiver operating characteristic curve values were detected in aspartate aminotransferase-to-alanine aminotransferase ratio (0.615) for ≥F2; in FI based on four factors (FIB-4; 0.634) for ≥F3; in FIB-4 (0.678) for ≥F4 and in FIB-4 (0.814) for cirrhosis. Conclusion: FIB-4 and FI showed better performance in defining advanced fibrosis (≥F4) and cirrhosis.

Novel biomarker-based score (SAD-60) for predicting mortality in patients with COVID-19 pneumonia: a multicenter retrospective cohort of 1013 patients.

Background: The aim was to explore a novel risk score to predict mortality in hospitalized patients with COVID-19 pneumonia. Methods: This was a retrospective, multicenter study. Results: A total of 1013 patients with COVID-19 were included. The mean age was 60.5 ± 14.4 years, and 581 (57.4%) patients were male. In-hospital death occurred in 124 (12.2%) patients. Multivariate analysis revealed peripheral capillary oxygen saturation (SpO2), albumin, D-dimer and age as independent predictors. The mortality score model was given the acronym SAD-60, representing SpO2, Albumin, D-dimer, age ≥60 years. The SAD-60 score (0.776) had the highest area under the curve compared with CURB-65 (0.753), NEWS2 (0.686) and qSOFA (0.628) scores. Conclusion: The SAD-60 score has a promising predictive capacity for mortality in hospitalized patients with COVID-19.

The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors.

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.

Factors Associated with Self-Reported Dysphagia in Older Adults Receiving Meal Support.

OBJECTIVES: Dysphagia is common in older adults. However, there are no current estimates of dysphagia in community-dwelling older adults those receiving meal support. It is unknown whether dysphagia is associated with other measures of physical function (activities of daily living [ADL] ability or nutrition status). The study purposes were to determine the prevalence of self-reported dysphagia and to identify factors associated with self-reported dysphagia in community-dwelling older adults receiving meal support. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: 476 community-dwelling older adults (78.5±0.51 years) across five Elder Nutrition Program meal services in Wisconsin participated in the study. MEASUREMENTS: Data were collected through administration of validated ADL and nutrition questionnaires (nutritional status, functional status with ADLs, chewing ability, dental conditions, and prior diagnoses of dysphagia, pneumonia, and dementia). For self-reported dysphagia, the validated 10-item eating assessment tool (EAT-10) was used. RESULTS: The prevalence of self-reported dysphagia (EAT-10 score of ≥ 3) was 20.4%. Multivariate logistic regression results indicated that poor nutritional status (OR=3.1, p=0.04), difficulty chewing (OR=2.2, p=0.03), prior dysphagia diagnosis (OR=34.8, p<0.001), prior pneumonia diagnosis (OR=2.1, p=0.04), and meal service site (OR=2.68, p=0.02) were associated with self-reported dysphagia. CONCLUSION: Approximately one in five community-dwelling older adults receiving meal support had self-reported dysphagia. Increased risk for poor nutrition, reduced chewing ability, prior dysphagia and pneumonia diagnosis, and meal service site were identified as factors associated with dysphagia on the EAT-10. Results highlight the need for further studies across more sites to identify dysphagia risk indicators in community-dwelling older adults receiving meal support state-wide.

National Early Warning Score 2 and laboratory predictors correlate with clinical deterioration in hospitalized patients with COVID-19.

Aim: We aimed to determine the prognostic values of the National Early Warning Score 2 (NEWS2) and laboratory parameters during the first week of COVID-19. Materials & methods: All adult patients who were hospitalized for confirmed COVID-19 between 11 March and 11 May 2020 were retrospectively included. Results: Overall, 611 patients were included. Our results showed that NEWS2, procalcitonin, neutrophil/lymphocyte ratio and albumin at D0, D3, D5 and D7 were the best predictors for clinical deterioration defined as a composite of ICU admission during hospitalization or in-hospital death. Procalcitonin had the highest odds ratio for clinical deterioration on all days. Conclusion: This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for clinical deterioration in patients with COVID-19.

Lay abstract The COVID-19 pandemic is a grueling problem worldwide. There is a lack of knowledge about the predictive value of National Early Warning Score 2 (NEWS2) for severe COVID-19 illness. We analyzed the prognostic value of NEWS2 and laboratory parameters during the clinical course of COVID-19. This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for intensive care unit admission during hospitalization or in-hospital death.

Understanding the future research needs in Postural Orthostatic Tachycardia Syndrome (POTS): Evidence mapping the POTS adult literature.

POTS is under diagnosed with an estimated prevalence of 0.2%. North American and Australian researchers, as well as patient groups have called for more research into POTS. However, there has been no comprehensive appraisal of the current POTS evidence base. AIM: To map the POTS evidence base. METHODS: Two reviewers systematically searched 12 databases until July 1st 2019 using the search term "Postural Tachycardia Syndrome" (n = 7280) and categorised the literature. Inclusion criteria included all adult published literature with no language restrictions. 779 papers are analysed and mapped. RESULTS: Seven themes were identified: symptomology and quality of life 16.8% (n = 132), biomedical topics 16.5% (n = 130), co-morbidities 10.3% (n = 81), non-pharmacological management 9.8% (n = 77), aetiologies 6.9% (n = 53), pharmacological management 6.7% (n = 53), and clinical management 6.6% (n = 52). There 45 subthemes. Quality appraisal of the research studies (n = 233) evaluated design, sample size, outcome measures, data analysis and research biases. 74.8% (n = 175) were observational designs and 25.2% (n = 59) were experimental designs (16 using a randomised controlled design, 11 of which had a sample size greater than 21). 47.4% (n = 111) of studies only measured duration of effect for <1 day. 11.5% (n = 27) of studies reported outcomes using an unvalidated subjective measurement tool. CONCLUSION: The volume of adult POTS literature is small and the validity and reliability of the research lacks rigour. The evidence map methodology provides POTS researchers with a benchmark for research thus far. This paper adds an in-depth research appraisal to the broad calls for action, highlighting the pressing need for multicentre, good quality research in POTS, to support guidelines and consensus development in the future.

Economic Studies Reinforce Efforts to Safeguard Specialty Crops in the United States.

Pathogen-tested foundation plant stocks are the cornerstone of sustainable specialty crop production. They provide the propagative units that are used to produce clean planting materials, which are essential as the first-line management option of diseases caused by graft-transmissible pathogens such as viruses, viroids, bacteria, and phytoplasmas. In the United States, efforts to produce, maintain, and distribute pathogen-tested propagative material of specialty crops are spearheaded by centers of the National Clean Plant Network (NCPN). Agricultural economists collaborated with plant pathologists, extension educators, specialty crop growers, and regulators to investigate the impacts of select diseases caused by graft-transmissible pathogens and to estimate the return on investments in NCPN centers. Economic studies have proven valuable to the NCPN in (i) incentivizing the use of clean planting material derived from pathogen-tested foundation plant stocks; (ii) documenting benefits of clean plant centers, which can outweigh operating costs by 10:1 to 150:1; (iii) aiding the development of disease management solutions that are not only ecologically driven but also profit maximizing; and (iv) disseminating integrated disease management recommendations that resonate with growers. Together, economic studies have reinforced efforts to safeguard specialty crops in the United States through the production and use of clean planting material.

Treatment outcomes in patients with drug-resistant TB-HIV co-infection treated with bedaquiline and linezolid.

BACKGROUND: Bedaquiline (BDQ) has not been extensively studied among patients co-infected with HIV drug-resistant tuberculosis (DR-TB). We compared treatment outcomes in DR-TB patients treated with BDQ- and linezolid (LZD) containing regimens to historic controls treated with second-line injectable-containing regimens.METHODS: Retrospective cohort study of consecutive DR-TB patients initiated on BDQ- and LZD-containing regimens at a TB referral hospital in KwaZulu-Natal, South Africa. Participants were prospectively followed through 24 months for treatment outcome and adverse events. Outcomes were compared to a historic control cohort of DR-TB HIV patients enrolled at the same facility prior to BDQ introduction.RESULTS: Adult DR-TB patients initiating BDQ between January 2014 and November 2015 were enrolled (n = 151). The majority of patients were female (52%), HIV co-infected (77%) and on antiretroviral therapy (100%). End of treatment outcomes included cure (63%), TB culture conversion (83%), completion (0.7%), loss to follow-up (15%), treatment failure (5%), and death (17%). Compared to historic controls (n = 105), patients treated with BDQ experienced significantly higher TB culture conversion and cure, with significantly lower mortality. Adverse effects were common (92%), and most frequently attributed to LZD (24.1%). QT segment prolongation was common but without clinical sequelae.CONCLUSION: Treatment with BDQ- and LZD-containing regimens was associated with improved treatment outcomes and survival in DR-TB HIV patients.

Akt Pathway Inhibitors.

Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.

Akt Pathway Inhibition of the Solenopsin Analog, 2-Dodecylsulfanyl-1,-4,-5,-6-tetrahydropyrimidine.

BACKGROUND/AIM: The P13K/Akt signaling pathway is a growth-regulating cellular pathway that is constitutively activated in a variety of human cancers. In previous studies, we reported that a solenopsin analog, compound B (MU-06-SC-608-7), shows inhibitory effects on Akt phosphorylation at a key activation site, as well as on proliferation of tumorigenic cells at sub-micromolar concentrations. The purpose of this study was to evaluate the effect of compound B on downstream effectors of Akt kinase, phosphorylation of Akt at a second activation site, Akt kinase activity in vitro, tumorigenic cell viability and other signaling pathways. MATERIALS AND METHODS: Western blot analyses were performed using WBras1 epithelial and H2009 human carcinoma cells and cell viability assays were performed on H2009 cells. In vitro Akt kinase assays were performed using a commercially available kit. RESULTS: Compound B decreased the phosphorylation of Akt at the Thr308 activation site and key downstream effectors of Akt kinase, but did not directly inhibit Akt kinase. Substantial decreases in cell viability were observed at concentrations above 5 µM. No effect was seen on ERK or JNK pathways. CONCLUSION: The results earmark this compound for further studies as a potential targeted cancer therapy.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo.

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Discovery and biological activity of computer-assisted drug designed Akt pathway inhibitors.

The P13K/Akt pathway is a growth-regulating cellular signaling pathway that is over-activated in numerous human cancers. A novel series of Akt pathway inhibitors were identified using iterative pharmacophore modeling, energy-based calculations, and property predictions of known Akt inhibitors. Inhibitory effects on activation of Akt and growth of human neoplastic cells are reported. Results show variable inhibitory effects of three selected compounds on Akt phosphorylation at a key activation site, and on proliferation of tumorigenic cells. We identify one lead compound with potent inhibitory activity on both human carcinoma cell proliferation and Akt activation.

Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4.

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii.

Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a KI value of 1.5µM. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The KI for this compound was found to be 34µM, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO.

Oxidation of monoterpenes in Protium heptaphyllum oleoresins.

Protium heptaphyllum (Burseraceae) oleoresins are rich in volatile monoterpenes, exhibiting a chemical composition that can be strongly altered with time. The present work aimed to discuss the temporal change of the volatile composition of these oleoresins, and search for related supporting evidence. Samples of P. heptaphyllum oleoresin were collected separately for fresh (n = 10) and aged (n = 8) oleoresins, with the essential oils obtained by hydrodistillation analyzed by GC-FID and GC-MS. Fresh oleoresins were characterized by a high content of terpinolene (28.2-69.7%), whereas aged ones contained large amounts of p-cymene (18.7-43.0%) and p-cymen-8-ol (8.2-31.8%). Multivariate analyses were performed based on the yield and major essential oil components to clearly demonstrate the existence of two subsets (fresh and aged oleoresins). In addition, an analysis of the partial genome sequencing of the species was carried out, producing the largest amount of data for the genus Protium. Subsequently, were searched for nucleotide sequences responsible for the enzymes involved in the biosynthesis of monoterpenes. Two hypotheses were formulated to understand the oxidation process during aging of the oleoresins: (i) a natural chemical oxidation of terpenes and (ii) an oxidation catalyzed by enzymes produced by microorganisms associated with the plant. The results suggested that terpinolene was most likely oxidized to p-cymene, which, in turn, was oxidized into p-cymen-8-ol during natural aging of the exudate due to abiotic factors.

Comparison of osteoconductive properties of three different ß-tricalcium phosphate graft materials: a pilot histomorphometric study in a pig model.

AIMS: The aim of this study was to compare the de novo bone formation ability and osteoconductive effects of three different ß-tricalcium phosphate (ß-TCP) graft materials. The micro-architectural parameters of the newly formed bone tissues were also compared among the different graft materials. MATERIAL AND METHODS: Eight male Swiss domestic pigs were used in the study. Five bony defects were made with a trephine bur. Three of the defects were filled with Cerasorb®, Kasios® and Poresorb®. The fourth defect was filled with an autogenous bone graft. The last defect remained empty. All subjects were sacrificed after 8 weeks. RESULTS: When compared to a negative control group, significant healing was observed in all the groups except the Cerasorb group. The osteoconductivity of the Poresorb group was better than that of the other groups (p < 0.05). The difference in the osteoconductivity of the Kasios and Cerasorb groups was statistically significant (p < 0.05). Comparison of the micro-architectural properties of newly formed bone tissues retrieved from the defects showed that those filled with Poresorb were the best. CONCLUSION: ß-TCP materials show different results in terms of the volume and characteristics of new bone formation, although they have a similar chemical structure.