Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Human-aided dispersal and population bottlenecks facilitate parasitism escape in the most invasive mosquito species.

During biological invasion process, species encounter new environments and partially escape some ecological constraints they faced in their native range, while they face new ones. The Asian tiger mosquito Aedes albopictus is one of the most iconic invasive species introduced in every inhabited continent due to international trade. It has also been shown to be infected by a prevalent yet disregarded microbial entomoparasite Ascogregarina taiwanensis. In this study, we aimed at deciphering the factors that shape the global dynamics of A. taiwanensis infection in natural A. albopictus populations. We showed that A. albopictus populations are highly colonized by several parasite genotypes but recently introduced ones are escaping it. We further performed experiments based on the invasion process to explain such pattern. To that end, we hypothesized that (i) mosquito passive dispersal (i.e. human-aided egg transportation) may affect the parasite infectiveness, (ii) founder effects (i.e. population establishment by a small number of mosquitoes) may influence the parasite dynamics, and (iii) unparasitized mosquitoes are more prompt to found new populations through active flight dispersal. The two first hypotheses were supported as we showed that parasite infection decreases over time when dry eggs are stored and that experimental increase in mosquitoes' density improves the parasite horizontal transmission to larvae. Surprisingly, parasitized mosquitoes tend to be more active than their unparasitized relatives. Finally, this study highlights the importance of global trade as a driver of biological invasion of the most invasive arthropod vector species.

Efficient production of human interleukin-3 from Escherichia coli using protein disulfide isomerase b'a' domain.

Human interleukin-3 (IL3) is a multifunctional cytokine essential for both clinical and biomedical research endeavors. However, its production in Escherichia coli has historically been challenging due to its aggregation into inclusion bodies, requiring intricate solubilization and refolding procedures. This study introduces an innovative approach employing two chaperone proteins, maltose binding protein (MBP) and protein disulfide isomerase b'a' domain (PDIb'a'), as N-terminal fusion tags. Histidine tag (H) was added at the beginning of each chaperone protein gene for easy purification. This fusion of chaperone proteins significantly improved IL3 solubility across various E. coli strains and temperature conditions, eliminating the need for laborious refolding procedures. Following expression optimization, H-PDIb'a'-IL3 was purified using two chromatographic methods, and the subsequent removal of the H-PDIb'a' tag yielded high-purity IL3. The identity of the purified protein was confirmed through liquid chromatography coupled with tandem mass spectrometry analysis. Biological activity assays using human erythroleukemia TF-1 cells revealed a unique two-step stimulation pattern for both purified IL3 and the H-PDIb'a'-IL3 fusion protein, underscoring the protein's functional integrity and revealing novel insights into its cellular interactions. This study advances the understanding of IL3 expression and activity while introducing novel considerations for protein fusion strategies.

Platelet-rich fibrin as an apical barrier for MTA placement in the treatment of teeth with open apices: a pilot study.

OBJECTIVE: The aim of the present pilot study was to assess the effectiveness of the platelet-rich fibrin (PRF) apical barrier for the placement of MTA for the treatment of teeth with periapical lesions and open apices. METHODS: A total of thirty teeth on twenty-eight patients with open apices and periapical periodontitis were enrolled and divided into two groups in the present pilot study. In the PRF group (fourteen teeth in thirteen patients), nonsurgical endodontic treatment was performed using PRF as an apical matrix, after which the apical plug of the MTA was created. For the non-PRF group (fourteen teeth in fourteen patients), nonsurgical endodontic therapy was performed using only the MTA for an apical plug with no further periapical intervention. Clinical findings and periapical digital radiographs were used for evaluating the healing progress after periodic follow-ups of 1, 3, 6, and 9 months. The horizontal dimension of the periapical lesion was gauged, and the changes in the dimensions were recorded each time. The Friedman test, Dunn-Bonferroni post hoc correction, and Mann-Whitney U test were used for statistical analysis, with P < 0.05 serving as the threshold for determining statistical significance. RESULTS: All patients in both groups in the present pilot study had no clinical symptoms after 1 month, with a significant reduction in the periapical lesion after periodic appointments. The lesion width of the PRF group was significantly smaller than that of the non-PRF group in the sixth and ninth month after treatment. CONCLUSIONS: PRF is a promising apical barrier matrix when combined with MTA for the treatment of teeth with open apices and periapical periodontitis. Small number of study subjects and the short time of follow-up period limit the generalizability of these results. TRIAL REGISTRATION: TCTR, TCTR20221109006. Registered 09 November 2022 - Retrospectively registered, https://www.thaiclinicaltrials.org/show/TCTR20221109006 .

Dapagliflozin Reduces Systemic Inflammation in Patients with Type 2 Diabetes Without Known Heart Failure.

Objective: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. Research and Design Methods: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); cardiac tissue inflammation was assessed by T2 mapping. Results: Between the baseline and 12-month time point, plasma IL-1B was reduced (-1.8 pg/mL, P=0.003) while ketones were increased (0.26 mM, P=0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (-158.9 pmole/min/106cells, P=0.0497 vs -45.2 pmole/min/106cells, P=0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. ECV and T2 relaxation time did not change in both study groups. Conclusion: This study demonstrates that 12 months of dapagliflozin reduces IL-1B mediated systemic inflammation but affect cardiac fibrosis in T2D. Clinical Trialgov Registration: NCT03782259.

Sesquiterpenoids and hexanorcucurbitacin from Aquilaria malaccensis agarwood with anti-inflammatory effects by inhibiting the STAT1/AKT/MAPK/NLRP3 pathway.

Seven unknown compounds 1-7, including four sesquiterpenoids, one azulene-type, one indene-type, and one rare hexanorcucurbitacin, together with eleven knowns ones (8-16), were isolated from the agarwood chips of Aquilaria malaccensis. The structures of the isolated compounds were elucidated by extensive spectroscopic methods such as mass spectrometry, UV, IR, NMR spectroscopy. The precise stereo-chemical configurations of new compounds were determined by calculated ECD spectra data, as well as a single-crystal X-ray diffraction analysis. The isolated compounds 1-7 were evaluated by estimating the levels of nitric oxide (NO), TNF-α, and the expression of enzyme iNOS, and COX-2. Among them, a rare hexanortriterpenoid (7) derived from a cucurbitane-type triterpenoid showed the significantly attenuated neuro-inflammatory effects via the STAT1/AKT/MAPK/NLRP3 signaling pathway on the mechanistic studies.

TAXN: Translate Align Extract Normalize, a Multilingual Extraction Tool for Clinical Texts.

Several studies have shown that about 80% of the medical information in an electronic health record is only available through unstructured data. Resources such as medical terminologies in languages other than English are limited and restrain the NLP tools. We propose here to leverage English based resources in other languages using a combination of translation, word alignment, entity extraction and term normalization (TAXN). We implement this extraction pipeline in an open-source library called "medkit". We demonstrate the interest of this approach through a specific use-case: enriching a phenotypic dictionary for post-acute sequelae in COVID-19 (PASC). TAXN proved to be efficient to propose new synonyms of UMLS terms using a corpus of 70 articles in French with 356 terms enriched with at least one validated new synonym. This study was based on freely available deep-learning models.

Near-Infrared Transparent Transition-Metal-Doped Indium Oxide Thin-Film Heater for LiDAR.

The evolving need for all-weather light detection and ranging (LiDAR) sensors and cameras for autonomous vehicles, remote sensing surveillance, and space exploration has spurred the development of transparent heaters. While LiDAR photon sources have shifted from the visible to the near-infrared (NIR) range, the use of transparent conductive oxides (TCOs) for heaters leads to significant optical losses due to their high plasmonic absorption and reflection in the NIR range. Although different TCO compositions can be employed to preserve transparency and electrical conductivity in this range, the choice of dopants, their concentrations, and the underlying mechanisms remain largely unknown. In this study, we present TCOs specifically designed for NIR applications with a focus on identifying new compositions that strike a balance between NIR transparency and electrical conductivity. We present a 4B-6B transition-metal-doped indium oxide thin-film heater that exhibits impressive NIR transmittance (>90%) surpassing that of commonly used indium tin oxide films. By incorporating effective dopants such as titanium, hafnium, and tungsten, we successfully reduced the resistivity and enhanced the electrical conductivity of indium oxide films. To enhance the practical utility of the film, we implemented post-treatments comprising argon plasma treatment and encapsulation with low-molecular-weight poly(dimethylsiloxane), which resulted in significantly improved performance. The optimized film exhibited a sheet resistance of 520 Ω/sq and excellent optical transmittance at 850 nm (89.1%), 905 nm (89.7%), and 1550 nm (92%). Moreover, we successfully integrated defogging and defrosting capabilities into a commercial LiDAR camera and demonstrated its reliable operation in challenging environments.

Novel Anti-Mesothelin Nanobodies and Recombinant Immunotoxins with Pseudomonas Exotoxin Catalytic Domain for Cancer Therapeutics.

Recombinant immunotoxins (RITs) are fusion proteins consisting of a targeting domain linked to a toxin, offering a highly specific therapeutic strategy for cancer treatment. In this study, we engineered and characterized RITs aimed at mesothelin, a cell surface glycoprotein overexpressed in various malignancies. Through an extensive screening of a large nanobody library, four mesothelin-specific nanobodies were selected and genetically fused to a truncated Pseudomonas exotoxin (PE24B). Various optimizations, including the incorporation of furin cleavage sites, maltose-binding protein tags, and tobacco etch virus protease cleavage sites, were implemented to improve protein expression, solubility, and purification. The RITs were successfully overexpressed in Escherichia coli, achieving high solubility and purity post-purification. In vitro cytotoxicity assays on gastric carcinoma cell lines NCI-N87 and AGS revealed that Meso(Nb2)-PE24B demonstrated the highest cytotoxic efficacy, warranting further characterization. This RIT also displayed selective binding to human and monkey mesothelins but not to mouse mesothelin. The competitive binding assays between different RIT constructs revealed significant alterations in IC50 values, emphasizing the importance of nanobody specificity. Finally, a modification in the endoplasmic reticulum retention signal at the C-terminus further augmented its cytotoxic activity. Our findings offer valuable insights into the design and optimization of RITs, showcasing the potential of Meso(Nb2)-PE24B as a promising therapeutic candidate for targeted cancer treatment.

Untargeted Metabolomics Approach for the Differentiation between Panax vietnamensis var. vietnamensis and Panax vietnamensis var. fuscidiscus.

Panax vietnamensis var. vietnamensis (PVV) and Panax vietnamensis var. fuscidiscus (PVF) both belong to Panax vietnamensis species and are chemically and morphologically similar, making it hard to distinguish for the consumer. Herein, 42 PVF and 12 PVV samples were collected in Quang Nam and Lai Chau Province, respectively, and subsequently characterized by ITSr-DNA sequence data to verify their origins. Next, untargeted metabolomics combined with multivariate statistical analysis was developed to differentiate PVV and PVF. The metabolic profiles of PVV and PVF were found to be distinct and classified well using Partial Least-Squares Discriminant Analysis (PLS-DA) in the training set. Among them, seven ginsenosides were of high abundance in PVV, while six were of high abundance in PVF. Next, the test set was used to validate 13 putative differential markers found in the training set, illustrating a complete match with the expression patterns of these ginsenosides in the training set. Finally, PLS-DA and linear Support Vector Machine models both indicated distinct ginsenoside profiles of PVV and PVF without misclassification in the test set. Conclusively, the developed untargeted metabolomics approach might serve as a powerful tool for the authentication of PVV and PVF at the metabolome level.

Preparations and characterizations of effervescent granules containing azithromycin solid dispersion for children and elder: Solubility enhancement, taste-masking, and digestive acidic protection.

Azithromycin, a macrolide antibiotics, is one of the frequently used drugs in the children and elder. However, due to these population difficulty in swallowing and inefficient absorption, and azithromycin inherent poor solubility, bitter taste, and instability in the stomach acidic condition, it is a challenge to reach high oral bioavailability of this drug. To overcome these issues, we developed and characterized the effervescent granules containing azithromycin solid dispersion. Firstly, the solid dispersion was prepared, employing both wet grinding and solvent evaporation methods, with different types/amounts of polymers. The optimal solid dispersion with ß-cyclodextrin at a drug:polymer ratio of 1:2 (w/w), prepared by the solvent evaporation method, significantly enhanced the azithromycin solubility 4-fold compared to the free drug, improved its bitterness from "bitter" to "normal", possessed intermolecular bonding between the drug and polymer, and transformed the azithromycin molecules from crystalline to amorphous state. Secondly, the effervescent granules incorporating the solid dispersion were formulated with varied excipients of sweeteners, gas-generators, pH modulators, and glidants/lubricants. The optimal formula satisfied all the properties stated in the Vietnamese Pharmacopoeia. In summary, the final effervescent granules product could be further investigated in in-vivo and in clinical settings to become a potential azithromycin delivery system with high bioavailability for the children and elder.

Spatiotemporal Evolution of SARS-CoV-2 Alpha and Delta Variants during Large Nationwide Outbreak of COVID-19, Vietnam, 2021.

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions.

A phylogenetic study of dengue virus in urban Vietnam shows long-term persistence of endemic strains.

Dengue virus (DENV) causes repeated outbreaks of disease in endemic areas, with patterns of local transmission strongly influenced by seasonality, importation via human movement, immunity, and vector control efforts. An understanding of how each of these interacts to enable endemic transmission (continual circulation of local virus strains) is largely unknown. There are times of the year when no cases are reported, often for extended periods of time, perhaps wrongly implying the successful eradication of a local strain from that area. Individuals who presented at a clinic or hospital in four communes in Nha Trang, Vietnam, were initially tested for DENV antigen presence. Enrolled positive individuals then had their corresponding household members invited to participate, and those who enrolled were tested for DENV. The presence of viral nucleic acid in all samples was confirmed using quantitative polymerase chain reaction, and positive samples were then whole-genome sequenced using an amplicon and target enrichment library preparation techniques and Illumina MiSeq sequencing technology. Generated consensus genome sequences were then analysed using phylogenetic tree reconstruction to categorise sequences into clades with a common ancestor, enabling investigations of both viral clade persistence and introductions. Hypothetical introduction dates were additionally assessed using a molecular clock model that calculated the time to the most recent common ancestor (TMRCA). We obtained 511 DENV whole-genome sequences covering four serotypes and more than ten distinct viral clades. For five of these clades, we had sufficient data to show that the same viral lineage persisted for at least several months. We noted that some clades persisted longer than others during the sampling time, and by comparison with other published sequences from elsewhere in Vietnam and around the world, we saw that at least two different viral lineages were introduced into the population during the study period (April 2017-2019). Next, by inferring the TMRCA from the construction of molecular clock phylogenies, we predicted that two of the viral lineages had been present in the study population for over a decade. We observed five viral lineages co-circulating in Nha Trang from three DENV serotypes, with two likely to have remained as uninterrupted transmission chains for a decade. This suggests clade cryptic persistence in the area, even during periods of low reported incidence.

Piezocatalytic 2D WS2 Nanosheets for Ultrasound-Triggered and Mitochondria-Targeted Piezodynamic Cancer Therapy Synergized with Energy Metabolism-Targeted Chemotherapy.

Piezoelectric nanomaterials that can generate reactive oxygen species (ROS) by piezoelectric polarization under an external mechanical force have emerged as an effective platform for cancer therapy. In this study, piezoelectric 2D WS2 nanosheets are functionalized with mitochondria-targeting triphenylphosphonium (TPP) for ultrasound (US)-triggered, mitochondria-targeted piezodynamic cancer therapy. In addition, a glycolysis inhibitor (FX11) that can inhibit cellular energy metabolism is loaded into TPP- and poly(ethylene glycol) (PEG)-conjugated WS2 nanosheet (TPEG-WS2 ) to potentiate its therapeutic efficacy. Upon US irradiation, the sono-excited electrons and holes generated in the WS2 are efficiently separated by piezoelectric polarization, which subsequently promotes the production of ROS. FX11-loaded TPEG-WS2 (FX11@TPEG-WS2 ) selectively accumulates in the mitochondria of human breast cancer cells. In addition, FX11@TPEG-WS2 effectively inhibits the production of adenosine triphosphate . Thus, FX11@TPEG-WS2 exhibits outstanding anticancer effects under US irradiation. An in vivo study using tumor-xenograft mice demonstrates that FX11@TPEG-WS2 effectively accumulated in the tumors. Its tumor accumulation is visualized using in vivo computed tomography . Notably, FX11@TPEG-WS2 with US irradiation remarkably suppresses the tumor growth of mice without systemic toxicity. This study demonstrates that the combination of piezodynamic therapy and energy metabolism-targeted chemotherapy using mitochondria-targeting 2D WS2 is a novel strategy for the selective and effective treatment of tumors.

Multiorgan Dysfunction With Severe Cardiac Injury Secondary to Septic Cellulitis Due to Vibrio parahaemolyticus.

Vibrio parahaemolyticus infection commonly manifests as gastroenteritis, including diarrhea, abdominal pain, nausea, vomiting, and fever. Although uncommon, V. parahaemolyticus has also been associated with wound infection and septic shock. These two manifestations have not been well-reported in medical literature, yet may yield a high risk of death, thus requiring emergent interventions. We present a case of a 42-year-old patient who developed septic shock secondary to a bullous necrotic wound and diarrhea due to V. parahaemolyticus. Multi-organ dysfunction syndrome with extreme cardiac injury developed very early in the course of the disease, prompting ICU admission and management with antibiotics, fluid resuscitation, vasopressors, blood purification, and surgical debridement. The treatment achieved a good clinical outcome. To the best of our knowledge, this is the first case report of V. parahaemolyticus-induced cardiomyopathy. V. parahaemolyticus should be considered as one of the causative agents in patients with sepsis due to cellulitis, particularly in patients with a suggestive history, such as exposure to seawater or eating seafood.

Modification at the C2'-O-Position with 2-Methylbenzothiophene Induces Unique Structural Changes and Thermal Transitions on Duplexes of RNA and DNA.

Oligonucleotides can be chemically modified for a variety of applications that include their use as biomaterials, in therapeutics, or as tools to understand biochemical processes, among others. This work focuses on the functionalization of oligonucleotides of RNA and DNA (12- or 14-nucleotides long) with methylbenzothiophene (BT), at the C2'-O-position, which led to unique structural features. Circular dichroism (CD) analyses showed that positioning the BT units on one strand led to significant thermal destabilization, while duplexes where each strand contained 4-BT rings formed a distinct arrangement with cooperativity/interactions among the modifications (evidenced from the appearance of a band with positive ellipticity at 235 nm). Interestingly, the structural arrays displayed increased duplex stabilization (>10 °C higher than the canonical analogue) as a function of [Na+] with an unexpected structural rearrangement at temperatures above 50 °C. Density functional theory-polarizable continuum model (DFT-PCM) calculations were carried out, and the analyses were in agreement with induced structural changes as a function of salt content. A model was proposed where the hydrophobic surface allows for an internal nucleobase rearrangement into a more thermodynamically stable structure, before undergoing full denaturation, with increased heat. While this behavior is not common, B- to Z-form duplex transitions can occur and are dependent on parameters that were probed in this work, i.e., temperature, nature of modification, or ionic content. To take advantage of this phenomenon, we probed the ability of the modified duplexes to be recognized by Zα (an RNA binding protein that targets Z-form RNA) via electrophoretic analysis and CD. Interestingly, the protein did not bind to canonical duplexes of DNA or RNA; however, it recognized the modified duplexes, in a [monovalent/divalent salt] dependent manner. Overall, the findings describe methodology to attain unique structural motifs of modified duplexes of DNA or RNA, and control their behavior as a function of salt concentration. While their affinity to RNA binding proteins, and the corresponding mechanism of action, requires further exploration, the tunable properties can be of potential use to study this, and other, types of modifications. The novel arrays that formed, under the conditions described herein, provide a useful way to explore the structure and behavior of modified oligonucleotides, in general.

Physical oral care prevents ventilator-associated pneumonia in Vietnam: A prospective interventional study.

BACKGROUND: Ventilator-associated pneumonia (VAP) has emerged as a critical issue in the intensive care unit (ICU) because of its high burden on patients and medical staff. Here, we examined the potential for reducing VAP incidence through physical oral care interventions without any medication. METHODS: This prospective interventional study compared VAP incidence during an 8-month baseline period (usual oral care) and a 9-month intervention period (physical oral care with sponge brush) among patients who received mechanical ventilation for >48 h in a tertiary care hospital in Vietnam from 2017 to 2019. Physical oral care was provided by general ICU nurses who had been trained by dentists and infection control nurses. VAP was diagnosed using the Clinical Pulmonary Infection Score. RESULTS: In total, 423 patients were enrolled in the baseline group and 454 patients were enrolled in the intervention group; 303 and 300 patients, respectively, were included in the analysis. Two hundred thirty-eight VAP episodes were identified: 135 (44.6%) during the baseline period and 103 (34.3%) during the intervention period. Univariate analysis revealed significant reduction of VAP occurrence in the intervention period (odds ratio = 0.65; 95% confidence interval = 0.47-0.90; P = 0.010). The incidences of VAP per 1000 ventilator-days were 63.4 (135/2128) during the baseline period and 48.4 (103/2128) during the intervention period (P = 0.038). CONCLUSIONS: Physical oral care without any medication (e.g., chlorhexidine) reduced VAP incidence in the ICU. This method could be used to reduce VAP incidence, particularly in countries with limited medical resources.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity.

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective: To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods: Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results: Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of -6.3% ((-11.3; -1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((-0.1; 11.5); P = 0.054). Conclusion: Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Some Antioxidant Properties of Components from the Flower of Ochna integerrima and Their Beneficial Effects on HaCaT Keratinocytes and in Silico Analysis on Tyrosinase.

Four compounds, luteolin (1), 6-γ,γ-dimethylallylquercetin 7-O-ß-D-glucopyranoside (2), 6-γ,γ-dimethylallylkaempferol 7-O-ß-D-glucopyranoside (3), and 6-γ,γ-dimethylallyldihydrokaempferol 7-O-ß-D-glucoside (4), were isolated for the first time from AcOEt extract of the O. integerrima flower. We then evaluated the antioxidant effects of AcOEt, butanol, and MeOH extracts and their effects on H2 O2 against oxidative stress in HaCaT keratinocyte cell lines. Furthermore, 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH⋅) radical scavenging activities of 1-4 were determined and their mechanisms of action on tyrosinase were predicted by in silico studies. The results revealed that the AcOEt extract and 1-3 exhibited good DPPH⋅ radical scavenging activity. Furthermore, this extract also had a significant protective effect against H2 O2 -induced oxidative stress in HaCaT cells. In silico studies indicated that the activity of 1-3 may be due to tyrosinase inhibition with MM-GBSA free binding energies of -78.9, -70.1, and -71.1 kcal mol-1 , respectively, compared to 4 with an energy -56.9 kcal mol-1 .