High Efficacy Research Articles

High efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in Black adults in the United States, including those with pre-existing HIV resistance and suboptimal adherence.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA<50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA<50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

Adjusting susceptibilities of C57BL/6 mice to orthoflaviviruses for evaluation of antiviral drugs by altering the levels of interferon alpha/beta receptor function

The purpose of this study was to optimize the infectivity of four different orthoflaviviruses in mice for evaluating antiviral drugs by using wild-type mice with intact interferon responses, type 1 interferon alpha/beta receptor knockout mice, or by injecting wild type C57BL/6 mice with varying doses of anti-type 1 interferon receptor antibody (MAR1-5A3) to optimize the infectivity and lethality. West Nile virus productively infected wild-type C57BL/6 mice to cause lethality, whereas Usutu virus required a complete absence of type 1 interferon receptor function. Deer tick virus (lineage 2 Powassan virus) and Japanese encephalitis viruses required a dampening of type 1 interferon responses by adjusting the doses of MAR1-5A3 antibody injections. Challenge dose-responsive mortality, weight loss, and viral titers of these two viruses were observed if the type 1 interferon responses were dampened with MAR1-5A3. Conversely, without MAR1-5A3 injections, these disease phenotypes were not viral challenge dose-responsive. From these different interferon-responsive models, the appropriate lethality was identified to determine that 7-deaza-2'-C-methyladenosine has high efficacy for West Nile and Usutu viruses, and low efficacy for deer tick and Japanese encephalitis viruses.

Anti-CLL1 liposome loaded with miR-497-5p and venetoclax as a novel therapeutic strategy in acute myeloid leukemia

Acute myeloid leukemia (AML) is a lethal hematologic malignancy. Chemotherapy resistance results in a dismal survival of 1-2 years in older adults with AML. Therefore, novel therapies are urgently required. In this context, microRNA (miRNA)-based treatments remain an untapped strategy in AML. Using patient-derived specimens, we found increased inflammatory cytokines including IL-6 in serum of older adults with AML, and decreased miR-497-5p in CD34+ leukemic blasts. Target prediction revealed that miR-497-5p could directly target mitogen-activated protein kinase-1 (MAP2K1) mRNA, to indirectly target cytokines and JAK/STAT signaling pathway through p38-MAPK signaling pathway, potentially inhibiting leukemic growth, and overcoming chemoresistance from venetoclax. To improve miRNA delivery and minimize off-target effects, which represent key barriers to clinical translation, we developed liposomes for co-delivery of miR-497-5p and venetoclax. We decorated our liposomes with a peptide targeting CLL1, which is present on 92% leukemia blasts while being absent in normal hematopoietic cells. This targeted approach demonstrated high efficacy in inhibiting AML growth in mice with minimal toxicity, as well as reduced exposure to chemoresistance. Our findings suggested that anti-CLL1-decorated, miR-497-5p and venetoclax-loaded liposomes represent a promising novel miRNA-based therapeutic, which should be further investigated as a strategy to reduce venetoclax resistance in AML.

Hydrophilic Magnetic COFs: The Answer to Photocatalytic Degradation and Removal of Imidacloprid Insecticide

The widespread use of imidacloprid (IMI) in pest control presents significant environmental challenges due to its persistence and low removal efficiency. This study introduces magnetic Covalent Organic Frameworks (COFs) functionalized with Fe₃O₄ nanoparticles (Fe₃O₄@HMN-COF, Fe₃O₄@MAN-COF, and Fe₃O₄@SIN-COF) as efficient adsorbents for IMI removal from water. These COFs, engineered with nitrogen-rich structures and extensive π-electron systems, achieve superior adsorption through π-π interactions, hydrophobic interactions, and hydrogen bonding. Characterization via FT-IR, XRD, and nitrogen sorption isotherms confirmed their high hydrophilicity, stability, and large surface areas. The magnetic properties of the COFs facilitated easy separation from water, enhancing practicality. Kinetic studies for all COFs indicated a pseudo-second-order model, suggesting chemisorption, with adsorption capacities of 600 mg/g for Fe₃O₄@HMN-COF, 480 mg/g for Fe₃O₄@MAN-COF, and 375 mg/g for Fe₃O₄@SIN-COF. Thermodynamic analyses revealed spontaneous and endothermic adsorption processes. Reusability tests showed minimal capacity loss over multiple cycles, underscoring their practical applicability. Practical tests in honey and fruit samples confirmed high efficacy, demonstrating the COFs' versatility. The study also optimized the photocatalytic degradation of imidacloprid using these COFs, with Fe₃O₄@HMN-COF achieving 98.5% efficiency under optimal conditions (10 mg/L IMI, 0.01 g catalyst dose, pH 11, 30°C, UV light). These findings highlight the potential of magnetic COFs for sustainable environmental remediation of pesticide-contaminated water.

Factors affecting the therapeutic effects of multiple intra-articular injections of platelet-rich-plasma for knee osteoarthritis

BackgroundPlatelet-rich-plasma (PRP) is rapidly spreading as a conservative treatment option for knee osteoarthritis (KOA), however, its therapeutic efficacy is controversial. This study aimed to investigate the factors affecting the therapeutic effect of intra-articular PRP therapy for KOA in patients who received multiple PRP injections (PRP-I). MethodsThis is a historical cohort study included 1057 knees of 701 patients who received PRP-I during KOA treatment from 2018 to 2020. The difference in visual analog scale (VAS) scores before and after PRP-I was defined as the amount of change in VAS (ΔVAS). A linear mixed-effects model was employed with ΔVAS as a random effect and age, sex, BMI, KL classification, pre-treatment VAS, treatment duration, and the number of PRP injections as fixed effects. Evaluations using the Kellgren-Lawrence (KL) classification were added. ResultsAge, KL grade, and VAS score before treatment and after three, four, and five PRP-I were significantly associated with ΔVAS score. According to KL grade, age was significantly associated with ΔVAS score in the KL grade 4 group. VAS score before treatment was significantly associated with ΔVAS score, regardless of KL grade. Three-time PRP-I were significantly associated with ΔVAS in the KL-grade 1 and 2 groups. For KL grade 4, two or more PRP-I were significantly associated with the high efficacy. ConclusionsAge, pain before treatment, KL grade and number of injections were associated with pain reduction after intra-articular PRP-I for KOA treatment. Pain reduction can be expected after PRP-I when patients are younger or experience severe pain before treatment. Three-time PRP-I are recommended to reduce pain in early-stage KOA and more than three times in advanced-stage KOA. Trial registrationRetrospectively registration.

Natural products for the treatment of allergic rhinitis: focus on cellular signaling pathways and pharmacological targets.

Allergic rhinitis is an inflammatory disease dependent on immunoglobulin E and causes inflammation of the nasal mucosa, leading to decreased quality of life for affected patients. Since common treatments, including corticosteroids and antihistamines, have temporary therapeutic effects and numerous side effects, investigating natural compounds effective in improving allergic rhinitis with low complications and high efficacy can be significant and necessary. This study aims to present a comprehensive and critical evaluation of the effect of natural compounds in improving allergic rhinitis. Studies were identified through systematic searches of ScienceDirect, PubMed, Scopus, and Web of Sciences databases. Eligibility checks were conducted based on predefined selection criteria. Forty-six articles were included in this study. Phytochemicals, including flavonoids, alkaloids, terpenoids, and other compounds showed significant anti-inflammatory and antihistaminic effects. These compounds alleviate allergic rhinitis symptoms by inhibiting inflammatory mediators, oxidative stress, apoptosis, and key signaling pathways such as MAPK/NFκB and TLR4/MyD88/NF-κB. Phytochemicals exhibit anti-inflammatory and antioxidant properties, making them.

LncOCMRL1 promotes oral squamous cell carcinoma growth and metastasis via the RRM2/EMT pathway

BackgroundLong noncoding RNAs (lncRNAs) are widely involved in cancer development and progression, but the functions of most lncRNAs have not yet been elucidated. Metastasis is the main factor restricting the therapeutic outcomes of various cancer types, including oral squamous cell carcinoma (OSCC). Therefore, exploring the key lncRNAs that regulate OSCC metastasis and elucidating their molecular mechanisms will facilitate the development of new strategies for effective OSCC therapy.MethodsWe analyzed the lncRNA expression profiles of tumor tissues from OSCC patients with and without cervical lymph node metastasis, and OSCC cell lines. We revealed high expression of oral squamous cell carcinoma metastasis-related lncRNA 1 (lncOCMRL1) in OSCC patient tumor tissues with lymph node metastasis and highly metastatic OSCC cell lines. The effects of lncOCMRL1 knockdown on the invasion, migration and proliferation abilities of OSCC cells were explored through qRT-PCR, Transwell, colony formation, and cell proliferation experiments. The mechanism by which lncOCMRL1 promotes OSCC metastasis and proliferation was explored through RNA pull-down, silver staining, mass spectrometry, RIP, and WB experiments. To increase its translational potential, we developed a reduction-responsive nanodelivery system to deliver siRNA for antitumor therapy.ResultsWe determined that lncOCMRL1 is highly expressed in OSCC metastatic tumor tissues and cells. Functional studies have shown that high lncOCMRL1 expression can promote the growth and metastasis of OSCC cells both in vivo and in vitro. Mechanistically, lncOCMRL1 could induce epithelial-mesenchymal transition (EMT) via the suppression of RRM2 ubiquitination and thereby promote the proliferation, invasion, and migration of OSCC cells. We further constructed reduction-responsive nanoparticles (NPs) for the systemic delivery of siRNAs targeting lncOCMRL1 and demonstrated their high efficacy in silencing lncOCMRL1 expression in vivo and significantly inhibited OSCC tumor growth and metastasis.ConclusionsOur results suggest that lncOCMRL1 is a reliable target for blocking lymph node metastasis in OSCC.

Novel heterocyclic amide derivatives containing a diphenylmethyl moiety: systematic optimizations, synthesis, antifungal activity and action mechanism.

The development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x-ray diffraction analysis. In this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC50 = 1.11 μg mL-1). Meanwhile, the anti-R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 μg mL-1, which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad. The above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. © 2024 Society of Chemical Industry.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, exhibits favourable effects on pancreatic β-cells and hepatic steatosis in obese type 2 diabetic db/db mice.

Tirzepatide, a dual agonist of glucagon-like peptide receptor and glucose-dependent insulinotropic polypeptide receptor, is expected to exhibit high clinical efficacy in obese type 2 diabetic patients. We evaluated the effects of tirzepatide on pancreatic β-cells and the liver, an insulin-target organ, in a mouse model of obese type 2 diabetes mellitus. Obese type 2 diabetic db/db mice (BKS.Cg-/+ Leprdb/+ Leprdb/Jcl*) were used in this study. Starting at 7 weeks of age, mice were treated with tirzepatide (30 nmol/kg, subcutaneous injection twice a week) or semaglutide (200 nmol/kg, subcutaneous injection twice a week). The control group received phosphate-buffered saline (40-50 μL/subcutaneous injection twice a week). After 4 weeks of drug administration, pancreatic β-cells and the liver were removed and examined. Compared to the control group, blood glucose and body weight were significantly reduced in the group that received either tirzepatide or semaglutide (p < 0.001 and p < 0.05, respectively). Fasting insulin was significantly higher in the semaglutide and tirzepatide groups compared to the control group (p < 0.001). β-Cell mass and quality of insulin granules in β-cells similarly increased in the semaglutide and tirzepatide groups compared to the control group (p < 0.05 and p < 0.001, respectively). The fat staining area in the liver in oil red O staining and the liver-spleen ratio in computed tomography showed improvement only in the tirzepatide group (p < 0.001 and p < 0.005, respectively). Liver macrophage M1/M2 ratio similarly improved with semaglutide and tirzepatide (p < 0.05). Tirzepatide and semaglutide exhibited similar potent glucose-lowering effects. At concentrations used in the present experiments, tirzepatide exhibited more beneficial effects on β-cell-related gene expression, insulin granule count and glucose-stimulated insulin secretion compared to semaglutide. In addition, tirzepatide exhibited a stronger favourable effect on hepatic fat deposition and improved inflammation in the liver. This is the first report showing that tirzepatide, a novel diabetes drug, exhibits a superior effect on pancreatic β-cells and the liver of obese type 2 diabetic mice.

Fourteen-year follow-up results of imatinib therapy in patients with unresectable and metastatic gastrointestinal stromal tumors.

Imatinib therapy is the gold standard for the treatment of unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, few studies have reported the long-term outcomes of the treatment. Seventy patients who underwent imatinib therapy for unresectable and metastatic GISTs were enrolled between 2001 and 2009, and follow-up data were collected until October 2023. One hundred and sixty-eight months had passed since the final enrollment. The outcome measures were patient survival and the status of GIST and imatinib therapy. The cumulative incidence of disease progression (PD) and the chronological changes in PD hazard rate (HR) were also analyzed. The 5-, 10-, 15-, and 20-year overall survival rates were 64.3%, 30.0%, 16.8%, and 12.2%, respectively. Sixty of the 70 enrolled patients died before the data cutoff date: 47 (78.3%) patients died of GIST progression while the remaining 13 (21.7%) died of diseases other than GISTs. The cumulative incidence of PD logarithmically increased, and PD continued even after 10years of treatment. PD HR decreased over time to reach the lowest value at 9.6years after the initiation of treatment (HR 0.00027; 95% CI 0.00007-0.00174) and after that formed a small peak at 13years (HR 0.00144; 95% CI 0.00043-0.00436). Imatinib therapy showed high clinical efficacy in terms of long-term survival in GIST patients. However, patients undergoing imatinib therapy were at continuous risk of PD even after the 10-year treatment. Long-term treatment and follow-up beyond 10years are necessary for unresectable and metastatic GIST patients.

Current trends in vestibular schwannoma management at a referral center in Indonesia: A cross-sectional study with retrospective data collection

Background. Vestibular schwannoma (VS) is the most common benign brain tumor of the cerebellopontine angle. Due to its location, this pathology can create both focal and general deficits. The registry system for VS in Indonesia is developing, including in the author’s institution, which eventually shows a changing trend in managing VS. Methods. We retrospectively collected data from all patients diagnosed with vestibular schwannoma, based on histological or radiological results. Treatments included craniotomy and/or Gamma Knife Radiosurgery (GKRS) from 2018 to 2023. Results. Data from 88 patients were analyzed. The number of treated patients has increased annually. VS predominantly affects females (64%). The proportion between GKRS and craniotomy procedures also shifted throughout the year. Common symptoms included hearing loss (63.6%), disequilibrium (50%), and headaches (39.7%). The most common tumor size was medium (15-30 mm; n=37; 42%). Tumors that fell into the intrameatal and small (&lt;15 mm) categories were all treated with GKRS, whereas the other groups were divided into GKRS and craniotomy. GKRS demonstrated high efficacy in tumor control and favorable hearing and facial nerve preservation, whereas craniotomy remained crucial for larger tumors. Conclusion. The number of VS diagnosed each year has increased in our center, accompanied by a noticeable shift in preference from GKRS to craniotomy, which is influenced by the integration of intraoperative monitoring. Treatment preference was further determined based on the clinical profile and tumor size. In the future, there is a need to develop a national registry to better reflect the true incidence of VS within the Indonesian population.

Artificial Intelligence Applications in Medical Mycology: Current and Future

The application of artificial intelligence (AI) in the medical mycology field represents a new era in the diagnosis and management of fungal infections. AI technologies, particularly machine learning (ML) and deep learning (DL) methods, enhance diagnostic accuracy by leveraging large datasets and complex algorithms. This review examines current applications of AI in laboratory and clinical settings for fungal diagnostics. In the laboratory, AI models analyze microscopic images from potassium hydroxide (KOH) examinations, fungal culture tests, and histopathologic slides, which improves the detection rates of fungal pathogens significantly. In the clinical setting, AI assists the diagnosis of fungal infections using medical images, exhibiting high efficacy in binary classification tasks. However, challenges include small sample sizes, class imbalances, reliance on expert-labeled data, and the black box nature of AI models. Explainable AI offers potential solutions by providing human-comprehensible insights into AI decisionmaking processes. In addition, human-computer collaboration can enhance diagnostic accuracy, particularly for less experienced clinicians. The development of generative AI models, e.g., large language models and multimodal AI, promises to create extensive datasets and integrate various data sources for comprehensive diagnostics. Addressing these limitations through prospective clinical validation and continuous feedback will be essential for realizing the full potential of AI in medical mycology.

Mosaic HIV-1 vaccine and SHIV challenge strain V2 loop sequence identity and protection in primates

The failure of human vaccine efficacy trials assessing a mosaic HIV-1 vaccine calls into question the translatability of preclinical SHIV challenge studies that demonstrated high efficacy of this vaccine in primates. Here we present a post hoc immune correlates analysis of HIV-1 Env peptide-binding antibody responses from the NHP13-19 study identifying the V2 loop as the principal correlate of protection in primates. Moreover, we found high V2 loop sequence identity between the Mos1 vaccine component and the SHIV challenge strain, while the vaccine showed considerably lower V2 identity to globally circulating HIV-1 sequences. Thus, the induction of immune responses against the V2 epitope, which had exceptional identity between the vaccine and challenge Env strains, may have contributed to the high protection in primates.

Design, synthesis, and bioactivity investigation of novel cyclic lipopeptide antibiotics targeting top-priority multidrug-resistant gram-negative bacteria

ObjectivesPolymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity. MethodsTo design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe6-L-Leu7) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12. ResultsThis research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity. ConclusionReducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab3 by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab9 could be shortened by one carbon among the Dab1,5 and Dab8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa.

Evaluating treatment practices and challenges in systemic Juvenile Idiopathic Arthritis: a comprehensive survey analysis

ObjectiveThis study aims to assess current diagnostic and management for systemic Juvenile Idiopathic Arthritis (sJIA) among physicians, evaluate the challenges encountered in diagnosis and treatment, and identify the educational needs and professional development engagements of physicians managing sJIA.MethodsA nationwide survey was conducted from November 2023 to March 2024 across tertiary and secondary pediatric and general hospitals in China. The survey targeted physicians with at least three years of specialty experience, resulting in 310 valid responses from 25 provinces, autonomous regions, and municipalities. The survey collected data on diagnostic practices, treatment approaches, and professional development related to sJIA. Data collection was facilitated through WeChat, and statistical analysis was performed using descriptive statistics. Ethical approval was obtained from the Ethics Committee of Beijing Children’s Hospital, with informed consent provided electronically by participants.ResultsThe survey indicated that all physicians encountered suspected or confirmed cases of sJIA, highlighting its prevalence and the diagnostic challenges associated. Regarding diagnostic standards, 53.9% of physicians used the “Consensus on the Diagnosis and Treatment of sJIA and Macrophage Activation Syndrome,” 18.1% followed the International League of Associations for Rheumatology (ILAR) standards, and 24.8% adhered to the Pediatric Rheumatology International Trials Organization (PRINTO) standards. In treatment strategies, glucocorticoids and IL-6 receptor monoclonal antibodies were extensively used, with the latter receiving “excellent” and “satisfactory” ratings of 46.5% and 36.1%, respectively, demonstrating high efficacy and acceptance. Main challenges included high treatment costs, complexity of diagnosis, patient compliance issues, and potential long-term side effects of biologics. Additionally, 126 doctors (40.7%) actively participated in more than three academic conferences or systematic learning courses related to sJIA, indicating a strong demand for ongoing education, particularly in new treatment developments and diagnostic skills.ConclusionThe findings emphasize the necessity for standardized diagnosis and customized treatment plans tailored to patient-specific conditions in managing sJIA.Key Points• The survey highlights the prevalence and clinical challenges of sJIA among physicians, emphasizing the importance of vigilant diagnosis, multi-system involvement, and differential diagnosis to improve treatment outcomes and patient quality of life.

A multi-epitope protein vaccine encapsulated in alginate nanoparticles as a candidate vaccine against Shigella sonnei

Shigellosis, caused by the Gram-negative bacterium Shigella, is a major global health challenge. Despite extensive research over the past two decades, no commercial vaccine is available to prevent Shigella infection. Developing multi-epitope vaccines offers a promising and innovative approach to tackling infectious diseases. In this study, we produced a multi-epitope vaccine candidate using E. coli BL21 (DE3) plysS bacteria and purified the vaccine protein with Ni-NTA affinity chromatography. We then prepared alginate nanoparticles containing the vaccine protein, with a particle size of 122 ± 6 nm, PDI 0.17, SPAN 0.83, and zeta potential of -27 ± 2 mV. Successful protein loading was confirmed through nanodrop and ATR-FTIR analyses. To evaluate the immunogenicity of the encapsulated vaccine, mice were orally vaccinated, and their serum was analyzed for IgG, IL-4, and IFN-γ levels cytokines. The results showed a significant increase in IgG level in the vaccinated group compared to controls. Additionally, the vaccinated group exhibited a notable increase in IL-4 and IFN-γ cytokines, indicating a robust Th-cell-mediated immune response essential for combating Shigella. Our nano-vaccine demonstrated high efficacy in activating both humoral and cellular immunity, effectively protecting against the bacteria. The alginate-based oral vaccine candidate thus emerges as a promising strategy for developing a multi-epitope vaccine candidate against Shigella.

Predicting chronic post-traumatic head and neck pain: the role of bedside parameters

Abstract Traumatic brain injury (TBI) annually impacts 69 million individuals worldwide. Mild TBI constitutes approximately 90% of all TBIs. Chronic pain post-mTBI occurs in 29% to 58% of patients. This study aims to introduce a predictive model for chronic pain development in individuals diagnosed with mild traumatic brain injury (mTBI) immediately postinjury. We included individuals who had sustained mTBI in motor vehicle accident (MVA). All patients had initial assessments within the first 72 hours (representing the subacute period) after the injury and performed follow-ups for 1 year. Machine learning model was applied to the integrated measures of clinical pain, pain-related psychological parameters, mTBI clinical signs, and sociodemographic information. This study included 203 patients experiencing acute head or neck pain attributable to mTBI post-MVA. We categorized these patients into 2 groups: patients who progressed to develop chronic head or neck pain (n = 89, 43.8%) and patients who recovered (low/mild pain) (n = 114, 56.2%). Severity of the subacute neck pain, number of painful body areas, and education years were identified as the most significant factors predicting chronic pain. The optimized predictive model demonstrated high efficacy, with an accuracy of 83%, a sensitivity of 92%, and an area under the receiver operating characteristic curve of 0.8. Our findings indicate feasibility in predicting chronic post-MVA pain within the critical 72-hour window postinjury using simple bedside metrics. This approach offers a promising avenue for the early detection of individuals at increased risk for chronic pain, enabling the implementation of targeted early interventions.

Infrequent Resolution of Vaso-Occlusive Crises in Routine Clinical Care Among Patients Mimicking the Exa-Cel Trial Population: A Cohort Study of Medicaid Enrollees.

The CRISPR-based gene editing therapy exagamglogene autotemcel (exa-cel) recently received FDA approval for patients with severe sickle cell disease (SCD). The approval was based on a phase III trial (CLIMB SCD 121), which showed 97% efficacy of this treatment in eliminating vaso occlusive crises (VOCs) for 12 consecutive months. To help contextualize results from this trial, we aimed to investigate the proportion of patients with severe SCD who remain VOC-free for a 1-year period in routine clinical care. Using Medicaid claims data (2000-2018), we identified a cohort of patients, 12-35 years old with severe SCD, defined by ≥ 2 VOCs per year for 2 consecutive years, who met other exa-cel trial inclusion criteria to mimic a trial-like population. A VOC was identified using ICD diagnosis codes during hospitalization and ER visits. The primary outcome was the proportion of patients with no VOCs during a 1-year follow-up. A total of 7,425 patients with severe SCD [mean (SD) age: 20.5 (6.0) years, 54.6% females, 84% African Americans], had a mean of 5.2 VOCs, 5.1 ER visits and 3.5 hospitalizations per year during the baseline period. The proportion of patients with no VOCs during the 1-year follow-up was 7.7% (95% confidence interval: 7.1%-8.3%). In conclusion, less than one in 12 patients with severe SCD achieved VOC-free status within 1 year in routine clinical care. These findings suggest that the high efficacy observed for exa-cel in the trial, if replicated in routine clinical care, could translate into a significant public health impact.

Seed coating with biocontrol bacteria encapsulated in sporopollenin exine capsules for the control of soil-borne plant diseases

Coating seeds with biocontrol agents represents an effective approach for managing soil-borne plant diseases. However, improving the viability of biocontrol microorganisms on the seed surface or in the rhizosphere remains a big challenge due to biotic and abiotic stresses. In this work, we developed a microbial seed coating strategy that uses sporopollenin exine capsules (SECs) as carriers for the encapsulation of the biofilm-like biocontrol bacteria. SECs was extracted from camellia bee pollen, and then characterized by Fourier Transform infrared spectroscopy (FTIR), elemental analysis and thermal gravity analysis (TG). The Paenibacillus polymyxa ZF129, a biocontrol bacterium, was introduced into SECs using the vacuum-incubation method and characterized by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Notably, the ZF129 cell formed a biofilm-like structure inside the SECs, which enhanced their tolerance to acidic stress. As a proof of concept, we applied ZF129-loaded SECs to coat pak choi seeds using a straightforward plate-shaking technique. The coated seeds demonstrated a high control efficacy of up to 60.46 % against clubroot disease. Overall, this study sheds light on the application of SECs as promising carrier for the encapsulation of biofilm-like biocontrol bacteria, further augmenting the biocontrol functionality of microbial seed coating.

Design, Synthesis, and Antifungal Evaluation of Novel Pyrazole-5-sulfonamide Derivatives for Plant Protection.

To develop further novel environmentally friendly antifungal agents with high efficacy, a series of pyrazole-5-sulfonamide derivatives were designed and synthesized by using the active molecules synthesized in previous works as lead compounds. Their antifungal activities were evaluated in vitro against ten highly destructive plant pathogenic fungi. The bioassay results indicated that more than half of the target compounds displayed potent antifungal activities (inhibition rate ≥85%) against Valsa mali and Sclerotinia sclerotiorum at 20 mg/L. Among them, compound C22 exhibited significant broad-spectrum antifungal activities against V. mali, S. sclerotiorum, Rhizoctonia solani, Botrytis cinerea, and Trichoderma viride, with EC50 values of 0.45, 0.49, 3.06, 0.57, and 1.43 mg/L, respectively. Moreover, compounds C21 and C22 exhibited remarkable protective effects on apple Valsa canker similar to tebuconazole (89.5%) at 50 mg/L. Preliminary antifungal mechanism investigations demonstrated that compound C22 may have inhibited V. mali mycelial growth by inducing oxidative damage to the mycelium and compromising the integrity of the cell membrane. Meanwhile, compounds C21 and C22 exhibited no obvious toxicity to worker bees (Apis mellifera ligustica). Taken together, these pyrazole-5-sulfonamide derivatives, particularly compound C22, possess huge potential to be developed as novel environmentally friendly fungicides with high efficacy.