Combined Treatment Research Articles

Combined transarterial chemoembolization and tislelizumab for patients with unresectable hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) often presents as unresectable, necessitating effective treatment modalities. Combining transarterial chemoembolization (TACE) with immunotherapy and targeted therapy has shown promise, yet real-world evidence is needed. AIM To investigate effectiveness and safety of TACE with tislelizumab ± targeted therapy for unresectable HCC in real-world setting. METHODS This retrospective study included patients with unresectable HCC receiving combined treatment of TACE and tislelizumab. The clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). All patients were evaluated according to the mRECIST criteria. The adverse event (AE) was also assessed. RESULTS In this study of 56 patients with median follow-up of 10.9 months, 7 had previous immunotherapy. Tislelizumab was administered before TACE in 21 (37.50%) and after in 35 (62.50%) patients, with 91.07% receiving concurrent targeted therapy. Median PFS was 14.0 (95%CI: 7.0-18.00) months, and OS was 28 (95%CI: 2.94-53.05) months. Patients with prior immunotherapy had shorter PFS (6 vs. 18 months, P = 0.006). Overall ORR and DCR were 82.14% and 87.50%. Grade ≥ 3 treatment-related AEs included increased alanine aminotransferase (8.93%), aspartate aminotransferase (10.71%), and total bilirubin (3.57%). CONCLUSION The combination of TACE and tislelizumab, with or without targeted therapy, demonstrated promising efficacy and safety in unresectable HCC, especially in immunotherapy-naive patients, warranting further prospective validation studies.

Levels of Natural Antibodies Before and After Immunoglobulin Replacement Treatment Affect the Clinical Phenotype in Common Variable Immunodeficiency

Natural antibodies (NAbs) occurring in individuals without prior exposure to specific antigens, provide direct first barrier protection against pathogens, and exert immunoregulation thus actively contributing to the maintenance of immune homeostasis, controlling inflammatory processes and preventing autoimmunity. Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by a compromised immune function that brings into focus the role of NAbs. Our aim was to explore whether NAb levels could serve as potential key indicators in CVID for monitoring disease progression and predicting outcomes. In this study, we analyzed a Hellenic cohort of 56 patients with CVID (31 newly diagnosed and 25 under immunoglobulin replacement therapy-IgRT) and 33 healthy controls, for total Ig levels and serum IgM and IgG NAb levels against five informative target-antigens of NAbs, namely, actin, DNA, carbonic anhydrase, F(ab΄)2 fragments of human IgG and TriNitroPhenyl. In addition, follow-up pre- and post- IgRT samples were analyzed in ten (10) patients of our cohort. Results showed that Ig-treated patients exhibited significantly lower IgM NAb levels than untreated patients and healthy controls against all panel antigens. In the follow-up samples, pre-treatment IgM NAb levels negatively correlated with total serum IgM. This imbalance was only partially restored after IgRT, with a significant decrease in IgM NAb levels observed in nine out of ten patients. Moreover, post-treatment patients with recurrent infections presented significantly lower IgM NAb levels, a reduction also observed in patients with bronchiectasis independently of treatment status. On the contrary, post-treatment patients with enteropathy had significantly higher IgM NAb levels against all panel antigens, an increase also noted in patients with autoimmune diseases. Regarding IgG NAbs, replacement therapy restored levels to those of healthy controls. In conclusion, impaired NAb levels are found in CVID patients, particularly related to certain phenotypes. Moreover, the significant decrease in IgM NAb levels after IgRT suggests a potential association with disease course and complications. The results suggest that administration of human IgM NAbs may be an effective combinatorial treatment in selected patients. Further research is needed to understand the functional roles of NAbs in CVID and its complex clinical phenotypes.

Comparative Cost-Effectiveness of Atezolizumab Versus Durvalumab as First-Line Combination Treatment with Chemotherapy for Patients with Extensive-Disease Small-Cell Lung Cancer in Japan

Comparative Cost-Effectiveness of Atezolizumab Versus Durvalumab as First-Line Combination Treatment with Chemotherapy for Patients with Extensive-Disease Small-Cell Lung Cancer in Japan

Vibration of effects resulting from treatment selection in mixed-treatment comparisons: a multiverse analysis on network meta-analyses of antidepressants in major depressive disorder

ObjectiveIt is frequent to find overlapping network meta-analyses (NMAs) on the same topic with differences in terms of both treatments included and effect estimates. We aimed to evaluate the impact...

Evaluation of Efficacy of Present Fixed Dose Combinations for Daily Antitubercular Treatment Under RNTCP

Evaluation of Efficacy of Present Fixed Dose Combinations for Daily Antitubercular Treatment Under RNTCP

Add-on multidrug treatment based on quadruple therapy successfully treated worsening heart failure caused by anthracycline-induced cardiomyopathy in a survivor of cancer as a young adult: a case report

BackgroundThe overall mortality and morbidity benefit in patients with heart failure with a reduced ejection fraction is greatest with a treatment combination of sacubitril/valsartan, beta-blockers, mineralocorticoid-receptor antagonists, and sodium-glucose transporter-2 inhibitors, termed the “fantastic four” or “quadruple therapy.” The addition of vericiguat (an oral soluble guanylate cyclase stimulator) is believed to aid in managing worsening heart failure after quadruple therapy. Among childhood and young adult cancer survivors, cardiovascular complications that develop more than 10 years after anthracycline-based chemotherapy have a poor prognosis. Therefore, this study reports the efficacy of multidrug regimen based on quadruple therapy for worsening heart failure in cancer survivors with anthracycline-induced cardiomyopathy.Case presentationA survivor of cancer as a young adult who received high-dose anthracycline chemotherapy presented with acute decompensated heart failure 20 years post-chemotherapy and worsening heart failure 1.5 years after discharge. The patient showed signs of improvement after a step-wise introduction of carvedilol, empagliflozin, sacubitril/valsartan, ivabradine, and spironolactone for worsening heart failure. Vericiguat was accelerated owing to the risk of more severe cardiovascular events associated with ongoing aortic stenosis and the poor prognosis of anthracycline-induced cardiomyopathy. Heart failure symptoms continued to improve, with significant cardiac reverse remodeling, and the patient successfully underwent aortic valve replacement for severe aortic stenosis.ConclusionsOur case highlighted that multidrug treatment with add-on vericiguat and ivabradine based on quadruple therapy can potentially treat worsening heart failure in young adult cancer survivors with severe anthracycline-induced cardiomyopathy.

Simultaneously enhancing strength and toughness of coir fiber through NaOH and sodium alginate treatment

Coir fibers are commonly subjected to alkali treatment to eliminate impurities and tune their mechanical properties. However, this process can damage the fibers’ microstructures, posing a challenge in significantly enhancing both strength and toughness simultaneously. Herein, we successfully enhanced both strength and toughness of coir fibers through a combined treatment with NaOH and sodium alginate aqueous solution. Coir fibers treated with 5 wt% NaOH solution, followed by 0.5 wt% sodium alginate solution, exhibit a tensile modulus of 2475.0 MPa, a tensile strength of 126.4 MPa, and a toughness of 30.7 MJ/m³, representing improvements of 57.1 %, 72.7 %, and 116.2 %, respectively, compared to the raw fibers. Mechanistic studies revealed that NaOH treatment effectively removes pectin, hemicellulose and lignin from coir fibers but introduces numerous defects. Sodium alginate can repair these defects by forming hydrogen bonds with the rich oxygen-containing group of coir fibers. The combined treatment also increases the crystallinity of coir fibers from 30.3 % for the raw fibers to 44.1 % by removing a large number of amorphous substances. Additionally, the combined treatment reduces the microfibril angle from ∼63.6° to ∼46.6° by elongating the helix structure and filling the gaps between helical fibers. Our cost-effective strategy not only promotes the applications of coir fibers but also provides guidance for the modification of other natural plant fibers.

Combination of immune checkpoint inhibitors and radiotherapy in locally advanced esophagogastric junction adenocarcinoma: A review

AbstractEsophagogastric adenocarcinoma (EGJ‐AC) poses a significant global health burden, characterized by high incidence rates and poor prognosis. Despite advancements in treatment modalities, including surgery, chemotherapy, and radiation therapy (RT), locally advanced EGJ‐AC management remains challenging. Various preclinical and clinical studies have provided insights into the synergistic effects of combining immune checkpoint inhibitors (ICIs) with RT, further supporting the combination therapy in EGJ‐AC. Immunotherapy, particularly ICIs, has emerged as a promising therapeutic approach in various malignancies, including EGJ‐AC. This narrative review aims to critically examine the rationale behind combining ICIs with standard treatment modalities, including RT or chemoradiotherapy, in the preoperative setting for locally advanced EGJ‐AC. A comprehensive literature search identified eight phase 2 randomized clinical trials evaluating the safety profile and oncologic outcomes of adding ICI agents to neoadjuvant chemoradiotherapy in this population. The results of enrolled trials show that the combination of ICIs with standard treatment modalities is a promising approach for improving survival and pathological response in patients with locally advanced EGJ‐AC. This combination treatment was associated with mostly grade 1–2 immune‐related toxicities, indicating its safety and tolerability. There were higher rates of complete or major pathologic responses compared to historical controls. Further studies, including large‐scale randomized controlled trials, are needed to address remaining questions regarding the efficacy, safety, and long‐term outcomes of combination therapy in this population.

Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process

BackgroundSevere malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65).MethodsC57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses.ResultsPbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi.ConclusionsTherapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.

Novel drug combinations suggested for treating pancreatic cancer

Pancreatic cancer (PC) is a type of gastrointestinal tumor with poor anticipation and high level of death rate, being a fatal disease in which the overall 5-year survival rate is less than 4%1. PC poorly responds to most chemotherapeutic agents and the main current systemic chemotherapy treatments for patients with advanced disease are the drug combinations FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (Abraxane). Therefore, there is a profound world-wide unmet medical need for new drug combination treatments having significant positive impact on the survival and day-to-day functioning of PC patients. It is suggested herein that treatment of drug combinations of bevacizumab plus bortezomib or dacarbazine and decitabine and optionally interferon α can be beneficial for patients suffering from locally advanced and metastatic PC, subject to creating predictive models to determine possible drug resistance and receiving positive results in clinical trials.

Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer

Metastatic ovarian cancer (MOC) is highly deadly, due in part to the limited efficacy of standard-of-care chemotherapies to metastatic tumors and non-adherent cancer cells. Here, we demonstrated the effectiveness of a combination therapy of GRP78-targeted (TNPGRP78pep) and non-targeted (NP) nanoparticles to deliver a novel DM1-prodrug to MOC in a syngeneic mouse model. Cell surface-GRP78 is overexpressed in MOC, making GRP78 an optimal target for selective delivery of nanoparticles to MOC. The NP + TNPGRP78pep combination treatment reduced tumor burden by 15-fold, compared to untreated control. Increased T cell and macrophage levels in treated groups also suggested antitumor immune system involvement. The NP and TNPGRP78pep components functioned synergistically through two proposed mechanisms of action. The TNPGRP78pep targeted non-adherent cancer cells in the peritoneal cavity, preventing the formation of new solid tumors, while the NP passively targeted existing solid tumor sites, providing a sustained release of the drug to the tumor microenvironment.

Postoperative Pain Management in Patients Undergoing Hernia Repair Surgery. A cross-sectional study

Background: Hernia repair surgery is the most frequently performed surgical operation across the world and pain management after the surgery is important to avoid chronic pain and improve the quality of life. Objectives: to assess the effectiveness of acetaminophen monotherapy against combination analgesic regimens (acetaminophen plus pethidine or parecoxib) in managing postoperative pain in individuals having hernia repair surgery. Methods: This was a cross-sectional study on patients who were 18-65 years old and had elective hernia repair surgery. Participants were assigned to three groups: Group A was given IV acetaminophen along with IM pethidine, Group B was given IV acetaminophen with IV parecoxib and Group C was given IV acetaminophen alone. Pain was evaluated by Numeric Rating Scale (NRS) at various time intervals within 24 hours following surgery. Data were analysed employing repeated measures analysis of variance (ANOVA) and multiple regression analysis. Results: The research had a total of 259 patients. In comparison to Group C, patients in Groups A and B consistently reported far lower pain scores. Group C had the greatest mean pain score (7.91) at 45 minutes post-surgery, whereas Groups A and B demonstrated lower ratings (5.99 and 6.87). Pethidine and parecoxib when paired with acetaminophen were equally effective, as evidenced by the lack of a significant difference between Groups A and B. If acetaminophen monotherapy was used, combination treatment produced better pain relief. Conclusion: Following hernia repair surgery, combination analgesic regimens comprising acetaminophen and either pethidine or parecoxib are more successful at reducing postoperative pain than acetaminophen monotherapy. As a normal procedure, multimodal analgesia should be taken into account to reduce the incidence of chronic pain and enhance patient recovery.

Changes in Quality Characteristics and Metabolite Composition of Low-Temperature and Nitrogen-Modified Atmosphere in Indica Rice during Storage

A low temperature (LT) is used to delay grain deterioration effectively. In practical applications, a nitrogen-modified atmosphere (N2) is also an effective way of preventing grain pests and delaying grain deterioration. However, there are few studies on grain quality changes using a combination treatment of an LT and N2 during storage. In this study, the storage quality, processing characteristics, and metabolites of rice under conventional storage (CS), LT (20 °C), N2 (95%), and LT+N2 treatments were analyzed for 180 days, under a controlled humidity of 65% ± 2%. The results showed that compared to the CS, LT, and N2 treatments, the LT+N2 treatment had the best effect in retarding the increase in MDA and electrical conductivity and deferring the decrease in CAT activity. In addition, the LT+N2 treatment maintained the color of the rice better and sustained a better processing quality. Non-targeted metabolomics analysis further confirmed that the LT+N2 treatment maintained the vigor of the rice and retarded its spoilage by activating the metabolisms of amino acids, carbohydrates, and flavonoids. These results suggest a favorable practice for preventing storage deterioration and increasing the processing quality for rice storage. They provided new insights into the mechanisms of rice quality changes using the combination treatment of an LT and N2.

Efficacy of Shugan Hewei formula combined with rabeprazole in refractory gastroesophageal reflux disease: randomized, double-blind, placebo-controlled trial

ObjectivesTo assess the efficacy of the Chinese herbal medication Shugan Hewei formula (SHF) combined with rabeprazole in patients with refractory gastroesophageal reflux disease (rGERD).MethodA total of 264 participants were randomly assigned to the treatment group (n = 132) receiving SHF granules (20 mg) combined with rabeprazole (10 mg) and the control group (n = 132) receiving placebo SHF granules (20 mg) combined with rabeprazole (20 mg). Both groups undergo 8 weeks of treatment and 2 weeks of follow-up.ResultsThe treatment group showed higher total clinical symptom efficacy and lower total symptom scores compared to the control group. The treatment group was superior to the control group in reducing rGERD major symptom scores, including heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation. Additionally, treatment group (Z = 8.169, P < 0.001) and control group (Z = 9.800, P < 0.001) treatments were all significantly attenuated esophageal inflammation, demonstrating comparable efficacy. Patients with esophagitis grade A decreased from 40.34% to 17.23%, and those with grade B decreased from 11.76% to 3.78% in the treatment group. The results of the SF-36 scale showed that combination therapy was more effective in improving role limitations due to physical health, vitality, general health, total somato-physical health, and psychiatric mental health.ConclusionOur study reveals that the combined treatment of SHF with rabeprazole is more efficacious in managing patients with rGERD when contrasted with sole rabeprazole treatment.

Effect of Nano Urea on Growth, Yield and Nutrient uptake of Finger Millet (Eleusine coracana L.)

Aim: The foliar application of nano urea is aimed at reducing the soil application of conventional urea. Nano fertilizers enhance crop growth and yield while enhancing nutrient uptake and reducing costs. They provide precise nutrient management, match crop growth stages, and offer an increased surface area for metabolic reactions. This boosts photosynthesis, leading to higher dry matter production and crop yield. Foliar application of nano urea (liquid) at tillering and booting stages in finger millet fulfills the nitrogen requirement and reflects higher crop productivity. Higher productivity of crops in a sustainable manner could be achieved by applying an appropriate combination of conventional fertilizers and nano fertilizers. Study Design: The experiment was laid out in split design with three replications. Place and Duration of Study: A field experiment was conducted in deep black soils at Agricultural Research Station, Siruguppa, during kharif 2022. Methodology: There were sixteen treatment combinations, consisting of different doses of nitrogen (no nitrogen, 50% RDN, 75% RDN and 100% RDN) with different concentrations of nano urea and conventional urea sprayed at tillering and booting stages for HR-13 variety of finger millet. Results: Application of 100% RDN has recorded significantly higher plant height, tillers plant-1, total dry matter accumulation, grain yield and straw yield (129.82 cm, 10.10, 36.17 g plant-1, 36.87 q ha-1 and 71.72 q ha-1, respectively) in comparison to no nitrogen and 50% RDN. However, 75% RDN (123.04 cm, 9.61, 34.02 g plant-1, 34.84 q ha-1 and 68.01 q ha-1, respectively) found on par with 100% RDN. Among foliar nitrogen, spray of nano urea @ 4 ml L-1 recorded significantly higher plant height (121.59 cm), tillers plant-1 (9.37), total dry matter accumulation (33.16 g plant-1), grain yield (31.97 q ha-1) and straw yield (65.52 q ha-1) compared to 0.5% and 1% conventional urea. However, nano urea @ 2 ml L-1 was on par with 4 ml L-1 nano urea and 1% conventional urea. Similar trend was recorded with regard to nutrient uptake by finger millet. Conclusion: Foliar application of nano urea reduced the dosage of conventional urea by 25 per cent.

Co-utilization of microalgae and heterotrophic microorganisms improves wastewater treatment efficiency

Wastewater treatment using the activated sludge method requires a large amount of electricity for aeration. Therefore, wastewater treatment using co-culture systems of microalgae and heterotrophic microorganisms, which do not require aeration, has attracted attention as an energy-saving alternative to the method. In this study, we investigated different combinations of microalgae and heterotrophic microorganisms to improve the efficiency of wastewater treatment. Three types of microalgae and five heterotrophic microorganisms were used in combination for wastewater treatment. The combination of Chlamydomonas reinhardtii NIES-2238 and Saccharomyces cerevisiae SH-4 showed the highest wastewater treatment efficiency. Using this combination for artificial wastewater treatment, the removal rates of total organic carbon, PO43−, and NH4+ reached 80%, 93%, and 63%, respectively, after 18 h of treatment. To the best of our knowledge, this is the first study to show that a combination of green algae and yeast improves the efficiency of wastewater treatment. Transcriptome analysis revealed that the combined wastewater treatment altered the expression of 1371 and 692 genes in C. reinhardtii and S. cerevisiae, respectively. One of the main reasons for the improved wastewater treatment performance of the combination of green algae and yeast was the increased expression of genes related to the uptake of phosphate and ammonium ions in the green algae. As both the green algae C. reinhardtii and the yeast S. cerevisiae are highly safe microorganisms, the establishment of their effective combination for wastewater treatment is highly significant.Key points• Combination of various microalgae and heterotrophic microorganisms was tested• Combination of green algae and yeast showed the highest efficiency• This is the first report that this combination is effective for wastewater treatment

Galantamine and wedelolactone combined treatment suppresses LPS-induced NLRP3 inflammasome activation in microglial cells

Context Inflammasome NLR family pyrin domain-containing 3 (NLRP3) is associated with neurological disorders. Neuroinflammation can be suppressed by inhibiting NLRP3 inflammasome activation, decreasing neurodegenerative disorder progression. We devised a therapeutic technique that can reduce neuroinflammation induced by microglial activation, avoiding neurodegeneration. We aimed to investigate the mechanisms underlying the pharmacological effects of galantamine and wedelolactone by evaluating the response of the nuclear factor kappa B (NF-κB) signaling pathway and NLRP3 inflammasome in lipopolysaccharide (LPS)-activated N9 microglia. Methods LPS and adenosine triphosphate were used to activate the NLRP3 inflammasome in N9 microglial cells, which were pretreated with galantamine and wedelolactone. Caspase-1, NLRP3, NF-κB, and interleukin (IL)-1β levels were measured using RT-qPCR and immunostaining. Results Combined administration of galantamine and wedelolactone rescued microglial cells from LPS-induced cell death. Furthermore, treatment with galantamine and wedelolactone led to the suppression of NF-κB expression. NLRP3, caspase-1, and IL-1β levels were decreased by the combined treatment. Discussion and Conclusion The concurrent administration of galantamine and wedelolactone effectively suppresses the production of inflammatory cytokines and NLRP3 inflammasome activation in microglia. This inhibitory effect is likely linked to the NF-κB signaling pathway modulation. Therefore, this combined treatment is a potential therapeutic approach for neuroinflammatory diseases.

Effect of extracorporeal shock wave combined with autologous platelet-rich plasma injection on rotator cuff calcific tendinitis: study protocol for a randomized controlled trial

BackgroundRotator cuff calcific tendinitis (RCCT) is a common shoulder disease whose main symptoms include shoulder pain, limited mobility, and calcification deposits in the shoulder. Traditional treatment methods have certain limitations, so finding new treatment methods has become the focus of research. Extracorporeal shock wave (ESW) and platelet-rich plasma (PRP) treatments have attracted much attention due to their non-invasive and tissue repair-promoting properties; however, the efficacy of their combined treatment in RCCT remains unclear.MethodsThis study is designed as a single-center, assessment-blind, randomized controlled clinical trial with three parallel groups. Sixty subjects will be recruited and randomly divided into the ESW group, PRP group, and ESW combined with PRP group, in a 1:1:1 ratio. The entire intervention period is 4 weeks, and the follow-up period is 4 weeks. Outcomes will be measured at baseline (T0), after 1 week of intervention (T1), after 2 weeks of intervention (T2), after 4 weeks of intervention (T3), and after an additional 4 weeks of follow-up period (T4). The primary endpoint is the VAS score. Secondary endpoints are ASES, CMS, UCLA, and the location and size of calcified areas.DiscussionThis study aims to evaluate the efficacy of ESW therapy combined with PRP in treating RCCT. We compare the effects of single and combined treatments to explore their impact on disease symptoms, functional improvement, and calcification regression. This provides a scientific basis for identifying more effective treatment options.Trial registrationClinicalTrials.gov NCT06372600. Registered on April 17, 2024; version 1.

Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n = 15). All patients received remdesivir and some also received nirmatrelvir-ritonavir (n = 3) or therapeutic monoclonal antibodies (n = 4). Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient sequentially treated with nirmatrelvir-ritonavir and remdesivir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.

Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.

Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes. This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle. This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical. Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.