Sequential Use Research Articles

Innovative complex method of therapy of hypertrophic skin scars

Many methods of therapy for GR are currently insufficiently studied in terms of a high evidence base, and the data are contradictory, which determinesthe relevance of research aimed at developing and studying the effectiveness and safety of new methods that can influence the main links in thepathogenesis of pathological scars. The aim of our study was to scientifically substantiate and develop a combined method of therapy for patients withsevere hypertrophic scars lasting up to 1 year using a neodymium laser and pneumokinetic therapy with 5-fluorouracil and durant corticosteroid basedon a study of hemodynamic processes. The study group included 34 patients with hypertrophic scars who underwent two procedures of pneumokinetictherapy with GCS and 5-FU, with an interval of two months. After another one month, laser therapy with a neodymium laser (1064nm) was performed.The results of the LDF study confirmed the early results obtained on the initial changes in the microcirculatory bed in hypertrophic scars, as well as dataon the high efficiency of the developed method of pneumokinetic therapy of GCS + 5-FU and the sequential use of a neodymium laser (1064 nm).

Abstract 18325: Comparative and Incremental Diagnostic and Prognostic Yield of Exercise ECG, CMR and SPECT in Patients With Suspected Ischaemic Heart Disease: A CE-MARC Sub-Study

Background: Guidelines recommend exercise ECG and stress imaging as first line diagnostic tests for the management of patients with suspected ischemic heart disease (IHD). We compared 1) the accuracy in detection of angiographically defined IHD and 2) the prognostic significance of exercise ECG, single photon emission computed tomography (SPECT) and cardiovascular magnetic resonance (CMR), as well as the sequential use of exercise ECG and an imaging test, in the CE-MARC study. Methods and Results: Of 752 patients in CE-MARC, 580 had exercise ECG and angiography, and 503 also had SPECT and CMR. The sensitivity, specificity, positive and negative predictive values (95%CI) of exercise ECG were 68.3 (61.9,74.0), 72.5 (67.6,76.9), 61.0 (54.8,66.8), 78.4 (73.7,82.5). Exercise ECG was significantly less sensitive than CMR and less specific than CMR and SPECT. Furthermore a positive exercise ECG result was not predictive of MACE at follow-up (HR 1.14 [95% CI 0.75 to 1.72], p = 0.53). Sequential SPECT following an inconclusive exercise ECG compared to SPECT alone resulted in improved sensitivity (86.3% vs. 65.5%) and negative predictive value (79.0% vs. 87.9%) but at a cost of reduced specificity and positive predictive values (83.7% vs. 64.1%; 72.1% vs. 60.7%), and was not prognostically significant (HR 2.31 [95% CI, 0.88 to 6.08], p = 0.091). CMR alone had greater diagnostic and prognostic yield than exercise ECG, SPECT or a combination of the two. Sequential CMR in patients with inconclusive exercise ECG did not outperform CMR alone, but allowed effective prognostication (p = 0.011), contrary to SPECT (p = 0.081). Conclusions: In patients recruited to CE-MARC, exercise ECG was less sensitive than CMR and less specific than both CMR and SPECT. Positive exercise ECG results had no clear prognostic value. CMR alone was more sensitive and offered greater prognostic yield than exercise ECG, SPECT, or a combination of both. Diagnostic and prognostic yield of CMR was not improved by combination with exercise ECG. Importantly, sequential use of CMR, but not SPECT, improved prognostication following an inconclusive exercise ECG.

Larvae of Colorado potato beetle (Leptinotarsa decemlineata Say) resistant to double-stranded RNA (dsRNA) remain susceptible to small-molecule pesticides.

Implementation of resistance management tools is crucial for the continued efficacy of insect control technologies. An important aspect of insect resistance management (IRM) is the combined or sequential use of different modes-of-action to reduce selection pressure and delay evolution of resistance. This is especially important for insect pests with established ability to develop resistance to insecticides, such as the Colorado potato beetle (Leptinotarsa decemlineata, CPB). A new class of insecticides, based on double-stranded RNA (dsRNA) activating the gene silencing RNA-interference (RNAi) pathway, are currently under review for regulatory approval and commercial use in the USA against CPB. However, there is no information available on the potential for cross-resistance between RNAi insecticides and other classes of insecticides used against CPB. Herein, we aim to fill this knowledge gap by capitalizing on the availability of a CPB strain highly resistant to dsRNAs and test its susceptibility to diverse small-molecule insecticide classes compared to reference dsRNA-susceptible CPB strains. Differences in activity were observed among the four insecticides tested, with abamectin demonstrating highest activity against all three strains of CPB. However, no differences were observed among the dsRNA-resistant and susceptible CPB strains for any of the tested compounds. Overall, these results demonstrate lack of cross-resistance to commonly used chemical insecticides in the dsRNA-resistant strain of CPB. These data support the use of these different insecticide classes along with RNAi-based insecticides as part of an effective insect resistance management framework aimed at delaying resistance in CPB. © 2023 Society of Chemical Industry.

Analysis of Perioperative Factor Replacement Therapy for Hemophilia

Background Hemophilia is a hereditary bleeding disorder, especially in severe hemophilia, that can lead to spontaneous bleeding. For hemophilia patients with inhibitors, even minor acute bleeding events or surgical procedures can have catastrophic consequences. Some hemophiliacs are forced to make surgical choices. There are many risks in perioperative period when hemophiliacs undergo major surgery. Seeking effective and safe perioperative clotting factor replacement therapy or bypass therapy is the basis of successful surgery. Aims To seek effective and safe perioperative coagulation factor replacement therapy or bypass therapy. Methods HA patients were treated with FVIII preparation during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FVIII level in IU/dL desired, then multiply by 0.5. Example: 50 kg × 40 (IU/dL level desired) × 0.5 = 1000 IU of FVIII. HB patients were treated with PCC or FIX during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FIX level in IU/dL desired. Example: 50 kg body weight × 40 (IU/dL level desired) = 2000 IU of plasma-derived FIX. For hemophilia patients with low titer inhibitors, estimate the amount of FVIII required as a neutralizing inhibitor loading dose as recommended by WFH. The following formula is used to estimate the amount of FVIII needed as a loading dose to neutralize the inhibitor: [body weight (kg) × 80 × [(1 − hematocrit) × antibody titer (BU)]. An additional 50 IU/kg above the calculated loading dose is added to achieve a measurable FVIII activity. Patients with hemophilia combined with high titer inhibitors were treated with rFVIIa combined with PCC SCBT regimen. Sequential use refers to alternating rFVIIa and aPCC every 3 hours. Results 69 patients with indications for surgery and/or desire for surgery who underwent different types of surgery with clotting factor replacement therapy or bypass therapy were evaluated (Table 1). There were 37 cases of severe hemophilia and 32 cases of non-severe hemophilia. There were 63 cases of HA, including 50 cases of negative inhibitor and 13 cases of positive inhibitor. After meeting the inclusion and exclusion criteria, 69 patients were evaluated for different types of surgery under clotting factor replacement therapy or bypass therapy during perioperative period. 59 cases underwent major operations, including: 49 cases underwent joint replacement, among which 34 cases underwent single joint replacement and 6 cases underwent double joint replacement and so on. 10 cases underwent minor operations. There were 14 cases of hemophilia with inhibitors, of which 13 were major operations with 175.38 (85.00-270.00) minutes of operation and 2 were minor operations with 45.00 minute of operation. In 12 patients with severe hemophilia and high titer inhibitors, the perioperative consumption of factor FVII was as follows: 447.62 (331.04-738.48)ug/kg on the day of surgery, and the total consumption was 2484.21 (1499.40-4500.00)ug/kg. The perioperative consumption of factor PCC was as follows: 126.10 (0-206.45)ug/kg on the day of surgery, and the total consumption was 1332.84 (529.20-1970.00)ug/kg. The mean preoperative FVIII:C level of the HA patients was 1.19 (0.00~6.00)%, the mean preoperative FIX:C level was 0.022 (0.01~0.07)% of the HB patients.The average intraoperative blood loss of the 69 patients was 537.98 (0-3000) ml. 20 patients received intraoperative transfusion of blood products (red blood cells or fresh frozen plasma) and 49 patients did not receive intraoperative transfusion of blood products. In 55 hemophiliacs without inhibitor, no inhibitor was found after surgery. Conclusion(s) It is safe and effective to adopt different schemes for perioperative alternative therapy for different hemophilia types.

Sequential Administration of Selinexor and CAR-T Therapy in Relapsed/ Refractory Multiple Myeloma

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins and is approved for use in patients with relapsed refractory multiple myeloma(RRMM). Anti-BCMA directed CAR-T therapy for patients with relapsed/refractory multiple myeloma (RRMM) is a promising new class of therapy, which has shown a high level of efficacy. Sequential administration of selinexor followed by CD19 CAR-T has shown enhanced efficacy in human phase II trials and animal models of human non-hodgkin lymphoma(Stadel et al., 2022). In this retrospective single institutional study, we report outcomes of patients with RRMM who were treated with Selinexor based regimen prior to apheresis for CAR-T therapy. Methods: We conducted a retrospective study on an IRB-approved protocol for all patients who were treated with Selinexor based regimen immediately prior to apheresis as a prior line of therapy at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Response to CAR-T was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). Results: Between September 9, 2021, and April 3, 2023, 7 patients received CAR-T who were treated with Selinexor immediately prior to apheresis. The median age was 65.7 years (range: 55.1-77.1 years). Patients had a median of 6 (range: 4-10) lines of therapy (LOT) prior to CAR-T. 5 out of the 7 patients had double hit myeloma (all 5 with 17p and one other high risk). Four patients were treated with selinexor, carfilzomib and dexamethasone; two patients were treated with selinexor, daratumumab and dexamethasone and one patient was treated with selinexor, pomalidomide and dexamethasone. Four patients received Idecabtagene vicleucel (ide-cel) and three patients received ciltacabtagene autoleucel (cilta-cel). ORR was 100% with all 7 pts achieving very good partial response or better (>=VGPR). 2 patients had bone marrow biopsies that confirmed MRD -ve sCR in both patients. None of the patients have progressed so far, although median follow-up is short at 5.6 months. All patients had hematologic toxicities, 4/7 with grade III anemia (57.1%), 3/7 (42.8%) with grade or higher thrombocytopenia and 4/7 (57.1%) had grade 3 neutropenia. 2 of 7 patients had prolonged cytopenia for >6 months because of pre-existing underlying diagnoses of CCUS and MDS. 5 out of 7 patients had grade 1 Cytokine release syndrome (CRS). The other two patients did not experience CRS. Time of CRS onset was variable 2-10 days. No ICANS or infectious complications were observed. Conclusions: These results suggest that sequential use of Selinexor and CART in high risk RRMM may be an effective treatment strategy to provide deep and durable responses. The findings of our study are promising although it is limited by a small sample size and short follow-up. Further investigation in a larger study and longer follow up would be important to confirm our findings.

Multicenter Study of Mantle Cell Lymphoma Outcomes Following First-Line Bendamustine-Rituximab and Second-Line Bruton's Tyrosine Kinase Inhibitor Therapy

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

Can machine learning methods be used for identification of at-risk neonates in low-resource settings? A prospective cohort study

IntroductionTimely identification of at-risk neonates (ARNs) in the community is essential to reduce mortality in low-resource settings. Tools such as American Academy of Pediatrics pulse oximetry (POx) and WHO Young...

Improving the efficiency of hydraulic fracturing in wells with depleted gas reservoirs

The reasons for the low production rate of gas wells in depleted gas reservoirs are presented, including low natural permeability of productive formations and contamination of the bottomhole zone with solid phase and liquid. The methods of gas inflow stimulation to the bottom of wells are presented, among which hydraulic fracturing (HF) is worthy of attention for low permeability formations and deterioration of the bottomhole zone. The essence of hydraulic fracturing is described. Conventional and high-power hydraulic fracturing, its technology, scope, materials and chemicals used, and technological efficiency are characterized. During hydraulic fracturing in wells at depths of more than 600 m, to which the main proven gas reserves are confined, vertical and near-vertical fractures will mainly form. With a small reservoir thickness, vertical fractures can damage the cement stone behind the production casing, which in depleted gas reservoirs will help create conductive channels from the gas reservoir to the upper horizons. With a vertical fracture, gas flow to the well will be in one direction along the fracture and other volumes of the wellbore zone within the fracture radius will not be fully covered by filtration. To improve the efficiency of hydraulic fracturing in wells in depleted gas reservoirs, it is proposed to create a horizontal fracture in thin formations or several vertical fractures in formations of large thickness by preliminary hydraulic sandblasting perforation (HSP) or gas hydrosandblasting perforation (GHBP). When preliminary creating horizontal channels in the bottomhole zone, tubing with a perforator is gradually rotated to a certain angle, and when creating vertical channels, they are gradually raised to a certain height. After the perforation channels are created, hydraulic fracturing is performed. With the sequential use of hydraulic sandblasting perforation and hydraulic fracturing, it is possible to create a grid of cracks of increased length in the bottomhole zone in the specified directions. Using known analytical dependences, the length of individual perforation channels during gas-hydro-sandblasting perforation with a nozzle diameter of 4.5 and 6 mm in the perforator and the fracture radius during hydraulic fracturing were determined. The degree of increase in gas flow rate separately from hydraulic fracturing and hydraulic fracturing from their sequential implementation is estimated

Thread lifting as a modern method of non-radical face rejuvenation

Purpose of the study: The purpose of this review of scientific literature is to collect, systematize and update modern ideas about the types, methods and principles of thread lifting, taking into account the basic requirements for efficiency and safety.In this paper, we reviewed publications presented in scientific databases: Web of Science, Scopus, PubMed, Cochran library, Medline, and PubMed Central. The keywords for searching for materials were: thread lift, thread lift history, thread lift sutures, face thread lift, polylactic threads, polydioxanone threads.The earliest approach to the effective use of thread rejuvenation techniques was the use of non-absorbable threads based on polypropylene, which are still successfully used along with modern threads, among which a special place is occupied by absorbable threads and new modifications of non-absorbable ones, complemented by various fixing design features (notches, cones).A large selection of threads, techniques and principles of correction allows specialists to create an individual management plan for each patient, and continuity and synergy between the sequential use of different modifications of threads allows one to prolong the results obtained and delay or refuse more radical anti-aging surgeries on the face.At the same time, as a result of the review of the scientific literature, no published studies were found on the comparative analysis of thread and surgical methods of rejuvenation, which requires further study.

Long-term results of therapy with sequential use of rituximab and belimumab in patients with systemic lupus erythematosus

Objective: To evaluate the efficacy of combination therapy with rituximab (RTM) and belimumab (BLM) in patients with systemic lupus erythematosus (SLE) during long-term follow-up. Material and methods. Twelve patients with definite high- and moderate activity SLE were included in the study. Nine of them had skin and joint manifestations, and the others had renal, peripheral nervous system involvement, and vasculitis. Patients received RTM at a dose of 500–2000 mg with premedication with 6-methylprednisolone and then BLM according to the standard regimen of 10 mg/kg once a month. Patients were divided into two groups according to the timing of assessment of long-term outcomes. In the 1st group, data were evaluated after 7–9 years (n = 4), and in the 2nd group – after 2–4 years (n = 8) after the prescription of biologic disease-modifying antirheumatic drugs (bDMARDs). Efficacy and tolerability of therapy, SLE activity, and dose of oral glucocorticoids (GC) were evaluated. Results and discussion. Against the background of combination therapy, clinical and immunological response was achieved in 11 of 12 patients after one year (median SLEDAI-2K at baseline – 10 [9.5; 14.5] points, 6 and 12 months after administratrion of BLM – 4 [2; 6] points). When bDMARDs were prescribed in the first two years of the disease, patients responded better to therapy and showed more significant positive dynamics in clinical and laboratory parameters. Subsequently, BLM therapy was limited to an average of 2 years, during which a stable remission was achieved. Prescribing bDMARDs allowed GC to be used as initial therapy in an exacerbation of SLE in medium and low doses (subsequently further reduced). Clinical remission was achieved and maintained in 7 patients, exacerbation at different time points after discontinuation of bDMARDs occurred in 3 patients, efficacy waned in one patient, and no result was achieved with combination therapy in another patient. Conclusion. The most pronounced positive result can be expected when a bDMARDs are prescribed as early as possible after diagnosis of SLE (in the first 2 years of the disease). It is advisable to administer BLM infusions as recommended once a month without long breaks between injections for at least 2 years and to continue until a durable effect is achieved. The use of low-dose GC and its discontinuation is an achievable goal, but careful monitoring of patients is needed to detect early symptoms of exacerbation.

Cellular response to exposure to ionizing radiation and light in the presence of a photosensitizer

This study has been conducted to investigate the effects of X-ray irradiation in combination with photodynamic therapy on human lung adenocarcinoma cell line A549 used as a lung cancer model. It has been established that the concomitant use of these two types of radiation leads to much lower survival rate of tumor cells than that observed after the sequential use of these types of radiation or exposure to each type of radiation measured separately. For different combinations of the two mentioned types of radiation, the mRNA expression levels of some genes involved in cell cycle regulation (p21, DINOL), apoptosis (BAX, PUMA), and DNA repair (PARP1, OGG1, Rad51, Lig4) were determined in cells. The highest level of expression after exposure to different combinations of radiation was observed for the lncRNA DINOL gene. The increased expression of the BAX and PUMA genes indicates the development of apoptosis. The results obtained confirm that there is synergism in X-ray radiation and photodynamic therapy due to the concomitant use of these types of radiation.

Effectiveness comparison of third-generation EGFR-TKI as initial and sequential therapy in adjuvant treatment for EGFR mutation-sensitive stage IIIA non-small cell lung cancer after surgery

IntroductionAlthough third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) Osimertinib has been approved as adjuvant therapy for resected stage IIIA non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations, the optimal treatment sequencing of EGFR-TKIs, particularly whether Osimertinib should be the initial or sequential therapy following the first-generation EGFR-TKIs remains uncertain. MethodsA retrospective analysis was conducted on a cohort of patients with EGFR-mutated stage IIIA NSCLC who received treatment with either first-generation EGFR-TKIs or Osimertinib (third-generation) alone, or in sequential combination, at a single institution. The data analysis involved using the Kaplan-Meier method, log-rank test, and Cox regression. ResultsOut of the total 148 patients with stage IIIA NSCLC included in the study, 76 individuals underwent treatment with either first-generation EGFR-TKIs (referred to as subgroup “1″) or exclusively Osimertinib (subgroup “0 + 3″), or a sequential combination of the two (subgroup “1 + 3″) following surgery. Both univariate and multivariate analyses demonstrated that there were no discernible disparities in terms of disease-free survival and overall survival between subgroup " 1″ and " 1 + 3,” nor between subgroup " 0 + 3″ and “1 + 3". ConclusionThe findings from this study indicate that the introduction of third-generation EGFR-TKI Osimertinib did not yield enhanced survival benefits when compared to the first-generation drug in patients with stage IIIA completely resected NSCLC who were administered EGFR-TKIs as part of their postoperative adjuvant treatment. Additionally, within the observed sample size of this cohort, the sequential use of Osimertinib alongside first-generation EGFR-TKI did not demonstrate superiority over using either the first-generation EGFR-TKI or Osimertinib alone in terms of postoperative survival.

Combined or Sequential Treatment with Immune Checkpoint Inhibitors and Car-T Cell Therapies for the Management of Haematological Malignancies: A Systematic Review.

The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.

COVID-19 after hematopoietic cell transplantation and chimeric antigen receptor (CAR)-T-cell therapy.

More than 3 years have passed since Coronavirus disease 2019 (COVID-19) was declared a global pandemic, yet COVID-19 still severely impacts immunocompromised individuals including those treated with hematopoietic cell transplantation (HCT) and chimeric antigen receptor-T-cell therapies who remain at high risk for severe COVID-19 and mortality. Despite vaccination efforts, these patients have inadequate responses due to immunosuppression, which underscores the need for additional preventive approaches. The optimal timing, schedule of vaccination, and immunological correlates for protective immunity remain unknown. Antiviral therapies used early during disease can reduce mortality and severity due to COVID-19. The combination or sequential use of antivirals could be beneficial to control replication and prevent the development of treatment-related mutations in protracted COVID-19. Despite conflicting data, COVID-19 convalescent plasma remains an option in immunocompromised patients with mild-to-moderate disease to prevent progression. Protracted COVID-19 has been increasingly recognized among these patients and has been implicated in intra-host emergence of SARS-CoV-2 variants. Finally, novel SARS-CoV2-specific T-cells and natural killer cell-boosting (or -containing) products may be active against multiple variants and are promising therapies in immunocompromised patients.

Рецидивуючий бактеріальний вагіноз: варіативний підхід з урахуванням можливих патогенетичних аспектів

Purpose - to evaluate the effectiveness, duration of the clinical result, safety and tolerability of the complex treatment of recurrent bacterial vaginosis (BV) with the sequential use of an antibacterial agent and probiotic suppositories. Materials and methods. 91 women of reproductive age with a symptomatic course and a diagnosis of recurrent BV participated in the study. Primary decontamination of the vaginal tract was performed by all subjects and consisted of a 10-day intravaginal administration of the drug Terzhinan. Subsequently, the participants were randomized into three comparable groups. After primary remediation, no additional medication was prescribed to patients in the Group 1 (n=30). Subjects of the Groups 2 (n=30) and 3 (n=31) were recommended daily administration of vaginal probiotic suppositories Bifolak for a 10-day course, followed by prolongation of their use twice a week for 2 months in the Group 3. The effectiveness of BV therapy was evaluated immediately after antibacterial treatment and after a 6-month follow-up period based on the results of clinical examination, microscopic analysis of smears, and determination of vaginal pH with litmus strips. Results. At the end of the 10-day course of vaginal sanitation, subjective and objective signs of bacterial infection were not detected among all study participants, the pH of the vaginal secretion was within physiological limits and did not differ statistically between the Groups. At the stage of the sixth month of observation, data from a gynecological examination, smear microscopy and pH-metry confirmed 4 recurrences of the disease in the Group 1. In the Group 2, whose women additionally received a ten-day course of probiotic therapy, the number of episodes of repeated development of the disease was significantly lower, and amounted to 1 case for the entire observation period. Patients of the Group 3 did not notice manifestations of reinfection during the study and had no objective signs of BV. The use of a probiotic for a continuous course of 10 days in the Group 2, as well as its prolongation in a maintenance regimen (twice a week for 2 months) in the Group 3, was combined with a stable normalization of the acidity of the vaginal secretion, which was evidenced by the preservation of optimal pH until the end of the observation period (4.07±0.14 and 3.94±0.17, respectively, in the Groups 2 and 3 against 4.43±0.14 in the Group 1, p<0.05). The complete absence of repeated cases of BV and the lower pH values (p>0,05) in the Group 3 allowed us to consider the greater anti-relapse effectiveness of the long-term use of the probiotic at the trend level. Conclusions. Traditional schemes for the use of antibacterial agents in the treatment of BV allow to achieve a clinical and laboratory effect at the end of the course, but do not ensure its complete preservation for a long period of time. The disadvantage of the etiotropic approach to the treatment of BV is the lack of attention to the competitive properties of the indigenous flora as a factor in countering dysbiosis. Taking into account the pathogenetic essence of BV, which consists in the violation of the growth balance between conditionally pathogenic microorganisms and its own flora, classical antibacterial schemes can be successfully supplemented by the external introduction of eubiotic strains. Our study showed the benefits of complex therapy with an antibacterial agent and a probiotic, which consisted in stabilizing the acidity of the vaginal space and reducing the rate of disease recurrence, with a tendency to increase the effect in parallel with the duration of treatment. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Synthetic contraceptive hormones occlude the ability of nicotine to reduce ethanol consumption in ovary-intact female rats

Rates of tobacco and alcohol use in women are rising, and women are more vulnerable than men to escalating tobacco and alcohol use. Many women use hormonal birth control, with the oral contraceptive pill being the most prevalent. Oral contraceptives contain both a progestin (synthetic progesterone) and a synthetic estrogen (ethinyl estradiol; EE) and are contraindicated for women over 35 years who smoke. Despite this, no studies have examined how synthetic contraceptive hormones impact this pattern of polysubstance use in females. To address this critical gap in the field, we treated ovary-intact female rats with either sesame oil (vehicle), the progestin levonorgestrel (LEVO; contained in formulations such as Alesse®), or the combination of EE+LEVO in addition to either undergoing single (nicotine or saline) or polydrug (nicotine and ethanol; EtOH) self-administration (SA) in a sequential use model. Rats preferred EtOH over water following extended EtOH drinking experience as well as after nicotine or saline SA experience, and rats undergoing only nicotine SA (water controls) consumed more nicotine as compared to rats co-using EtOH and nicotine. Importantly, this effect was occluded in groups treated with contraceptive hormones. In the sequential use group, both LEVO alone and the EE+LEVO combination occluded the ability of nicotine to decrease EtOH consumption. Interestingly, demand experiments suggest an economic substitute effect between nicotine and EtOH. Together, we show that chronic synthetic hormone exposure impacts nicotine and EtOH sequential use, demonstrating the crucial need to understand how chronic use of different contraceptive formulations alter patterns of polydrug use in women.

Fenton-like process evaluation of textile effluent discolouration using pyrite tailings: Influence of dissolved iron

This study investigated the discoloration of real textile effluents using raw pyritic waste (RPW) as a Fenton-like process catalyst, as well as the influence of particle size and pre-treatment with distilled water only. The RPW was collected from a waste pile, following the ABNT NBR 10007:2004 standard, and ground to obtain particles with an average diameter of 0.75 and 1.5 mm. RPW and Washed Pyritic Waste (WPW) samples were characterized by XRF, FTIR and XRD. The operational conditions were assessed from an experimental design, varying the catalyst concentrations, H2O2 and the reaction time. XRD results showed the majority presence of FeS2 in the samples and the pre-treatment removed impurities, such as quartz and soluble compounds, from the catalyst surface. The experimental design determined that the 0.75 mm size was more efficient in removing colour from the effluent. The optimal condition was defined as 2 g/L of catalyst, 2 g/L of H2O2 and 2 h. The effluent colour degradation capacity was greater than 90% for RPW and WPW samples. However, WPW released less iron into the resulting solution (10.51 mg/L). The catalyst proved to be stable for sequential use and after five cycles, the discoloration rate was greater than 80%. Root growth was verified for the Allium cepa test using the post-treatment and neutralized effluent. The results indicate a potential use of pyritic wastes from coal mining as catalysts for the Fenton process for real textile effluents discoloration, adding environmentally friendly value to a material considered an environmental liability.

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial

Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200mg (n=15) or 300mg (n=15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200mg, 80%; 300mg, 60%). The median progression-free survival was 12.9 months (200mg, 15.8 months; 300mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200mg: 60%; 300mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Chinese Thoracic Oncology Group (CTONG).

New selective and sustainable ultrasound-assisted extraction procedure to recover carnosic and rosmarinic acids from Rosmarinus officinalis by sequential use of bio-based solvents

Carnosic (CA) and rosmarinic (RA) acids are the primary phenolic acids in hydrophilic rosemary extracts. Their combination exhibits high antioxidant activity and can be explored in several applications. This study aimed to develop an extraction procedure using bio-based solvents to recover two rosemary extracts, one rich in CA and the other in RA. By using ultrasound-assisted extraction (UAE) and a pool of 34 solvents, we evaluated nominal power (W), extraction time (min), and solvent water percentage (% H2O) regarding yield and selectivity. The authors propose a sequential UAE procedure validated by applying ethanol 99.5 % (v/v), 240 W, and 5 min to recover a rich fraction of 24.0 mgCA.gbiomass−1; followed by a second step using AmAc:LA (1:2 M ratio), 20 % H2O (m/m), 320 W, and 5 min that resulted in 8.4 mgRA.gbiomass−1. Our results indicate that modulating the solvent composition and process temperature is critical to increasing extraction yields and selectivity.

Six compared with 12 hours of Foley balloon placement for labor induction in nulliparous women with unripe cervices: a randomized controlled trial

Planned 6 versus 12 hours placement of the double-balloon catheter shortens the induction to delivery interval. The Foley catheter is low-cost and has at least comparable effectiveness to the proprietary double balloon labor induction devices. 6 hours placement with the Foley balloon in nulliparas has not been evaluated. To evaluate 6 vs 12 hours Foley balloon placement for cervical ripening in the labor induction of nulliparas. A randomized controlled trial was conducted in University Malaya Medical Center from January 2022 to August 2022. Nulliparas aged 18 years or above, with a term, singleton pregnancy in cephalic presentation, intact membranes, reassuring fetal heart rate tracing, unripe cervix, without any significant contractions, were recruited at admission for labor induction. Participants were randomized after successful Foley balloon insertion, for the balloon to be left passively in place for 6 or 12 hours, then removed to check for a ripened cervix. Amniotomy was performed once the cervix had ripened followed by titrated oxytocin infusion to expedite labor and delivery. Primary outcome was the induction to delivery interval. Secondary outcomes were mostly from the core outcome set (CROWN) for induction of labor trial reporting1 such as change in Bishop score after intervention, use of additional method for cervical ripening, time to delivery after double-balloon device removal, mode of delivery, indication for cesarean section, duration of oxytocin infusion, blood loss during delivery, presence of third- or fourth-degree perineal tear, maternal infection, maternal satisfaction regional analgesia in labor, length of hospital stay, Intensive Care Unit (ICU) admission, cardiorespiratory arrest, need for hysterectomy. The neonatal outcomes are Apgar score at 1 and 5 minutes, neonatal ICU (NICU) admission, cord pH, neonatal sepsis, fetal birth weight, birth trauma, hypoxic ischemic encephalopathy or need for therapeutic hypothermia. Data were analyzed with the t-test, Mann-Whitney U test, Chi square test and Fisher exact test as appropriate for the data type. 240 women were randomized, 120 to each arm. The induction to delivery interval was median[interquartile range] 21.3[16.2-27.9] vs 26.0[21.5-30.9] hours P<0.001 for 6 vs 12 hours placement respectively. Of the secondary outcomes, the sequential use of additional cervical ripening agent (mostly Foley reinsertion) was 33/19(27.5%) vs 17/120(14.2%) RR 1.94 95% CI 1.15-3.29 p=0.011, Bishop score increase was 3[2-3.75] vs 3[2.25-4] p=0.002 and rate of recommendation to a friend was 83/118(70.3%) vs 101/119(84.9%) RR 0.83 95% CI 0.72-0.95 p=0.007 for 6 vs 12 hours placement respectively. Cesarean delivery rate was 52/119(43.7%) vs 64/120(53.3%) RR 0.82 95% CI 0.63-0.07 p=0.136 and maternal satisfaction score (0-10 numerical rating scale) was 7[6-9] vs 7[7-9] p=0.880 for 6 vs 12 hours respectively. Planned 6 vs 12 hours Foley balloon placement shortens time to birth despite less cervical ripening at Foley removal and more additional cervical ripening agent use. However, 6 hours placement was less likely to be recommended to a friend.