Use In Combination Research Articles

Optimal etching process and cladding dimension for improved coating of porous hemispherical ZnO nanostructure on FBG humidity sensor

Fiber Bragg grating (FBG) based sensors require functional chemical coating for relative humidity (RH) sensing. However, the cladding of the fiber may impede the mechanical strain that is induced in the sensing region of the FBG. This study focuses on the humidity sensing performance of FBGs etched with several different diameters. Silica-based uniform FBG was chemically etched before being coated with a ZnO nanostructure reinforced with hexamethylenetetramine (HMT) additives. ZnO-HMT was produced using a low-temperature modified hydrothermal method and then coated on FBG etched with various diameters. Morphology observations with elemental analysis confirmed the formation and presence of ZnO-HMT coatings on the sensors. Results interpreted from an optical spectrum analyzer have shown wavelength shifts of 0.0004 nm/%RH with linearity of ∼98% for samples etched for 10 min. Both sensitivity and linearity deteriorated as the FBG was etched to thinner diameters. Sensor sensitivity improves by at least 20%–30% when compared to the uncoated version of FBG. It can be concluded that with zinc-based coatings, FBG sensing performance can be improved only to a certain extent through etching durations. Thinner cladding may not be suitable for use in combination with zinc-based nanostructures. The optimized FBG etching when used in conjunction with zinc oxide improves upon its non-etched counterparts and increases its potency in industrial applications.

Real-world patient characteristics and treatment patterns associated with tucatinib therapy in patients with HER2+ metastatic breast cancer.

1051 Background: Tucatinib (TUC) is an oral HER2-targeted therapy approved by the FDA in Apr 2020 for use in combination with trastuzumab and capecitabine (TRA+CAP) for patients with previously treated HER2+ metastatic breast cancer (MBC). In the randomized HER2CLIMB trial, median (95% CI) overall survival (mOS) and progression-free survival (PFS) for patients receiving TUC with TRA+CAP were 21.9 (18.3, 31.0) and 7.8 (7.5, 9.6) months, respectively. Median duration of therapy was 7.3 months. HER2CLIMB used a standard of care comparator arm and included patients with active and stable brain metastasis (BM). HER2CLIMB was conducted prior to approval of fam-trastuzumab deruxtecan (T-DXd) so did not assess the impact of TUC-based therapy following T-DXd. Objective: Describe patient characteristics, treatment patterns, and clinical outcomes for TUC-based treatment in the real-world setting. Methods: This retrospective study included patients in the Komodo Health dataset (aggregating data from patient administrative health claims in the United States) diagnosed with MBC between Jan 1, 2017 and Sep 3, 2022 and initiating TUC post- approval in Apr 2020. Patient characteristics were described in the baseline period (≤6 months from TUC initiation). Key outcomes were time to next treatment (TTNT; as a proxy for PFS), time to discontinuation (TTD), and persistence (proportion continuing treatment at each timepoint) in all TUC-treated patients, and in patients receiving TUC immediately following T-DXd. Results: Of 16,990 patients identified with HER2+ MBC, 528 received TUC-based treatment. Of these, 57 (11%), 164 (31%), 154 (29%), and 153 (29%) received TUC in first-line (1L), second-line (2L), third-line (3L), and fourth-line or later (4L+), respectively. Median follow-up from TUC initiation was 9 months. Overall, 400 patients (76%) had BM prior to initiating TUC (43 [75%], 138 [84%], 111 [72%], and 108 [71%] in 1L, 2L, 3L, and 4L+, respectively). Median (95% CI) TTNT was 10.7 (9.4, 13.1) months overall and 11.5 (9.6, 14.4) in patients receiving TUC in 2L or 3L. Median (95% CI) TTD was 8.5 (7.2, 9.3) months overall, and 9.1 (7.7, 9.9) in patients receiving TUC in 2L or 3L. TUC persistence in the overall cohort was 46% (91/200) at 12 months and 35% (40/115) at 18 months. Sixty-one patients (12%) received TUC immediately following T-DXd (median 4L; 12 in 2L/3L, 49 in 4L+); of whom 36 (59%) had BM prior to initiating TUC. TTNT and TTD for patients treated with TUC following T-DXd were 7.5 (5, 13.3) and 7.3 (3.2, 9.5) months, respectively. Conclusions: In the real-world setting, a higher proportion of patients receiving TUC had BM compared with the HER2CLIMB patient population. TUC-based treatment in the real world is used in multiple lines of therapy and is associated with a similar TTNT and TTD to PFS observed in HER2CLIMB, inclusive of a cohort of patients who received TUC following T-DXd therapy.

AB-101, an allogeneic, non–genetically modified, natural killer (NK) cell therapy, evaluated as monotherapy or in combination with rituximab in R/R non-Hodgkin lymphoma.

7529 Background: AB-101 is a non-genetically modified, cord blood-derived, allogeneic, cryopreserved, NK cell therapy for use in combination with monoclonal antibody (mAb) or innate cell engager therapies. AB-101 is being developed to enhance response to mAb therapy through the antibody-dependent cellular cytotoxicity (ADCC) mechanism. Many cancer patients (pts) are unable to mount a robust ADCC response, rendering mAb therapy less effective for these pts. AB-101 has attributes that enhance NK cell activity: Consistent phenotype for tumor engagement and cytotoxicity; Selected killer immunoglobulin-like receptor B (KIR B) haplotype; V/V CD16 polymorphism at F158 for enhanced ADCC. AB-101 outpatient administration provides optimized NK cells to pts, potentially enhancing their anti-tumor activity in combination with mAb that utilize the ADCC mechanism. We have initiated a Ph 1/2 clinical trial evaluating the combination of AB-101 with rituximab (RTX) in pts with R/R NHL of B-cell origin. Methods: Two AB-101 dose levels, 1 or 4e9 cells, will be evaluated as monotherapy or combination with RTX. All enrolled pts will receive at least 1 cycle of 4 weekly AB-101 doses, with cyclophosphamide/fludarabine lymphodepletion (LD). Pts receiving the combination may receive up to 4 treatment cycles. Results: Dose escalation is ongoing with 17 pts enrolled. Pts were elderly (median of 68 yrs) and heavily pretreated (median of 4 prior lines) with 64% having had prior CD19 CAR-T. Pts had DLBCL (9), FL (5), MCL (2), and LPL/WM (1). 11 monotherapy pts and 6 RTX combination pts were treated at time of abstract. 16 pts received AB-101 at 1e9 cells/dose; 1 pt received 4e9 cells/dose. 4 of 6 combination pts have received > 1 cycle. AB-101 was generally well tolerated. The most common G3+ AEs were LD-related neutropenia and lymphopenia. All AB-101 related AEs were G1/2. ICANs and GVHD, events associated with allogeneic cell therapy, were not reported; Gr 1 CRS occurred in 2 pts and resolved within 24h. SAEs were reported in 9 pts. The most common SAEs were associated with either infections (n = 3) or PD (n = 3) and one related SAE of Gr 1 fever was reported. No pts discontinued treatment due to an AB-101-related AE. ORR for the RTX cohort was 67% (4/6) with a CR rate of 50% (3/6). 3 of 4 responses were observed in pts who failed prior CAR-T therapy. ORR for the monotherapy cohorts was 27% (3/11). Conclusions: 4 weekly doses of AB-101 given alone or with RTX appeared to be safe and well tolerated without the serious/severe toxicities associated with CAR-T therapies. Preliminary efficacy of the combination treatment is encouraging. The study is ongoing and continues to enroll the combination cohorts and the 4e9 cells/dose level. Updated safety, efficacy, and exploratory PK/PD/immunogenicity results will be provided during the presentation. Clinical trial information: NCT04673617 .

Patient-reported outcomes in patients with metastatic non-squamous non-small cell lung cancer from the PERLA trial comparing first-line chemotherapy plus dostarlimab or pembrolizumab.

9099 Background: PERLA (NCT04581824) is a global, randomized, Phase II, double-blind study assessing the efficacy and safety of chemotherapy (CT) combined with programmed death 1 (PD-1) inhibitors dostarlimab (dostCT) and pembrolizumab (pembCT) as first-line (1L) treatment (tx) for patients (pts) with metastatic non-oncogene-driven, non-squamous, NSCLC. DostCT had similar efficacy and safety to pembCT [1]. Exploratory analyses of patient-reported outcomes (PROs) from PERLA have been conducted. Methods: In PERLA, pts with ECOG status 0–1 were randomized 1:1 to receive ≤35 cycles (C) of dostCT or pembCT Q3W (CT was ≤35 cycles [C] of 500 mg/m2 pemetrexed every 3 weeks [Q3W] and ≤4C of cisplatin or carboplatin). PROs were collected at baseline (BL), Q3W until C4, Q9W until C16, Q12W until end of tx and at 30-day safety follow-up. Change from BL in EORTC QLQ-C30 & QLQ-LC13 were analyzed using a longitudinal mixed model, with a ≥10-point change from BL considered clinically meaningful; scores were categorized as improved, stable, or worsened. Time to deterioration (TTD) in QLQ-C30 and selected QLQ-LC13 symptoms were estimated using Kaplan–Meier methods. Results: Analysis populations for dostCT/pembCT included 102/99 pts for QLQ-C30 and 96/90 pts for QLQ-LC13. Completion rates for QLQ-C30 and QLQ-LC13 were >80% up to C4 in both tx arms, decreasing after C7. At C13, 55.0% [n=33/60] and 54.2% [n=32/59] of dostCT pts, and 37.1% [n=23/62] and 35.7% [n=20/56] of pembCT pts completed QLQ-C30 and QLQ-LC13, respectively. Overall, least squares (LS) mean QLQ-C30 and QLQ-LC13 scores remained stable up to C13. Relative to BL, average pt functioning (e.g., physical, role) and cancer symptoms (e.g., pain, cough, dyspnea) were stable through C13 (~1 yr on tx); no clinically meaningful difference in LS mean QLQ-C30 or QLQ-LC13 scores were observed between tx arms. Across most QLQ-C30 and QLQ-LC13 subscales, >60% pts in both tx arms had stable or improved responses up to C13. At C13, meaningful improvements in chest pain and dyspnea were reported in a higher % of dostCT pts (34.4% [n=11/32] and 40.6% [n=13/32], respectively) than pembCT pts (10.0% [n=2/20] and 25.0% [n=5/20], respectively). TTD for QLQ-C30 and QLQ-LC13 subscales were comparable between tx arms, except for longer median TTD in dyspnea in dostCT pts (N=96) than pembCT pts (N=90) (4.24 vs 1.54 months; HR 0.64 [95% CI: 0.44–0.93]). Conclusions: HRQoL was similar and stable through C13 in both tx arms. These results supplement efficacy and safety data reported in PERLA and support further investigation of dostarlimab as an appropriate PD-1 inhibitor for use in combination with standard of care and novel therapies in metastatic NSCLC.

Phase II results of ivonescimab (AK112/ SMT112), a novel PD-1/VEGF bispecific, in combination with chemotherapy for first line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) in EGFR/ALK.

9087 Background: Since the initial approval of bevacizumab (bev) with chemo in NSCLC, the subsequent focus of bev use in combination with PD1 therapy for first line metastatic disease has largely focused on non-squamous (non-SCC) histology. Ivonescimab is a novel anti-PD-1/VEGF bispecific antibody. The bispecific approach to these targets has the potential to recalibrate the malignant immuno-architecture in favor of a more immune-responsive and anti-tumor microenvironment. Cooperative VEGF binding with the bispecific has been shown to elevate affinity of ivonescimab to PD-1 by more than 10-fold. Ivonescimab has a mean T1/2 of 6-7 days while bev T1/2 is 20 days. Therefore, we aimed to assess the efficacy and safety of ivonescimab combined with chemotherapy for first line advanced or metastatic NSCLC in patients (pts) with squamous (SCC) or non-SCC NSCLC. Methods: An open-label, multi-center phase II study evaluating the efficacy and safety of ivonescimab combined with chemotherapy in pts with advanced or metastatic NSCLC. Pts were enrolled into 3 cohorts based on prior therapy and presence of AGA. Data from pts with prior therapy for advanced or metastatic disease were presented in ASCO 2022 and here we report additional pts and longer-term data from pts with NSCLC without AGA receiving first line therapy for advanced/metastatic disease. Pts were treated with 10 or 20 mg/kg ivonescimab once every 3wks combined with carboplatin and pemetrexed (non-SCC) or carboplatin and paclitaxel (SCC). The primary endpoint was ORR per RECIST by investigator. Results: 135 pts with advanced or metastatic NSCLC received ivonescimab plus chemotherapy including 63 with SCC and 72 with non-SCC. Median age was 61 yrs (. 78% male, 3% and 97% pts had ECOG PS 0 and 1, respectively, and 20% pts had baseline brain metastasis. Median follow-up was 11.5 mo. Pts with SCC experienced a 75% ORR with median DOR 15.4 mo, 95% DCR, the 9-mo PFS and OS rate was 67% and 93%, respectively. Pts with non-SCC experienced a 55% ORR, DOR was not reached, 100% DCR, the 9-mo PFS rate and OS rate was 61% and 81%, respectively. The most common treatment related adverse events (TRAEs)≥ 10% were epistaxis, proteinuria, rash, amylase increased, anemia, ALT increased, infusion related reaction, AST increased, pruritus, decreased appetite, and WBC decreased. Grade ≥3 TRAEs occurred in 28.1% TRAE leading to discontinuation occurred in 6.7% of pts. Conclusions: Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely in combination with platinum doublet chemotherapy to patients with SCC and non-SCC histology. Clinical trial information: NCT04736823 .

EPS3.10 Novel CFTR modulator combinations directly address the ΔF508-CFTR NBD1 stability defect and enable full CFTR correction

Objectives: CFTR mutations cause Cystic Fibrosis (CF). CFTR modulating drugs have improved CF outcomes, however, current drugs do not restore normal CFTR function to most patients. ΔF508, the most prevalent CF mutation, causes a loss of F508 within CFTR’s first Nucleotide Binding Domain (NBD1). This destabilizes NBD1 and impairs CFTR folding and function. ΔF508 also impairs CFTR domain-domain assembly, weakening the interface of NBD1 with CFTR’s fourth intracellular loop (ICL4) and transmembrane domain 1 (TMD1). Combining CFTR suppressor mutations that stabilize NBD1 with others that improve CFTR assembly can correct ΔF508 to wild-type (WT) levels. Without NBD1 stabilization, correction is significantly reduced. Drugs that stabilize NBD1 thus have the potential to improve treatment, but no current drugs fully address this defect. To restore WT function to ΔF508-CFTR, Sionna aims to discover and develop small molecule NBD1 stabilizers and CFTR assembly correctors for use in combination.

Treatment patterns and unmet need for patients with advanced non-small cell lung cancer and poor performance status: A real-world evidence study.

9077 Background: Performance Status (PS) is prognostic for poorer survival in oncology. Poor PS (pPS) may lead to inferior outcomes both as an independent factor and by limiting the range of available treatment options and the ability of patients to tolerate those regimens. Despite high real-world prevalence, patients with pPS are consistently underrepresented in clinical trials. Limited information is available regarding current treatment patterns for patients with pPS and advanced or metastatic non-small cell lung cancer (mNSCLC). Methods: We conducted a retrospective analysis using the nationwide de-identified Flatiron Health electronic health record (EHR)-derived database, selecting patients with mNSCLC diagnosed between 2017-2022 without EGFR or ALK genomic tumor aberrations. We estimated the prevalence of pPS (ECOG 2-3) within this cohort, and described common systemic treatment patterns by year and by PD-L1 status. For the subset of patients treated with pemetrexed/pembrolizumab/carboplatin (PPC), we estimated the association between pPS versus good PS (gPS - 0/1) and early discontinuation ( < 4 cycles) or dose reduction (AUC < 4) of carboplatin using logistic regression controlling for observable confounders. Results: One quarter (24%) of the 22,575 patients in our sample had pPS. Relative to patients with gPS, patients with pPS were more likely to be older (mean age 72 vs. 69y, p < 0.001), to have stage IV cancer (62% vs 56%, p < 0.001) and less likely to have known PD-L1 status (60% vs. 63%, p = 0.002). The fraction of patients with no documented treatment was substantially higher among pPS versus gPS (37% vs. 21%). In the subset of patients with PS3, 53% of patients had no documented treatment. The most common treatment regimens among pPS patients were mono-immunotherapy (mono-IO - 19%) and PPC (15%). Use of mono-IO was positively correlated with higher PD-L1 expression (44% vs. 14% vs. 5.9% in PD-L1 high/low/negative, respectively). No documented treatment was negatively correlated with PD-L1 status (26% vs. 35% vs. 42%). Among patients with PS3, higher rates of no documented treatment were observed (39% vs. 50% vs 58% for PD-L1 high/low/negative, respectively). Anti-CTLA-4 combination use was low regardless of PS. pPS was associated with greater likelihood of early carboplatin discontinuation, (adjusted odds ratio, aOR 2.06), and dose reduction (aOR 1.75), both p < 0.001. Conclusions: One quarter of patients with mNSCLC have pPS. These patients are almost twice as likely to receive no treatment as those with gPS, and within the subset treated with the most common platinum containing regimen (PPC), pPS patients are also more likely to both initiate carboplatin at a reduced dose, and to discontinue it prior to completion. This suggests a substantial unmet need for this important subset of patients with mNSCLC.

Attitude of healthcare professionals toward the use of complementary and alternative medication during anti-cancer therapy.

Patients with cancer often use complementary and alternative medication (CAM). This research aims to study the current attitude of healthcare professionals toward the use of CAM to improve current care. A questionnaire on both the current practice and opinions about CAM use was sent to healthcare professionals in Amsterdam UMC, who work for the department of hematology or oncology. Oncologists, hematologists, residents, (specialized) nurses, dieticians, (hospital)pharmacists, and pharmacy technicians were asked to participate in this study. Among eligible healthcare professionals, 77 responded to the questionnaire (34%). Overall, 87% of healthcare professionals indicate it is important to be aware of their patient's CAM use, and all find the potential of drug-herb interactions important. However, more than half of the healthcare professionals inquire about the patient's CAM use infrequently. In addition, only 15% of the healthcare professionals stated they had sufficient knowledge of CAM to advise patients on their use of CAM. Healthcare professionals are aware of the potential risks of CAM use in combination with anti-cancer treatment. However, CAM use is not yet discussed with every patient. This may be due to healthcare professionals' lack of knowledge about CAM.

Self-assembled ultraflexible probes for long-term neural recordings and neuromodulation.

Ultraflexible microelectrode arrays (MEAs) that can stably record from a large number of neurons after their chronic implantation offer opportunities for understanding neural circuit mechanisms and developing next-generation brain-computer interfaces. The implementation of ultraflexible MEAs requires their reliable implantation into deep brain tissues in a minimally invasive manner, as well as their precise integration with optogenetic tools to enable the simultaneous recording of neural activity and neuromodulation. Here, we describe the process for the preparation of elastocapillary self-assembled ultraflexible MEAs, their use in combination with adeno-associated virus vectors carrying opsin genes and promoters to form an optrode probe and their in vivo experimental use in the brains of rodents, enabling electrophysiological recordings and optical modulation of neuronal activity over long periods of time (on the order of weeks to months). The procedures, including device fabrication, probe assembly and implantation, can be completed within 3 weeks. The protocol is intended to facilitate the applications of ultraflexible MEAs for long-term neuronal activity recording and combined electrophysiology and optogenetics. The protocol requires users with expertise in clean room facilities for the fabrication of ultraflexible MEAs.

Polatuzumab vedotin (Polivy) for Lymphoma

Polatuzumab vedotin-piiq (Polivy – Genentech), a CD79b-directed antibody and microtubule inhibitor conjugate, has been approved by the FDA for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for first-line treatment of diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or high-grade B-cell lymphoma (HGBL) in adults who have an International Prognostic Index (IPI) score ≥2.

Anti-inflammatory mechanism of the optimized active ingredients of Sargentodoxa cuneata and Patrinia villosa

Pelvic inflammatory disease (PID) is a common gynecological infection. The combined use of Sargentodoxa cuneata (da xue teng) and Patrinia villosa (bai jiang cao) has been shown to inhibit PID progression. The active components of S. cuneata (emodin, Emo) and P. villosa (acacetin, Aca; oleanolic acid, OA; sinoacutine, Sin) have been identified but the mode of action of this combination of compounds against PID has not been clarified. Therefore, this study aims to investigate the mechanism of these active components against PID through network pharmacological, molecular docking and experimental validation. The results showed the optimal combination of components was 40 µM Emo + 40 µM OA, 40 µM Emo + 40 µM Aca, and 40 µM Emo + 150 µM Sin by cell proliferation and NO release. The potential key targets of this combination in the treatment of PID include SRC, GRB2, PIK3R1, PIK3CA, PTPN11, and SOS1, which act on signaling pathways such as EGFR, PI3K/Akt, TNF, and IL-17. Emo, Aca, OA, and their optimal combination inhibited the expression of IL-6, TNF-α, MCP-1, IL-12p70, IFN-γ, and the M1 phenotype markers CD11c and CD16/32, and promoted the expression of the M2 phenotype markers CD206 and arginase 1 (Arg1). Western blotting confirmed that Emo, Aca, OA, and their optimal combination significantly inhibited the expression of glucose metabolism-related proteins PKM2, PD, HK I, and HK II. This study proved the advantage of combination use of active components from S. cuneata and P. villosa, and clarified that they exert the anti-inflammatory effect by regulation of M1/M2 phenotype transition and regulation of glucose metabolism. The results provide a theoretical basis for the clinical treatment of PID.

The clinic-based predictive modeling for prognosis of patients with cryptococcal meningitis

BackgroundCryptococcal meningitis (CM) is the most common fungal infection of the central nervous system that can cause significant morbidity and mortality. Although several prognostic factors have been identified, their clinical efficacy and use in combination to predict outcomes in immunocompetent patients with CM are not clear. Therefore, we aimed to determine the utility of those prognostic factors alone or in combination in predicting outcomes of immunocompetent patients with CM.MethodsThe demographic and clinical data of patients with CM were collected and analyzed. The clinical outcome was graded by the Glasgow outcome scale (GOS) at discharge, and patients were divided into good (score of 5) and unfavorable (score of 1–4) outcome groups. Prognostic model was created and receiver-operating characteristic curve analyses were conducted.ResultsA total of 156 patients were included in our study. Patients with higher age at onset (p = 0.021), ventriculoperitoneal shunt placement (p = 0.010), Glasgow Coma Scale (GCS) score of less than 15(p< 0.001), lower CSF glucose concentration (p = 0.037) and immunocompromised condition (p = 0.002) tended to have worse outcomes. Logistic regression analysis was used to create a combined score which had a higher AUC (0.815) than those factors used alone for predicting outcome.ConclusionsOur study shows that a prediction model based on clinical characteristics had satisfactory accuracy in prognostic prediction. Early recognition of CM patients at risk of poor prognosis using this model would be helpful in providing timely management and therapy to improve outcomes and to identify individuals who warrant early follow-up and intervention.

Effects of morphine and P2Y inhibitor amongst patients with acute coronary syndrome: A meta-analysis of comparative studies

BackgroundP2Y inhibitor and morphine are widely used in caring for patients with the acute coronary syndrome (ACS), but there are some concerns about the combination use due to interaction in metabolism. Therefore, this study aimed to examine whether using morphine with antiplatelets in patients with ACS affects the clinical outcomes based on currently available evidence. MethodsThree databases were searched for comparative studies on this topic by using relevant keywords of ACS and morphine. Two authors independently extracted study information, mortality, major adverse cardiac event (MACE), major bleeding, and length of hospital stay. Then, they evaluated the quality of evidence independently. Meta-analysis was planned to be conducted in random-effects model. Risk ratio (RR) was used for most outcomes except hospital stay, and Peto odds ratio (POR) was used if there were any zero cells. Pooled estimate was presented with 95% confidence interval (CI). ResultsFourteen studies (n = 73,033) met eligibility criteria, and there was non-significant difference in mortality between antiplatelet with and without morphine (RR = 1.13, 95%CI: 0.78 to 1.64). Antiplatelet therapy without morphine significantly reduced the risk of MACE (RR = 0.78, 95%CI: 0.67 to 0.89; I-square = 0%), but increased the odds of major bleeding (POR = 1.87, 95%CI: 1.04 to 3.35; I-square = 0%) as compared with the combined use of antiplatelet therapy and morphine. ConclusionIn conclusion, there is no statistically significant difference in mortality in patients with ACS using morphine or not, but clinicians ought to make a trade-off between a lower risk of MACE and a higher risk of major bleeding before adding morphine to antiplatelet therapy.

Combined Effect of Trehalose and Serendipita indica Inoculation Might Participate in Solanum lycopersicum Induced Cold Tolerance.

The exploitation of symbiotic interactions between fungi and plants, coupled with the application of osmoprotectants such as trehalose (Tre), presents a promising strategy for mitigating environmental stress. To determine the mechanism of Serendipita indica and Tre-mediated cold stress tolerance, a comparative experiment was designed to study the impact of S. indica, Tre and their combination on tomato plants grown under cold stress. The results showed that cold stress significantly decreased biomass, relative water content, photosynthetic pigments and elements concomitantly with increasing antioxidant activities, malondialdehyde (MDA), electrolyte leakage, hydrogen peroxide and proline content. Meanwhile, S. indica and Tre treatments promoted biomass and enhanced carbohydrate, protein, proline, potassium, phosphorous, antioxidant enzymes and photosynthetic pigments content under cold stress. Furthermore, single or dual application of endophyte and Tre mitigated physiological disorders induced by cold stress and increased the integrity of cell membranes by decreasing hydrogen peroxide, MDA, and electrolyte leakage (EL). Our findings suggest that S. indica and Tre combination could significantly promote cold stress tolerance compared with single treatment. This study is novel in showing the cold adaptation of tomato plants by combination use of S. indica and Tre, which can be a promising strategy for improving cold tolerance. The underlying molecular mechanisms of sugar-fungus interaction must be further investigated.

Methionine, cysteine, and butylated hydroxytoluene enhance cryosurvival of ram semen on post-thaw and post-incubation time points.

Despite there have been many experiments conducted about antioxidants, the best sole or combination use of antioxidants to include as a standard ingredient to freezing extenders is yet to be found. This study was designed to investigate the different doses of methionine (2.5 and 5mM), cysteine (1 and 2mM), and butylated hydroxytoluene (BHT) (1 and 2mM) for ram semen cryopreservation on post-thaw and post-incubation (6h) time points over spermatological parameters. Semen samples were collected from Kivircik rams via electro-ejaculator in breeding season. After essential spermatological evaluations, appropriate samples were pooled then split into 7 equal aliquots to create study groups (antioxidant free control, 2.5mM methionine, 5mM methionine, 1mM cysteine, 2mM cysteine, 1mM BHT, and 2mM BHT). Semen samples were put into French straws (0.25mL), and freezing procedure (two-step) was conducted via a programmable gamete freezer. At both time points, motility, HOST, PSA-FITC, and TUNEL assays were made to discover the impacts of cryopreservation and incubation process over sperm cells. Antioxidant supplemented groups yielded better results compared to the control groups in terms of various spermatological parameters not only at post-thaw time point but after incubation for 6h of time. The study demonstrated that supplementing sperm freezing extenders with previous antioxidants may create new approaches to cryopreservation procedures, and through increasing success rate of freezing, fertility results may increase to better results in near future.

Clinical Outcome of Cefiderocol for Infections with Carbapenem-Resistant Organisms.

Cefiderocol is a novel cephalosporin recently approved by the FDA to aid clinicians in the fight against multidrug-resistant (including carbapenem-resistant) gram-negative organisms. The primary objective of this study is to evaluate the 14- and 28-day mortality associated with cefiderocol. We performed a retrospective chart review of all adult patients admitted at Stony Brook University Hospital between October 2020 and December 2021 and received cefiderocol for at least 3 days. Patients were excluded if they received more than one course of cefiderocol therapy or remained hospitalized at the time of this study. A total of 22 patients met the inclusion criteria. The all-cause mortality on day 28 for all patients was 13.6%, whereas this rate for patients with BSI was 0%, with cUTI was 0% and with LRTI was 16.7%. The all-cause mortality on day 28 for patients who received the dual antibiotics (in conjunction with cefiderocol) was 0%, compared to 25% for patients who only received cefiderocol (p = 0.25). We noted treatment failure in two patients (9.1%). Our findings suggest that cefiderocol could possibly be associated with lower all-cause mortality than previously thought. In our study, we did not find any significant difference between cefiderocol's use in combination with another antibacterial agent and its use as a monotherapy.

THE RELATIONSHIP BETWEEN ADDITIONAL TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION AND INCREASING THE EFFECTIVENESS OF PHYSICAL EXERCISE IN REDUCE PAIN IN LOW BACK PAIN

Low back pain (LBP) is a common problem that affects many people around the world. Physical exercise is one of the most commonly used interventions for LBP, but its effectiveness can be limited by pain experienced during exercise. Transcutaneous Electrical Nerve Stimulation (TENS) is a non-invasive technique that has been found to be effective in reducing pain in LBP patients. The aim of this literature review is to investigate the relationship between the addition of TENS to physical exercise and its effectiveness in reducing pain in LBP patients. A comprehensive search of databases was conducted, and studies that met the inclusion criteria were analyzed. The results of this review suggest that the addition of TENS to physical exercise can be effective in reducing pain in LBP patients. TENS can prepare the muscles of the body before exercise, making physical exercise more effective and reducing pain. However, the effectiveness of TENS may be limited to the short-term, and more research is needed to fully understand the long-term effects of TENS as an adjunct for physical exercise. Furthermore, the optimal dosage, duration, and frequency of TENS use in combination with physical exercise for LBP patients remains to be determined. Overall, the addition of TENS to physical exercise can be a useful adjunct in reducing pain in LBP patients, but more research is needed to fully understand its potential benefits and limitations.

Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS

BackgroundIn the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.MethodsWe analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.ResultsMOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.ConclusionsMOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.

Polysaccharides from Chinese herbs as natural weapons against colorectal cancer.

Colorectal cancer (CRC) ranks third and second among the most widespread cancers worldwide and the most common causes of human death due to cancer, respectively. Further, for unknown reasons, numbers of young patients diagnosed with colon cancer has increased. Polysaccharides are important functional phytochemicals reported to have anti-CRC effects. Moreover, CRC development and progression is closely related to the gut microbiome. Although approaches for treating CRC have been the subject of some review papers, research into traditional Chinese medicine (TCM) treatments for CRC and the underlying mechanisms involving polysaccharides have not been reviewed. Here, we reviewed the mechanisms underlying treatment of CRC using TCM polysaccharides, based on the etiology of CRC, and common treatment methods applied. The relationship between intestinal microbes and CRC, the mechanism by which TCM polysaccharides induce CRC cell apoptosis, and how TCM polysaccharides promote immune responses are discussed, as well as TCM polysaccharide use in combination with chemotherapy. TCM polysaccharides provide options for CRC treatment, due to their advantages of having multiple targets, eliciting modest adverse reactions, and wide range of available sources.

A photothermal cellulose-based material for rapid anti-bacteria and HCHO removal via sequential formation of MnO2 coatings and amine-quinone networks

Nowadays, with the rapid growth of population and acceleration of global urbanization, the microbial contamination on textiles and continuous formaldehyde (HCHO) releases from indoor decoration have aroused public attentions along with the textile consumption. Herein, a green, novel method for preparation of a multifunctional cotton fabric was reported, via the combination use of mussel-inspired fabrication of amine-quinone networks (AQN) and in-situ deposition of manganese dioxide (MnO2). Unlike the conventional methods under extreme conditions, in this method, the MnO2 particles were efficiently deposited on the fiber surfaces at room temperature within 30 min in the presence of reductive AQN surface composed of polyethyleneimine (PEI) and dopamine, and the MnO2-deposited cotton fabric exhibits efficient photothermal antibacterial capability against both Staphylococcus aureus and Escherichia coli, with inactivation efficiencies over 97% after 20 min of irradiation. In addition, this multi-functional fabric shows prominent UV-shielding property (UPF > 100) and HCHO purification ability, making 106.04 μg of HCHO rapidly removed within 30 min by 2.5 g of modified cotton. Therefore, we believe that the functional fabric exhibits wide applications in the fields of home textiles for antibacterial and air purification under mild conditions, and the special AQN structure can be further expanded to fabrications of other multifunctional nano-composites.