Group R2 Research Articles

D 6 h Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

<i>D</i> ^{6 <i>h</i>} Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

Structural Analysis and Protein Binding of Cephalosporins.

Cephalosporins are a widely used subclass of β-lactam antibiotics that demonstrate variable protein binding independent of generation or antibiotic coverage. Prior work analyzed carbon3 (C3) and carbon7 (C7) substituents (locations of R2 and R1 groups respectively) for protein binding interactions. This study builds upon these results with statistical analysis of additional agents of the class. Chemical structures of 23 cephalosporins were used to identify the presence of 40 functional groups, and correlative relationships were identified using established protein binding data. Four functional groups were significantly correlated with protein binding: tetrazole (positive association), pyridinium, primary amine, and quaternary amine (negative associations). Cephalosporins with a negative charge at physiological pH were associated with increased protein binding. Analysis of tetrazole-containing cephalosporins and ceftriaxone indicates the need for further study of the potential role in protein binding of neutral or negatively charged aromatic nitrogen heterocycles linked at the C3 position by a thiomethylene group.

Effect of resection margin status on recurrence pattern and survival in distal pancreatectomy for left-sided pancreatic ductal adenocarcinoma.

The association of resection margin status with recurrence and survival after pancreatectomy for pancreas ductal adenocarcinoma (PDAC) remains controversial. The aim of this study was to identify the effect of R1 resection on recurrence pattern and survival after distal pancreatectomy for left-sided PDAC. Patients who underwent distal pancreatectomy for PDAC at two high-volume institutions between January 2010 and December 2017 were retrospectively reviewed. Perioperative characteristics, pathological outcomes, recurrence pattern, and survival data were collected to compare R0 resection and R1 resection. Among 558 patients who underwent distal pancreatectomy for PDAC, 158 patients (28.3%) showed R1 resection margin. R1 patients were associated with large tumor size (3.3cm vs. 3.7 cm, p=.006) and lower number of positive lymph nodes (1.3 vs. 2.0, p=.001). Median overall survival (37.3months vs. 20.1 months, p < .001) and recurrence-free survival (14.6months vs. 6.9 months, p < .001) significantly differed between the R0 and R1 groups. Disease recurrence patterns were not statistically different between the two groups (p=.182). Among the recurrence patterns, peritoneal carcinomatosis had the shortest recurrence-free survival (5.6months, p < .05) and overall survival (13.6months, p < .05) compared with all other recurrence patterns. R1 resection margin after distal pancreatectomy was associated with poor survival and early recurrence. There is no significant difference in recurrence pattern between R0 and R1. Among the recurrence patterns, peritoneal carcinomatosis showed the worst prognosis.

Computational modeling studies reveal the origin of the binding preference of 3-(3,4-di hydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids for AKR1C3 over its isoforms.

As a key regulator for hormone activity, human aldo-keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone-dependent or independent malignancies. It is a promising target for treating castration-resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000-fold anti-AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end-point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely "Inward" and "Outward," of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an "Inward" to an "Outward" state. Further 3D-QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next-generation AKR1C3 inhibitors with enhanced efficacy and reduced "off-target" effect for CRPC therapy.

Five-Year Results and Overall Survival Update from the Phase 3 Randomized Study Augment: Lenalidomide Plus Rituximab (R2) Vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: The combination of lenalidomide + rituximab (R2) showed superior efficacy vs rituximab + placebo (R-placebo) in patients (pts) with relapsed refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved for the treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL) in the US, Japan, and Brazil, and for FL in Europe. Reported here are updated long-term follow-up results from AUGMENT. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase 3 study of R2 vs R-placebo (control) in pts with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 mo after last rituximab dose). Pts were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 y), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 y. R2 pts received oral lenalidomide 20 mg/d, d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control pts received rituximab and placebo on the same schedule. Dose modifications were prespecified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). During the follow-up period, pts were followed every 6 mo to assess endpoints, including overall survival (OS), time-to-next antilymphoma treatment (TTNLT), progression, second primary malignancies (SPMs), and histological transformation. Results: A total of 358 pts were randomized (n = 178 R2; n = 180 control); baseline characteristics were similar in both groups. As of January 26, 2022 at a median follow-up of 65.9 mo, median PFS per 2007 IWG criteria as assessed by Investigator was 27.6 mo for R2 vs 14.3 mo for control, with HR = 0.50 (95% CI, 0.38-0.66; P < 0.0001). Although median OS was not reached for either group, there was an improvement in OS for R2 (HR = 0.59, 95% CI, 0.37-0.95, P = 0.0285; Figure). 5-y OS rates for the R2 vs control groups were 83.2% (95% CI, 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1). Median TTNLT (after 12 cycles of time-limited therapy) was 73.1 mo for R2 vs 31.8 mo for control with HR = 0.53 (95% CI, 0.39-0.71; P < 0.0001). In the R2 group, 73 pts (41%) received ≥ 1 subsequent antilymphoma treatment compared with 109 (61%) in the control group, most commonly rituximab in both groups (25% and 34%). 3 (2%) and 5 (3%) pts received lenalidomide as part of any subsequent anti-lymphoma treatment in the R2 and control groups, respectively. The updated overall safety profile of both groups was consistent with the 1st analysis. SPMs occurred in 13 (7%) R2-treated and 21 (12%) control pts, an increase from 6 (3%) and 10 (6%), respectively, in the previous analysis. 9 pts died of SPM (n = 3 R2, n = 6 R-placebo), an increase from 2 pts (both R-placebo) in the previous analysis. The incidence rate of SPMs per 100 y was 1.62 (95% CI, 0.94-2.78) in the R2 group vs 2.66 (95% CI, 1.73-4.07) in the control group. Fewer histological transformations occurred in the R2 arm than in the control group (n = 10 vs n = 15, respectively). The updated incidence rate of histological transformation in the overall population was 1.24% (95% CI, 0.66-2.3) in the R2 arm and 1.85% (95% CI, 1.12-3.07) in the control arm. Conclusions: R2 continues to demonstrate superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of PFS (as assessed by Investigator in long-term follow up). The updated results for OS are consistent with the improvement observed in PFS. The OS KM curve separation after 5 y continues to favor R2, providing evidence for a survival benefit. The updated TTNLT KM curves continue to demonstrate that fewer R2-treated patients needed subsequent antilymphoma treatment to date, well beyond the 1-y treatment period. The safety profile of R2 and R-placebo remain consistent with the primary analysis, with continued lower rates of SPM and rates of histologic transformation comparable to historical experience. These updated results, including OS data, provide further support for the use of the R2 regimen as a standard of care for pts with R/R iNHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Basal Cell Carcinoma of the Head and Neck-A Retrospective Single-Centre Comparison of the Recurrence Rate after R0 or R1 Resection.

The treatment guidelines for basal cell carcinoma (BCC) postulate complete surgical excision using microscopically controlled resection (MOHS) as the gold standard. The need to obtain a small safety margin in the complex anatomical area of the head and neck is very challenging due to the individual characteristics (localization, histology, and size) of tumors and the fact that the postoperative loss of quality of life depends on the surgical defect size. The R1 status is histopathologically defined when the safety margin is less than 1 mm even if there are no tumor cells actually infiltrating the resection margin. Therefore, some studies have already favored a watch-and-wait-strategy in R1 situations. We aimed to evaluate the outcome and recurrence rate of resected BCCs of the head and neck, especially in a histologically proven R1 situation. The outcomes of all resected BCCs observed during a 5-year period (January 2009-December 2013) in a tertiary care center were analyzed. Our standard operating procedure was microscopically controlled surgical excision with reresections until an R0 situation was achieved. In selected patients, an R1 status has been accepted after at least two resections. From the included 191 BCCs, the R1 status was accepted as the final result in 46 (24.1%) cases which had surgically clear margins and were closely followed-up. From 54 patients in the R0 and 40 patients in the R1 group who completed the follow-up (2.4 ± 0.4 years), we observed 0 and 2 local recurrences, respectively (p = 0.19). In cases where frequent follow-up can be secured and the surgical area is delicate, a surgical closure at R1 status can be justified as the recurrence rate is not significantly higher compared with R0.

The Impact of Involved Resection Margin on Recurrence and Survival After Pancreaticoduodenectomy for Periampullary Carcinoma, with Emphasis on Pancreatic Head Carcinoma.

The supposed adverse effect of involved resection margin during pancreaticoduodenectomy (PD) for periampullary carcinoma or pancreatic head carcinoma (CaP) on long-term oncological outcomes is still inconclusive. This is a retrospective study on periampullary carcinoma undergoing PD. Patients with R0 (margin clear) resection were compared to patients with R1 (microscopically directly involved margin) resection. Patients with gross involved margin (R2 resection) were excluded. Long-term oncological outcomes measured included incidence and site of recurrent disease, overall survival (OS) and disease-free survival (DFS). A subgroup analysis was made on patients with CaP. Between January 2003 and December 2019, 203 PD were identified for present study. The incidence of R1 resection was common (12% in periampullary carcinoma and 20% in CaP). In periampullary carcinoma, R1 resection had greater proportion of CaP, lesser proportion of carcinoma of ampulla (CaA), more perineural invasion, more lymph node (LN) metastasis. R1 group had a shorter OS and DFS, but no difference in the incidence and site of recurrent disease. In the subgroup of CaP (91 patients), R1 group did not differ from R0 group except for more LN metastasis. There was no difference in incidence and site of recurrent disease, OS and DFS. On multivariable analysis, R1 resection was not an independent factor for OS and DFS for periampullary carcinoma or for CaP only. Involved resection margin was not uncommon. It was not associated with higher incidence of recurrent disease including local recurrence, and was not an independent prognosticator for OS and DFS.

Expanding the Chemical Space of Drug-like Passerini Compounds: Can α-Acyloxy Carboxamides Be Considered Hard Drugs?

With their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable α-acyloxy carboxamides. When the group directly attached to the ester moiety (R3) is an ortho-substituted or ortho,ortho'-disubstituted aromatic ring, α-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester function is also stable toward hydrolysis when the R1 group is a bulky substituent regardless of the nature of the R3 substituent.

Is Chitosan Dental Dressing Better Than Cotton Gauze in Achieving Hemostasis in Patients on Antithrombotics?

Tooth extraction leads to bleeding which may be longer in patients on antithrombotics. This study was aimed to evaluate the hemostatic and wound healing efficacy of chitosan-based dressing in comparison to the cotton pressure pack after tooth extraction in patients receiving single or dual antithrombotics. This is a prospective, randomized split mouth study. Patients undergoing tooth extractions taking either single or dual antithrombotics, with an international normalized ratio (INR) value≤3 were enrolled at JSS Dental College & Hospital, Mysuru, India during February 2020 to January 2022. The study compared the efficiency of chitosan dressing in achieving quicker hemostasis in comparison to cotton pressure pack. The primary outcome was time to achieve hemostasis and the secondary outcomes were alveolar clinical healing index and alveolar osteitis. The covariates were gender, age, reason for extraction, INR, type of antithrombotic therapy, and the disease condition. Of the 54 enrolled subjects, 39 were males and 15 were females, aged between 33 and 86years. Thirty six patients were on single antithrombotics, whereas 18 patients were on dual antithrombotics. The reason for extraction was periodontitis in 37 patients and dental caries in 17 patients. The time to achieve hemostasis was lesser with chitosan dental dressing when compared to cotton pressure packs (96±4 and 797±23seconds; P<.001). In the chitosan group, the time to hemostasis was similar irrespective of single or dual antithrombotic therapy (90±6 and 109±8seconds, respectively). On the contrary, in the cotton pressure pack group, patients on dual antithrombotics had longer time to achieve hemostasis compared to those on single antithrombotics (940±20 and 726±26seconds; P<.001). The time to achieve hemostasis was dependent on INR only in cotton pressure pack group (r2=0.7756). The alveolar clinical healing index was better in 88.9% with chitosan and only 3.7% with cotton pressure packs. None of the patients treated with chitosan presented with alveolar osteitis, as opposed to 3.7% of patients with cotton pressure packs. When compared to cotton pressure packs, chitosan-based dressing was more effective in controlling postoperative bleeding in patients treated with single and dual antithrombotic therapy.

R1 Vascular or Parenchymal Margins: What Is the Impact after Resection of Intrahepatic Cholangiocarcinoma?

Simple SummaryThe long-term outcome of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) is not well studied. Although the importance of the resection margin depth is clear, we aimed to clarify the impact of the R1 resection, by focusing on the outcomes between R0 resection and the two R1 types. The R1par resection presented a DFS and an OS intermediate between R0 and R1vasc. It appeared that a R1vasc resection should be avoided in patients with iCCA because it did not provide satisfactory oncological outcomes. Further studies could help to understand the best therapeutic procedure for these patients and the role of neo-adjuvant therapies in case of foreseeable R1vasc resection.Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients who underwent iCCA resection between 2000 and 2019 in two tertiary French medical centers. We report overall survival (OS) and disease-free-survival (DFS). Univariate and multivariate analyses were performed to determine associated factors. Results: 195 patients were analyzed. The number of R0, R1par and R1vasc patients was 128 (65.7%), 57 (29.2%) and 10 (5.1%), respectively. The 1- and 2-year OS rates in the R0, R1par and R1vasc groups were 83%, 87%, 57% and 69%, 75%, 45%, respectively (p = 0.30). The 1- and 2-year DFS rates in the R0, R1par and R1vasc groups were 58%, 50%, 30% and 43%, 28%, 10%, respectively (p = 0.019). Resection classification (HR 1.56; p = 0.003) was one of the independent predictors of DFS in multivariate analysis. Conclusions: the survival outcomes after R1par resection are intermediate to those after R0 or R1vasc resection. R1vasc resection should be avoided in patients with iCCA as it does not provide satisfactory oncological outcomes.

Assessment of Surgeon Performance of Advanced Open Surgical Skills Using a Microskills-Based Novel Curriculum

The increase in minimally invasive surgical procedures has eroded exposure of general surgery residents to open operations. High-fidelity simulation, together with deliberate instruction, is needed for advanced open surgical skill (AOSS) development. To collect validity evidence for AOSS tools to support a shared model for instruction. This prospective cohort study included postresidency surgeons (PRSs) and second-year general surgery residents (R2s) at a single academic medical center who completed simulated tasks taught within the AOSS curriculum between June 1 and October 31, 2021. The AOSS curriculum includes 6 fine-suture and needle handling tasks, including deep suture tying (with and without needles) and continuous suturing using the pitch-and-catch and push-push-pull techniques (both superficial and deep). Teaching and assessment are based on specific microskills using a 3-dimensional printed iliac fossa model. The PRS group was timed and scored (5-point Likert scale) on 10 repetitions of each task. Six months after receiving instruction on the AOSS tasks, the R2 group was similarly timed and scored. The PRS group included 14 surgeons (11 male [79%]; 8 [57%] attending surgeons) who completed the simulation; the R2 group, 9 surgeons (5 female [55%]) who completed the simulation. Score and time variability were greater for the R2s compared with the PRSs for all tasks. The R2s scored lower and took longer on (1) deep pitch-and-catch suturing (69% of maximum points for a mean [SD] of 142.0 [31.7] seconds vs 77% for a mean [SD] of 95.9 [29.4] seconds) and deep push-push-pull suturing (63% of maximum points for a mean [SD] of 284.0 [72.9] seconds vs 85% for a mean [SD] of 141.4 [29.1] seconds) relative to the corresponding superficial tasks; (2) suture tying with a needle vs suture tying without a needle (74% of maximum points for a mean [SD] of 64.6 [19.8] seconds vs 90% for a mean [SD] of 54.4 [15.6] seconds); and (3) the deep push-push-pull vs pitch-and-catch techniques (63% of maximum points for a mean [SD] of 284.0 [72.9] seconds vs 69% of maximum points for a mean [SD] of 142.0 [31.7] seconds). For the PRS group, time was negatively associated with score for the 3 hardest tasks: superficial push-push-pull (ρ = 0.60; P = .02), deep pitch-and-catch (ρ = 0.73; P = .003), and deep push-push-pull (ρ = 0.81; P < .001). For the R2 group, time was negatively associated with score for the 2 easiest tasks: suture tying without a needle (ρ = 0.78; P = .01) and superficial pitch-and-catch (ρ = 0.79; P = .01). The findings of this cohort study offer validity evidence for a novel AOSS curriculum; reveal differential difficulty of tasks that can be attributed to specific microskills; and suggest that position on the surgical learning curve may dictate the association between competency and speed. Together these findings suggest specific, actionable opportunities to guide instruction of AOSS, including which microskills to focus on, when individual rehearsal vs guided instruction is more appropriate, and when to focus on speed.

Evaluation of CNTs and SiC Whiskers Effect on the Rheology and Mechanical Performance of Metakaolin-Based Geopolymers

Despite geopolymers having emerged as a more sustainable alternative to Portland cement, their rheological properties still need to be thoroughly investigated, aiming at the material’s applicability. Additionally, studies that evaluated the fresh state of geopolymer composites with nanomaterials are scarce. Thus, two metakaolin-based geopolymer systems were reinforced with nanomaterials with a similar geometry: carbon nanotubes (CNT) and silicon carbide whiskers (SCW). The nanomaterials incorporation was assessed by rotational rheometry (conducted up to 110 min), isothermal calorimetry, compressive strength after 7 and 28 days, and the microstructure was investigated using X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR). CNT and SCW incorporation (0.20 wt.%) did not significantly affect the yield stress and viscosity of the R2-group (based on metakaolin type 2), while increasing the rheological parameters up to 56.0% for the R1-group (based on metakaolin type 1). Both additions modified the reaction kinetics. Increments of up to 40.7% were observed in the compressive strength of geopolymer pastes with the incorporation of a SCW content of 0.2 wt.%. XRD and FTIR results suggest similar structural modifications between precursors. Nevertheless, R2 showed substantial transformations while the R1 group exhibited anhydrous material that can react over time. Overall, incorporating CNT and SCW contributed to higher mechanical increments on systems with average mechanical strength (R1) compared to systems with higher potential mechanical performance (R2).

245.9: Influence of Tacrolimus CYP3A5 Polymorphisms on the Doselevel Response After Pediatric Kidney Transplantation

Background: Tacrolimus exhibits wide inter and intra-patient variability. CYP3A5 tacrolimus polymorphisms predict its metabolization. We aim to identify the influence of polymorphisms on the pharmacological parameters. The present report is part of the exploratory data analysis of a pediatric trial that used the initial tacrolimus dose according to the CYP3A5 genotype in kidney transplant recipients. Methods: We performed an exploratory data analysis of pharmacological parameters from a single-center, non-randomized, open-label clinical trial in children from 0-to 18 years of age who received a kidney transplant at the Hospital Infantil de México, Federico Gómez from January 2013 to December 2018. All children were genotyped before transplantation and assigned to one of two groups: the Genotype-guided group, which initial dose was according to the CYP3A5 polymorphisms and the Conventional-dose group (see abstract AID-1780), with further dose adjustments on the decision of the clinicians. We followed them for six weeks and recorded tacrolimus dose received, trough level achieved, deltas of dose and trough levels between time points (weekly). Results: We included 81 subjects; 40 received the genotype-guided dose, the mean age at transplantation was 13.3 y/o, 51.8% were female. After six weeks of transplantation, linear regressions showed no linear associations between tacrolimus dose and levels in the genotype-guided dose group (r2=0.0003, p=0.78) or the conventional-dose group (r2=0.0008, p=67). However, there were linear associations between the delta-dose and delta-levels in the genotype-guided dose group (r2=0.138, p=<0.0001) and conventional-dose group (r2=0.081, p=<0.0001). The subgroup analysis by genotype showed that AG1*3 polymorphism had a linear association between the tacrolimus delta-dose and delta-level (r2=0.168, p=<0.001). Furthermore, It reached statistical significance in the tacrolimus dose vs level analysis (r2=0.0308, p= 0.02). The GG3*3 polymorphism showed an association only in the delta-dose vs delta-level analysis (r2=0.057, p=<0.001), while the AA1*1 genotype did not show any linear associations between tacrolimus dose vs trough level or deltas (r2=0.006, p=0.64 and r2=0.108, p=0.08 respectively) (Figure). Conclusion: The tacrolimus delta-dose and delta-level across the different polymorphisms translate the clinician’s decisions. The trough levels’ response to dose adjustments might be guided by the CYP3A5 genotypes, specifically the AG1*3. Further studies are needed to estimate more accurate associations.

Incidence and Visual Outcomes of Endophthalmitis After Intravitreal Injection of Dexamethasone Implant vs Ranibizumab.

To compare the incidence and visual outcomes of endophthalmitis after injection of an intravitreal dexamethasone implant and injection of intravitreal ranibizumab. This retrospective cohort study assessed endophthalmitis in eyes receiving an intravitreal injection of a 0.7 mg dexamethasone implant (DEX group), 0.5 mg ranibizumab (R5 group), or 0.3 mg ranibizumab (R3 group) between January 1, 2016, and May 31, 2018, at 2 large retina practices in the United States. Suspected endophthalmitis occurred in 5 eyes after 4973 DEX injections, 43 eyes after 163 974 R5 injections, and 6 eyes after 18 954 R3 injections. Suspected endophthalmitis was significantly more common in the DEX group (1/995) than in the R5 group (1/3813) (P = .008) but not than in the R3 group (1/3159) (P = .10). Visual acuity outcomes were similar in the 3 groups. Suspected endophthalmitis might be more common after 0.7 mg dexamethasone injections than after 0.5 mg ranibizumab injections. Culture-positive endophthalmitis rates were similar across all 3 medications.

Fast start-up of ANAMMOX biofilm processes at low temperatures by economical quorum sensing regulation: The importance of endogenous N-acyl-homoserine lactones from enhanced inoculated sludge

The start-up of anaerobic ammonia oxidation (ANAMMOX) processes at low temperatures is quite difficult. In this study, the fast start-up (43 days) of ANAMMOX biofilm processes at 18 ± 3 °C was achieved by adding enhanced ANAMMOX granules (LT-granules) into the inoculated denitrification sludge. The results showed that the addition of LT-granules significantly reduced the duration of the three start-up phases (cell lysis phase, activity lag phase, and activity elevation phase) of reactor R2 compared with the control group R1 without LT-granules. It was demonstrated that LT-granules released high contents of N-hexanoyl-DL-homoserine lactone (C6-HSL), N-octanoyl-DL-homoserine lactone (C8-HSL), and N-3-oxohexanoyl-L-homoserine lactone (3OC6-HSL). The C6-HSL and C8-HSL from LT-granules were strongly positively correlated with the concentrations of polysaccharides (TB-PS) and proteins (TB-PN) in tightly bound extracellular polymeric substances (TB-EPS) in R2 biofilms, respectively. Thus, LT-granules promoted the release of TB-PS and TB-PN from the biofilm in R2 during activity lag and activity elevation phases, improving the biofilm adhesion performance. Furthermore, it was proved that the C6-HSL, C8-HSL, and 3OC6-HSL from LT-granules significantly stimulated the relative abundance of Candidatus Brocadia genus and the expression of functional genes hzo and hzsA in R2 biofilms during activity lag and activity elevation phases. These are the main reasons why adding LT-granules promoted the start-up of reactor R2 at 18 ± 3 °C effectively. This study is the first work to accelerate the start-up of the ANAMMOX biofilm system at the low temperature by the economical quorum sensing (QS) regulation based on endogenous N-acyl-homoserine lactone signals (AHLs) and supply a new way for the rapid start-up of ANAMMOX processes in the low-temperature environment.

Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701) showed that lenalidomide plus rituximab (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated follicular lymphoma (FL). We report the second interim analysis of the RELEVANCE trial after 6 years of follow-up. Patients with previously untreated grade 1-3a FL were assigned 1:1 to R2 or R-chemo, followed by rituximab maintenance. Coprimary end points were complete response (confirmed/unconfirmed) at week 120 and progression-free survival (PFS). At median follow-up of 72 months, 6-year PFS was 60% and 59% for R2 and R-chemo, respectively (hazard ratio = 1.03 [95% CI, 0.84 to 1.27]). Six-year overall survival was estimated to be 89% in both groups. Median PFS and overall survival were not reached in either group. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R2 and R-chemo groups, respectively. The transformation rate per year in the R2 and R-chemo groups was 0.68% and 0.45%, and secondary primary malignancies occurred in 11% and 13% (P = .34), respectively. No new safety signals were observed. R2 continues to demonstrate comparable, durable efficacy and safety versus R-chemo in previously untreated patients with FL and provides an acceptable chemo-free alternative.

Predicting the maximum absorption wavelength of azo dyes using an interpretable machine learning strategy

The maximum absorption wavelength (λmax) is one of the most important properties of azo dyes. It is essential to obtain λmax of azo dyes for the development of new molecules in a short time. Herein, the machine learning algorithm “XGBoost” was used to establish a model for predicting λmax of azo dyes. It was found that the coefficient of determinations (R2) of leave-one-out cross-validation (LOOCV) and test set were 0.87, 0.73, respectively. According to SHapley Additive exPlanations (SHAP) analysis, the number of sulfur atoms of R2 group has a strong positive correlation with λmax. The more C–N pairs of topological distance 4 appear in R1 group, the more likely the molecular λmax is red-shifted. Further, the high-throughput screening strategy was adopted to screen out 26 azo molecules with larger λmax from nearly 20,000 virtual samples. These molecular λmax are expected to be red shifted from the 610 nm in the dataset. Our study provides a convenient way to search for azo dyes with larger λmax.

Design, Synthesis, Mode of Action and Herbicidal Evaluation of Quinazolin-4(3H)-one Derivatives Based on Aryloxyphenoxypropionate Motif

To discover new acetyl-CoA carboxylase (ACCase) inhibiting-based herbicides, twenty-nine novel quinazolin-4(3H)-one derivatives were designed and synthesized based on the aryloxyphenoxypropionate motif. The bioassay results showed that most of the target compounds showed better pre-emergent herbicidal activity against monocotyledonous weeds in a greenhouse. Especially, when applied at 375 g ha−1 under pre-emergence conditions, compound QPP-7 displayed excellent herbicidal activity against monocotyledonous weeds (i.e., E. crusgalli, D. sanguinalis, P. alopecuroides, S. viridis, E. indica, A. fatua, E. dahuricu, S. alterniflora) with inhibition rate &gt;90%, and displayed excellent crop safety to O. sativa, T. aestivum, G. spp, and A. hypogaea. The study of structure-activity relationship (SAR) revealed that the herbicidal activity of target compounds is strongly influenced by the spatial position of R group and the bulk of R1 group on quinazolin-4(3H)-one, and the (R = 6-F, R1 = Me) pattern is confirmed as the optimal orientation. Furthermore, the molecular docking study and the good inhibitory activity of QPP-7 against E. crusgalli ACCase enzyme (IC50 = 54.65 nM) indicated that it may be a ACCase inhibitor. Taken together, the present work demonstrated that compound QPP-7 could serve as a potential lead structure for further developing novel ACCase inhibiting-based herbicide.

Investigation of the non-small cell lung cancer patients with uncertain resection: A population-based study

ObjectivesWe aimed to investigate the clinical features, prognosis and predictive factors for the non-small cell lung cancer (NSCLC) patients with uncertain resection [R(un)]. Materials and methodsKaplan-Meier method with a log-rank test was used to compare overall survival (OS) and disease-free survival (DFS) between groups. The least absolute shrinkage and selection operator (LASSO)-penalized Cox multivariable analysis was used to identify the prognostic factors. Random forest was used to determine the important predictive factors of R(un) resection. ResultsA total of 2,782 eligible cases (R0 group: 1,897 cases; R(un) group: 885 cases) were included in this study. The rate of conventional R0 to R(un) reclassification was 31.8%. Patients with R(un) resection were more likely to have left-sided tumors, receive open surgery, and be diagnosed with advanced tumors. The survivals of the patients with R(un) resection were inferior to those of the patients with R0 resection in the entire cohort and in the nodal category, histology and adjuvant therapy subgroups. The LASSO-penalized multivariable Cox analysis confirmed that R(un) resection was an adverse prognostic factor for both OS and DFS. At last, surgical extent, surgical approach and tumor location were proven as the predictive factors for R(un) resection. ConclusionNSCLC patients with R(un) resection was not rare. R(un) had an adverse impact on the survivals of resected patients. Patients received non-lobectomy and open surgery, and patients with left-sided tumors were more likely to be suffered from R(un) resection.

Intraoperative Positive Pancreatic Parenchymal Resection Margin: Is It a True Indication of Completion Total Pancreatectomy after Partial Pancreatectomy for Pancreatic Ductal Adenocarcinoma?

Background: Total pancreatectomy (TP) can be performed in cases with positive resection margin after partial pancreatectomy for pancreatic cancer. However, despite complete removal of the residual pancreatic parenchyme, it is questionable whether an actual R0 resection and favorable survival can be achieved. This study aimed to identify the R0 resection rate and postoperative outcomes, including survival, following completion TP (cTP) performed due to intraoperative positive margin. Methods: From 1995 to 2015, 1096 patients with pancreatic ductal adenocarcinoma underwent elective pancreatectomy at the Samsung Medical Center. Among these, 25 patients underwent cTP, which was converted during partial pancreatectomy because of a positive resection margin. To compare survival after R0 resection between the cTP R0 and pancreaticoduodenectomy (PD) R0 cases, propensity score matching was conducted to balance the baseline characteristics. Results: The R0 rate of cTP performed due to intraoperative positive margin was 84% (21/25). The overall 5-year survival rate (5YSR) in the 25 cTP cases was 8%. There was no difference in the 5YSR between the cTP R0 and cTP R1 groups (9.5% versus 0.0%, p = 0.963). However, the 5YSR of the cTP R0 group was significantly lower than that of the PD R0 group (9.5% versus 20.0%, p = 0.022). There was no distinct difference in postoperative complications between the cTP R0 versus cTP R1 and cTP R0 versus PD R0 groups. Conclusions: In cases with intraoperative positive pancreatic parenchymal resection margin, survival after cTP was not favorable. Careful patient selection is needed to perform cTP in such cases.