Nanoscale goldbeating: Solid-state transformation of 0D and 1D gold nanoparticles to anisotropic 2D morphologies.

Goldbeating is the ancient craft of thinning bulk gold (Au) into gossamer leaves. Pioneered by ancient Egyptian craftsmen, modern mechanized iterations of this technique can fabricate sheets as thin as ∼100 nm. We take inspiration from this millennia-old craft and adapt it to the nanoscale regime, using colloidally synthesized 0D/1D Au nanoparticles (AuNPs) as highly ductile and malleable nanoscopic Au ingots and subjecting them to solid-state, uniaxial compression. The applied stress induces anisotropic morphological transformation of AuNPs into 2D leaf form and elucidates insights into metal nanocrystal deformation at the extreme length scales. The induced 2D morphology is found to be dependent on the precursor 0D/1D NP morphology, size (0D nanosphere diameter and 1D nanorod diameter and length), and their on-substrate arrangement (e.g., interparticle separation and packing order) prior to compression. Overall, this versatile and generalizable solid-state compression technique enables new pathways to synthesize and investigate the anisotropic morphological transformation of arbitrary NPs and their resultant emergent phenomena.

All-Inside Versus Outside-in Repair of Triangular Fibrocartilage Complex Peripheral Tears.

PURPOSE: Triangular fibrocartilage complex (TFCC) peripheral tears with persistent wrist pain can be treated with arthroscopic surgical repair owing to vascularization of the peripheral region. The safety and efficacy of all-inside repair has been shown in prior case series. The purpose of this study was to compare two methods of arthroscopic peripheral TFCC repair: all-inside vertical mattress and outside-in horizontal mattress. METHODS: A 5-year retrospective review was performed on patients treated from 2016 to 2021 with wrist arthroscopy and TFCC repair for Palmer 1B tears. Patients with ulnar extrinsic ligament repair, distal radioulnar joint instability, concomitant ulnar shortening osteotomy, and extensor carpi ulnaris instability were excluded. Patient therapy and office visit records were reviewed. Outcomes including Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH); range of motion; grip strength; immobilization time; complications; and need for revision procedures were compared. RESULTS: Fifty-two patients were included in the study, 32 in the outside-in group and 20 in the all-inside group. The average follow-up length was 24.8 weeks, with similar range of motion and strength in both groups. The average postoperative QuickDASH score was 13 in the outside-in group and 9 in the all-inside group at 43.5 months, compared with the preoperative QuickDASH scores of 47 and 50, respectively. Mean immobilization time was longer for outside-in than for all-inside (5.25 vs 2.0 weeks, respectively). CONCLUSIONS: All-inside arthroscopic peripheral TFCC repair showed range of motion, grip strength, complications, revisions, and postoperative improvement in QuickDASH scores similar to those with the outside-in technique. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV; retrospective comparative study.

Combined Photoredox and Carbene Catalysis for the Synthesis of γ-Aryloxy Ketones.

N-heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C-C bonds in the synthesis of substituted ketones under single-electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ-aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α-aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical. Subsequent radical-radical coupling reaction with an azolium radical affords the γ-aryloxy ketone products.

Smart fracture plate for quantifying fracture healing: Preliminary efficacy in a biomechanical model.

The diagnosis of fracture nonunion following plate osteosynthesis is subjective and frequently ambiguous. Initially following osteosynthesis, loads applied to the bone are primarily transmitted through the plate. However, as callus stiffness increases, the callus is able to bear load proportional to its stiffness while forces through the plate decrease. The purpose of this study was to use a "smart" fracture plate to distinguish between phases of fracture healing by measuring forces transmitted through the plate. A wireless force sensor and small adapter were placed on the outside of a distal femoral locking plate. The adapter converts the slight bending of the plate under axial load into a transverse force which is measurable by the sensor. An osteotomy was created and then plated in the distal femur of biomechanical Sawbones. Specimens were loaded to simulate single-leg stance first with the osteotomy defect empty (acute healing), then sequentially filled with silicone (early callus) and then polymethyl methacrylate (hard callus). There was a strong correlation between applied axial load and force measured by the "smart" plate. Data demonstrate statistically significant differences between each phase of healing with as little as 150 N of axial load applied to the femur. Forces measured in the plate were significantly different between acute (100%), early callus (66.4%), and hard callus (29.5%). This study demonstrates the potential of a "smart" fracture plate to distinguish between phases of healing. These objective data may enable early diagnosis of nonunion and enhance outcomes for patients.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones.

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.

Prognosis for patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains poor. Development of more effective and less toxic targeted therapies is necessary for HNSCC patients. Checkpoint kinase 1 (CHK1) plays a vital role in cell cycle regulation and is a promising therapeutic target in HNSCC. Prexasertib, a CHK1 inhibitor, induces DNA damage and cell death, however, its effect on the tumor immune microenvironment (TIME) is largely unknown. Therefore, we evaluated a short-term and long-term effects of prexasertib in HNSCC and its TIME. Prexasertib caused increased DNA damage and cell death in vitro and significant tumor regression and improved survival in vivo. The gene expression and multiplex immunohistochemistry (mIHC) analyses of the in vivo tumors demonstrated increased expression of genes that are related to T-cell activation and increased immune cell trafficking, and decreased expression of genes that related to immunosuppression. However, increased expression of genes related to immunosuppression emerged over time suggesting evasion of immune surveillances. These findings in gene expression analyses were confirmed using mIHC which showed differential modulation of TIME in the tumor margins and as well as cores over time. These results suggest that evasion of immune surveillance, at least in part, may contribute to the acquired resistance to prexasertib in HNSCC.

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids.

As a key element in the construction of complex organic scaffolds, the formation of C-C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C-C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical-radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Comprehensive Review of Rock Climbing Injuries.

Increasing numbers of people are participating in the sport of rock climbing, and its growth is expected to continue with the sport's Olympic debut in 2020. Extreme loading of the upper extremities, contorted positioning of the lower extremities, rockfall, and falling from height create an elevated and diverse injury potential that is affected by experience level and quantity of participation. Injuries vary from acute traumatic injuries to chronic overuse injuries. Unique sport-specific injuries to the flexor tendon pulley system exist, but the remaining musculoskeletal system is not exempt from injury. Orthopaedic evaluation and surgery is frequently required. Understanding the sport of rock climbing and its injury patterns, treatments, and prevention is necessary to diagnose, manage, and counsel the rock-climbing athlete.

Synthesis and Evaluation of Azolium-Based Halogen-Bond Donors.

A method for the synthesis of iodinated imidazolium and triazolium N-heterocyclic halogen-bond-donor catalysts has been developed. This approach was applied to the synthesis of a variety of 1,2,4-triazolium salts to prepare a series of novel chiral halogen-bond-donor catalysts. The counterions of the iodinated triazoliums can be readily exchanged with chiral and achiral non-coordinating counterions to produce unique scaffolds. Their ability to promote/catalyse a conjugate addition reaction with indole was investigated. Through these initial studies, a set of general guidelines and considerations for the application of these halogen-bond donors in organocatalysis have been established.

Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective.

BACKGROUND: A nivolumab dosage regimen of 480 mg intravenously (i.v.) every 4 weeks (Q4W) was approved by FDA for the majority of the approved indications for nivolumab. METHODS: The proposed new dosage regimen was supported by pharmacokinetic modeling and simulation, dose/exposure-response relationships for efficacy and safety in the indicated patient populations, and the clinical safety data with the 480 mg Q4W dosage regimen. Pharmacokinetic exposures achieved with 480 mg Q4W were predicted for 4166 patients in 21 clinical studies with various types of solid and hematological tumors. Exposure-response analyses were conducted to predict 480 mg Q4W safety and efficacy across all FDA-approved indications for nivolumab. RESULTS: For the overall population, the geometric mean exposure achieved with 480 mg i.v. Q4W was 5.2% higher for steady state Cavg and 15.6% lower for Ctrough than those with 3 mg/kg i.v. Q2W, the approved dosage regimen. The simulated concentration-time course achieved with 480 mg Q4W regimen was below the median concentration achieved with 10 mg/kg i.v. Q2W that was also studied in clinical trials. The predicted probability of adverse events was similar between 480 mg Q4W and that observed with the 3 mg/kg Q2W regimen. Efficacy results were found to be similar between Q2W and Q3W dosage regimens in patients with renal cell carcinoma. The predicted efficacy for each indication suggested that the efficacy with 480 mg Q4W is unlikely to be compromised compared with that observed with 3 mg/kg Q2W. CONCLUSIONS: The model-informed analyses of predicted exposure, efficacy and safety based on data from extensive clinical experience with nivolumab suggest that the benefit-risk profile of 480 mg Q4W regimen is comparable to the approved 3 mg/kg Q2W regimen, thus providing the regulatory basis for the approval of 480 mg Q4W regimen in the absence of clinical efficacy data with this new dosage regimen.

Prostheses for reverse total shoulder arthroplasty.

INTRODUCTION: Historically, patients with rotator cuff arthropathy had limited reconstructive options. The early generations of reverse total shoulder arthroplasty (rTSA) designs had increased failure rates due to loosening of glenoid baseplates secondary to excessive torques. In 1985, Paul Grammont introduced a prosthetic design changing the center of rotation that addressed this major complication. The Grammont principles remain the foundation of modern reverse total shoulder prostheses, although the original design has undergone several adaptations. We reviewed here the various aspects of prosthetic designs including baseplates, glenospheres, humeral components, and polyethylene bearing interfaces. AREAS COVERED: We discuss the evolution, biomechanics, prosthetic options, and future direction for rTSA. A literature search using the PubMed database including review articles, biomechanical studies, and clinical trials pertaining to rTSA prothesis and outcomes. EXPERT COMMENTARY: Despite an expansion in the understanding of the biomechanics of the rotator cuff deficient shoulder and its effect on the reverse total shoulder prostheses, Grammont principles remain the foundation of contemporary rTSA designs. Further clinical studies are needed to assess how modern prosthetic modifications effect clinical and radiographic outcomes. Additionally, implants are being used in younger individuals with expanded indications, therefore, close clinical monitoring is needed to better evaluate their prosthetic longevity.

Enantioselective Synthesis of α-Amidoboronates Catalyzed by Planar-Chiral NHC-Cu(I) Complexes.

The first highly selective catalytic hydroboration of alkyl-substituted aldimines to provide medicinally relevant α-amidoboronates is disclosed. The Cu(I)-catalyzed borylation proceeds with excellent facial selectivity when a set of planar-chiral N-heterocyclic carbenes (NHCs) were employed as ligands. Density functional theory computations suggest that interactions between BPin and the planar-chiral catalyst are responsible for the observed stereoselectivity. Important pharmacophores, such as the boronate analogue of isoleucine, can be prepared using a chromatography-free protocol starting from commercially available reagents. The application of these NHC ligands in these Cu(I)-catalyzed processes offers a significant contribution to existing strategies for laboratory-scale preparation of enantioenriched α-amidoboronates.

Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) permits rapid evaluation of new therapeutic strategies in cancer. However, RECIST does not capture the heterogeneity of response in highly active therapies. Depth of tumor response may provide a more granular view of response. We explored the association between, depth of response (DepOR), with overall survival (OS) and progression-free survival (PFS) for patients with NSCLC being treated with an ALK inhibitor (ALKi) or an anti-PD-1 antibody (Ab). METHODS: Experimental arms from two randomized controlled trials (RCTs) of an ALKi and two RCTs of an anti-PD-1 Ab were separately pooled. Patient responses were grouped into DepOR 'quartiles' by percentage of maximal tumor shrinkage (Q1 = 1%-25%, Q2 = 26%-50%, Q3 = 51%-75%, and Q4 = 76%-100%), Q0 had no shrinkage. We carried out a retrospective exploratory responder analysis to evaluate the association between DepOR and OS or PFS using hazard ratios (HR) generated by the Cox proportional hazards model. RESULTS: In the pooled ALK analysis there were 12, 39, 70, 144, and 40 patients in quartiles 0-4, respectively. The DepOR versus PFS/OS analyses HR were: 0.19/0.94 for Q1 0.11/0.56 for Q2, 0.05/0.28 for Q3, and 0.03/0.05 for Q4. In the PD-1 trials within quartiles 0-4 there were 168, 70, 44, 45, and 28 patients, respectively. The DepOR versus PFS/OS analyses HR were 0.3/0.52 for Q1, 0.22/0.47 for Q2, 0.09/0.07 for Q3, and 0.07/0.14 for Q4. CONCLUSIONS: Our analysis suggests a greater DepOR is associated with longer PFS and OS for patients receiving ALKi or anti-PD1 Ab. Overall, this suggests that DepOR may provide an additional outcome measure for clinical trials, and may allow better comparisons of treatment activity.

Pd-Catalyzed Carboamination of Alkylidenecyclopropanes: Synthesis of Congested Pyrrolidines and Piperidines.

The synthesis of densely functionalized N-heterocycles is an ongoing challenge in chemical synthesis. Herein, we report an efficient method for the construction of pyrrolidine and piperidine scaffolds using a palladium-catalyzed carboamination of alkylidenecyclopropanes.

Can we predict the need for clean intermittent catheterization after orthotopic neobladder construction?

INTRODUCTION: We aimed to identify peri-operative and pathologic characteristics that may predict the need for clean intermittent catheterization (CIC) following radical cystectomy (RC) with orthotopic neobladder (ONB) in order to improve patient counseling on choice of urinary diversion. MATERIALS AND METHODS: Between July 2004 and February 2013, all patients who underwent RC with ONB were identified. Peri-operative clinical and pathological features were evaluated and correlated with patients reported need for CIC. The independent T-test was performed for continuous variables and Chi-square test was performed for categorical variables. Multivariate forward stepwise logistic regression analysis was used to identify variables that correlated with need for CIC after ONB. RESULTS: During the study period, 114 patients underwent RC with ONB creation. On univariate analysis, patients with higher body mass index, younger age, and non-vaginal or non-nerve-sparing procedures were more likely to require catheterization for complete emptying. Multivariate analysis demonstrates that conservative surgery (nerve sparing in males or vaginal sparing in females) was associated with a significantly lower rate of requiring CIC (Odds Ratio [OR] 0.20, P < 0.01). Surprisingly, older age was also associated with a slightly lower, but statistically significant, rate of requiring CIC (OR 0.92,P < 0.01). CONCLUSIONS: When counseling patients regarding the different types of diversions after RC, the potential need for long-term CIC after ONB must be discussed. The clinical factors that appear to increase the need for CIC include non-conservative RC (non-nerve sparing in males and non-vaginal sparing in females) and, to a certain degree, younger age.

Life cycle assessment of a novel closed-containment salmon aquaculture technology.

In salmonid aquaculture, a variety of technologies have been deployed that attempt to limit a range of environmental impacts associated with net-pen culture. One such technology employs a floating, solid-walled enclosure as the primary culture environment, providing greater potential control over negative interactions with surroundings waters while limiting energy use required for water circulation, thermo-regulation and supplemental oxygen provision. Here, we utilize life cycle assessment to model contributions to a suite of global-scale resource depletion and environmental concerns (including global warming potential, acidification potential, marine eutrophication potential, cumulative energy use, and biotic resource use) of such a technology deployed commercially to rear Chinook salmon in coastal British Columbia, Canada. Results indicate that at full grow-out, feed provisioning and on-site energy use dominate contributions across four of five impact categories assessed. For example, per tonne of salmon harvested, feed contributed approximately 72% to global warming potential, 72% to acidification potential, and accounted for 100% of biotic resource use. However, for both feed and on-site energy use, impacts are heavily influenced by specific sources of inputs; therefore efforts to improve the environmental performance of this technology should focus on reducing these in favor of less impactful alternatives.

Effect of self-efficacy and physical activity goal achievement on arthritis pain and quality of life in patients with rheumatoid arthritis.

OBJECTIVE: To examine physical activity and achievement of physical activity goals in relation to self-reported pain and quality of life among patients with rheumatoid arthritis (RA). METHODS: At baseline, 271 patients with RA were asked to specify a physical activity goal, and filled in questionnaires assessing physical activity, motivation, and self-efficacy for physical activity, arthritis pain, and quality of life. Six months later, patients indicated to what extent they had achieved their baseline physical activity goal and completed the same set of questionnaires. These data were used to construct multiple mediation models that placed physical activity and physical activity goal achievement as mediators between self-efficacy and motivation on one hand, and arthritis pain and quality of life on the other. RESULTS: A total of 106 patients with RA completed both questionnaires. Self-efficacy at baseline predicted subsequent level of physical activity and achievement of physical activity goals. Goal achievement had a direct effect upon quality of life outcomes. Bootstrapping confidence intervals revealed indirect effects of self-efficacy upon arthritis pain and quality of life through goal achievement, but not through physical activity. CONCLUSION: Higher levels of self-efficacy for physical activity increase the likelihood that patients will achieve their physical activity goals. Achievement of physical activity goals seems to be related to lower self-reported arthritis pain, and higher levels of quality of life. In practice, clinicians can foster self-efficacy and goal achievement by assisting patients in setting realistic and attainable exercise goals, developing action plans, and by providing feedback on goal progress.