Large Spin-Orbit Splitting of Deep In-Gap Defect States of Engineered Sulfur Vacancies in Monolayer WS_{2}.

Structural defects in 2D materials offer an effective way to engineer new material functionalities beyond conventional doping. We report on the direct experimental correlation of the atomic and electronic structure of a sulfur vacancy in monolayer WS_{2} by a combination of CO-tip noncontact atomic force microscopy and scanning tunneling microscopy. Sulfur vacancies, which are absent in as-grown samples, were deliberately created by annealing in vacuum. Two energetically narrow unoccupied defect states followed by vibronic sidebands provide a unique fingerprint of this defect. Direct imaging of the defect orbitals, together with ab initio GW calculations, reveal that the large splitting of 252±4 meV between these defect states is induced by spin-orbit coupling.

Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression.

The kidney controls systemic calcium and phosphate levels and disturbances of its control mechanisms can lead to a variety of diseases. The insulin-sensitizing adipokine adiponectin is renoprotective and accelerates functional recovery following renal injury. However, unlike other adipokines, adiponectin is reduced in obesity. High adiponectin levels are also correlated with bone loss, suggestive of an additional action in mineral metabolism. Using knockout, wild-type, and adiponectin-overexpressing transgenic mice, we sought to identify the mechanistic basis for adiponectin's ability to regulate calcium and phosphate balance at the level of the kidney. Adiponectin knockout mice exhibited lower serum calcium, lower urinary calcium excretion, and markedly lower serum fibroblast growth factor 23 (FGF23) levels, although circulating klotho concentrations were significantly higher than in wild-type littermates. The transgenic mice exhibited lower bone mass and strength, particularly compared to adiponectin knockout mice. The transgenic mice were hyper-responsive to a 2% phosphate-enriched diet, exhibiting 2-fold higher serum FGF23 and concomitantly higher fractional phosphate excretion. These mice also excreted more calcium with calcium-enriched diet and had less renal klotho protein expression. In contrast, the knockout mice exhibited a smaller increase in FGF23 and maintained elevated klotho levels on both mineral challenges. Kidney-specific adiponectin expression in doxycycline-inducible adiponectin mice and adiponectin addition in vitro confirmed adiponectin's ability to reduce tubular epithelial cell klotho secretion. Thus, adiponectin alters calcium and phosphate balance and renal mineral excretion, in part, through klotho. This work highlights the profound effects of adipose tissue on renal function and has identified a new mechanism by which adiponectin may regulate bone mass.

Walk-in clinics versus physician offices and emergency rooms for urgent care and chronic disease management.

BACKGROUND: Walk-in clinics are growing in popularity around the world as a substitute for traditional medical care delivered in physician offices and emergency rooms, but their clinical efficacy is unclear. OBJECTIVES: To assess the quality of care and patient satisfaction of walk-in clinics compared to that of traditional physician offices and emergency rooms for people who present with basic medical complaints for either acute or chronic issues. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers on 22 March 2016 together with reference checking, citation searching, and contact with study authors to identify additional studies. We applied no restrictions on language, publication type, or publication year. SELECTION CRITERIA: Study design: randomized trials, non-randomized trials, and controlled before-after studies. POPULATION: standalone physical clinics not requiring advance appointments or registration, that provided basic medical care without expectation of follow-up. Comparisons: traditional primary care practices or emergency rooms. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane and the Cochrane Effective Practice and Organisation of Care (EPOC) Group. MAIN RESULTS: The literature search identified 6587 citations, of which we considered 65 to be potentially relevant. We reviewed the abstracts of all 65 potentially relevant studies and retrieved the full texts of 12 articles thought to fit our study criteria. However, following independent author assessment of the full texts, we excluded all 12 articles. AUTHORS' CONCLUSIONS: Controlled trial evidence about the mortality, morbidity, quality of care, and patient satisfaction of walk-in clinics is currently not available.

A Biomechanical Analysis of Interference Screw Versus Bone Tunnel Fixation of Flexor Hallucis Longus Tendon Transfers to the Calcaneus.

The flexor hallucis longus tendon transfer is commonly used to restore function in chronic Achilles tendon ruptures and chronic Achilles tendinopathy. The tendon is often secured to the calcaneus either through a bone tunnel or by an interference screw. We hypothesized that tenodesis using the bone tunnel method would be mechanically superior to interference screw fixation for flexor hallucis longus transfers. Eight matched pairs of cadaveric specimens were assigned randomly to the bone tunnel or interference screw technique and were loaded to failure. Biomechanical analysis was performed to evaluate the ultimate strength, peak stress, Young's modulus, failure strain, and strain energy. Unpaired comparison, paired comparison, and linear regression analyses were used to determine statistical significance. A slight 22% ± 9% decrease in Young's modulus and a 52% ± 18% increase of strain energy were found in the interference screw group. However, no differences in ultimate strength, peak stress, or failure strain were seen between the 2 groups on paired comparison. Our findings suggest that interference screw fixation provides similar spontaneous biomechanical properties to the use of a bone tunnel for flexor hallucis longus transfer to the calcaneus. The interference screw is a practical option for fixation of the flexor hallucis longus tendon to the calcaneus and can be performed through a single incision approach.

Topographical variations of the strain-dependent zonal properties of tibial articular cartilage by microscopic MRI.

The topographical variations of the zonal properties of canine articular cartilage over the medial tibia were evaluated as the function of external loading by microscopic magnetic resonance imaging (µMRI). T2 and T1 relaxation maps and GAG (glycosaminoglycan) images from a total of 70 specimens were obtained with and without the mechanical loading at 17.6 µm depth resolution. In addition, mechanical modulus and water content were measured from the tissue. For the bulk without loading, the means of T2 at magic angle (43.6 ± 8.1 ms), absolute thickness (907.6 ± 187.9 µm) and water content (63.3 ± 9.3%) on the meniscus-covered area were significantly lower than the means of T2 at magic angle (51.1 ± 8.5 ms), absolute thickness (1251.6 ± 218.4 µm) and water content (73.2 ± 5.6%) on the meniscus-uncovered area. However GAG (86.0 ± 15.3 mg/ml) on the covered area was significantly higher than GAG (70.0 ± 8.8 mg/ml) on the uncovered area. Complex relationships were found in the tissue properties as the function of external loading. The tissue parameters in the superficial zone changed more profoundly than the same properties in the radial zone. The tissue parameters in the meniscus-covered areas changed differently when comparing with the same parameters in the uncovered areas. This project confirms that the load-induced changes in the molecular distribution and structure of cartilage are both depth-dependent and topographically distributed. Such detailed knowledge of the tibial layer could improve the early detection of the subtle softening of the cartilage that will eventually lead to the clinical diseases such as osteoarthritis.

Toward Precision Perioperative Therapy in GI Malignancies.

PURPOSE: The term precision oncology typically refers to molecularly guided therapies against cancer. Less appreciated but also critically important is molecular identification of patients with resectable disease who are most likely to benefit from perioperative drugs, and tailored selection of such drugs. We call this idea precision perioperative therapy. Over the past several years, use of precision perioperative approaches for patients with localized GI cancers has expanded in clinical trials and practice. Here, we summarize the status of the field and highlight areas of future innovation. METHODS: Using PubMed, we reviewed articles published from 2017 to 2023 in English. We used search terms "adjuvant," "perioperative," "neoadjuvant," and "precision medicine" for various types of GI malignancies. Information about ongoing clinical trials was accessed through ClinicalTrials.gov, accessed January 2023. RESULTS: Paradigms such as minimal residual disease detection via circulating tumor DNA and perioperative immunotherapy in lieu of chemotherapy for mismatch repair-deficient disease may lead to reduced toxicity and improved long-term outcomes in select populations. Molecularly targeted drugs that have shown activity against metastatic disease may also hold promise in the curable setting. CONCLUSION: The field is very much in development, but emerging data demonstrate early promise. We are optimistic that ongoing research efforts will increasingly bring precision perioperative therapy to patients with resectable GI malignancies.

Methods for tuning plasmonic and photonic optical resonances in high surface area porous electrodes.

Surface plasmons have found a wide range of applications in plasmonic and nanophotonic devices. The combination of plasmonics with three-dimensional photonic crystals has enormous potential for the efficient localization of light in high surface area photoelectrodes. However, the metals traditionally used for plasmonics are difficult to form into three-dimensional periodic structures and have limited optical penetration depth at operational frequencies, which limits their use in nanofabricated photonic crystal devices. The recent decade has seen an expansion of the plasmonic material portfolio into conducting ceramics, driven by their potential for improved stability, and their conformal growth via atomic layer deposition has been established. In this work, we have created three-dimensional photonic crystals with an ultrathin plasmonic titanium nitride coating that preserves photonic activity. Plasmonic titanium nitride enhances optical fields within the photonic electrode while maintaining sufficient light penetration. Additionally, we show that post-growth annealing can tune the plasmonic resonance of titanium nitride to overlap with the photonic resonance, potentially enabling coupled-phenomena applications for these three-dimensional nanophotonic systems. Through characterization of the tuning knobs of bead size, deposition temperature and cycle count, and annealing conditions, we can create an electrically- and plasmonically-active photonic crystal as-desired for a particular application of choice.

Anisotropic 2D excitons unveiled in organic-inorganic quantum wells.

Two-dimensional (2D) excitons arise from electron-hole confinement along one spatial dimension. Such excitations are often described in terms of Frenkel or Wannier limits according to the degree of exciton spatial localization and the surrounding dielectric environment. In hybrid material systems, such as the 2D perovskites, the complex underlying interactions lead to excitons of an intermediate nature, whose description lies somewhere between the two limits, and a better physical description is needed. Here, we explore the photophysics of a tuneable materials platform where covalently bonded metal-chalcogenide layers are spaced by organic ligands that provide confinement barriers for charge carriers in the inorganic layer. We consider self-assembled, layered bulk silver benzeneselenolate, [AgSePh]∞, and use a combination of transient absorption spectroscopy and ab initio GW plus Bethe-Salpeter equation calculations. We demonstrate that in this non-polar dielectric environment, strongly anisotropic excitons dominate the optical transitions of [AgSePh]∞. We find that the transient absorption measurements at room temperature can be understood in terms of low-lying excitons confined to the AgSe planes with in-plane anisotropy, featuring anisotropic absorption and emission. Finally, we present a pathway to control the exciton behaviour by changing the chalcogen in the material lattice. Our studies unveil unexpected excitonic anisotropies in an unexplored class of tuneable, yet air-stable, hybrid quantum wells, offering design principles for the engineering of an ordered, yet complex dielectric environment and its effect on the excitonic phenomena in such emerging materials.

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

Characterizing transition-metal dichalcogenide thin-films using hyperspectral imaging and machine learning.

Atomically thin polycrystalline transition-metal dichalcogenides (TMDs) are relevant to both fundamental science investigation and applications. TMD thin-films present uniquely difficult challenges to effective nanoscale crystalline characterization. Here we present a method to quickly characterize the nanocrystalline grain structure and texture of monolayer WS2 films using scanning nanobeam electron diffraction coupled with multivariate statistical analysis of the resulting data. Our analysis pipeline is highly generalizable and is a useful alternative to the time consuming, complex, and system-dependent methodology traditionally used to analyze spatially resolved electron diffraction measurements.

Musculoskeletal effects of obesity.

PURPOSE OF REVIEW: The problem of obesity has become a global concern, with increased prevalence reported in the literature. Numerous comorbid conditions are known to be associated with obesity; its relationship with the development and function of the musculoskeletal system in the growing child is poorly understood. This article reviews the current literature on the various musculoskeletal effects associated with obesity in children and adolescents. RECENT FINDINGS: The association between obesity and various musculoskeletal disorders such as slipped capital femoral epiphysis and Blount disease is well reported. Its effects on the structure and function of the musculoskeletal system have not been well documented. Recent studies suggest an increased association between obesity and musculoskeletal pain and increased fracture risk. The limitations imposed by increasing body mass appear to be directly reflected in the child's level of activity and overall functional capacity. SUMMARY: Obesity continues to pose a serious health concern. Its impact on the development of the child's musculoskeletal system is still poorly understood. Recent data suggests that obesity affects the child's locomotor system both functionally and structurally. As the obesity epidemic grows, newer studies will be needed to help us fully understand the true impact of obesity on the musculoskeletal system of the growing child.

Very High Refractive Index Transition Metal Dichalcogenide Photonic Conformal Coatings by Conversion of ALD Metal Oxides.

Materials for nanophotonic devices ideally combine ease of deposition, very high refractive index, and facile pattern formation through lithographic templating and/or etching. In this work, we present a scalable method for producing high refractive index WS2 layers by chemical conversion of WO3 synthesized via atomic layer deposition (ALD). These conformal nanocrystalline thin films demonstrate a surprisingly high index of refraction (n > 3.9), and structural fidelity compatible with lithographically defined features down to ~10 nm. Although this process yields highly polycrystalline films, the optical constants are in agreement with those reported for single crystal bulk WS2. Subsequently, we demonstrate three photonic structures - first, a two-dimensional hole array made possible by patterning and etching an ALD WO3 thin film before conversion, second, an analogue of the 2D hole array first patterned into fused silica before conformal coating and conversion, and third, a three-dimensional inverse opal photonic crystal made by conformal coating of a self-assembled polystyrene bead template. These results can be trivially extended to other transition metal dichalcogenides, thus opening new opportunities for photonic devices based on high refractive index materials.

Effects of Defects on Band Structure and Excitons in WS2 Revealed by Nanoscale Photoemission Spectroscopy.

Two-dimensional materials with engineered composition and structure will provide designer materials beyond conventional semiconductors. However, the potentials of defect engineering remain largely untapped, because it hinges on a precise understanding of electronic structure and excitonic properties, which are not yet predictable by theory alone. Here, we utilize correlative, nanoscale photoemission spectroscopy to visualize how local introduction of defects modifies electronic and excitonic properties of two-dimensional materials at the nanoscale. As a model system, we study chemical vapor deposition grown monolayer WS2, a prototypical, direct gap, two-dimensional semiconductor. By cross-correlating nanoscale angle-resolved photoemission spectroscopy, core level spectroscopy, and photoluminescence, we unravel how local variations in defect density influence electronic structure, lateral band alignment, and excitonic phenomena in synthetic WS2 monolayers.

How Substitutional Point Defects in Two-Dimensional WS2 Induce Charge Localization, Spin-Orbit Splitting, and Strain.

Control of impurity concentrations in semiconducting materials is essential to device technology. Because of their intrinsic confinement, the properties of two-dimensional semiconductors such as transition metal dichalcogenides (TMDs) are more sensitive to defects than traditional bulk materials. The technological adoption of TMDs is dependent on the mitigation of deleterious defects and guided incorporation of functional foreign atoms. The first step toward impurity control is the identification of defects and assessment of their electronic properties. Here, we present a comprehensive study of point defects in monolayer tungsten disulfide (WS2) grown by chemical vapor deposition using scanning tunneling microscopy/spectroscopy, CO-tip noncontact atomic force microscopy, Kelvin probe force spectroscopy, density functional theory, and tight-binding calculations. We observe four different substitutional defects: chromium (CrW) and molybdenum (MoW) at a tungsten site, oxygen at sulfur sites in both top and bottom layers (OS top/bottom), and two negatively charged defects (CD type I and CD type II). Their electronic fingerprints unambiguously corroborate the defect assignment and reveal the presence or absence of in-gap defect states. CrW forms three deep unoccupied defect states, two of which arise from spin-orbit splitting. The formation of such localized trap states for CrW differs from the MoW case and can be explained by their different d shell energetics and local strain, which we directly measured. Utilizing a tight-binding model the electronic spectra of the isolectronic substitutions OS and CrW are mimicked in the limit of a zero hopping term and infinite on-site energy at a S and W site, respectively. The abundant CDs are negatively charged, which leads to a significant band bending around the defect and a local increase of the contact potential difference. In addition, CD-rich domains larger than 100 nm are observed, causing a work function increase of 1.1 V. While most defects are electronically isolated, we also observed hybrid states formed between CrW dimers. The important role of charge localization, spin-orbit coupling, and strain for the formation of deep defect states observed at substitutional defects in WS2 as reported here will guide future efforts of targeted defect engineering and doping of TMDs.

Medicare Spending for Breast, Prostate, Lung, and Colorectal Cancer Patients in the Year of Diagnosis and Year of Death.

OBJECTIVE: To characterize spending patterns for Medicare patients with incident breast, prostate, lung, and colorectal cancer. DATA SOURCES/STUDY SETTING/STUDY DESIGN: 2007-2012 data from the Surveillance, Epidemiology, and End Results Program linked with Medicare fee-for-service claims. DATA COLLECTION/EXTRACTION METHODS: We calculate per-patient monthly and yearly mean and median expenditures, by cancer type, stage at diagnosis, and spending category, over the years of diagnosis and death. PRINCIPAL FINDINGS: Over the year of diagnosis, mean spending was $35,849, $26,295, $55,597, and $63,063 for breast, prostate, lung, and colorectal cancer, respectively. Over the year of death, spending was similar across different cancer types and stage at diagnosis. CONCLUSIONS: Characterization of Medicare spending according to clinically meaningful categories may assist development of oncology alternative payment models and cost-effectiveness models.

Reconstituting Mouse Lungs with Conditionally Reprogrammed Human Bronchial Epithelial Cells.

We developed methods for conditionally reprogramming (CR) primary human bronchial epithelial cells (HBECs) to extend their functional lifespan and permit their differentiation into both upper and lower airway lung epithelium. We also developed a bioreactor to support vascular perfusion and rhythmic breathing of decellularized mouse lungs reconstituted with CR HBECs isolated from patients with and without cystic fibrosis (CF). While conditionally reprogrammed cells only differentiate into an upper airway epithelium after 35 days at the air-liquid interface, in reconstituted lungs these cells differentiate into upper airway bronchial epithelium and lower airway alveolar structures after 12 days. Rapid scale-up and the ability to obtain clonal derivatives of primary patient-derived HBECs without the need for genetic manipulation may permit rapid reconstitution of the lung epithelium; facilitating the study of lung disease in tissue-engineered models.

Efficacy, Safety, and Regulatory Approval of Food and Drug Administration-Designated Breakthrough and Nonbreakthrough Cancer Medicines.

Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non-breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non-breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non-breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non-breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy-designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non-breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non-breakthrough-designated drugs.