A wirelessly programmable, skin-integrated thermo-haptic stimulator system for virtual reality.

Sensations of heat and touch produced by receptors in the skin are of essential importance for perceptions of the physical environment, with a particularly powerful role in interpersonal interactions. Advances in technologies for replicating these sensations in a programmable manner have the potential not only to enhance virtual/augmented reality environments but they also hold promise in medical applications for individuals with amputations or impaired sensory function. Engineering challenges are in achieving interfaces with precise spatial resolution, power-efficient operation, wide dynamic range, and fast temporal responses in both thermal and in physical modulation, with forms that can extend over large regions of the body. This paper introduces a wireless, skin-compatible interface for thermo-haptic modulation designed to address some of these challenges, with the ability to deliver programmable patterns of enhanced vibrational displacement and high-speed thermal stimulation. Experimental and computational investigations quantify the thermal and mechanical efficiency of a vertically stacked design layout in the thermo-haptic stimulators that also supports real-time, closed-loop control mechanisms. The platform is effective in conveying thermal and physical information through the skin, as demonstrated in the control of robotic prosthetics and in interactions with pressure/temperature-sensitive touch displays.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Investigation of causal relationships between cortical structure and osteoporosis using two-sample Mendelian randomization.

The mutual interaction between bone characteristics and brain had been reported previously, yet whether the cortical structure has any relevance to osteoporosis is questionable. Therefore, we applied a two-sample bidirectional Mendelian randomization analysis to investigate this relationship. We utilized the bone mineral density measurements of femoral neck (n = 32,735) and lumbar spine (n = 28,498) and data on osteoporosis (7300 cases and 358,014 controls). The global surficial area and thickness and 34 specific functional regions of 51,665 patients were screened by magnetic resonance imaging. For the primary estimate, we utilized the inverse-variance weighted method. The Mendelian randomization-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis were conducted to assess heterogeneity and pleiotropy. We observed suggestive associations between decreased thickness in the precentral region (OR = 0.034, P = 0.003) and increased chance of having osteoporosis. The results also revealed suggestive causality of decreased bone mineral density in femoral neck to declined total cortical surface area (ß = 1400.230 mm2, P = 0.003), as well as the vulnerability to osteoporosis and reduced thickness in the Parstriangularis region (ß = -0.006 mm, P = 0.002). Our study supports that the brain and skeleton exhibit bidirectional crosstalk, indicating the presence of a mutual brain-bone interaction.

Hepatocyte estrogen sulfotransferase inhibition protects female mice from concanavalin A-induced T cell-mediated hepatitis independent of estrogens.

Autoimmune hepatitis (AIH) is a typical T cell-mediated chronic liver disease with a higher incidence in females. However, the molecular mechanism for the female predisposition is poorly understood. Estrogen sulfotransferase (Est) is a conjugating enzyme best known for its function in sulfonating and deactivating estrogens. The goal of this study is to investigate whether and how Est plays a role in the higher incidence of AIH in females. Concanavalin A (ConA) was used to induce T cell-mediated hepatitis in female mice. We first showed that Est was highly induced in the liver of ConA-treated mice. Systemic or hepatocyte-specific ablation of Est, or pharmacological inhibition of Est, protected female mice from ConA-induced hepatitis regardless of ovariectomy, suggesting the effect of Est inhibition was estrogen independent. In contrast, we found that hepatocyte-specific transgenic reconstitution of Est in the whole-body Est knockout (EstKO) mice abolished the protective phenotype. Upon the ConA challenge, EstKO mice exhibited a more robust inflammatory response with elevated production of proinflammatory cytokines and changed liver infiltration of immune cells. Mechanistically, we determined that ablation of Est led to the hepatic induction of lipocalin 2 (Lcn2), whereas ablation of Lcn2 abolished the protective phenotype of EstKO females. Our findings demonstrate that hepatocyte Est is required for the sensitivity of female mice to ConA-induced and T cell-mediated hepatitis in an estrogen-independent manner. Est ablation may have protected female mice from ConA-induced hepatitis by upregulating Lcn2. Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH.

Pd-Mn/NC Dual Single-Atomic Sites with Hollow Mesopores for the Highly Efficient Semihydrogenation of Phenylacetylene.

The direct pyrolysis of metal-zeolite imidazolate frameworks (M-ZIFs) has been widely recognized as the predominant approach for synthesizing atomically dispersed metal-nitrogen-carbon single-atom catalysts (M/NC-SACs), which have exhibited exceptional activity and selectivity in the semihydrogenation of acetylene. However, due to weak adsorption of reactants on the single site and restricted molecular diffusion, the semihydrogenation of large organic molecules (e.g., phenylacetylene) was greatly limited for M/NC-SACs. In this work, a dual single-atom catalyst (h-Pd-Mn/NC) with hollow mesopores was designed and prepared using a general host-guest strategy. Taking the semihydrogenation of phenylacetylene as an example, this catalyst exhibited ultrahigh activity and selectivity, which achieved a turnover frequency of 218 molC═CmolPd-1 min-1, 16-fold higher than that of the commercial Lindlar catalyst. The catalyst maintained high activity and selectivity even after 5 cycles of usage. The superior activity of h-Pd-Mn/NC was attributed to the 4.0 nm mesopore interface of the catalyst, which enhanced the diffusion of macromolecular reactants and products. Particularly, the introduction of atomically dispersed Mn with weak electronegativity in h-Pd-Mn/NC could drive the electron transfer from Mn to adjacent Pd sites and regulate the electronic structure of Pd sites. Meanwhile, the strong electronic coupling in Pd-Mn pairs enhanced the d-electron domination near the Fermi level and promoted the adsorption of phenylacetylene and H2 on Pd active sites, thereby reducing the energy barrier for the semihydrogenation of phenylacetylene.

Atomic-Level Asymmetric Tuning of the Co1-N3P1 Catalyst for Highly Efficient N-Alkylation of Amines with Alcohols.

Despite the extensive development of non-noble metals for the N-alkylation of amines with alcohols, the exploitation of catalysts with high selectivity, activity, and stability still faces challenges. The controllable modification of single-atom sites through asymmetric coordination with a second heteroatom offers new opportunities for enhancing the intrinsic activity of transition metal single-atom catalysts. Here, we prepared the asymmetric N/P hybrid coordination of single-atom Co1-N3P1 by absorbing the Co-P complex on ZIF-8 using a concise impregnation-pyrolysis process. The catalyst exhibits ultrahigh activity and selectivity in the N-alkylation of aniline and benzyl alcohol, achieving a turnover number (TON) value of 3480 and a turnover frequency (TOF) value of 174-h. The TON value is 1 order of magnitude higher than the reported catalysts and even 37-fold higher than that of the homogeneous catalyst CoCl2(PPh3)2. Furthermore, the catalyst maintains its high activity and selectivity even after 6 cycles of usage. Controlling experiments and isotope labeling experiments confirm that in the asymmetric Co1-N3P1 system, the N-alkylation of aniline with benzyl alcohol proceeds via a transfer hydrogenation mechanism involving the monohydride route. Theoretical calculations prove that the superior activity of asymmetric Co1-N3P1 is attributed to the higher d-band energy level of Co sites, which leads to a more stable four-membered ring transition state and a lower reaction energy barrier compared to symmetrical Co1-N4.

Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.

USP15, activated by TFAP4 transcriptionally, stabilizes SHC1 via deubiquitination and deteriorates renal cell carcinoma.

Ubiquitin-specific peptidase 15 (USP15), a critical deubiquitinating enzyme, has been demonstrated to improve substrate stabilization by hydrolyzing the bond between the substrate and ubiquitin, and is implicated in multiple carcinogenic processes. Prompted by the information cited from The Cancer Genome Atlas (TCGA) database and the Cancer Proteogenomic Data Analysis Site (cProSite), USP15 is selectively overexpressed in clear cell renal cell carcinoma (ccRCC) samples. We aimed to investigate the function of USP15 on ccRCC malignant features, which was emphasized in its deubiquitination of SHC adaptor protein 1 (SHC1). The overexpression of USP15 promoted the capacity of proliferation, migration, and invasion in ccRCC CAKI1 and 769-P cells, and these malignant biological properties were diminished by USP15 deletion in 786-O cells. USP15 accelerated tumor growth and lung metastasis in vivo. In addition, deubiquitinase USP15 was further identified as a new protector for SHC1 from degradation by the ubiquitination pathway, the post-translational modification. In sequence, transcription factor activating enhancer binding protein 4 (TFAP4) was shown to be partly responsible for USP15 expression at the level of transcription, as manifested by the chromatin immunoprecipitation and pull-down assay. Based on the in vitro and in vivo data, we postulate that USP15 regulated by TFAP4 transcriptionally deteriorates ccRCC malignant biological properties via stabilizing SHC1 by deubiquitination.

Autoantibody repertoire profiling in tissue and blood identifies colorectal cancer-specific biomarkers.

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.

Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth.

Cancer immunotherapy has seen significant success in the last decade for cancer management by enhancing endogenous cancer immunity. However, immunotherapies developed thus far have seen limited success in the majority of high-grade serous carcinoma (HGSC) ovarian cancer patients. This is largely due to the highly immunosuppressive tumour microenvironment of HGSC and late-stage identification. Thus, novel treatment interventions are needed to overcome this immunosuppression and complement existing immunotherapies. Here, we have identified through analysis of > 600 human HGSC tumours a critical role for Let-7i in modulating the tumoural immune network. Tumoural expression of Let-7i had high positive correlation with anti-cancer immune signatures in HGSC patients. Confirming this role, enforced Let-7i expression in murine HGSC tumours resulted in a significant decrease in tumour burden with a significant increase in tumour T cell numbers in tumours. In concert with the improved tumoural immunity, Let-7i treatment also significantly increased CD86 expression in antigen presenting cells (APCs) in the draining lymph nodes, indicating enhanced APC activity. Collectively, our findings highlight an important role of Let-7i in anti-tumour immunity and its potential use for inducing an anti-tumour effect in HGSC.

Clinical outcomes and biomarker exploration of first-line PD-1 inhibitors plus chemotherapy in patients with low PD-L1-expressing of gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.

Diagnostic Value of Clear Cell Likelihood Score v1.0 and v2.0 for Common Subtypes of Small Renal Masses: A Multicenter Comparative Study.

BACKGROUND: Clear cell likelihood score (ccLS) is reliable for diagnosing small renal masses (SRMs). However, the diagnostic value of Clear cell likelihood score version 1.0 (ccLS v1.0) and v2.0 for common subtypes of SRMs might be a potential score extension. PURPOSE: To compare the diagnostic performance and interobserver agreement of ccLS v1.0 and v2.0 for characterizing five common subtypes of SRMs. STUDY TYPE: Retrospective. POPULATION: 797 patients (563 males, 234 females; mean age, 53 ± 12 years) with 867 histologically proven renal masses. FIELD STRENGTH/SEQUENCES: 3.0 and 1.5 T/T2 weighted imaging, T1 weighted imaging, diffusion-weighted imaging, a dual-echo chemical shift (in- and opposed-phase) T1 weighted imaging, multiphase dynamic contrast-enhanced imaging. ASSESSMENT: Six abdominal radiologists were trained in the ccLS algorithm and independently scored each SRM using ccLS v1.0 and v2.0, respectively. All SRMs had definite pathological results. The pooled area under curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the diagnostic performance of ccLS v1.0 and v2.0 for characterizing common subtypes of SRMs. The average κ values were calculated to evaluate the interobserver agreement of the two scoring versions. STATISTICAL TESTS: Random-effects logistic regression; Receiver operating characteristic analysis; DeLong test; Weighted Kappa test; Z test. The statistical significance level was P < 0.05. RESULTS: The pooled AUCs of clear cell likelihood score version 2.0 (ccLS v2.0) were statistically superior to those of ccLS v1.0 for diagnosing clear cell renal cell carcinoma (ccRCC) (0.907 vs. 0.851), papillary renal cell carcinoma (pRCC) (0.926 vs. 0.888), renal oncocytoma (RO) (0.745 vs. 0.679), and angiomyolipoma without visible fat (AMLwvf) (0.826 vs. 0.766). Interobserver agreement for SRMs between ccLS v1.0 and v2.0 is comparable and was not statistically significant (P = 0.993). CONCLUSION: The diagnostic performance of ccLS v2.0 surpasses that of ccLS v1.0 for characterizing ccRCC, pRCC, RO, and AMLwvf. Especially, the standardized algorithm has optimal performance for ccRCC and pRCC. ccLS has potential as a supportive clinical tool. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Enhanced Electrical and Optical Properties of Bismuth Tantalum Oxide Thin Films through Graphene Oxide Doping.

In this study, a hybrid thin film was fabricated by doping graphene oxide in a bismuth tantalum oxide solution in the sol-gel state. The thin film was produced by a brush-coating process. The graphene oxide doping ratios used were 0, 5, and 15 wt %. In the process of producing the thin film, the prepared sol-gel solution generates contraction forces, owing to the shear stress from the bristles of the brush, forming a microgroove structure. This structure was confirmed through atomic force microscopy, transmission electron microscopy, and energy-dispersive spectroscopy analyses. As a result of line profile analysis in atomic force microscopy, the groove heights of the thin film surface at 0, 5, and 15 wt % doping were 110, 130, and 160 nm, respectively, and the width of all grooves was 1 µm. The width of all thin films was approximately 1 µm, and microgrooves were confirmed. Moreover, the hybrid thin-film formation was confirmed by X-ray photoelectron spectroscopy. By comparing the electrical properties of the bismuth tantalum oxide thin film without graphene oxide doping and the thin film doped with 15 wt % graphene oxide, it was demonstrated that the electro-optical properties increased excellently with graphene oxide doping. Typically, the threshold voltage was reduced by approximately 0.26 V. Based on these observations, graphene oxide doped bismuth tantalum oxide hybrid thin films can be considered as promising candidates for thin-film applications in next-generation displays.

Regioselective N-Trideuteromethylation of Tautomeric Polyaza Heterocycles.

Methods for regioselective N-trideuteromethylation of tautomeric polyaza heterocycles are highly sought-after. Disclosed herein is an N-trideuterated methylation reaction of imidazoles and pyrazoles with high regioselectivity and deuterium purity using easily available CF3SO3CD3 as the -CD3 source. This method enables the easy synthesis of important deuterium-labeled azoles, including dimetridazole-d3, ipronidazole-d3, hydroxy dimetridazole-d3, and ronidazole-d3.

Linkages among stem xylem transport, biomechanics, and storage in lianas and trees across three contrasting environments.

PREMISE: Stem xylem transports water and nutrients, mechanically supports aboveground tissues, and stores water and nonstructural carbohydrates. These three functions are associated with three types of cells-vessel, fiber, and parenchyma, respectively. METHODS: We measured stem theoretical hydraulic conductivity (Kt), modulus of elasticity (MOE), tissue water content, starch, soluble sugars, cellulose, and xylem anatomical traits in 15 liana and 16 tree species across three contrasting sites in Southwest China. RESULTS: Lianas had higher hydraulic efficiency and tissue water content, but lower MOE and cellulose than trees. Storage traits (starch and soluble sugars) did not significantly differ between lianas and trees, and trait variation was explained mainly by site, highlighting how environment shapes plant storage strategies. Kt was significantly positively correlated with vessel diameter and vessel area fraction in lianas and all species combined. The MOE was significantly positively correlated with fiber area fraction, wood density, and cellulose in lianas and across all species. The tissue water content was significantly associated with parenchyma area fraction in lianas. Support function was strongly linked with transport and storage functions in lianas. In trees, transport and support functions were not correlated, while storage function was tightly linked with transport and support functions. CONCLUSIONS: These findings enhance our understanding of the relationship between stem xylem structure and function in lianas and trees, providing valuable insights into how plants adapt to environmental changes and the distinct ecological strategies employed by lianas and by trees to balance the demands of hydraulic transport, mechanical support, and storage.

Phase-Modified Strongly Coupled δ/ε-MnO2 Homojunction Cathode for Kinetics-Enhanced Zinc-Ion Batteries.

Rechargeable Zn-MnO2 batteries using mild water electrolytes have garnered significant interest owing to their impressive theoretical energy density and eco-friendly characteristics. However, MnO2 suffers from huge structural changes during the cycles, resulting in very poor stability at high charge-discharge depths. Briefly, the above problems are caused by slow kinetic processes and the dissolution of Mn atoms in the cycles. In this paper, a 2D homojunction electrode material (δ/ε-MnO2) based on δ-MnO2 and ε-MnO2 has been prepared by a two-step electrochemical deposition method. According to the DFT calculations, the charge transfer and bonding between interfaces result in the generation of electronic states near the Fermi surface, giving δ/ε-MnO2 a more continuous distribution of electron states and better conductivity, which is conducive to the rapid insertion/extraction of Zn2+ and H+. Moreover, the strongly coupled Mn-O-Mn interfacial bond can effectively impede dissolution of Mn atoms and thus maintain the structural integrity of δ/ε-MnO2 during the cycles. Accordingly, the δ/ε-MnO2 cathode exhibits high capacity (383 mAh g-1 at 0.1 A g-1), superior rate performance (150 mAh g-1 at 5 A g-1), and excellent cycling stability over 2000 cycles (91.3% at 3 A g-1). Profoundly, this unique homojunction provides a novel paradigm for reasonable selection of different components.

Complex oiling-out behavior of procaine with stable and metastable liquid phases.

During the crystallization of a solute from solvent(s), spontaneous liquid-liquid phase separation (LLPS) might occur, under certain conditions. This phenomenon, colloquially referred to as "oiling-out" in the pharmaceutical industry, often leads to undesired outcomes, including undesired particle properties, encrustation, ineffective impurity rejection, and excessively long process time. Therefore, it is critical to understand the thermodynamic driving force and phase boundaries of this phenomenon, such that rational strategies can be developed to avoid oiling-out or minimize its negative impact. In this study, we systematically evaluated the oiling-out behavior of procaine, a low melting point drug, in the solvent systems heptane, and ethanol-heptane as a function of temperature and solvent composition. In the procaine-heptane binary system, we observed a region where the LLPS is metastable with respect to crystallization, which is most commonly observed in the crystallization of modern active pharmaceutical ingredients (APIs); however, we also identified a region of the phase diagram where the LLPS is stable with respect to crystallization, and therefore will persist indefinitely. In the procaine-ethanol-heptane ternary system we identified five different regions, including a homogeneous liquid (L) region, two solid-liquid (SLI and SLII) regions, a liquid-liquid (LILII) region, and a solid-liquid-liquid (SLILII) region. The binary and ternary phase diagrams were also predicted using a state-of-the-art thermodynamic model: the SAFT-γ-Mie equation of state, and the results were compared with experimental data. Our findings highlight the complexity of oiling-out behavior. This work also represents a combined modeling and experimental platform to identify phase boundaries that will enable rational selection of strategies to crystallize active pharmaceutical ingredients with oiling-out risks.

COVID-19 vaccination affects short-term anti-coagulation levels in warfarin treatment.

Vaccines against SARS-CoV-2 have been recommended across the world, yet no study has investigated whether COVID-19 vaccination influences short-term warfarin anti-coagulation levels. Patients on stable warfarin treatment who received anti-SARS-CoV-2 vaccination were prospectively enrolled and followed up for three months. INR values less than 10 days before vaccination (baseline), 3-5 days (short-term) and 6-14 days (medium-term) after vaccination were recorded as INR0, INR1, and INR2, respectively. The variations of INR values within individuals were compared, and the linear mixed effect model was used to evaluate the variations of INR values at different time points. Logistic regression analysis was performed to determine covariates related to INR variations after COVID-19 vaccination. Vaccination safety was also monitored. There was a significant difference in INR values between INR0 and INR1 (2.15 vs. 2.26, p = 0.003), yet no marked difference was found between INR0 and INR2. The linear mixed effect model also demonstrated that INR variation was significant in short-term but not in medium-term or long-term period after vaccination. Logistic regression analysis showed that no investigated covariates, including age, vaccine dose, genetic polymorphisms of VKORC1 and CYP2C9 etc., were associated with short-term INR variations. Two patients (2.11%) reported gingival hemorrhage in the short-term due to increased INR values. The overall safety of COVID-19 vaccines for patients on warfarin was satisfying. COVID-19 vaccines may significantly influence warfarin anticoagulation levels 3-5 days after vaccination. We recommend patients on warfarin to perform at least one INR monitoring within the first week after COVID-19 vaccination.

Wireless, soft electronics for rapid, multisensor measurements of hydration levels in healthy and diseased skin.

Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner. Recent alternatives exploit thermal measurements using soft wireless devices that adhere gently and noninvasively to the surface of the skin, but with limited operating range (∼1 cm) and high sensitivity to subtle environmental fluctuations. This paper introduces a set of ideas and technologies that overcome these drawbacks to enable high-speed, robust, long-range automated measurements of thermal transport properties via a miniaturized, multisensor module controlled by a long-range (∼10 m) Bluetooth Low Energy system on a chip, with a graphical user interface to standard smartphones. Soft contact to the surface of the skin, with almost zero user burden, yields recordings that can be quantitatively connected to hydration levels of both the epidermis and dermis, using computational modeling techniques, with high levels of repeatability and insensitivity to ambient fluctuations in temperature. Systematic studies of polymers in layered configurations similar to those of human skin, of porcine skin with known levels of hydration, and of human subjects with benchmarks against clinical devices validate the measurement approach and associated sensor hardware. The results support capabilities in characterizing skin barrier function, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, for use in the clinic or in the home.

An overview of global CME/CPD systems.

PURPOSE: Engagement in CME/CPD has a positive impact on healthcare professionals' (HCPs) knowledge, skills, and performance, and on patient outcomes, therefore it is critical to better understand the components of CME/CPD systems that foster engagement, high-quality education, and impact. METHODS: An assessment of CME/CPD systems was conducted using a mixed-methods approach that included interviews with in-country subject matter experts and qualitative and quantitative data from practicing in-country physicians. RESULTS: Results demonstrate areas of consistency in CME/CPD systems across world regions that included: types of educational providers; types of credit; educational formats; self-tracking of participation; high-degree of compliance when education is mandatory; overall satisfaction with available education; strong support for interprofessional education; and lack of alignment or evaluation of engagement in education with population health outcomes. Areas of variation included: whether engagement in education is required as a condition to practice medicine; whether regulations are uniformly applied; if mechanisms to ensure independence existed; and physician perceptions of independence. CONCLUSION: Results of this assessment maybe used by a variety of different stakeholders to assess how well country-level CME/CPD systems are meeting the needs of practicing physicians and determine what, if any, changes might need to be implemented to improve outcomes.