Analytical validation of the amplification refractory mutation system polymerase chain reaction-capillary electrophoresis assay to diagnose spinal muscular atrophy.

OBJECTIVES: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletion and compound heterozygous mutations in survival motor neuron 1 (SMN1), with severity tied to the copy number of survival motor neuron 2 (SMN2). This study aimed to develop a rapid and comprehensive method for the diagnosis of SMA. METHODS: A total of 292 children with clinically suspected SMA and 394 family members were detected by the amplification refractory mutation system polymerase chain reaction-capillary electrophoresis (ARMS-PCR-CE) method, which targeted 19 reported mutations, and the results were compared with those in multiplex ligation-dependent probe amplification (MLPA). Individuals with identified point mutations were further confirmed by SMN1 long-range PCR and Sanger sequencing. RESULTS: A total of 202 children with SMA, 272 carriers, and 212 normal individuals were identified in this study. No difference was found in the R-value distribution of exons 7 and 8 in SMN1 and SMN2 among these cohorts, with coefficients of variation consistently below 0.08. To detect exon 7 and 8 copy numbers in SMN1 and SMN2, the ARMS-PCR-CE results were concordant with those of MLPA. Approximately 4.95 % (10/202) of the study patients had compound heterozygous mutations. CONCLUSIONS: The ARMS-PCR-CE assay is a comprehensive, rapid, and accurate diagnostic method for SMA that simultaneously detects copy numbers of exons 7 and 8 in SMN1/SMN2, as well as 19 point mutations in SMN1 and 2 enhancers in SMN2. This approach can effectively reduce the time frame for diagnosis, facilitating early intervention and preventing birth defects.

BMSC loaded photo-crosslinked hyaluronic acid/collagen hydrogel incorporating FG4592 for enhanced cell proliferation and nucleus pulposus differentiation.

Intervertebral disc degeneration arises from damage or degeneration of the nucleus pulposus (NP). In this study, we developed a photo-crosslinkable hydrogel incorporating FG4592 to support the growth and differentiation of bone-marrow-derived mesenchymal stem cells (BMSC). Initially, hyaluronic acid was modified with tyramine and combined with collagen to introduce riboflavin as a photo-crosslinker. This hydrogel transitioned from liquid to gel upon exposure to blue light in 3 min. The results showed that the hydrogel was biodegradable and had mechanical properties comparable to those of human NP tissues. Scanning electron microscopy after BMSC seeding in the hydrogel revealed an even distribution, and cells adhered to the collagen fibers in the hydrogel with minimal cell mortality. The effect of FG4592 on BMSC proliferation and differentiation was examined, revealing the capability of FG4592 to promote BMSC proliferation and direct differentiation resembling human NP cells. After cultivating BMSCs in the photo-crosslinked hydrogel, there was an upregulation in the expression of glycosaminoglycans, aggrecan, type II collagen, and keratin 19 proteins. Cross-species analyses of rat and human BMSCs revealed consistent results. For potential clinical applications, BMSC loaded with photo-crosslinked hydrogels can be injected into damaged intervertebral disc to facilitate NP regeneration.

Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.

Amphiphilic NLC-Gel formulation loaded with Sebacoyl dinalbuphine ester and Nalbuphine for localized postoperative pain management.

Opioids are powerful analgesics; however, their significant systemic adverse effects and the need for frequent administration restrict their use. Nalbuphine (NA) is a κ-agonist narcotic with limited adverse effects, but needs to be frequently administrated due to its short elimination half-life. Whereas sebacoyl dinalbuphine ester (SDE) is a NA prodrug, which can effectively prolong the analgesic effect, but lacks immediate pain relief. Therefore, in this study, a rapid and sustained local delivery formulation to introduce NA and SDE directly into surgical sites was developed. An amphiphilic nanostructured lipid carrier (NLC) poloxamer 407 (P407) gel (NLC-Gel) was developed to permit concurrent delivery of hydrophobic SDE from the NLC core and hydrophilic NA from P407, offering a dual rapid and prolonged analgesic effect. Benefiting from the thermal-sensitive characteristic of P407, the formulation can be injected in liquid phase and instantly transit into gel at wound site. NLC-Gel properties, including particle size, drug release, rheology, and stability, were assessed. In vivo evaluation using a rat spinal surgery model highlighted the effect of the formulation through pain behavior test and hematology analysis. NLC-Gels demonstrated an analgesic effect comparable with that of commercial intramuscular injected SDE formulation (IM SDE), with only 15 % of the drug dosage. The inclusion of supplemental NA in the exterior gel (PA12-Gel + NA) provided rapid drug onset owing to swift NA dispersion, addressing acute pain within hours along with prolonged analgesic effects. Our findings suggest that this amphiphilic formulation significantly enhanced postoperative pain management in terms of safety and efficacy.

Risk factors affecting spinal fusion: A meta-analysis of 39 cohort studies.

PURPOSE: We performed a meta-analysis to identify risk factors affecting spinal fusion. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library from inception to January 6, 2023, for articles that report risk factors affecting spinal fusion. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effects models for each factor for which the interstudy heterogeneity I2 was < 50%, while random-effects models were used when the interstudy heterogeneity I2 was ≥ 50%. Using sample size, Egger's P value, and heterogeneity across studies as criteria, we categorized the quality of evidence from observational studies as high-quality (Class I), moderate-quality (Class II or III), or low-quality (Class IV). Furthermore, the trim-and-fill procedure and leave-one-out protocol were conducted to investigate potential sources of heterogeneity and verify result stability. RESULTS: Of the 1,257 citations screened, 39 unique cohort studies comprising 7,145 patients were included in the data synthesis. High-quality (Class I) evidence showed that patients with a smoking habit (OR, 1.57; 95% CI, 1.11 to 2.21) and without the use of bone morphogenetic protein-2 (BMP-2) (OR, 4.42; 95% CI, 3.33 to 5.86) were at higher risk for fusion failure. Moderate-quality (Class II or III) evidence showed that fusion failure was significantly associated with vitamin D deficiency (OR, 2.46; 95% CI, 1.24 to 4.90), diabetes (OR, 3.42; 95% CI, 1.59 to 7.36), allograft (OR, 1.82; 95% CI, 1.11 to 2.96), conventional pedicle screw (CPS) fixation (OR, 4.77; 95% CI, 2.23 to 10.20) and posterolateral fusion (OR, 3.63; 95% CI, 1.25 to 10.49). CONCLUSIONS: Conspicuous risk factors affecting spinal fusion include three patient-related risk factors (smoking, vitamin D deficiency, and diabetes) and four surgery-related risk factors (without the use of BMP-2, allograft, CPS fixation, and posterolateral fusion). These findings may help clinicians strengthen awareness for early intervention in patients at high risk of developing fusion failure.

Preparation of PANI/CuPc/PDMS Composite Elastomer with High Dielectric Constant and Low Modulus Assisted by Electric Fields.

Dielectric elastomer is a kind of electronic electroactive polymer, which plays an important role in the application of soft robots and flexible electronics. In this study, an all-organic polyaniline/copper phthalocyanine/silicone rubber (PANI/CuPc/PDMS) dielectric composite with superior comprehensive properties was prepared by manipulating the arrangement of filler in a polymer matrix assisted by electric fields. Both CuPc particles and PANI particles can form network structures in the PDMS matrix by self-assembly under electric fields, which can enhance the dielectric properties of the composites at low filler content. The dielectric constant of the assembled PANI/CuPc/PDMS composites can reach up to 140 at 100 Hz when the content of CuPc and PANI particles is 4 wt% and 2.5 wt%, respectively. Moreover, the elastic modulus of the composites remains below 2 MPa, which is important for electro-deforming. The strain of assembled PANI/CuPc/PDMS three-phase composites at low electric field strength (2 kV/mm) can increase up to five times the composites with randomly dispersed particles, which makes this composite have potential application in the field of soft robots and flexible electronics.

Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIM: This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and cardiometabolic-specific mortality were evaluated. METHODS: We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020. RESULTS: The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (Pfor trend < 0.001). DISCUSSION: Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.

PIM1 inhibitor SMI-4a attenuated concanavalin A-induced acute hepatitis through suppressing inflammatory responses.

Background: Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis. Methods: C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB. Results: Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3. Conclusions: In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.

Associations of diabetes status and glucose measures with outcomes after endovascular therapy in patients with acute ischemic stroke: an analysis of the nationwide TREAT-AIS registry.

Background: Hyperglycemia affects the outcomes of endovascular therapy (EVT) for acute ischemic stroke (AIS). This study compares the predictive ability of diabetes status and glucose measures on EVT outcomes using nationwide registry data. Methods: The study included 1,097 AIS patients who underwent EVT from the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke. The variables analyzed included diabetes status, admission glucose, glycated hemoglobin (HbA1c), admission glucose-to-HbA1c ratio (GAR), and outcomes such as 90-day poor functional outcome (modified Rankin Scale score ≥ 2) and symptomatic intracranial hemorrhage (SICH). Multivariable analyses investigated the independent effects of diabetes status and glucose measures on outcomes. A receiver operating characteristic (ROC) analysis was performed to compare their predictive abilities. Results: The multivariable analysis showed that individuals with known diabetes had a higher likelihood of poor functional outcomes (odds ratios [ORs] 2.10 to 2.58) and SICH (ORs 3.28 to 4.30) compared to those without diabetes. Higher quartiles of admission glucose and GAR were associated with poor functional outcomes and SICH. Higher quartiles of HbA1c were significantly associated with poor functional outcomes. However, patients in the second HbA1c quartile (5.6-5.8%) showed a non-significant tendency toward good functional outcomes compared to those in the lowest quartile (<5.6%). The ROC analysis indicated that diabetes status and admission glucose had higher predictive abilities for poor functional outcomes, while admission glucose and GAR were better predictors for SICH. Conclusion: In AIS patients undergoing EVT, diabetes status, admission glucose, and GAR were associated with 90-day poor functional outcomes and SICH. Admission glucose was likely the most suitable glucose measure for predicting outcomes after EVT.

Elastic and Self-Healing Copolymer Coatings with Antimicrobial Function.

The revolutionary self-healing function for long-term and safe service processes has inspired researchers to implement them in various fields, including in the application of antimicrobial protective coatings. Despite the great advances that have been made in the field of fabricating self-healing and antimicrobial polymers, their poor transparency and the trade-off between the mechanical and self-healing properties limit the utility of the materials as transparent antimicrobial protective coatings for wearable optical and display devices. Considering the compatibility in the blending process, our group proposed a self-healing, self-cross-linkable poly{(n-butyl acrylate)-co-[N-(hydroxymethyl)acrylamide]} copolymer (AP)-based protective coating combined with two types of commercial cationic antimicrobial agents (i.e., dimethyl octadecyl (3-trimethoxysilylpropyl) ammonium chloride (DTSACL) and chlorhexidine gluconate (CHG)), leading to the fabrication of a multifunctional modified compound film of (AP/b%CHG)-grafted-a%DTSACL. The first highlight of this research is that the reactivity of the hydroxyl group in the N-(hydroxymethyl)acrylamide of the copolymer side chains under thermal conditions facilitates the "grafting to" process with the trimethoxysilane groups of DTSACL to form AP-grafted-DTSACL, yielding favorable thermal stability, improvement in hydrophobicity, and enhancement of mechanical strength. Second, we highlight that the addition of CHG can generate covalent and noncovalent interactions in a complex manner between the two biguanide groups of CHG with the AP and DTSACL via a thermal-triggered cross-linking reaction. The noncovalent interactions synergistically serve as diverse dynamic hydrogen bonds, leading to complete healing upon scratches and even showing over 80% self-healing efficiency on full-cut, while covalent bonding can effectively improve elasticity and mechanical strength. The soft nature of CHG also takes part in improving the self-healing of the copolymer. Moreover, it was discovered that the addition of CHG can enhance antimicrobial effectiveness, as demonstrated by the long-term superior antibacterial activity (100%) against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria and the antifouling function on a glass substrate and/or a silica wafer coated by the modified polymer.

A composite score based on cardiovascular parameters can predict the mortality risk of patients with newly diagnosed interstitial lung disease: A prospective observational study.

BACKGROUND: It is crucial to identify factors that can predict the risk of mortality in patients newly diagnosed with interstitial lung disease (ILD). This study sought to develop and assess a composite scoring system for mortality prediction among ILD patients based on cardiovascular parameters, which were previously reported as predictors of survival. METHODS: We prospectively enrolled patients with newly diagnosed ILD and monitored their survival status for 24 months. Surviving and deceased patients were compared regarding their baseline characteristics including clinical, pulmonary, and cardiovascular parameters. A system of composite scores was established based on significant cardiovascular parameters and the Gender-Age-Physiology (GAP) score. Receiver operating characteristic curves were generated to identify their optimal cut-off values. Univariate as well as multiple multivariate regression models were built to investigate the mortality prediction of different individual and combined parameters. RESULTS: Ninety-six patients newly diagnosed with ILD underwent cardiovascular evaluation. In univariate analysis, three cardiovascular parameters were identified as significant predictors of mortality risk in ILD patients, either individually or as a combination of composite scores: tricuspid regurgitation velocity > 3.1 m/s; N-terminal pro-B-type natriuretic peptide level > 300 pg/ml and computed tomography pulmonary artery/ascending aorta diameter ratio > 0.9. In multivariate analysis, a composite score of those parameters [hazard ratio (HR) = 2.37 (confidence interval [CI]:1.06-5.33); p = 0.037; Score 1] and GAP score [HR = 1.62 (CI: 1.11-2.36); p = 0.012] were the most significant predictors for mortality among ILD patients. Combination of Score 1 and GAP score (Score 2) can increase the accuracy of survival predictions (area under the curve 0.83; p < 0.001). CONCLUSIONS: A composite score based on cardiovascular parameters and the GAP score can be used to predict the risk of mortality of patients with ILD. Such a score achieved better diagnostic accuracy than the GAP score alone. Nevertheless, further larger-scale randomized controlled trials are required for evaluation of the newly proposed score and confirmation of our results.

Versatile Deprotonation-Induced Exfoliation and Functionalization of Biological Nanofibrils for Actuation and Fluorescence.

Biological nanofibrils not only are characteristic of many species of biomasses but also serve as a promising type of sustainable nanomaterials for various applications. However, their production has long relied on an invasive and energy-consuming mechanical shear. A noninvasive and versatile approach remains challenging to exfoliate different types of biomasses into nanofibrils. In this study, we showed a versatile and nonaggressive intercalative deprotonation agent of organic base, which could efficiently deprotonate various biomasses for energy-saving exfoliation and functionalization, including cellulose, chitin, and silk. Both carboxylic nanofibrils and nanofibrils with pristine chemical structures could be produced in high yields through manual shaking or sonication. By further grafting photoresponsive groups via transesterification, intelligent NFs were generated featuring ultraviolet-responsive fluorescence and hydrophilicity. These responsive fluorescence and actuation behaviors promised their potential as green encryption and anticounterfeiting nanomaterials.

28.02 W LD side-pumped CW laser operated at 2.8†µm in YSGG/Er:YSGG/YSGG crystal.

We demonstrated a 978 nm laser diode (LD) side-pumped YSGG/Er:YSGG/YSGG composite crystal with a size of Ф 3 mm × 65 mm and continuous-wave (CW) mode. By optimizing resonator length and output mirror transmittance, a maximum output power of 28.02 W is generated, corresponding to slope efficiency of 17.55% and optical-optical efficiency of 12.29%, respectively. The thermal focal lengths are obtained by resonator stability condition. The laser wavelength is centered near 2.8 µm. Moreover, the beam quality factors M x2/M y2 are fitted to be 8.14 and 7.35, respectively. The above results indicate that a high-performance 2.8 µm CW laser can be achieved by LD side-pumped YSGG/Er:YSGG/YSGG composite crystal with excellent heat dissipation ability, which promotes effectively the development and applications of the mid-infrared solid-state lasers.

Optimized MLPA workflow for spinal muscular atrophy diagnosis: identification of a novel variant, NC_000005.10:g.(70919941_70927324)del in isolated exon 1 of SMN1 gene through long-range PCR.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare autosomal recessive hereditary neuromuscular disease caused by survival motor neuron 1 (SMN1) gene deletion or mutation. Homozygous deletions of exon 7 in SMN1 result in 95% of SMA cases, while the remaining 5% are caused by other pathogenic variants of SMN1. METHODS: We analyzed two SMA-suspected cases that were collected, with no SMN1 gene deletion and point mutation in whole-exome sequencing. Exon 1 deletion of the SMN gene was detected using Multiplex ligation-dependent probe amplification (MLPA) P021. We used long-range polymerase chain reaction (PCR) to isolate the SMN1 template, optimized-MLPA P021 for copy number variation (CNV) analysis within SMN1 only, and validated the findings via third-generation sequencing. RESULTS: Two unrelated families shared a genotype with one copy of exon 7 and a novel variant, g.70919941_70927324del, in isolated exon 1 of the SMN1 gene. Case F1-II.1 demonstrated no exon 1 but retained other exons, whereas F2-II.1 had an exon 1 deletion in a single SMN1 gene. The read coverage in the third-generation sequencing results of both F1-II.1 and F2-II.1 revealed a deletion of approximately 7.3 kb in the 5' region of SMN1. The first nucleotide in the sequence data aligned to the 7385 bp of NG_008691.1. CONCLUSION: Remarkably, two proband families demonstrated identical SMN1 exon 1 breakpoint sites, hinting at a potential novel mutation hotspot in Chinese SMA, expanding the variation spectrum of the SMN1 gene and corroborating the specificity of isolated exon 1 deletion in SMA pathogenesis. The optimized-MLPA P021 determined a novel variant (g.70919941_70927324del) in isolated exon 1 of the SMN1 gene based on long-range PCR, enabling efficient and affordable detection of SMN gene variations in patients with SMA, providing new insight into SMA diagnosis to SMN1 deficiency and an optimized workflow for single exon CNV testing of the SMN gene.

Exercise capacity-hemodynamics mismatch in elderly patients with pulmonary hypertension: A nationwide multicenter study from Taiwan Society of Cardiology Pulmonary Hypertension Registry (TAIPANS).

Background: Demographics of pulmonary hypertension (PH) has changed a lot over the past forty years. Several recent registries noted an increase in mean age of PH but only a few of them investigated the characteristics of elderly patients. Thus, we aimed to analyze the characteristics of PH in such a population in this study. Methods: This multicenter study enrolled patients diagnosed with PH in group 1, 3, 4, and 5 consecutively from January 1, 2019 to December 31, 2020. A total of 490 patients was included, and patients were divided into three groups by age (≤45 years, 45-65 years, and >65 years). Results: The mean age of PH patients diagnosed with PH was 55.3 ± 16.3 years of age. There was higher proportion of elderly patients classified as group 3 PH (≤45: 1.3, 45-65: 4.5, >65: 8.1 %; p = 0.0206) and group 4 PH (≤45: 8.4, 45-65: 14.5, >65: 31.6 %; p < 0.0001) than young patients. Elderly patients had shorter 6-min walking distance (6 MWD) (≤45 vs. >65, mean difference, 77.8 m [95% confidence interval (CI), 2.1-153.6 m]), lower mean pulmonary arterial pressure (mPAP) (≤45 vs. >65, mean difference, 10.8 mmHg [95% CI, 6.37-15.2 mmHg]), and higher pulmonary arterial wedge pressure (PAWP) (≤45 vs. 45-65, mean difference, -2.1 mmHg [95% CI, -3.9 to -0.3 mmHg]) compared to young patients. Elderly patients had a poorer exercise capacity despite lower mPAP level compared to young population, but they received combination therapy less frequently compared to young patients (triple therapy in group 1 PH, ≤45: 16.7, 45-65: 11.3, >65: 3.8 %; p = 0.0005). Age older than 65 years was an independent predictor of high mortality for PH patients. Conclusions: Elderly PH patients possess unique hemodynamic profiles and epidemiologic patterns. They had higher PAWP, lower mPAP, and received combination therapy less frequently. Moreover, ageing is a predictor of high mortality for PH patients. Exercise capacity-hemodynamics mismatch and inadequate treatment are noteworthy in the approach of elderly population with PH.

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

Ferric- and calcium-loaded red soil assist colonization of submerged macrophyte for the in-situ remediation of eutrophic shallow lake: From mesocosm experiment to field enclosure application.

Eutrophication and its resulting harmful algal blooms greatly reduce the ecosystem services of natural waters. The use of modified clay materials to assist the phytoremediation of eutrophic water is a promising technique. In this study, ferric chloride and calcium hydroxide were respectively loaded on red soil for algal flocculation and phosphorus inactivation. A two-by-two factorial mesocosm experiment with and without the application of ferric- and calcium- loaded red soil (FA), and with and without planting the submerged macrophyte Vallisneria natans was conducted for the in-situ repair of eutrophic water and sediment. Furthermore, field enclosure application was carried out to verify the feasibility of the technology. At the end of the mesocosm experiment, the total phosphorus, total nitrogen, and ammonia nitrogen concentrations in water were reduced by 81.8 %, 63.3 %, and 62.0 %, respectively, and orthophosphate phosphorus concentration in the sediment-water interface decreased by 90.2 % in the FA + V. natans group compared with those in the control group. The concentration and proportion of chlorophyll-a in cyanobacteria decreased by 89.8 % and 71.2 %, respectively, in the FA + V. natans group. The content of active phosphorus in V. natans decreased and that of inert phosphorus increased in the FA + V. natans group, compared with those in the V. natans alone group, thus may reducing the risk of phosphorus release after decomposing of V. natans. The sediment bacterial diversity index did not change significantly among treatments. Field enclosure application have also been successful, with chlorophyll-a concentration in the water of treated enclosure decreased from above 200 µg/L to below 10 µg/L, and phosphorus concentration in the water decreased from >0.6 mg/L to <0.02 mg/L. These results demonstrated that the FA in combination with submerged macrophyte planting had great potential for the in-situ remediation of eutrophic water, especially those with severe algal blooms.

A Stable Matrix Assisting Highly Compatible and Maintainable Lithium-Garnet Interface for Solid-State Batteries.

Solid-state Li metal batteries (SSLMBs) are attractive due to their capability to simultaneously offer high energy density and high-level safety when combining Li metal anodes, solid-state electrolytes (SSEs), and high-voltage cathodes together. However, SSLMBs may well incur short circuits caused by Li dendrites penetrations, which mainly originate from the instability and poor contact between Li metal and SSEs. Herein, by taking full advantage of the reaction products of Li and Li1.3Al0.3Ti1.7(PO4)3 (LATP), a lithium-LATP composite anode (Li-LATP) is obtained, in which a stable matrix is formed to enhance the contact between Li and the garnet-type SSEs, alleviating the volume change and preserving an intact interface during the charge/discharge process. Consequently, the Li-LATP/garnet/Li-LATP symmetric cell displays a fairly low interfacial resistance of 6 Ω cm2 and stable cycling performance for over 2500 h with a low overpotential. Furthermore, the LiCoO2/garnet/Li-LATP full cell also shows a high discharge capacity of 159 mAh g-1 and great cycling performance.

Na2.5Cr0.5Zr0.5Cl6: A New Halide-Based Fast Sodium-Ion Conductor.

All-solid-state batteries employing solid electrolytes (SEs) have received widespread attention due to their high safety. Recently, lithium halides are intensively investigated as promising SEs while their sodium counterparts are less studied. Herein, a new sodium-ion conductor with a chemical formula of Na2.5Cr0.5Zr0.5Cl6 is reported, which exhibits high room temperature ionic conductivity of 0.1 mS cm-1 with low migration energy barrier of ≈0.41 eV. Na2.5Cr0.5Zr0.5Cl6 has a Fm-3m structure with 41.67 mol.% of cationic vacancies owing to the occupation of Cr (8.33 mol.%) and Zr (8.33 mol.%) ions at Na sites. Supercell calculations show that the lowest columbic energy configuration has Cr/Zr/V (where V is the vacancy) clusters in the structure. Nonetheless, the clusters have mixed effects on the sodium ion conduction pathway, based on the Bond Valence Energy Landscape calculation. A global 3D Na-ion transport percolation network can be revealed in the lowest energy supercell. Effective pathways are connected through the NaCl6 and VCl6 nodes. Besides, Raman spectroscopy and 23Na solid-state nuclear magnetic resonance spectroscopy further prove the tunable structure of the SEs with different Cr to Zr ratios. The optimization between the concentration of Na+ and vacancies is crucial to create an improved network of Na+ diffusion channels.

Large-Scale Cancer Genomic Analysis Reveals Significant Disparities between Microsatellite Instability and Tumor Mutational Burden.

BACKGROUND: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. METHODS: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. RESULTS: Patients (31-89%) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who received immunotherapy exhibited significantly higher overall survival [HR, 0.61; 95% confidence interval (CI), 0.44-0.86] and progression-free survival (HR, 0.65; 95% CI, 0.47-0.91) compared to the TMB-low group; no significant benefit was observed in the MSI-H group. Patients with TMB and MSI phenotypes showed further improvement in overall survival and PFS. We identified several mutated genes associated with MSI-H phenotypes, including known mismatch repair genes and novel mutated genes, such as ARID1A and ARID1B. CONCLUSIONS: Our results demonstrate that TMB-H and/or a combination of MSI-H can serve as biomarkers for immunotherapies in lung cancer. IMPACT: These findings suggest that distinct or combined biomarkers should be considered for immunotherapy in human cancers because notable discrepancies exist between MSI-H and TMB-H across different cancer types.