H4-methylation regulators mediated epitranscriptome patterns and tumor microenvironment infiltration characterization in hepatocellular carcinoma.

Epigenetic modifications are involved in the remodeling of the tumor microenvironment (TME) and the regulation of immune response. Nonetheless, the role of histone H4 methylation (H4M) modification in the TME and immune regulation of hepatocellular carcinoma (HCC) is unknown. As a result, the purpose of this research is to discover H4M-mediated modification patterns and their effects on TME and immunologic characteristics in HCC. A total of 2305 samples were enrolled from 13 different cohorts. With the help of consensus clustering analysis, three distinct H4M modification patterns were identified. The cell-infiltrating characteristics of TME under these three patterns were highly consistent with their enriched biological processes and clinical outcome. The H4Mscore was then created using principal component analysis algorithm to quantify the H4M modification pattern of each individual tumor and was systematically correlated with representative tumor characteristics. We found that analyzing H4M modification patterns within individual tumors could predict TME infiltration, homologous recombination deficiency (HRD), intratumor heterogeneity, proliferation activity, mRNA stemness index, and prognosis. The group with a low H4Mscore had an inflamed TME phenotype and a better immunotherapy response, as well as a better survival outcome. The prognostic value of H4Mscore was validated in three internal cohorts and five external cohorts, respectively. In external immunotherapy cohorts, the low H4Mscore was also linked to an enhanced response to anti-PD-1/L1 and anti-CTLA4 immunotherapy and a better prognosis. This study revealed that H4M modification played an important role in forming TME diversity and complexity. Evaluating the H4M modification pattern of individual tumors could help us learn more about TME and develop more effective immunotherapy strategies.

Monitoring of T790M in plasma ctDNA of advanced EGFR-mutant NSCLC patients on first- or second-generation tyrosine kinase inhibitors.

BACKGROUND: The T790M mutation is the major resistance mechanism to first- and second-generation TKIs in EGFR-mutant NSCLC. This study aimed to investigate the utility of droplet digital PCR (ddPCR) for detection of T790M in plasma circulating tumor DNA (ctDNA), and explore its impact on prognosis. METHODS: This prospective study enrolled 80 advanced lung adenocarcinoma patients treated with gefitinib, erlotinib, or afatinib for TKI-sensitizing mutations between 2015 and 2019. Plasma samples were collected before TKI therapy and at tri-monthly intervals thereafter. Genotyping of ctDNA for T790M was performed using a ddPCR EGFR Mutation Assay. Patients were followed up until the date of death or to the end of 2021. RESULTS: Seventy-five of 80 patients experienced progressive disease. Fifty-three (71%) of 75 patients underwent rebiopsy, and T790M mutation was identified in 53% (28/53) of samples. Meanwhile, plasma ddPCR detected T790M mutation in 23 (43%) of 53 patients. The concordance rate of T790M between ddPCR and rebiopsy was 76%, and ddPCR identified 4 additional T790M-positive patients. Ten (45%) of 22 patients who did not receive rebiopsy tested positive for T790M by ddPCR. Serial ddPCR analysis showed the time interval from detection of plasma T790M to objective progression was 1.1 (0-4.1) months. Compared to 28 patients with rebiopsy showing T790M, the overall survival of 14 patients with T790M detected solely by ddPCR was shorter(41.3 [95% CI, 36.6-46.0] vs. 26.6 months [95% CI, 9.9-43.3], respectively). CONCLUSION: Plasma ddPCR-based genotyping is a useful technology for detection and monitoring of the key actionable genomic alteration, namely, T790M, in patients treated with gefitinib, erlotinib, or afatinib for activating mutations, to achieve better patient care and outcome.

Role of magnetic resonance imaging features in diagnosing and localization of disc rupture related to cervical spinal cord injury without radiographic abnormalities.

STUDY DESIGN: A retrospective study. OBJECTIVE: Traumatic cervical spinal cord injury (TSCI) is often associated with disc rupture. It was reported that high signal of disc and anterior longitudinal ligament (ALL) rupture on magnetic resonance imaging (MRI) were the typical signs of ruptured disc. However, for TSCI with no fracture or dislocation, there is still difficult to diagnose disc rupture. The purpose of this study was to investigate the diagnostic efficiency and localization method of different MRI features for cervical disc rupture in patient with TSCI but no any signs of fracture or dislocation. SETTING: Affiliated hospital of University in Nanchang, China. METHODS: Patients who had TSCI and underwent anterior cervical surgery between June 2016 and December 2021 in our hospital were included. All patients received X-ray, CT scan, and MRI examinations before surgery. MRI findings such as prevertebral hematoma, high-signal SCI, high-signal posterior ligamentous complex (PLC), were recorded. The correlation between preoperative MRI features and intraoperative findings was analyzed. Also, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these MRI features in diagnosing the disc rupture were calculated. RESULTS: A total of 140 consecutive patients, 120 males and 20 females with an average age of 53 years were included in this study. Of these patients, 98 (134 cervical discs) were intraoperatively confirmed with cervical disc rupture, but 59.1% (58 patients) of them had no definite evidence of an injured disc on preoperative MRI (high-signal disc or ALL rupture signal). For these patients, the high-signal PLC on preoperative MRI had the highest diagnostic rate for disc rupture based on intraoperative findings, with a sensitivity of 97%, specificity of 72%, PPV of 84% and NPV of 93%. Combined high-signal SCI with high-signal PLC had higher specificity (97%) and PPV (98%), and a lower FPR (3%) and FNR (9%) for the diagnosis of disc rupture. And combination of three MRI features (prevertebral hematoma, high-signal SCI and PLC) had the highest accuracy in diagnosing traumatic disc rupture. For the localization of the ruptured disc, the level of the high-signal SCI had the highest consistency with the segment of the ruptured disc. CONCLUSION: MRI features, such as prevertebral hematoma, high-signal SCI and PLC, demonstrated high sensitivities for diagnosing cervical disc rupture. High-signal SCI on preoperative MRI could be used to locate the segment of ruptured disc.

Saccharomyces cerevisiae: a patulin degradation candidate both in vitro and in vivo.

Patulin is one of the mycotoxins that exists in abundance in fruits and derivative products and is easily exposed in daily life, leading to various toxicities such as genotoxicity, teratogenicity, immunotoxicity, and carcinogenicity in the human body, while the efficient removal or degradation measures are still in urgent demand. In this work, Saccharomyces cerevisiae, a natural yeast with both patulin degradation and intestine damage protection abilities, was first applied to prevent and decrease the hazard after patulin intake. In vitro, Saccharomyces cerevisiae KD (S. cerevisiae KD) could efficiently degrade patulin at high concentrations. In a Canenorhabditis elegans (C. elegans) model fed on S. cerevisiae KD, locomotion, oxidative stress, patulin residual, intestine damage, and gene expression were investigated after exposure to 50 µg mL-1 patulin. The results demonstrated that S. cerevisiae KD could efficiently degrade patulin, as well as weaken the oxidative stress and intestinal damage caused by patulin. Moreover, S. cerevisiae KD could regulate the gene expression levels of daf-2 and daf-16 through the IGF-1 signaling pathway to control the ROS level and glutathione (GSH) content, thus decreasing intestinal damage. In summary, this work uncovers the outstanding characteristic of an edible probiotic S. cerevisiae KD in patulin degradation and biotoxicity alleviation and provides enlightenment toward solving the hazards caused by the accumulation of patulin.

Extracellular Matrix-Derived Biophysical Cues Mediate Interstitial Flow-Induced Sprouting Angiogenesis.

Sprouting angiogenesis is orchestrated by an intricate balance of biochemical and mechanical cues in the local tissue microenvironment. Interstitial flow has been established as a potent regulator of angiogenesis. Similarly, extracellular matrix (ECM) physical properties, such as stiffness and microarchitecture, have also emerged as important mediators of angiogenesis. However, the interplay between interstitial flow and ECM physical properties in the initiation and control of angiogenesis is poorly understood. Using a three-dimensional (3D) microfluidic tissue analogue of angiogenic sprouting with defined interstitial flow superimposed over ECM with well-characterized physical properties, we found that the addition of hyaluronan (HA) to collagen-based matrices significantly enhances sprouting induced by interstitial flow compared to responses in collagen-only hydrogels. We confirmed that both the stiffness and matrix pore size of collagen-only hydrogels were increased by the addition of HA. Interestingly, interstitial flow-potentiated sprouting responses in collagen/HA matrices were not affected when functionally blocking the HA receptor CD44. In contrast, enzymatic depletion of HA in collagen/HA matrices with hyaluronidase (HAdase) resulted in decreased stiffness, pore size, and interstitial flow-mediated sprouting to the levels observed in collagen-only matrices. Taken together, these results suggest that HA enhances interstitial flow-mediated angiogenic sprouting through its alterations to collagen ECM stiffness and pore size.

Human umbilical cord mesenchymal stem cells derived extracellular vesicles alleviate salpingitis by promoting M1-to-M2 transformation.

Background: With an increasing number of patients experiencing infertility due to chronic salpingitis after Chlamydia trachomatis (CT) infection, there is an unmet need for tissue repair or regeneration therapies. Treatment with human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EV) provides an attractive cell-free therapeutic approach. Methods: In this study, we investigated the alleviating effect of hucMSC-EV on tubal inflammatory infertility caused by CT using in vivo animal experiments. Furthermore, we examined the effect of hucMSC-EV on inducing macrophage polarization to explore the molecular mechanism. Results: Our results showed that tubal inflammatory infertility caused by Chlamydia infection was significantly alleviated in the hucMSC-EV treatment group compared with the control group. Further mechanistic experiments showed that the application of hucMSC-EV induced macrophage polarization from the M1 to the M2 type via the NF-κB signaling pathway, improved the local inflammatory microenvironment of fallopian tubes and inhibited tube inflammation. Conclusion: We conclude that this approach represents a promising cell-free avenue to ameliorate infertility due to chronic salpingitis.

Modified radial tongue-shaped flap following stepwise surgical release for Benson type I camptodactyly of the 5th digit.

To investigate the outcomes of the modified radial tongue-shaped flap following stepwise surgery release for treating Benson type I camptodactyly of the 5th digit. A retrospective analysis involving patients with Benson type I camptodactyly of the 5th digit was performed. A total of 8 patients with 12 affected digits were included. Extent of surgical release depended on the degree of soft tissue contracture. Skin release, subcutaneous fascial release, and flexor digitorum superficialis tenotomy were performed in all 12 digits, sliding volar plate release in 2 digits, and intrinsic tendon transfer in 1 digit. The mean total passive motion of proximal interphalangeal joint significantly increased from 32.5° ± 16° to 86.3° ± 20.4°, while mean total active motion significantly increased from 22° ± 10.5° to 73.8° ± 27.5° (P < 0.05). Treatment outcomes were excellent in 6 patients, good in 3, moderate in 2, and poor in 1. Scar hyperplasia occurred in 1 patient. The radial tongue-shaped flap allowed for full coverage of the volar skin defect, and was considered aesthetically favorable. In addition, the stepwise surgical approach not only achieved good curative effects, but also allowed for individualization of treatment.

An aerosol deposition based MEMS piezoelectric accelerometer for low noise measurement.

Potentially applied in low-noise applications such as structural health monitoring (SHM), a 1-axis piezoelectric MEMS accelerometer based on aerosol deposition is designed, fabricated, simulated, and measured in this study. It is a cantilever beam structure with a tip proof mass and PZT sensing layer. To figure out whether the design is suitable for SHM, working bandwidth and noise level are obtained via simulation. For the first time, we use aerosol deposition method to deposit thick PZT film during the fabrication process to achieve high sensitivity. In performance measurement, we obtain the charge sensitivity, natural frequency, working bandwidth and noise equivalent acceleration of 22.74 pC/g, 867.4 Hz, 10-200 Hz (within ±5% deviation) and 5.6 µ g / Hz (at 20 Hz). To demonstrate its feasibility for real applications, vibrations of a fan are measured by our designed sensor and a commercial piezoelectric accelerometer, and the results match well with each other. Moreover, shaker vibration measurement with ADXL1001 indicates that the fabricated sensor has a much lower noise level. In the end, we show that our designed accelerometer has good performance compared to piezoelectric MEMS accelerometers in relevant studies and great potential for low-noise applications compared to low-noise capacitive MEMS accelerometers.

Large Piezoelectric Response in a Metal-Free Three-Dimensional Perovskite Ferroelectric.

Metal-free perovskites with light weight and eco-friendly processability have received great interest in recent years due to their superior physical features in ferroelectrics, X-ray detection, and optoelectronics. The famous metal-free perovskite ferroelectric MDABCO-NH4-I3 (MDABCO = N-methyl-N'-diazabicyclo[2.2.2]octonium) has been demonstrated to exhibit excellent ferroelectricity comparable to that of inorganic ceramic ferroelectric BaTiO3, such as large spontaneous polarization and high Curie temperature (Ye et al. Science 2018, 361, 151). However, piezoelectricity as a vitally important index is far from enough in the metal-free perovskite family. Here, we report the discovery of large piezoelectric response in a new metal-free three-dimensional perovskite ferroelectric NDABCO-NH4-Br3 (NDABCO = N-amino-N'-diazabicyclo[2.2.2]octonium) by replacing the methyl group of MDABCO with the amino group. Besides the evident ferroelectricity, strikingly, NDABCO-NH4-Br3 shows a large d33 of 63 pC/N more than 4 times that of MDABCO-NH4-I3 (14 pC/N). The d33 value is also strongly supported by the computational study. To the best of our knowledge, such a large d33 value ranks the highest among the documented organic ferroelectric crystals to date and represents a major breakthrough in metal-free perovskite ferroelectrics. Combined with decent mechanical properties, NDABCO-NH4-Br3 is expected to be a competitive candidate for medical, biomechanical, wearable, and body-compatible ferroelectric devices.

Simultaneous Estimation of the Vertical Stiffness in the Knee and Hip for Healthy Human Subjects during Walking.

The stiffness of lower limb joints is a critical characteristic of walking. To investigate the potential of establishing a simple and universal model to describe the characteristics related to vertical vibration during human walking, vertical stiffness is introduced at the knee and hip. A multi-mass-spring model of the human body is established in the vertical direction. In the Fourier form, results of experiments on 14 healthy adults show that the vertical displacements of joints are a function of the leg length and walking cadence, while the ground reaction force is a function of the body weight and walking cadence. The obtained universal equations of vertical displacement and ground reaction force are employed as the input parameters to the proposed multi-mass-spring model. Thus, the vertical stiffness in the knee and hip can then be estimated simultaneously by the subject's weight, leg length, and walking cadence. The variation of vertical stiffness shows different time-varying trends in different gait phases across the entire gait cycle. Finally, the proposed model for vertical stiffness estimation is validated by the vertical oscillation of the pelvis. The average error across three gait cycles for all subjects is 20.48%, with a standard deviation of 5.44%. These results display that the vertical stiffness of knee and hip across the entire gait cycle can be directly estimated by individual parameters that are easy to measure. It provides a different view of human walking analysis and may be applied in future pathological gait recognition, bipedal robots, and lower limb exoskeletons.

Freshwater Water-Quality Criteria for Chloride and Guidance for the Revision of the Water-Quality Standard in China.

The chloride in water frequently exceeds the standard; directly quoting foreign water-quality criteria (WQC) or standards will inevitably reduce the scientific value of the water-quality standard (WQS) in China. Additionally, this may lead to the under- or overprotection of water bodies. This study summarized the sources, distribution, pollution status, and hazards of chloride in China's water bodies. Additionally, we compared and analyzed the basis for setting WQS limits for chloride in China; we systematically analyzed the basis for setting the WQC for chloride in foreign countries, especially the United States. Finally, we collected and screened data on the toxicity of chloride to aquatic organisms; we also used the species sensitivity distribution (SSD) method to derive the WQC value for chloride, which is 187.5 mg·L-1. We put forward a recommended value for freshwater WQS for chloride in China: less than 200 mg·L-1. The study of a freshwater WQC for chloride is not only a key point of environmental research, but also an urgent demand to ensure water ecological protection in China. The results of this study are of great significance for the environmental management of chloride, protection of aquatic organisms, and risk assessment, especially for the revision of WQSs.

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study.

The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

Outcomes and Prognostic Factors in Critical Patients with Hematologic Malignancies.

Patients with hematologic malignancies (HMs) have a significantly elevated risk of mortality compared to other cancer patients treated in the intensive care unit (ICU). The prognostic impact of numerous poor outcome indicators has changed, and research has yielded conflicting results. This study aims to determine the ICU and hospital outcomes and risk factors that predict the prognosis of critically ill patients with HMs. In this retrospective study, conducted at a referral hospital in Taiwan, 213 adult patients with HMs who were admitted to the medical ICU were evaluated. We collected clinical data upon hospital and ICU admission. Using a multivariate regression analysis, the predictors of ICU and hospital mortality were assessed. Then, a scoring system (Hospital outcome of critically ill patients with Hematological Malignancies (HHM)) was built to predict hospital outcomes. Most HMs (76.1%) were classified as high grade, and more than one-third of patients experienced a relapsed or refractory disease. The ICU and hospital mortality rates were 55.9% and 71.8%, respectively. Moreover, the disease severity was high (median Sequential Organ Failure Assessment (SOFA) score: 11 and Acute Physiology and Chronic Health Evaluation (APACHE II) score: 28). The multivariate analysis revealed that high-grade HMs, invasive mechanical ventilation requirement, renal replacement therapy initiation in the ICU, and a high SOFA score correlated with ICU mortality. Furthermore, a higher HHM score predicted hospital mortality. This study demonstrates that ICU mortality primarily correlates with the severity of organ dysfunction, whereas the disease status markedly influences hospital outcomes. Furthermore, the HHM score significantly predicts hospital mortality.

Lumbar paraspinal atypical spindle cell/pleomorphic lipomatous tumor: A report of a rare case.

The atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) was classified as a new tumor by the World Health Organization (WHO) in 2020. The tumor is benign and commonly occurs in the limbs. Paraspinal presentations are rare. A 38-year-old man presented at our clinic complaining of sudden onset back pain. No neurological deficit was found. The magnetic resonance imaging (MRI) revealed a well-defined heterogeneous mass in the left psoas muscle, from L1 to L3 extending over the L1 and L2 neuroforamen. The tumor was totally excised. Pathology led to an ASPLT diagnosis. Clinical symptoms improved and there was no postsurgical neurological deficit. This case of ASPLT, located in an uncommon location and present an unusual cluster of symptoms, could be treated by surgical excision, usually the first-treatment strategy. Totally, removal was achieved because there was a clear morphological margin. The risk of metastatic dissemination was minimal, though there remains a nonnegligible risk of local recurrence.

A photoluminescent chiral lead-free hybrid ferroelastic semiconductor with switchable second-harmonic generation.

Chiral organic-inorganic hybrid semiconductors (COIHSs) dominated by lead halides have recently gained tremendous interest. Here, we report a lead-free photoluminescent COIHS [R-3-hydroxylpiperidinium]2SbCl5 with a bandgap of 3.14 eV. It shows a ferroelastic phase transition at 341 K accompanied by a switchable second-harmonic generation response and presents clear ferroelastic domains, which are rarely found in lead-free COIHSs.

Evaluation of Lung Cancer Risk Among Persons Undergoing Screening or Guideline-Concordant Monitoring of Lung Nodules in the Mississippi Delta.

Importance: Guideline-concordant management of lung nodules promotes early lung cancer diagnosis, but the lung cancer risk profile of persons with incidentally detected lung nodules differs from that of screening-eligible persons. Objective: To compare lung cancer diagnosis hazard between participants receiving low-dose computed tomography screening (LDCT cohort) and those in a lung nodule program (LNP cohort). Design, Setting, and Participants: This prospective cohort study included LDCT vs LNP enrollees from January 1, 2015, to December 31, 2021, who were seen in a community health care system. Participants were prospectively identified, data were abstracted from clinical records, and survival was updated at 6-month intervals. The LDCT cohort was stratified by Lung CT Screening Reporting and Data System as having no potentially malignant lesions (Lung-RADS 1-2 cohort) vs those with potentially malignant lesions (Lung-RADS 3-4 cohort), and the LNP cohort was stratified by smoking history into screening-eligible vs screening-ineligible groups. Participants with prior lung cancer, younger than 50 years or older than 80 years, and lacking a baseline Lung-RADS score (LDCT cohort only) were excluded. Participants were followed up to January 1, 2022. Main Outcomes and Measures: Comparative cumulative rates of lung cancer diagnosis and patient, nodule, and lung cancer characteristics between programs, using LDCT as a reference. Results: There were 6684 participants in the LDCT cohort (mean [SD] age, 65.05 [6.11] years; 3375 men [50.49%]; 5774 [86.39%] in the Lung-RADS 1-2 and 910 [13.61%] in the Lung-RADS 3-4 cohorts) and 12 645 in the LNP cohort (mean [SD] age, 65.42 [8.33] years; 6856 women [54.22%]; 2497 [19.75%] screening eligible and 10 148 [80.25%] screening ineligible). Black participants constituted 1244 (18.61%) of the LDCT cohort, 492 (19.70%) of the screening-eligible LNP cohort, and 2914 (28.72%) of the screening-ineligible LNP cohort (P < .001). The median lesion size was 4 (IQR, 2-6) mm for the LDCT cohort (3 [IQR, 2-4] mm for Lung-RADS 1-2 and 9 [IQR, 6-15] mm for Lung-RADS 3-4 cohorts), 9 (IQR, 6-16) mm for the screening-eligible LNP cohort, and 7 (IQR, 5-11) mm for the screening-ineligible LNP cohort. In the LDCT cohort, lung cancer was diagnosed in 80 participants (1.44%) in the Lung-RADS 1-2 cohort and 162 (17.80%) in the Lung-RADS 3-4 cohort; in the LNP cohort, it was diagnosed in 531 (21.27%) in the screening-eligible cohort and 447 (4.40%) in the screening-ineligible cohort. Compared with Lung-RADS 1-2, the fully adjusted hazard ratios (aHRs) were 16.2 (95% CI, 12.7-20.6) for the screening-eligible cohort and 3.8 (95% CI, 3.0-5.0) for the screening-ineligible cohort; compared with Lung-RADS 3-4, the aHRs were 1.2 (95% CI, 1.0-1.5) and 0.3 (95% CI, 0.2-0.4), respectively. The stage of lung cancer was I to II in 156 of 242 patients (64.46%) in the LDCT cohort, 276 of 531 (52.00%) in the screening-eligible LNP cohort, and 253 of 447 (56.60%) in the screening-ineligible LNP cohort. Conclusions and Relevance: In this cohort study, the cumulative lung cancer diagnosis hazard of screening-age persons enrolled in the LNP was higher than that in a screening cohort, irrespective of smoking history. The LNP provided access to early detection for a higher proportion of Black persons.

Estimates of absolute crown strength and bite force in the lower postcanine dentition of Gigantopithecus blacki.

Gigantopithecus blacki is hypothesized to have been capable of processing mechanically challenging foods, which likely required this species to have high dental resistance to fracture and/or large bite force. To test this hypothesis, we used two recently developed approaches to estimate absolute crown strength and bite force of the lower postcanine dentition. Sixteen Gigantopithecus mandibular permanent cheek teeth were scanned by micro-computed tomography. From virtual mesial cross-sections, we measured average enamel thickness and bi-cervical diameter to estimate absolute crown strength, and cuspal enamel thickness and dentine horn angle to estimate bite force. We compared G. blacki with a sample of extant great apes (Pan, Pongo, and Gorilla) and australopiths (Australopithecus anamensis, Australopithecus afarensis, Australopithecus africanus, Paranthropus robustus, and Paranthropus boisei). We also evaluated statistical differences in absolute crown strength and bite force between the premolars and molars for G. blacki. Results reveal that molar crown strength is absolutely greater, and molar bite force absolutely higher, in G. blacki than all other taxa except P. boisei, suggesting that G. blacki molars have exceptionally high resistance to fracture and the ability to generate exceptionally high bite force. In addition, G. blacki premolars have comparable absolute crown strength and larger bite force capabilities compared with its molars, implying possible functional specializations in premolars. The dental specialization of G. blacki could thus represent an adaptation to further facilitate the processing of mechanically challenging foods. While it is currently not possible to determine which types of foods were actually consumed by G. blacki through this study, direct evidence (e.g. dental chipping and microwear) left by the foods eaten by G. blacki could potentially lead to greater insights into its dietary ecology.

Remarkable Enhancement of Piezoelectric Performance by Heavy Halogen Substitution in Hybrid Perovskite Ferroelectrics.

Piezoelectric materials that enable electromechanical conversion have great application value in actuators, transducers, sensors, and energy harvesters. Large piezoelectric (d33) and piezoelectric voltage (g33) coefficients are highly desired and critical to their practical applications. However, obtaining a material with simultaneously large d33 and g33 has long been a huge challenge. Here, we reported a hybrid perovskite ferroelectric [Me3NCH2Cl]CdBrCl2 to mitigate and roughly address this issue by heavy halogen substitution. The introduction of a large-size halide element softens the metal-halide bonds and reduces the polarization switching barrier, resulting in excellent piezoelectric response with a large d33 (∼440 pC/N), which realizes a significant optimization compared with that of previously reported [Me3NCH2Cl]CdCl3 (You et al. Science2017, 357, 306-309). More strikingly, [Me3NCH2Cl]CdBrCl2 simultaneously shows a giant g33 of 6215 × 10-3 V m/N, far exceeding those of polymers and conventional piezoelectric ceramics. Combined with simple solution preparation, easy processing of thin films, and a high Curie temperature of 373 K, these attributes make [Me3NCH2Cl]CdBrCl2 promising for high-performance piezoelectric sensors in flexible, wearable, and biomechanical devices.

Long-term pegylated growth hormone for children with growth hormone deficiency: a large, prospective, real-world study.

CONTEXT: The evidence of long-term polyethylene glycol recombinant human growth hormone (PEG-rhGH) in pediatric growth hormone deficiency (GHD) is limited. OBJECTIVE: This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in real world, as well as to examine the effects of dose on patient outcomes. DESIGN: A prospective, observational, post-trial study (NCT03290235). SETTING, PARTICIPANTS AND INTERVENTION: Children with GHD were enrolled from 81 centers in China in four individual clinical trials, and received weekly 0.2 mg/kg/week (high-dose) or 0.1-<0.2 mg/kg/week (low-dose) PEG-rhGH for 30 months. MAIN OUTCOMES MEASURES: Height standard deviation score (Ht SDS) at 12, 24, and 36 months. RESULTS: A total of 1170 children were enrolled in this post-trial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup, respectively. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. Besides, the changes in Ht SDS from baseline was significantly improved in the high-dose subgroup than in the low-dose subgroup at 6, 12, 24 and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious AEs. There was no serious AE related to the treatment, and no AEs leading to treatment discontinuation or death occurred. CONCLUSIONS: PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, while PEG-rhGH 0.2 mg/kg/week might show additional benefit.