Validity of the modified versions of SARC-F+EBM for sarcopenia screening and diagnosis in China: the PPLSS study.

BACKGROUND AND OBJECTIVES: It is recommended by Asian Working Group for Sarcopenia to early identify people at risk for sarcopenia using simple screening tools like SARC-F. The modified version SARC-F+EBM showed higher diagnostic performance. However, this cut-off value of body mass index (BMI) remained uncertain to be used in Chinese population. In this study, we used appropriate BMI recommended for Chinese older population and further modified SARC-F+EBM by combining calf circumference. METHODS AND STUDY DESIGN: Diagnostic tests were performed and the receiver operating characteristics analyses were conducted between the SARC-F, SARC-F+EBM (cut-off of BMI: ≤ 21 kg/m2), SARC-F+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2), SARC-CalF and SARC-CalF+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2) in 1660 community-dwelling participants aged ≥ 65 years from China. RESULTS: The participants had an average age of 71.7±5.1 years, of which 56.8% were women. All the modified models could enhance the areas under the receiver operating characteristic curve (AUC) of original SARC-F (all p<0.001). The SARC-F+EBM (CN) also showed a significantly higher sensitivity of 47.4% (p<0.001) and an AUC of 0.809 (p=0.005) than SARC-F+EBM. SARC-CalF+EBM (CN) was validated to be of great diagnostic value of the highest AUC of 0.88 among these sarcopenia screening tools, including SARC-F, SARC-CalF and SARC-F+EBM (CN) (all p<0.001). Using this study population as a reference, the optimal cut-off value of SARC-CalF+EBM (CN) is ≥12 points, with a sensitivity of 79.3% and a specificity of 80.7%. CONCLUSIONS: The SARC-F+EBM (CN) and SARC-CalF+EBM (CN) could enhance the diagnostic performance of SARC-F and SARC-F+EBM and are suitable sarcopenia screening tools for Chinese population.

Nano-Engineering Strategies for Tumor-Specific Therapy.

Nanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor-specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitive stimuli-responsiveness, into one sequence would be "smart" and highly effective. Herein, we systematically summarize the related principles, methods, and progress. At the end of the review, we predict the obstacles to precise nanoengineering and prospects for the future application of NDSs.

Fused-Ring Pyrrole-Based Near-Infrared Emissive Organic RTP Material for Persistent Afterglow Bioimaging.

Organic near-infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, developing near-infrared RTP materials for deep tissue imaging still faces challenges since the small band gap may increase the non-radiative decay, resulting in weak emission and short phosphorescence lifetime. In this study, fused-ring pyrrole-based structures were employed as the guest molecules for the construction of long wavelength emissive RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non-radiative decay of triplet excitons. Therefore, a near-infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor-targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time-resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long-wavelength and long-lifetime organic RTP materials and their applications in bioimaging.

Metal-polyphenol "prison" attenuated bacterial outer membrane vesicle for chemodynamics promoted in situ tumor vaccines.

As natural adjuvants, the bacterial outer membrane vesicles (OMV) hold great potential in cancer vaccines. However, the inherent immunotoxicity of OMV and the rarity of tumor-specific antigens seriously hamper the clinical translation of OMV-based cancer vaccines. Herein, metal-phenolic networks (MPNs) are used to attenuate the toxicity of OMV, meanwhile, provide tumor antigens via the chemodynamic effect induced immunogenic cell death (ICD). Specifically, MPNs are assembled on the OMV surface through the coordination reaction between ferric ions and tannic acid. The iron-based "prison" is locally collapsed in the tumor microenvironment (TME) with both low pH and high ATP features, and thus the systemic toxicity of OMV is significantly attenuated. The released ferric ions in TME promote the ICD of cancer cells through Fenton reaction and then the generation of abundant tumor antigens, which can be used to fabricate in-situ vaccines by converging with OMV. Together with the immunomodulatory effect of OMV, potent tumor repression on a bilateral tumor model is achieved with good biosafety.

Nanoprobe-based molecular imaging for tumor stratification.

The responses of patients to tumor therapies vary due to tumor heterogeneity. Tumor stratification has been attracting increasing attention for accurately distinguishing between responders to treatment and non-responders. Nanoprobes with unique physical and chemical properties have great potential for patient stratification. This review begins by describing the features and design principles of nanoprobes that can visualize specific cell types and biomarkers and release inflammatory factors during or before tumor treatment. Then, we focus on the recent advancements in using nanoprobes to stratify various therapeutic modalities, including chemotherapy, radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), ferroptosis, and immunotherapy. The main challenges and perspectives of nanoprobes in cancer stratification are also discussed to facilitate probe development and clinical applications.

Monitoring the Cascade of Tumor-specific Immune Response in vivo via Chemoenzymatic Proximity Labeling.

Monitoring the highly dynamic and complex immune response remains a great challenge owing to the lack of reliable and specific approaches. Here, we develop a strategy to monitor the cascade of tumor immune response through the cooperation of pore-forming alginate gel with chemoenzymatic proximity-labeling. A macroporous gel containing tumor-associated antigens, adjuvants, and pro-inflammatory cytokines is utilized to recruit endogenous DCs and enhance their maturation in vivo. The mature DCs are then modified with GDP-fucose-fucosyltransferase (GDP-Fuc-Fuct) via the self-catalysis of fucosyltransferase (Fuct). Following the migration of the obtained Fuct-DCs to the draining lymph nodes (dLNs), the molecular recognition mediated interaction of DCs and T cells leads to the successful decoration of T cells with GDP-Fuc-azide through the Fuct catalyzed proximity-labeling. Therefore, the activated tumor-specific T cells in dLNs and tumors can be identified through bioorthogonal labeling, opening up a new avenue for studying the immune mechanism of tumors in situ.

Enhanced Proliferation of Visualizable Mesenchymal Stem Cell-Platelet Hybrid Cell for Versatile Intracerebral Hemorrhage Treatment.

The intrinsic features and functions of platelets and mesenchymal stem cells (MSCs) indicate their great potential in the treatment of intracerebral hemorrhage (ICH). However, neither of them can completely overcome ICH because of the stealth process and the complex pathology of ICH. Here, we fabricate hybrid cells for versatile and highly efficient ICH therapy by fusing MSCs with platelets and loading with lysophosphatidic acid-modified PbS quantum dots (LPA-QDs). The obtained LPA-QDs@FCs (FCs = fusion cells) not only inherit the capabilities of both platelets and MSCs but also exhibit clearly enhanced proliferation activated by LPA. After systemic administration, many proliferating LPA-QDs@FCs rapidly accumulate in ICH areas for responding to the vascular damage and inflammation and then efficiently prevent both the primary and secondary injuries of ICH but with no obvious side effects. Moreover, the treatment process can be tracked by near-infrared II fluorescence imaging with highly spatiotemporal resolution, providing a promising solution for ICH therapy.

Biomimetic Nanovesicle with Mitochondria-Synthesized Sonosensitizer and Mitophagy Inhibition for Cancer Sono-Immunotherapy.

Mitochondria are crucial for both sonodynamic therapy and antitumor immunity. However, how to accurately damage mitochondria and meanwhile prevent the mitophagy and immune checkpoint inhibition is still a great challenge. Herein, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) are loaded into the tumor cell-derived microparticle (X-MP), which can direct the target delivery of the prepared HAL/3MA@X-MP to the tumor cells. HAL induces the confined biosynthesis and accumulation of sonosensitizer PpIX in mitochondria, leading to the localized generation of reactive oxygen species (ROS) upon ultrasound irradiation and, thus, the efficient mitochondrial damage. Meanwhile, 3MA not only inhibits mitophagy but also down-regulates the PD-L1 expression, promoting the immunogenic cell death (ICD) while blocking the immune checkpoint recognition. The smart synergism of precise mitochondrial damage, mitophagy inhibition and antitumor immunity results in potent therapeutic efficacy without obvious side effects.

Cell-Based Biomaterials for Coronavirus Disease 2019 Prevention and Therapy.

Coronavirus disease 2019 (COVID-19) continues to threaten human health, economic development, and national security. Although many vaccines and drugs have been explored to fight against the major pandemic, their efficacy and safety still need to be improved. Cell-based biomaterials, especially living cells, extracellular vesicles, and cell membranes, offer great potential in preventing and treating COVID-19 owing to their versatility and unique biological functions. In this review, the characteristics and functions of cell-based biomaterials and their biological applications in COVID-19 prevention and therapy are described. First the pathological features of COVID-19 are summarized, providing enlightenment on how to fight against COVID-19. Next, the classification, organization structure, characteristics, and functions of cell-based biomaterials are focused on. Finally, the progress of cell-based biomaterials in overcoming COVID-19 in different aspects, including the prevention of viral infection, inhibition of viral proliferation, anti-inflammation, tissue repair, and alleviation of lymphopenia are comprehensively described. At the end of this review, a look forward to the challenges of this aspect is presented.

Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity.

Efferocytosis inhibition is emerging as an attractive strategy for antitumor immune therapy because of the subsequent leak of abundant immunogenic contents. However, the practical efficacy is seriously impeded by the immunosuppressive tumor microenvironments. Here, we construct a versatile nanosystem that can not only inhibit the efferocytosis but also boost the following antitumor immunity. MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy.

The efficacy of parecoxib in improving pain after total knee or total hip arthroplasty: Systematic review and meta-analysis.

BACKGROUND: The cyclooxygenase-2 (COX-2) selective inhibitor parecoxib is widely used in the treatment of pain and inflammation. Parecoxib has been adopted for use for postoperative analgesia following a range of surgical procedures (orthopedic, general, gynecological, and dental surgery). Total knee or total hip arthroplasty (THA) surgery is mostly done in older patients, so postoperative analgesics need to be used more carefully, and the safety and efficacy of parecoxib in this type of surgery need to be further verified. The aim of this study was to investigate the effects of parecoxib on patient safety, cumulative morphine consumption and was at 24 and 48 hours in the analgesic treatment of total knee or THA for meta-analysis and systematic review, with few studies in this area so far. METHODS: We searched the Online Database Cochrane Library, PubMed, Web of Science, EMBASE, and CBM (SinoMed), CNKI, VIP, WANFANG up to January 2021. According to the value of I2, the random-effect model or fixed-effect model was supposed to combine data from studies, respectively. Publication bias was assessed through funneling plot and Beggs test. Review Manager 5.3 and Stata 16.0 software were applied to perform the statistical analyses. RESULTS: Eleven RCTs which involved 1690 participants were included in this study. The meta-analysis indicated parecoxib sodium could not significantly reduce the incidence of adverse events after total knee or THA compared with placebo. There was no statistical significance in incidence of nausea and vomiting. 24 hours resting VAS score was statistically significant between the group. The 48-hour resting VAS scores did not indicate a significant difference between the groups. CONCLUSION: Parecoxib can reduce the incidence of adverse events after total knee or total hip surgery to some extent but cannot reduce the incidence of nausea and vomiting. Twenty-four hour postoperative analgesia is better than placebo, but 48 hours after operation analgesia is the same as placebo.

In Vivo Imaging for the Visualization of Extracellular Vesicle-Based Tumor Therapy.

Extracellular vesicles (EVs) exhibiting versatile biological functions provide promising prospects as natural therapeutic agents and drug delivery vehicles. For future clinical translation, revealing the fate of EVs in vivo, especially their accumulation at lesion sites, is very important. The continuous development of in vivo imaging technology has made it possible to track the real-time distribution of EVs. This article reviews the applications of mammal-, plant-, and bacteria-derived EVs in tumor therapy, the labeling methods of EVs for in vivo imaging, the advantages and disadvantages of different imaging techniques, and possible improvements for future work.

Phytochemical natural killer cells reprogram tumor microenvironment for potent immunotherapy of solid tumors.

Natural killer cells (NKs) hold great promise in cancer treatment, but their application in solid tumors remains a great challenge because current solutions hardly can overcome various difficulties that faced. Herein, we endow NKs with the phytochemical feature for effective immunotherapy of solid tumors. NKs are decorated with natural thylakoid (Tk) membranes through an efficient and convenient membrane fusion strategy. Tk engineering effectively activates NKs, because the antioxidase on Tk induce glycogen synthase kinase-3ß inhibition, and subsequently increase the expression of activating receptor and cytotoxic effector molecules in NKs. After systemic administration, the phytochemical NKs (PC-NKs) can target tumor tissues, and then profoundly reprogram tumor microenvironment (TME) with the help of catalase on Tk, resulting in significantly enhanced direct killing of PC-NKs and immune activated TME. Therefore, potent therapeutic effects with few abnormalities are achieved, providing a novel idea for the development of highly efficient NKs for solid tumors.

Photoluminescent Inorganic Nanoprobe-based Pathogen Detection.

Pathogens are serious threats to human health, and traditional detection techniques suffer from various limitations. The unique optical properties of photoluminescent inorganic nanomaterials, such as high photoluminescence quantum yields, good photostability, and tunable spectra, make them ideal tools for the detection of pathogens with high specificity and sensitivity. In this review, the design strategies, working mechanisms, and applications of photoluminescent inorganic nanomaterial-based probes in pathogen detection are introduced. In particular, the design and construction of stimuli-responsive nanoprobes and their potential in these fields are highlighted.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

Impaired robust interhemispheric function integration of depressive brain from REST-meta-MDD database in China.

BACKGROUND: Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations. METHODS: In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns. RESULTS: As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q < 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs. CONCLUSIONS: We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

Smart Tumor-Cell-Derived Microparticles Provide On-Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy.

Positioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) into microparticles collected from X-ray-irradiated tumor cells (X-MP). After systemic administration, the developed HAL/3BP@X-MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co-localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.

Brain structural alterations in MDD patients with gastrointestinal symptoms: Evidence from the REST-meta-MDD project.

OBJECTIVE: While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure. METHOD: Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms. RESULTS: There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P < 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P < 0.01, voxel-P < 0.001). While these changed brain areas had significantly association with GI symptoms (P < 0.001), they were not correlated with depressive symptoms (P > 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p < 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe. CONCLUSION: MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.

Sterol metabolism and protein metabolism are differentially correlated with sarcopenia in Asian Chinese men and women.

OBJECTIVES: Our aim was to investigate the prevalence and predictive variables of sarcopenia. METHODS: We recruited participants from the Peking Union Medical College Hospital Multicenter Prospective Longitudinal Sarcopenia Study (PPLSS). Muscle mass was quantified using bioimpedance, and muscle function was quantified using grip strength and gait speed. Logistic regression revealed the relationships between sarcopenia and nutritional, lifestyle, disease, psychosocial and physical variables. RESULTS: The prevalence of sarcopenia and sarcopenic obesity was 9.2%-16.2% and 0.26%-9.1%, respectively. Old age, single status, undernourishment, higher income, smoking, low physical activity, poor appetite and low protein diets were significantly associated with sarcopenia. Multiple logistic regression analysis showed that age was a risk factor for all stages of sarcopenia, and participants above 80 years were greater than fivefold more susceptible to sarcopenia, while lower physical activity was an independent risk factor. The optimal cut-off value for age was 71 years, which departs from the commonly accepted cut-off of 60 years. Female participants were greater than twofold less susceptible to sarcopenia than male participants. The sterol derivative 25-hydroxyvitamin D was associated with fourfold lower odds of sarcopenia in male participants. Several protein intake variables were also correlated with sarcopenia. Based on these parameters, we defined a highly predictive index for sarcopenia. CONCLUSIONS: Our findings support a predictive index of sarcopenia, which agglomerates the complex influences that sterol metabolism and nutrition exert on male vs female participants.

Disrupted hemispheric connectivity specialization in patients with major depressive disorder: Evidence from the REST-meta-MDD Project.

BACKGROUND: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied. METHODS: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes). RESULTS: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities. LIMITATIONS: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results. CONCLUSIONS: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.