Deubiquitinase USP1 regulates sarbecovirus ORF6 protein function.

SARS-CoV-2 belongs to the subgenus Sarbecovirus, which universally encodes the accessory protein ORF6. SARS-CoV-2 ORF6 is an antagonist of the interferon (IFN)-mediated antiviral response and plays an important role in viral infections. However, the mechanism by which the host counteracts the function of ORF6 to restrict viral replication remains unclear. In this study, we found that most ORF6 proteins encoded by sarbecoviruses could be ubiquitinated and subsequently degraded via the proteasome pathway. Through extensive screening, we identified that the deubiquitinase USP1, which effectively and broadly deubiquitinates sarbecovirus ORF6 proteins, stabilizes ORF6 proteins, resulting in enhanced viral replication. Therefore, ubiquitination and deubiquitination of ORF6 are important for antagonizing IFN-mediated antiviral signaling and influencing the virulence of SARS-CoV-2. These findings highlight an essential molecular mechanism and may provide a novel target for therapeutic interventions against viral infections.IMPORTANCEThe ORF6 proteins encoded by sarbecoviruses are essential for effective viral replication and infection and are important targets for developing effective intervention strategies. In this study, we confirmed that sarbecovirus ORF6 proteins are important antagonists of the host immune response and identified the regulatory mechanisms of ubiquitination and deubiquitination of most sarbecovirus ORF6 proteins. Moreover, we revealed that DUB USP1 prevents the proteasomal degradation of all ORF6 proteins, thereby promoting the virulence of SARS-CoV-2. Thus, impeding ORF6 function is helpful for attenuating the virulence of sarbecoviruses. Therefore, our findings provide a deeper understanding of the molecular mechanisms underlying sarbecovirus infections and offer potential new therapeutic targets for the prevention and treatment of these infections.

Global, regional, and national burden of ischemic heart disease attributable to ambient PM2.5 from 1990 to 2019: An analysis for the global burden of disease study 2019.

Information on the spatio-temporal patterns of the burden of ischemic heart disease (IHD) caused by ambient ambient fine particulate matter (PM2.5) in the global level is needed to prioritize the control of ambient air pollution and prevent the burden of IHD. The Global Burden of Disease Study (GBD) 2019 provides data on IHD attributable to ambient PM2.5. The IHD burden and mortality attributable to ambient PM2.5 were analyzed by year, age, gender, socio-demographic index (SDI) level, geographical region and country. Estimated annual percentage change (EAPC) was calculated to estimate the temporal trends of age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years rate (ASDR) from 1990 to 2019. Globally, the ASMR and ASDR for ambient PM2.5-related IHD tended to level off generally, with EAPC of -0.03 (95% CI: -0.06, 0.12) and 0.3 (95% CI: 0.22, 0.37), respectively. In the past 30 years, there were obvious differences in the trend of burden change among different regions. A highest increased burden was estimated in low-middle SDI region (EAPC of ASMR: 3.73 [95% CI: 3.56, 3.9], EAPC of ASDR: 3.83 [95% CI: 3.64, 4.02]). In contrast, the burden in high SDI region (EAPC of ASMR: -4.48 [95% CI: -4.6, -4.35], EAPC of ASDR: -3.98 [95% CI: -4.12, -3.85]) has declined most significantly. Moreover, this burden was higher among men and older populations. EAPCs of the ASMR (R = -0.776, p < 0.001) and ASDR (R = -0.781, p < 0.001) of this burden had significant negative correlations with the countries' SDI level. In summary, although trends in the global burden of IHD attributable to ambient PM2.5 are stabilizing, but this burden has shifted from high SDI countries to middle and low SDI countries, especially among men and elderly populations. To reduce this burden, the air pollution management prevention need to be further strengthened, especially among males, older populations, and middle and low SDI countries.

Predictive value of monocyte to high-density lipoprotein cholesterol ratio and tumor markers in colorectal cancer and their relationship with clinicopathological characteristics.

OBJECTIVE: To evaluate the predictive value of monocyte (M) to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) and tumor markers in colorectal cancer (CRC) and their correlation with clinicopathological characteristics. METHODS: Hematology test data and medical records of 202 CRC patients and 201 healthy subjects were collected retrospectively. The diagnostic efficacy of MHR was evaluated using receiver operating characteristic (ROC) curves and risk factors for CRC were analyzed by multivariate logistic regression. RESULTS: CRC patients had significantly higher M, MHR, carcinoembryonic antigen (CEA), and carbohydrate antigen 199 (CA199) levels, but significantly lower HDL-C levels than healthy controls (all P < 0.05). Additionally, MHR was positively correlated with tumor differentiation in CRC patients (P = 0.049); CEA and CA199 levels in CRC patients increased with increased stage, lymph node metastasis and tumor size ≥ 5 cm (all P < 0.05). Furthermore, high levels of MHR, CA199 and CEA were independent risk factors for CRC. The area under ROC curve of MHR combined with CEA and CA199 was 0.882/0.869 for the diagnosis of CRC, respectively. CONCLUSION: This is the first study to explore the predictive value of MHR in CRC, and its continuous increase is an independent risk factor for CRC. MHR is a promising predictor for CRC progression along with CA199 and CEA.

Effect of citric acid residue and short-chain fatty acids on fermentation quality and aerobic stability of lucerne ensiled with lactic acid bacteria inoculants.

The experiment aimed to compare the effects of citric acid residue (CAR) to that of three commonly used short-chain fatty acids on the fermentation quality, aerobic stability and structural carbohydrate degradation of lucerne ensiled with lactic acid bacteria (LAB) inoculants. Fresh lucerne was ensiled with distilled water (control), LAB inoculant (L), CAR + LAB inoculant (CL), formic acid + LAB inoculant (FL), acetic acid + LAB inoculant (AL) and propanoic acid + LAB inoculant (PL) for 50 days. Chemical composition and microbial populations were determined after ensiling. The residual silages ensiled for 50 days were evaluated for aerobic stability. Compared with control, CL, FL, AL and PL treatments significantly (p < 0.05) decreased pH, ammonia nitrogen (NH3 -N) and butyric acid contents and increased lactic acid, acetic acid and propionic acid contents. Among them, CL silages had the lowest pH, dry matter and water-soluble carbohydrate (WSC) content, whereas the population of LAB and the lactic acid contents were highest. Besides, CL outperformed in enhancing fibre degradation, CL silages significantly decreased (p < 0.05) neutral detergent fibre, acid detergent fibre, hemicellulose and cellulose contents compared with control and had the highest Flieg's point. All treated-silages improved the aerobic stability compared with control, of which L improved 32 h, whereas CL, FL, AL and PL improved 46, 20, 46, >64 h, respectively. Applying a combination of CAR and LAB inoculant improved the fermentation quality and structural carbohydrate degradation of lucerne silage and had a similar effect on aerobic stability compared with other three short-chain fatty acids. The CAR had a comparable effect on enhancing the fermentation quality compared with three short-chain fatty acids. Thus, the combination of CAR and LAB inoculant might be used as an ideal additive for lucerne silage making with low WSC and high moisture content.

Combination of optimized tissue engineering bone implantation with heel-strike like mechanical loading to repair segmental bone defect in New Zealand rabbits.

In this study, effects of combining optimized tissue engineering bone (TEB) implantation with heel-strike like mechanical loading to repair segmental bone defect in New Zealand rabbits were investigated. Physiological characteristics of bone marrow mesenchymal stem cells (BMMSCs), compact bone cells (CBCs), and bone marrow and compact bone coculture cells (BMMSC-CBCs) were compared to select the optimal seed cells for optimized TEB construction. Rabbits with segmental bone defects were treated in different ways (cancellous bone scaffold for group A, cancellous bone scaffold and mechanical loading for group B, optimized TEB for group C, optimized TEB and mechanical loading for group D, n = 4), and the bone repair were compared. BMMSC-CBCs showed better proliferation capacity than CBCs (p < 0.01) and stronger osteogenic differentiation ability than BMMSCs (p < 0.05). Heel-strike like mechanical loading improved proliferation and osteogenic differentiation ability and expression levels of TGFß1 as well as BMP2 of seed cells in vitro (p < 0.05). At week 12 post-operation, group D showed the best bone repair, followed by groups B and C, while group A finished last (p < 0.05). During week 4 to 12 post-operation, group D peaked in terms of expression levels of TGFß1, BMP2, and OCN, followed by groups B and C, while group A finished last (p < 0.05). Thus, BMMSC-CBCs showed good proliferation and osteogenic differentiation ability, and they were thought to be better as seed cells than BMMSCs and CBCs. The optimized TEB implantation combined with heel-strike like mechanical loading had a synergistic effect on bone defect healing, and enhanced expression of TGFß1 and BMP2 played an important role in this process.

Combination of Heel-strike like Mechanical Loading with Deproteinized Cancellous Bone Scaffold Implantation to Repair Segmental Bone Defects in Rabbits.

Under physiological conditions bone defects often occur at mechanical load bearing sites and bone substitutes used for regeneration should be similarly subjected to mechanical loading stress. In this study, we investigated whether a novel heel-strike like mechanical loading method can be used as a complementary therapy to promote bone regeneration following bone substitute grafting. To test this, three groups of rabbits with segmental bone defects in the tibia were implanted with bovine deproteinized cancellous bone scaffold (DCBS), with one group also receiving heel-strike like mechanical loading generated by a rap stress stimulator. From weeks 4-12 post-operation X-ray and micro-CT scanning showed that rabbits receiving combination therapy had significantly more callus at the bone defect. Moreover, bone defects in the combination group were completely replaced with new bone at week 12, while the DCBS implantation alone group healed only partially and rabbits receiving neither DCBS nor mechanical loading developed only small calluses throughout the observation period. Analysis of micro-CT scanning results demonstrated that new bone density in the combination group was significantly higher than the DCBS only group at weeks 4 and 12 (p<0.05). H&E staining results also indicated a significantly higher percentage of new bone in the bone defect area and a lower percentage of residual scaffold in the combination group compared to the DCBS only group (p<0.05). Thus, this heel-strike like mechanical loading method appears to accelerate bone regeneration following substitute implantation by restoring a local mechanical loading environment in segmental bone defects.

Effect of Live Poultry Market Interventions on Influenza A(H7N9) Virus, Guangdong, China.

Since March 2013, three waves of human infection with avian influenza A(H7N9) virus have been detected in China. To investigate virus transmission within and across epidemic waves, we used surveillance data and whole-genome analysis of viruses sampled in Guangdong during 2013-2015. We observed a geographic shift of human A(H7N9) infections from the second to the third waves. Live poultry market interventions were undertaken in epicenter cities; however, spatial phylogenetic analysis indicated that the third-wave outbreaks in central Guangdong most likely resulted from local virus persistence rather than introduction from elsewhere. Although the number of clinical cases in humans declined by 35% from the second to the third waves, the genetic diversity of third-wave viruses in Guangdong increased. Our results highlight the epidemic risk to a region reporting comparatively few A(H7N9) cases. Moreover, our results suggest that live-poultry market interventions cannot completely halt A(H7N9) virus persistence and dissemination.

Isolation of H5N6, H7N9 and H9N2 avian influenza A viruses from air sampled at live poultry markets in China, 2014 and 2015.

Zoonotic infections by avian influenza viruses occur at the human-poultry interface, but the modes of transmission have not been fully investigated. We assessed the potential for airborne and fomite transmission at live poultry markets in Guangzhou city and in Hong Kong Special Administrative Region (SAR), China, during 2014 and 2015. Viral genome and infectious avian influenza A viruses of H5N6, H7N9, and H9N2 subtypes were detected predominantly from particles larger or equal to 1 µm in diameter in the air sampled with cyclone-based bioaerosol samplers at the live poultry markets in Guangzhou. Influenza A(H9N2) viruses were ubiquitously isolated every month during the study period from air and environmental swabs, and different lineages of H9N2 virus were isolated from markets where chickens and minor land-based poultry were sold. The use of de-feathering devices increased the quantity of virus-laden airborne particles while market closure reduced the amount of such particles. The results highlight the possibility of airborne transmission of avian influenza viruses among poultry or from poultry to humans within such settings. This may explain epidemiological observations in which some patients with H7N9 infection reported being in markets but no direct contact with live poultry or poultry stalls.

Brain functional connectivity alterations of Wernicke's area in individuals with autism spectrum conditions in multi-frequency bands: A mega-analysis.

Characterized by severe deficits in communication, most individuals with autism spectrum conditions (ASC) experience significant language dysfunctions, thereby impacting their overall quality of life. Wernicke's area, a classical and traditional brain region associated with language processing, plays a substantial role in the manifestation of language impairments. The current study carried out a mega-analysis to attain a comprehensive understanding of the neural mechanisms underpinning ASC, particularly in the context of language processing. The study employed the Autism Brain Image Data Exchange (ABIDE) dataset, which encompasses data from 443 typically developing (TD) individuals and 362 individuals with ASC. The objective was to detect abnormal functional connectivity (FC) between Wernicke's area and other language-related functional regions, and identify frequency-specific altered FC using Wernicke's area as the seed region in ASC. The findings revealed that increased FC in individuals with ASC has frequency-specific characteristics. Further, in the conventional frequency band (0.01-0.08 Hz), individuals with ASC exhibited increased FC between Wernicke's area and the right thalamus compared with TD individuals. In the slow-5 frequency band (0.01-0.027 Hz), increased FC values were observed in the left cerebellum Crus II and the right lenticular nucleus, pallidum. These results provide novel insights into the potential neural mechanisms underlying communication deficits in ASC from the perspective of language impairments.

[Research on the impact of metal implants with different materials on radiation dose distribution].

OBJECTIVE: To investigate the impact of metal implants with different materials on radiation dose distribution based on film measurement method. METHODS: Titanium plate, titanium intramedullary pin and stainless steel plate were set into phantom and irradiated separately by 6 MV and 15 MV X ray from linear accelerator. Dose distributions derived from different materials metal implants were measured and analyzed by film dosimeter. RESULTS: For 6 MV X ray, the maximum interface dose increments of titanium plate, titanium intramedullary pin and stainless steel plate were 12.3%, 15.4% and 20.3%. As the radiation energy was increased from 6 MV to 15MV, the maximum interface dose increment of the titanium plate rose from 12.3% to 15.1%, the maximum interface dose increment of the steel plate rose from 20.3% to 30.8%. CONCLUSIONS: Metal implants with different materials have obvious impact on radiation dose distribution. With the increase of the metal atomic number and energy of radiation, the degree of elevated dose also increases. These results suggest that correction of dose distribution is required for radiotherapy of patients with metal implants.

Is Sliding Compression Necessary for Intramedullary Nailing Fixation of AO/OTA Type A3.3 Intertrochanteric Fracture?

OBJECTIVES: The intramedullary nail is considered the gold standard for treating AO/OTA type A3.3 intertrochanteric fractures. However, it still faces a significant rate of failure, mainly due to the critical factor of comminuted lateral wall defects leading to inadequate proximal sliding compression. The primary objective of this study is to investigate the requirement of sliding compression in the treatment of unstable AO/OTA type A3.3 intertrochanteric fractures. To achieve this, we conduct a comparative analysis between two approaches: InterTAN alone and proximal femoral anti-rotation blade nailing (PFNA) combined with lateral wall reconstruction for treating AO/OTA type A3.3 intertrochanteric fractures with lateral wall damage. METHODS: A retrospective analysis was conducted on the clinical data of patients who underwent intramedullary nailing fixation for AO/OTA type A3.3 intertrochanteric fractures at our hospital from January 2012 to January 2022. Patient characteristics as well as treatment details, including operative time, intraoperative blood loss, weight-bearing time, fracture healing time, tip apex distance (TAD) loss, Harris hip scores (HHS), Parker-Palmer mobility score (PPMS), and postoperative complications, were collected and analyzed. Continuous variables were analyzed using independent sample t-tests, while categorical variables were examined using the chi-square test. For group comparisons, variance analysis was applied, and pairwise comparisons were conducted using the LSD-t test. RESULTS: These patients were divided into PFNA combined with lateral wall reconstruction group (sliding compression group) and InterTAN fixation group (static fixation group) based on surgical methods. The operation time, intraoperative bleeding loss, HHS at 12 months and PPMS at 12 months in the sliding compression group were significantly higher than those in the static fixation group, and time to weight-bearing and fracture healing time were significantly lower than those in the static fixation group (p < 0.05). There were no significant differences between two groups in terms of the TAD at 2 days, 2, and 12 months postoperatively, the incidence of complications (p > 0.05). At 6 months postoperatively, femoral neck length was shortened compared to 2 days postoperatively in both groups, and the sliding compression group had a significantly greater degree of femoral neck shortening than the static fixation group (p < 0.05). CONCLUSION: The use of PFNA with lateral wall reconstruction for A3.3 intertrochanteric fractures demonstrated superior mobility, efficiency, and reduced internal fixation failure rates compared to InterTAN. These findings suggest that sliding compression may be required for intramedullary nailing treatment.

Influence of Air Pollution Exposures on Cardiometabolic Risk Factors: a Review.

PURPOSE OF REVIEW: The increasing prevalence of cardiometabolic risk factors (CRFs) contributes to the rise in cardiovascular disease. Previous research has established a connection between air pollution and both the development and severity of CRFs. Given the ongoing impact of air pollution on human health, this review aims to summarize the latest research findings and provide an overview of the relationship between different types of air pollutants and CRFs. RECENT FINDINGS: CRFs include health conditions like diabetes, obesity, hypertension etc. Air pollution poses significant health risks and encompasses a wide range of pollutant types, air pollutants, such as particulate matter (PM), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O2). More and more population epidemiological studies have shown a positive correlation between air pollution and CRFs. Although various pollutants have diverse effects on specific cellular molecular pathways, their main influence is on oxidative stress, inflammation response, and impairment of endothelial function. More and more studies have proved that air pollution can promote the occurrence and development of cardiovascular and metabolic risk factors, and the research on the relationship between air pollution and CRFs has grown intensively. An increasing number of studies are using new biological monitoring indicators to assess the occurrence and development of CRFs resulting from exposure to air pollution. Abnormalities in some important biomarkers in the population (such as homocysteine, uric acid, and C-reactive protein) caused by air pollution deserve more attention. Further research is warranted to more fully understand the link between air pollution and novel CRF biomarkers and to investigate potential prevention and interventions that leverage the mechanistic link between air pollution and CRFs.

The association between childhood adiposity in northeast China and anthropogenic heat flux: A new insight into the comprehensive impact of human activities.

Anthropogenic heat has been reported to have significant health impacts, but research on its association with childhood adiposity is still lacking. In this study, we matched the 2008-2012 average anthropogenic heat flux, as simulated by a grid estimation model using inventory methods, with questionnaire and measurement data of 49,938 children randomly recruited from seven cities in Northeast China in 2012. After adjusting for social demographic and behavioral factors, we used generalized linear mixed-effect models to assess the association between anthropogenic heat flux and adiposity among children. We also examined the effect modification of various social demographic and behavioral confounders. We found that each 10 W/m2 increase in total anthropogenic heat flux and that from the industry source was associated with an increase of 5.82% (95% CI = 0.84%-11.05%) and 6.62% (95% CI = 0.87%-12.70%) in the odds of childhood adiposity. Similarly, the excess rate of adiposity among children were 5.26% (95% CI = -1.33%-12.29%) and 8.51% (95% CI = 2.24%-15.17%) per 1 W/m2 increase in the anthropogenic heat flux from transportation and buildings, and was 7.94% (95% CI = 2.28%-13.91%) per 0.001 W/m2 increase in the anthropogenic heat flux from human metabolism. We also found generally greater effect estimates among female children and children who were exposed to passive smoking during pregnancy, born by caesarean section, non-breastfed/mixed-fed, or lived within 20 m adjacent to the main road. The potential deleterious effect of anthropogenic heat exposure on adiposity among children may make it a new but major threat to be targeted by future mitigation strategies.

MSN@IL-4 Sustainingly Mediates Macrophagocyte M2 Polarization and Relieves Osteoblast Damage via NF-κB Pathway-Associated Apoptosis.

Background: The microenvironment of bone defects displayed that M2 polarization of macrophagocyte could promote the osteoblast growth and benefit the wound healing. Bone scaffold transplantation is considered to be one of the most promising methods for repairing bone defects. The present research was aimed at constructing a kind of novel bone scaffold nanomaterial of MSN@IL-4 for treating bone defects responding to the wound microenvironment of bone defects and elucidating the mechanics of MSN@IL-4 treating bone defect via controlling release of IL-4, inducing M2 polarization and active factor release of macrophagocyte, and eventually relieving osteoblast injury. Methods: MSN@IL-4 was firstly fabricated and its release of IL-4 was assessed in vitro. Following, the effects of MSN@IL-4 nanocomplex on the release of active factors of macrophage were examined using Elisa assay and promoting M2 polarization of the macrophage by immunofluorescence staining. And then, the effects of active factors from macrophage supernatant induced by MSN@IL-4 on osteoblast growth were examined by CCK-8, flow cytometry, and western blot assay. Results: The release curve of IL-4 in vitro displayed that there was more than 80% release ratio for 30th day with a sustained manner in pH 5.5. Elisa assay data showed that MSN@IL-4 nanocomplex could constantly promote the release of proproliferative cytokine IL-10, SDF-1α, and BMP-2 in macrophagocyte compared to only IL-4 treatment, and immunofluorescent image showed that MSN@IL-4 could promote M2 polarization of macrophagocytes via inducing CD206 expression and suppressing CD86 expression. Osteoblast injury data showed that the supernatant from macrophagocyte treated by MSN@IL-4 could promote the osteoblast proliferation by MTT assay. Flow cytometry data showed that the supernatant from macrophagocyte treated by MSN@IL-4 could suppress the osteoblast apoptosis from 22.1% to 14.6%, and apoptosis-related protein expression data showed that the supernatant from macrophagocyte treated by MSN@IL-4 could suppress the expression of Bax, cleaved caspase 3, and cleaved caspase 8. Furthermore, the immunofluorescent image showed that the supernatant from macrophagocyte treated by MSN@IL-4 could inhibit nucleus location of p65, and western blot data showed that the supernatant from macrophagocyte treated by MSN@IL-4 could suppress the phosphorylation of IKK and induce the expression of IκB. Conclusion: MSN@IL-4 could control the sustaining release of IL-4, and it exerts the protective effect on osteoblast injury via inducing M2 polarization and proproliferative cytokine of macrophagocyte and following inhibiting the apoptosis and NF-κB pathway-associated inflammation of osteoblast.

The atypical functional connectivity of Broca's area at multiple frequency bands in autism spectrum disorder.

As a developmental disorder, autism spectrum disorder (ASD) has drawn much attention due to its severe impacts on one's language capacity. Broca's area, an important brain region of the language network, is largely involved in language-related functions. Using the Autism Brain Image Data Exchange (ABIDE) dataset, a mega-analysis was performed involving a total of 1454 participants (including 618 individuals with ASD and 836 healthy controls (HCs). To detect the neural pathophysiological mechanism of ASD from the perspective of language, we conducted a functional connectivity (FC) analysis with Broca's area as the seed in multiple frequency bands (conventional: 0.01-0.08 Hz; slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz). We found that compared with HC, ASD patients demonstrated increased FC in the left thalamus, left precuneus, left anterior cingulate and paracingulate gyri, and left medial orbital of the superior frontal gyrus in the conventional frequency band (0.01-0.08 Hz). The results of the slow-5 frequency band (0.01-0.027 Hz) presented increased FC values of the left precuneus, left medial orbital of the superior frontal gyrus, right medial orbital of the superior frontal gyrus and right thalamus. No significant cluster was detected in the slow-4 frequency band (0.027-0.073 Hz). In conclusion, the abnormal functional connectivity in patients with ASD has frequency-specific properties. Furthermore, the slow-5 frequency band (0.01-0.027 Hz) mainly contributed to the findings of the conventional frequency band (0.01-0.08 Hz). The current study might shed new light on the neural pathophysiological mechanism of language impairments in people with ASD.

[Prevention and treatment of complications in the treatment of femoral shaft closed fracture with core drilling intramedullary nail].

OBJECTIVE: To summarize the complications of core drilling intramedullary nail in the treatment of femoral shaft closed fracture and explore the treatment strategy. METHODS: From August 2014 to June 2018, a total of 215 patients with closed femoral shaft fractures were treated with closed reduction core drill intramedullary nail, including 129 males and 86 females, aged from 18 to 62 years, with an average of (44.2±10.6) years old. The time from injury to operation was 3 to 21 days. There were 102 cases of AO type A fracture, 82 cases of AO type B fracture and 31 cases of AO type C fracture. The time of operation, the amount of blood loss during operation, the duration of hospitalization, the time of fracture healing and the HSS score of knee joint function at the last follow-up were recorded. The observation of complications included:iatrogenic fracture, core drill broken, core drill twist, postoperative infection, and fracture nonunion. RESULTS: The average operation time was (63.2± 15.6) min and intraoperative blood loss was (150.0±34.5) ml. All the incisions reached grade A healing. Patients were follow up for a mean of (18.5±3.2) months, the average hospital stay was (4.3±1.2) days, and the average fracture healing time was (5.6±2.3) months. At the final follow-up, the average HSS score of knee joint was 90.3±4.7. Related complications occurred in 37 cases (17.2%). The core drill related complications occurred in 13 cases (6.0%), including core drill broken in 5 cases (2.3%), core removal in 1 case and slotting in 4 cases;core drill twist in 8 cases (3.7%). After the core was cut, the core was removed. Similar complicationsof conventional intramedullary nail:iatrogenic fracture was performed in 12 cases (5.6%), including 10 cases of fracture end split and 2 cases of distal perimedullary fracture of intramedullary nail. The patients with cleavage at the fracture end were not treated after judging their stability, and the patients with fracture around the distal end of the intramedullary nail were fixed with auxiliary steel plate during operation;1 case(0.4%) with delayed infection after operation, debridement and external fixation was replaced and healed after bone transfer; fracture nonunion occurred in 11 cases (5.1%), of which 7 cases (3.3%) were hypertrophic nonunion and healed with additional plate. Atrophic nonunion occurred in 4 cases (1.9%), which healed after additional steel plate and bone graft. CONCLUSION: Core drilling intramedullary nail is an effective method for the treatment of closed femoral shaft fracture, and the complications include core drill related complications and conventional intramedullary nail similar complications. Accurate preoperative evaluation, careful operation during operation and early postoperative symptomatic treatment can effectively reduce the occurrence of related complications.

Intrinsic Brain Activity Alterations in Patients With Mild Cognitive Impairment-to-Normal Reversion: A Resting-State Functional Magnetic Resonance Imaging Study From Voxel to Whole-Brain Level.

Mild cognitive impairment (MCI) reversion refers to patients with MCI who revert from MCI to a normal cognitive state. Exploring the underlying neuromechanism of MCI reverters may contribute to providing new insights into the pathogenesis of Alzheimer's disease and developing therapeutic interventions. Information on patients with MCI and healthy controls (HCs) was collected from the Alzheimer's Disease Neuroimaging Initiative database. We redefined MCI reverters as patients with MCI whose logical memory scores changed from MCI to normal levels using the logical memory criteria. We explored intrinsic brain activity alterations in MCI reverters from voxel, regional, and whole-brain levels by comparing resting-state functional magnetic resonance imaging metrics of the amplitude of low-frequency of fluctuation (ALFF), the fractional amplitude of low-frequency fluctuation (fALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC) between MCI reverters and HCs. Finally, partial correlation analyses were conducted between cognitive scale scores and resting-state functional magnetic resonance imaging metrics of brain regions, revealing significant group differences. Thirty-two patients with MCI from the Alzheimer's Disease Neuroimaging Initiative database were identified as reverters. Thirty-seven age-, sex-, and education-matched healthy individuals were also enrolled. At the voxel level, compared with the HCs, MCI reverters had increased ALFF, fALFF, and PerAF in the frontal gyrus (including the bilateral orbital inferior frontal gyrus and left middle frontal gyrus), increased PerAF in the left fusiform gyrus, and decreased ALFF and fALFF in the right inferior cerebellum. Regarding regional and whole-brain levels, MCI reverters showed increased ReHo in the left fusiform gyrus and right median cingulate and paracingulate gyri; increased DC in the left inferior temporal gyrus and left medial superior frontal; decreased DC in the right inferior cerebellum and bilateral insular gyrus relative to HCs. Furthermore, significant correlations were found between cognitive performance and neuroimaging changes. These findings suggest that MCI reverters show significant intrinsic brain activity changes compared with HCs, potentially related to the cognitive reversion of patients with MCI. These results enhance our understanding of the underlying neuromechanism of MCI reverters and may contribute to further exploration of Alzheimer's disease.

Development of a PET radioligand selective for cerebral amyloid angiopathy.

INTRODUCTION: Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-ß (Aß) deposits in living people. However, this technique cannot distinguish between Aß deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aß immunotherapies in AD patients, such as CAA. METHODS: A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aß fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. RESULTS: Compound 1 displays characteristics of Aß binding dyes, such as thioflavin-S, in that it labels both parenchymal Aß plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aß amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aß deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. CONCLUSION: We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aß deposits in the vascular wall (i.e., "delivery selectivity").

Amplitude of low-frequency fluctuation (ALFF) alterations in adults with subthreshold depression after physical exercise: A resting-state fMRI study.

BACKGROUND: Physical exercise has been proved to reduce the risk of major depression in Subthreshold depression (StD) individuals effectively, yet little is known about the spontaneous brain activity changes associated with physical exercise. METHODS: A total of 70 adult subjects, including 38 StD and 32 healthy control (HC) subjects, underwent a resting-state functional magnetic resonance imaging (rs-fMRI) before and after eight-week aerobic exercise respectively. Then, the amplitude of low-frequency fluctuation (ALFF) alterations between the two groups were quantitatively analyzed. RESULTS: Before exercise intervention, the rs-fMRI data showed increased ALFF of the right putamen in the StD group compared with HC group. After exercise intervention, there was no significant ALFF change observed between the StD and HC groups. The longitudinal ALFF differences from pre- to post- exercise intervention showed significantly decreased ALFF in the right middle and inferior occipital gyrus, right middle and inferior temporal gyrus, right fusiform gyrus (FG), while increased ALFF in the right middle cingulate, right superior parietal louble, right inferior parietal lobule (IPL) (inferior parietal gyrus and supramarginal gyrus), and bilateral precuneus in the StD group. As for HC group, the results showed that decreased ALFF in the right FG and right parahippocampus, while increased ALFF in the right precuneus, right middle cingulate, right supplementary motor area, right superior parietal lobule and right paracentral lobule in the HC group. No significant correlation between changes of ALFF and clinical scale scores in the StD group. LIMITATIONS: The definitions of StD are varied in terms of different studies, the final sample size was relatively small, and the age range of the subjects in this study was narrow. Meanwhile, the exercise intervention trial was short-term. CONCLUSIONS: These results further support the standpoint that physical exercise has the potential to reshape the abnormal patterns of spontaneous brain activity in adults with StD.

The Predictive Value of Dynamic Intrinsic Local Metrics in Transient Ischemic Attack.

BACKGROUND: Transient ischemic attack (TIA) is known as "small stroke." However, the diagnosis of TIA is currently difficult due to the transient symptoms. Therefore, objective and reliable biomarkers are urgently needed in clinical practice. OBJECTIVE: The purpose of this study was to investigate whether dynamic alterations in resting-state local metrics could differentiate patients with TIA from healthy controls (HCs) using the support-vector machine (SVM) classification method. METHODS: By analyzing resting-state functional MRI (rs-fMRI) data from 48 patients with and 41 demographically matched HCs, we compared the group differences in three dynamic local metrics: dynamic amplitude of low-frequency fluctuation (d-ALFF), dynamic fractional amplitude of low-frequency fluctuation (d-fALFF), and dynamic regional homogeneity (d-ReHo). Furthermore, we selected the observed alterations in three dynamic local metrics as classification features to distinguish patients with TIA from HCs through SVM classifier. RESULTS: We found that TIA was associated with disruptions in dynamic local intrinsic brain activities. Compared with HCs, the patients with TIA exhibited increased d-fALFF, d-fALFF, and d-ReHo in vermis, right calcarine, right middle temporal gyrus, opercular part of right inferior frontal gyrus, left calcarine, left occipital, and left temporal and cerebellum. These alternations in the dynamic local metrics exhibited an accuracy of 80.90%, sensitivity of 77.08%, specificity of 85.37%, precision of 86.05%, and area under curve of 0.8501 for distinguishing the patients from HCs. CONCLUSION: Our findings may provide important evidence for understanding the neuropathology underlying TIA and strong support for the hypothesis that these local metrics have potential value in clinical diagnosis.