Evidence-based guidelines recommend intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury (TBI), but there is limited evidence that monitoring and treating ...intracranial hypertension reduces mortality. This study uses a large, prospectively collected database to examine the effect on 2-week mortality of ICP reduction therapies administered to patients with severe TBI treated either with or without an ICP monitor.
From a population of 2134 patients with severe TBI (Glasgow Coma Scale GCS Score <9), 1446 patients were treated with ICP-lowering therapies. Of those, 1202 had an ICP monitor inserted and 244 were treated without monitoring. Patients were admitted to one of 20 Level I and two Level II trauma centers, part of a New York State quality improvement program administered by the Brain Trauma Foundation between 2000 and 2009. This database also contains information on known independent early prognostic indicators of mortality, including age, admission GCS score, pupillary status, CT scanning findings, and hypotension.
Age, initial GCS score, hypotension, and CT scan findings were associated with 2-week mortality. In addition, patients of all ages treated with an ICP monitor in place had lower mortality at 2 weeks (p = 0.02) than those treated without an ICP monitor, after adjusting for parameters that independently affect mortality.
In patients with severe TBI treated for intracranial hypertension, the use of an ICP monitor is associated with significantly lower mortality when compared with patients treated without an ICP monitor. Based on these findings, the authors conclude that ICP-directed therapy in patients with severe TBI should be guided by ICP monitoring.
The impact of anesthetic technique on perioperative outcomes remains controversial. We studied a large national sample of primary joint arthroplasty recipients and hypothesized that neuraxial ...anesthesia favorably influences perioperative outcomes.
Data from approximately 400 hospitals between 2006 and 2010 were accessed. Patients who underwent primary hip or knee arthroplasty were identified and subgrouped by anesthesia technique: general, neuraxial, and combined neuraxial-general. Demographics, postoperative complications, 30-day mortality, length of stay, and patient cost were analyzed and compared. Multivariable analyses were conducted to identify the independent impact of choice of anesthetic on outcomes.
Of 528,495 entries of patients undergoing primary hip or knee arthroplasty, information on anesthesia type was available for 382,236 (71.4%) records. Eleven percent were performed under neuraxial, 14.2% under combined neuraxial-general, and 74.8% under general anesthesia. Average age and comorbidity burden differed modestly between groups. When neuraxial anesthesia was used, 30-day mortality was significantly lower (0.10, 0.10, and 0.18%; P < 0.001), as was the incidence of prolonged (>75th percentile) length of stay, increased cost, and in-hospital complications. In the multivariable regression, neuraxial anesthesia was associated with the most favorable complication risk profile. Thirty-day mortality remained significantly higher in the general compared with the neuraxial or neuraxial-general group for total knee arthroplasty (adjusted odds ratio OR of 1.83, 95% CI 1.08-3.1, P = 0.02; OR of 1.70, 95% CI 1.06-2.74, P = 0.02, respectively).
The utilization of neuraxial versus general anesthesia for primary joint arthroplasty is associated with superior perioperative outcomes. More research is needed to study potential mechanisms for these findings.
HLA‐G is considered as an immune checkpoint protein and a tumor‐associated antigen. In the previous work, it is reported that CAR‐NK targeting of HLA‐G can be used to treat certain solid tumors. ...However, the frequent co‐expression of PD‐L1 and HLA‐G) and up‐regulation of PD‐L1 after adoptive immunotherapy may decrease the effectiveness of HLA‐G‐CAR. Therefore, simultaneous targeting of HLA‐G and PD‐L1 by multi‐specific CAR could represent an appropriate solution. Furthermore, gamma‐delta T (γδT) cells exhibit MHC‐independent cytotoxicity against tumor cells and possess allogeneic potential. The utilization of nanobodies offers flexibility for CAR engineering and the ability to recognize novel epitopes. In this study, Vδ2 γδT cells are used as effector cells and electroporated with an mRNA‐driven, nanobody‐based HLA‐G‐CAR with a secreted PD‐L1/CD3ε Bispecific T‐cell engager (BiTE) construct (Nb‐CAR.BiTE). Both in vivo and in vitro experiments reveal that the Nb‐CAR.BiTE‐γδT cells could effectively eliminate PD‐L1 and/or HLA‐G‐positive solid tumors. The secreted PD‐L1/CD3ε Nb‐BiTE can not only redirect Nb‐CAR‐γδT but also recruit un‐transduced bystander T cells against tumor cells expressing PD‐L1, thereby enhancing the activity of Nb‐CAR‐γδT therapy. Furthermore, evidence is provided that Nb‐CAR.BiTE redirectes γδT into tumor‐implanted tissues and that the secreted Nb‐BiTE is restricted to the tumor site without apparent toxicity.
Elevated PD‐L1 in solid tumors increases the risk of immune escape from HLA‐G‐CAR cell therapy. The bicistronic mRNA construct that drives PD‐L1 Nb‐BiTE and HLA‐G Nb‐CAR in γδT cells via electroporation is designed to address this issue. This Nb‐CAR.BiTE‐γδT therapy can overcome HLA‐G and PD‐L1 dilemma and even kill tumor cells with inadequate antigen expression, resulting in potent anti‐tumor activity without apparent toxicity.
Microtubule‐associated protein Tau, abundant in the central nervous system (CNS), plays crucial roles in microtubule assembly and stabilization. Abnormal Tau phosphorylation and aggregation are a ...common pathogenic hallmark in Alzheimer's disease (AD). Hyperphosphorylation of Tau could change its conformation and result in self‐aggregation, increased oxidative stress, and neuronal death. In this study, we examined the potential of licochalcone A (a natural chalcone) and five synthetic derivatives (LM compounds) for inhibiting Tau misfolding, scavenging reactive oxygen species (ROS) and providing neuroprotection in human cells expressing proaggregant ΔK280 TauRD‐DsRed. All test compounds were soluble up to 100 μM in cell culture media and predicted to be orally bioavailable and CNS‐active. Among them, licochalcone A and LM‐031 markedly reduced Tau misfolding and associated ROS, promoted neurite outgrowth, and inhibited caspase 3 activity in ΔK280 TauRD‐DsRed 293 and SH‐SY5Y cells. Mechanistic studies showed that LM‐031 upregulates HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB‐dependent BDNF/AKT/ERK/BCL2 pathway in ΔK280 TauRD‐DsRed SH‐SY5Y cells. Decreased neurite outgrowth upon induction of ΔK280 TauRD‐DsRed was rescued by LM‐031, which was counteracted by knockdown of NRF2 or CREB. LM‐031 further rescued the downregulated NRF2 and pCREB, reduced Aβ and Tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin‐induced hyperglycemic 3 × Tg‐AD mice. Our findings strongly indicate the potential of LM‐031 for modifying AD progression by targeting HSPB1 to reduce Tau misfolding and activating NRF2 and CREB pathways to suppress apoptosis and promote neuron survival, thereby offering a new drug development avenue for AD treatment.
Through upregulating HSPB1 chaperone to reduce Tau misfolding, and enhancing NRF2 and CREB pathways to reduce ROS and apoptosis in ΔK280 TauRD‐DsRed SH‐SY5Y cells, as well as promoting neuron survival and cognitive function in hyperglycemic 3×Tg‐AD mice, LM‐031 (3‐benzoyl‐5‐hydroxychromen‐2‐one) displays potential for Alzheimer’s disease treatment.
Due to the poor prognosis of metastatic osteosarcoma, chemotherapy is usually employed in the adjuvant situation to improve the prognosis and the chances of long-term survival. ...4-3,5-Bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl-4-oxo-2-butenoic acid (CLEFMA) is a synthetic analog of curcumin and possesses anti-inflammatory and anticancer properties. To further obtain information regarding the apoptotic pathway induced by CLEFMA in osteosarcoma cells, microculture tetrazolium assay, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. CLEFMA dose-dependently decreased the cell viabilities of human osteosarcoma U2OS and HOS cells and significantly induced apoptosis in human osteosarcoma cells. In addition to the effector caspase 3, CLEFMA significantly activated both extrinsic caspase 8 and intrinsic caspase 9 initiators. Moreover, CLEFMA increased the phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2 and p38. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), CLEFMA's increases of cleaved caspases 3, 8, and 9 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Conclusively, CLEFMA activates both extrinsic and intrinsic apoptotic pathways in human osteosarcoma cells through JNK and p38 signaling. These findings contribute to a better understanding of the mechanisms responsible for CLEFMA's apoptotic effects on human osteosarcoma cells.
Despite the concern that sleep apnea (SA) is associated with increased risk for postoperative complications, a paucity of information is available regarding the effect of this disorder on ...postoperative complications and resource utilization in the orthopedic population. With an increasing number of surgical patients suffering from SA, this information is important to physicians, patients, policymakers, and administrators alike.
We analyzed hospital discharge data of patients who underwent total hip or knee arthroplasty in approximately 400 U.S. Hospitals between 2006 and 2010. Patient, procedure, and health care system-related demographics and outcomes such as mortality, complications, and resource utilization were compared among groups. Multivariable logistic regression models were fit to assess the association between SA and various outcomes.
We identified 530,089 entries for patients undergoing total hip and knee arthroplasty. Of those, 8.4% had a diagnosis code for SA. In the multivariate analysis, the diagnosis of SA emerged as an independent risk factor for major postoperative complications (OR 1.47; 95% confidence interval CI, 1.39-1.55). Pulmonary complications were 1.86 (95% CI, 1.65-2.09) times more likely and cardiac complications 1.59 (95% CI, 1.48-1.71) times more likely to occur in patients with SA. In addition, SA patients were more likely to receive ventilatory support, use more intensive care, stepdown and telemetry services, consume more economic resources, and have longer lengths of hospitalization.
The presence of SA is a major clinical and economic challenge in the postoperative period. More research is needed to identify SA patients at risk for complications and develop evidence-based practices to aid in the allocation of clinical and economic resources.
Osteosarcoma, the most common primary bone cancer that affects adolescents worldwide, has the early metastatic potential to be responsible for high mortality rates. Morin has a multipurpose role in ...numerous cancers, whereas little is known about its role in osteosarcoma migration and invasion. Therefore, we hypothesized that morin suppresses the invasive activities and the migratory potential of human osteosarcoma cells. Our results showed that morin reduced migration and invasion capabilities in human osteosarcoma U2OS and HOS cells. Moreover, morin inhibited the urokinase plasminogen activator (uPA) expression through a signal transducer and an activator of transcription‐3 (STAT3) phosphorylation. After STAT3 overexpression, the decrease of the migratory potential and uPA expression caused by 100 μM of morin in U2OS cells was countered, indicating that STAT3 contributes to the antimetastatic property of morin in human osteosarcoma cells by reducing uPA. In conclusion, morin may be a potential candidate for the antimetastatic treatment of human osteosarcoma.
Osteosarcoma, the most prevalent malignant bone tumor in the pediatric age group, is responsible for the great majority of cancer-associated deaths owing to its highly metastatic potential. The ...anti-metastatic effects of the new curcumin analogue L48H37 in human osteosarcoma are still unknown; hence, we investigated whether L48H37 represses human osteosarcoma cells' biological behavior of migratory potential and invasive activities and attempted to delve into its underlying mechanisms. L48H37 up to 5 μM inhibited, without cytotoxicity, the motility, migration, and invasion of human osteosarcoma U2OS and MG-63 cells. In U2OS cells, the human protease array revealed an obvious decrease in urokinase plasminogen activator (uPA) expression after L48H37 treatment, and L48H37 actually reduced the level, protein and mRNA expression, and promoter activity of uPA dose-dependently. L48H37 decreased the phosphorylation of STAT3, JAK1, JAK2, and JAK3 in U2OS cells, but did not affect the phosphorylation of ERK, JNK, p38, and Akt. Using colivelin, an activator of STAT3, the L48H37-induced decrease in uPA and migratory potential could be countered as expected. Collectively, L48H37 represses the invasion and migration capabilities of U2OS and MG-63 cells by the suppression of uPA expression and the inhibition of JAK/STAT signaling. These results suggest that L48H37 may be a potential candidate for anti-metastatic treatment of human osteosarcoma.
The presence of sleep apnea (SA) among surgical patients has been associated with significantly increased risk of perioperative complications. Although regional anesthesia has been suggested as a ...means to reduce complication rates among SA patients undergoing surgery, no data are available to support this association. We studied the association of the type of anesthesia and perioperative outcomes in patients with SA undergoing joint arthroplasty.
Drawing on a large administrative database (Premier Inc), we analyzed data from approximately 400 hospitals in the United States. Patients with a diagnosis of SA who underwent primary hip or knee arthroplasty between 2006 and 2010 were identified. Perioperative outcomes were compared between patients receiving general, neuraxial, or combined neuraxial-general anesthesia.
We identified 40,316 entries for unique patients with a diagnosis for SA undergoing primary hip or knee arthroplasty. Of those, 30,024 (74%) had anesthesia-type information available. Approximately 11% of cases were performed under neuraxial, 15% under combined neuraxial and general, and 74% under general anesthesia. Patients undergoing their procedure under neuraxial anesthesia had significantly lower rates of major complications than did patients who received combined neuraxial and general or general anesthesia (16.0%, 17.2%, and 18.1%, respectively; P = 0.0177). Adjusted risk of major complications for those undergoing surgery under neuraxial or combined neuraxial-general anesthesia compared with general anesthesia was also lower (odds ratio, 0.83 95% confidence interval, 0.74-0.93; P = 0.001 vs odds ratio, 0.90 95% confidence interval, 0.82-0.99; P = 0.03).
Barring contraindications, neuraxial anesthesia may convey benefits in the perioperative outcome of SA patients undergoing joint arthroplasty. Further research is needed to enhance an understanding of the mechanisms by which neuraxial anesthesia may exert comparatively beneficial effects.
The use of total joint arthroplasties is increasing worldwide. In this work we aim to elucidate recent trends in demographics and perioperative outcomes of patients undergoing total hip (THA) or ...total knee arthroplasty (TKA).
Data from the US Nationwide Impatient Sample between 1998 and 2008 were gathered for primary THAs and TKAs. Trends in patient age, comorbidity burden, length of hospitalization, frequency of major perioperative complications, and in-hospital mortality were analyzed. In-hospital outcomes were reported as events per 1000 inpatient days to account for changes in length of hospitalization over time. Deyo index, discharge status, and the interaction effect of time and discharge status were included in the adjusted trend analysis for morbidity.
Between 1998 and 2008, the average age of patients undergoing TKA and THA decreased by 2 to 3 years (P < 0.001). The average length of stay decreased by approximately 1 day over the time interval studied (P < 0.001). The percentage of patients being discharged home declined from 29.7% to 25.4% after TKA and from 29.3% to 24.2% after THA, in favor of dispositions to long- and short-term care facilities (P < 0.0001). Comorbidity burden as measured by the Deyo comorbidity index increased by 35% and 30% for TKA and THA patients, respectively (P < 0.0001). After TKA, there was an increase in the incidence of the following major complications: pulmonary embolism (coefficient estimate CE 0.069; 95% confidence interval CI, 0.059-0.079; P < 0.0001), sepsis (CE 0.034; 95% CI, 0.014-0.054; P = 0.001), nonmyocardial infarction cardiac complications (CE 0.038; 95% CI, 0.035-0.041; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.031-0.047; P < 0.0001). After THA, there was an increase in the incidence of the following major complications: pulmonary embolism (CE 0.031; 95% CI, 0.012-0.049; P = 0.001), sepsis (CE 0.060; 95% CI, 0.039-0.081; P < 0.0001), nonmyocardial infarction cardiac complications (CE 0.040; 95% CI, 0.036-0.043; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.029-0.048). In-hospital mortality declined after both TKA (CE -0.059; 95% CI, -0.077 to -0.040; P < 0.0001) and THA (CE -0.068; 95% CI, -0.086 to -0.051; P < 0.0001).
Between 1998 and 2008, trends show increases in several major in-hospital complications after THA and TKA, including pulmonary embolism, sepsis, nonmyocardial infarction cardiac complications, and pneumonia. Despite the increase in complications, declining in-hospital mortality was noted over this period.
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