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There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines. Granulocyte macrophage progenitors (GMPs) expressed the ß2 adrenergic receptor, a target of catecholamines. Ablation of splenic sympathetic neuronal signaling using surgical, chemical, and genetic approaches diminished GMP proliferation and myeloid cell development. Finally, mice lacking TH-producing leukocytes had reduced GMP proliferation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini promote GMP proliferation and myeloid cell development.
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Diabetes Mellitus/fisiopatología , Células Progenitoras de Granulocitos y Macrófagos/citología , Células Progenitoras de Granulocitos y Macrófagos/metabolismo , Mielopoyesis , Neuroinmunomodulación , Sistema Nervioso Simpático/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus/sangre , Modelos Animales de Enfermedad , Femenino , Humanos , Leucocitos/enzimología , Leucocitos/metabolismo , Masculino , Ratones , Células Mieloides/citología , Mielopoyesis/efectos de los fármacos , Neuroinmunomodulación/efectos de los fármacos , Norepinefrina/sangre , Transducción de Señal/efectos de los fármacos , Bazo/citología , Bazo/inervación , Bazo/metabolismo , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
There is an urgent and unmet clinical need to develop non-pharmacological interventions for chronic pain management due to the critical side effects of opioids. Low-intensity transcranial focused ultrasound is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly-focused 128-element ultrasound transducer to specifically target small mouse brains, employing dynamic focus steering. We demonstrate that transcranial focused ultrasound stimulation at pain processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (e.g., insula) and multi-session focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitive- and chronic hyperalgesia-associated neural signals following focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting inter-experiment intervals, and investigating effects on age, gender, genotype, and in a head-fixed awake model. Importantly, transcranial focused ultrasound was found to be safe, causing no adverse effects on motor function and brain's neuropathology. In conclusion, the validated proof of principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects.
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ABSTRACT: Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in sickle cell disease (SCD). Anemia, induced by chronic persistent hemolysis, is associated with the progressive deterioration of renal health, resulting in CKD. Moreover, patients with SCD experience acute kidney injury (AKI), a risk factor for CKD, often during vaso-occlusive crisis associated with acute intravascular hemolysis. However, the mechanisms of hemolysis-driven pathogenesis of the AKI-to-CKD transition in SCD remain elusive. Here, we investigated the role of increased renovascular rarefaction and the resulting substantial loss of the vascular endothelial protein C receptor (EPCR) in the progressive deterioration of renal function in transgenic SCD mice. Multiple hemolytic events raised circulating levels of soluble EPCR (sEPCR), indicating loss of EPCR from the cell surface. Using bone marrow transplantation and super-resolution ultrasound imaging, we demonstrated that SCD mice overexpressing EPCR were protective against heme-induced CKD development. In a cohort of patients with SCD, plasma sEPCR was significantly higher in individuals with CKD than in those without CKD. This study concludes that multiple hemolytic events may trigger CKD in SCD through the gradual loss of renovascular EPCR. Thus, the restoration of EPCR may be a therapeutic target, and plasma sEPCR can be developed as a prognostic marker for sickle CKD.
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Anemia de Células Falciformes , Receptor de Proteína C Endotelial , Hemo , Ratones Transgénicos , Insuficiencia Renal Crónica , Animales , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/sangre , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/etiología , Receptor de Proteína C Endotelial/metabolismo , Receptor de Proteína C Endotelial/genética , Ratones , Hemo/metabolismo , Humanos , Masculino , Femenino , Hemólisis , Riñón/metabolismo , Riñón/patologíaRESUMEN
OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.
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Eosinófilos , Factor de Crecimiento Similar a EGF de Unión a Heparina , Interleucina-4 , Regeneración Hepática , Macrófagos , Daño por Reperfusión , Animales , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Regeneración Hepática/fisiología , Daño por Reperfusión/metabolismo , Interleucina-4/metabolismo , Ratones , Eosinófilos/metabolismo , Macrófagos/metabolismo , Hígado/patología , Hígado/metabolismo , Hígado/irrigación sanguínea , Hepatocitos/metabolismo , Interleucina-13/metabolismo , Traslado Adoptivo , Ratones Endogámicos C57BLRESUMEN
Although progression-free survival (PFS) is a commonly used surrogate end-point for clinical trials of follicular lymphoma (FL), no analyses have evaluated the strength of surrogacy for PFS with overall survival (OS). A systematic review was performed and 20 studies (total participants, 10 724) met final inclusion criteria. PFS was weakly associated with OS (correlation coefficient; 0.383, p < 0.001). The coefficient of determination was 0.15 (95% CI: 0.002-0.35) suggesting 15% of OS variance could be explained by changes in PFS. This challenges the role for PFS as a surrogate end-point for clinical trials and drug approvals.
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Linfoma Folicular , Supervivencia sin Progresión , Linfoma Folicular/mortalidad , Linfoma Folicular/terapia , Humanos , BiomarcadoresRESUMEN
BACKGROUND & AIMS: This study aims to reevaluate upper reference limit (URL) for alanine aminotransferase (ALT) by considering the changing epidemiology of major liver diseases. We employed histological and metabolic parameters in Asian living liver donors. METHODS: We performed a retrospective analysis of 5455 potential living liver donors from 2005 to 2019. Participants were screened for hepatitis B, C, HIV, and alcohol use. Histologically and metabolically healthy participants were assessed using the Prati criteria (body mass index <23 kg/m2, triglyceride ≤200 mg/dL, fasting glucose ≤105 mg/dL, total cholesterol ≤220 mg/dL). The updated ALT-URL was determined as the 95th percentile among participants without hepatic steatosis and who met the Prati criteria. RESULTS: The median age was 30 years, with a male predominance (66.2%). Among 5455 participants, 3162 (58.0%) showed no hepatic steatosis, with 1553 (49.1%) meeting both the criteria for no steatosis and the Prati criteria for metabolic health. The updated URL for ALT in these participants was 34 U/L for males and 22 U/L for females, which was significantly lower than conventionally accepted values. Using this revised ALT-URL, 72.8% of males with ALT levels ≥34 U/L and 55.0% of females with ALT levels ≥22 U/L showed signs of steatosis, whereas 32.7% of males and 22.2% of females met the criteria for metabolic syndrome. CONCLUSIONS: Our study provided the newly established reference intervals for ALT levels in a metabolically and histologically verified Asian population. The proposed URL for ALT are 34 U/L and 22 U/L for males and females, respectively.
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BACKGROUND AND AIMS: Whether tenofovir or entecavir has different effects on the prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in secondary and tertiary preventive settings is still a matter of debate. This study aimed to compare the long-term prognosis of HCC between tenofovir and entecavir in patients with chronic hepatitis B. METHODS: Chronic hepatitis B patients diagnosed with HCC between November 2008 and December 2018 and treated with either entecavir or tenofovir at a tertiary center in Korea were included. The effect of tenofovir compared with entecavir on the prognosis of HBV-related HCC was assessed using multivariable-adjusted Cox and propensity score (PS)-matched analyses. Various predefined subgroup analyses were conducted. RESULTS: During a median follow-up period of 3.0 years, the mortality rate for entecavir-treated patients (n = 3469) was 41.2%, while tenofovir-treated patients (n = 3056) had a mortality rate of 34.6%. Overall survival (OS) was better in the tenofovir group (adjusted hazard ratio [aHR], 0.79; P < .001), which were consistently observed in the PS-matched analysis. The magnitude of the risk difference in OS was more prominent 2 years after the diagnosis of HCC (aHR, 0.50; P < .001) than 2 years before (aHR, 0.88; P = .005), and it was more pronounced in patients with earlier HCC stages. In all subgroups, except for those with shorter life expectancy, such as those with compromised liver function, tenofovir was associated with better OS compared with entecavir. CONCLUSIONS: Among patients with HBV-related HCC, those treated with tenofovir had a better prognosis than those treated with entecavir, particularly among those with prolonged survival.
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The global threat posed by the COVID-19 pandemic has catalyzed the development of point-of-care (POC) molecular diagnostics. While loop-mediated isothermal amplification (LAMP) stands out as a promising technique among FDA-approved methods, it is occasionally susceptible to a high risk of false positives due to nonspecific amplification of a primer dimer. In this work, we report an enhancing LAMP technique in terms of assay sensitivity and reliability through streamlined integration with a nonpowered nanoelectric preconcentration (NPP). The NPP, serving as a sample preparation tool, enriched the virus concentration in samples prior to the subsequent LAMP assay. This enrichment enabled not only to achieve more sensitive assay but also to shorten the assay time for all tested clinical samples by â¼10 min compared to the conventional LAMP. The shortened assay time suppresses the occurrence of nonspecific amplification by not providing the necessary incubation time, effectively suppressing misidentification by false positives. Utilizing this technique, we also developed a prototype of the POC NPP-LAMP kit. This kit offers a streamlined diagnostic process for nontrained individuals, from the sample enrichment, transfer of the enriched sample to LAMP assays, which facilitates on-site/on-demand diagnosis of SARS-CoV-2. This development holds the potential to contribute toward preventing not only the current outbreak but also future occurrences of pandemic viruses.
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COVID-19 , Pandemias , Humanos , Reproducibilidad de los Resultados , Técnicas de Diagnóstico Molecular/métodos , COVID-19/diagnóstico , Técnicas de Amplificación de Ácido Nucleico/métodos , Sensibilidad y Especificidad , ARN ViralRESUMEN
In a sheared steady state, glasses reach a nonequilibrium criticality called yielding criticality. We report that the qualitative nature of this nonequilibrium critical phenomenon depends on the details of the system and that responses and fluctuations are governed by different critical correlation lengths in specific situations. This scale separation of critical lengths arises when the screening of elastic propagation of mechanical signals is not negligible. We also discuss the determinant of the impact of screening effects from the viewpoint of the microscopic dissipation mechanism.
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BACKGROUND & AIMS: Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. RESULTS: The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. CONCLUSIONS: The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.
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Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/uso terapéutico , Metástasis Linfática , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Pulmón , Microambiente TumoralRESUMEN
BACKGROUND: The World Health Organization (WHO) has set targets to eliminate viral hepatitis, including hepatitis C virus (HCV) infection, by 2030. We present the results of the in-hospital Reflex tEsting ALarm-C (REAL-C) model, which incorporates reflex HCV RNA testing and sending alerts to physicians. METHODS: We conducted a retrospective study analysing the data of 1730 patients who newly tested positive for anti-HCV between March 2020 and June 2023. Three distinct periods were defined: pre-REAL-C (n = 696), incomplete REAL-C (n = 515) and complete REAL-C model periods (n = 519). The primary outcome measure was the HCV RNA testing rate throughout the study period. Additionally, we assessed the referral rate to the gastroenterology department, linkage time for diagnosis and treatment and the treatment rate. RESULTS: The rate of HCV RNA testing increased significantly from 51.0% (pre-REAL-C) to 95.6% (complete REAL-C). This improvement was consistent across clinical departments, regardless of patients' comorbidities. Among patients with confirmed HCV infection, the gastroenterology referral rate increased from 57.1% to 81.1% after the REAL-C model. The treatment rate among treatment-eligible patients was 92.4% during the study period. The mean interval from anti-HCV positivity to HCV RNA testing decreased from 45.1 to 1.9 days. The mean interval from the detection of anti-HCV positivity to direct-acting antiviral treatment also decreased from 89.5 to 49.5 days with the REAL-C model. CONCLUSION: The REAL-C model, featuring reflex testing and physician alerts, effectively increased HCV RNA testing rates and streamlined care cascades. Our model facilitated progress towards achieving WHO's elimination goals for HCV infection.
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Hepatitis C Crónica , Hepatitis C , Humanos , Hepacivirus/genética , Antivirales/uso terapéutico , Estudios Retrospectivos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hospitales , ARN ViralRESUMEN
BACKGROUND AND AIM: The steatosis-associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy-proven SLD and in different subgroups according to age, sex, and body mass index. METHODS: We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy-proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 index (FIB-4). RESULTS: The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low-risk" SAFE score was the highest (91.0%), followed by those with "intermediate-risk" (7.8%) and "high-risk" (1.2%) scores. The prevalence of fibrosis in subjects with low-risk, intermediate-risk, and high-risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB-4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB-4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30-39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99). CONCLUSION: While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited.
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Cholesterol (Chol) plays a crucial role in shaping the intricate physicochemical attributes of biomembranes, exerting a considerable influence on water molecules proximal to the membrane interface. In this study, we conducted molecular dynamics simulations on the bilayers of two lipid species, dipalmitoylphosphatidylcholine (DPPC) and palmitoyl sphingomyelin; they are distinct with respect to the structures of the hydrogen-bond (H-bond) acceptors. Our investigation focuses on the dynamic properties and H-bonds of water molecules in the lipid-membrane systems, with a particular emphasis on the influence of Chol at varying temperatures. Notably, in the gel phase at 303 K, the presence of Chol extends the lifetimes of H-bonds of the oxygen atoms acting as H-bond acceptors within DPPC with water molecules by a factor of 1.5-2.5. In the liquid-crystalline phase at 323 K, on the other hand, H-bonding dynamics with lipid membranes remain largely unaffected by Chol. This observed shift in H-bonding states serves as a crucial key to unraveling the subtle control mechanisms governing water dynamics in lipid-membrane systems.
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The present work shows that the free energy landscape associated with alanine dipeptide isomerization can be effectively represented by specific interatomic distances without explicit reference to dihedral angles. Conventionally, two stable states of alanine dipeptide in vacuum, i.e., C7eq (ß-sheet structure) and C7ax (left handed α-helix structure), have been primarily characterized using the main chain dihedral angles, φ (C-N-Cα-C) and ψ (N-Cα-C-N). However, our recent deep learning combined with the "Explainable AI" (XAI) framework has shown that the transition state can be adequately captured by a free energy landscape using φ and θ (O-C-N-Cα) [Kikutsuji et al., J. Chem. Phys. 156, 154108 (2022)]. In the perspective of extending these insights to other collective variables, a more detailed characterization of the transition state is required. In this work, we employ interatomic distances and bond angles as input variables for deep learning rather than the conventional and more elaborate dihedral angles. Our approach utilizes deep learning to investigate whether changes in the main chain dihedral angle can be expressed in terms of interatomic distances and bond angles. Furthermore, by incorporating XAI into our predictive analysis, we quantified the importance of each input variable and succeeded in clarifying the specific interatomic distance that affects the transition state. The results indicate that constructing a free energy landscape based on the identified interatomic distance can clearly distinguish between the two stable states and provide a comprehensive explanation for the energy barrier crossing.
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We investigated methods for cryopreserving sperm from the endangered gudgeon, Microphysogobio rapidus, by examining the effects of cryoprotective agent (CPA) concentration, diluent, and dilution ratio on post-thaw sperm quality. The quality of frozen sperm was evaluated in terms of motility and kinematic parameters, viability, DNA damage, and fertilization rate. We evaluated methanol, glycerol, dimethyl sulfoxide (DMSO), and ethylene glycol as CPAs. Sperm motility, velocity, and viability were significantly higher when methanol was used as the CPA (p < 0.05). The diluents tested were Ringer's solution, Kurokura's Extender, Common Carp Sperm Extender (CCSE), and buffered sperm motility-inhibiting saline solution (BSMIS); post-thaw motility was highest when Ringer's solution was used as the diluent. Next, various quantities of methanol were combined with Ringer's solution to identify the optimal dose of methanol. The dilution ratios tested ranged from 1:1 to 1:7. Cryopreserved sperm was thawed at 20 °C for 15 s. The use of 10% methanol with Ringer's solution at a dilution ratio of 1:5 resulted in the highest post-thaw sperm motility, viability, and velocity including VAP, VCL, and VSL. Post-thaw sperm showed significantly greater DNA damage than the control (fresh sperm) (p < 0.05). The fertilization rate was highest with fresh sperm (p < 0.05), followed by sperm frozen with 10% methanol + Ringer's solution. We recommend that the best way to preserve sperm in the studied species is to use a combination of Ringer's solution and 10% methanol at a 1:5 dilution ratio. Our findings will facilitate the artificial fertilization of M. rapidus.
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Criopreservación , Crioprotectores , Cyprinidae , Dimetilsulfóxido , Metanol , Preservación de Semen , Motilidad Espermática , Espermatozoides , Animales , Masculino , Criopreservación/métodos , Criopreservación/veterinaria , Crioprotectores/farmacología , Preservación de Semen/métodos , Preservación de Semen/veterinaria , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Cyprinidae/fisiología , Metanol/farmacología , Dimetilsulfóxido/farmacología , Glicerol/farmacología , Glicol de Etileno/farmacología , Daño del ADN/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , FemeninoRESUMEN
BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as Hunt and Hess (HH) grades IV and V, is a challenging disease because of its high mortality and poor functional outcomes. The effectiveness of bundled treatments has been demonstrated in critical diseases. Therefore, poor-grade aSAH bundled treatments have been established. This study aims to evaluate whether bundled treatments can improve long-term outcomes and mortality in patients with poor-grade aSAH. METHODS: This is a comparative study using historical control from 2008 to 2022. Bundled treatments were introduced in 2017. We compared the rate of favorable outcomes (modified Rankin Scale score 0-2) at 6 months and mortality before and after the introduction of the bundled treatments. To eliminate confounding bias, the propensity score matching method was used. RESULTS: A total of 90 consecutive patients were evaluated. Forty-three patients received bundled treatments, and 47 patients received conventional care. The proportion of patients with HH grade V was higher in the bundle treatment group (41.9% vs. 27.7%). Conversely, the proportion of patients with fixed pupils on the initial examination was higher in the conventional group (30.2% vs. 38.3%). After 1:1 propensity score matching, 31 pairs were allocated to each group. The proportion of patients with 6-month favorable functional outcomes was significantly higher in the bundled treatments group (46.4% vs. 20.7%, p = 0.04). The 6-month mortality rate was 14.3% in the bundled treatments group and 27.3% in the conventional group (p = 0.01). Bundled treatments (odd ratio 14.6 [95% confidence interval 2.1-100.0], p < 0.01) and the presence of an initial pupil reflex (odd ratio 12.0 [95% confidence interval 1.4-104.6], p = 0.02) were significantly associated with a 6-month favorable functional outcome. CONCLUSIONS: The bundled treatments improve 6-month functional outcome and mortality in patients with poor-grade aSAH.
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Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/diagnóstico , Resultado del Tratamiento , Puntaje de PropensiónRESUMEN
PURPOSE: To assess serial changes of preoperative bone marrow lesion (BML) following medial open-wedge high tibial osteotomy (MOWHTO) up to 2 years and evaluate whether postoperative change of BML affected patient-reported outcome measures (PROMs) at 2 years' follow-up. Factors related to the postoperative changes in BML also were evaluated. METHODS: The current study retrospectively assessed prospectively collected data of consecutive patients between December 2016 and March 2018 who underwent MOWHTO for symptomatic knee osteoarthritis with varus malalignment (≥5°) and a minimum 2-year follow-up. Serial magnetic resonance imaging scans at preoperative and postoperative 3, 6, 18, and 24 months were performed, and the extent of BML was evaluated consecutively using 2 validated methods. Clinically, preoperative and postoperative PROMs and their achievement of minimal clinically important difference values were evaluated. The associations of the extent of BMLs with PROMs at each follow-up period over time were analyzed using a linear mixed model. Furthermore, factors related to the postoperative changes of BML were assessed. RESULTS: Of 26 patients, 21 (80.8%) had preoperative BML at medial femoral and tibial condyles. The postoperative decrease in BML was noted in 17 (81.0%) and 18 (85.7%) at medial femoral and tibial condyles. The BML decreased at postoperative 3 months and, thereafter, the extent of BML gradually reduced until postoperative 24 months. The proportion of patients achieved minimal clinically important difference was 84.6% for total Western Ontario and McMaster Universities Osteoarthritis Index scores and 80.8%, 76.9%, and 84.6% for KOOS symptom, pain, and activity of daily living subscales. Postoperative decrease in BML was significantly associated with better PROMs over postoperative 24 months. Furthermore, normo-correction (2°-5° valgus) was a significant factor for decreased BML following MOWHTO. CONCLUSIONS: Preoperative BML gradually decreased with time following MOWHTO, and the postoperative decrease in BML related with better PROMs over postoperative 24 months. Moreover, postoperative valgus alignment was a significant factor relating the postoperative decrease of BML. LEVEL OF EVIDENCE: Level IV, retrospective case series.
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INTRODUCTION: Amid a national opioid epidemic, it is essential to review the necessity of opioid prescriptions. Research in adults has demonstrated patients often do not use their entire postoperative opioid prescription. Limited data suggest that the trend is similar in children. This study investigated the prescription volume and postoperative utilization rate of opioids among pediatric orthopaedic surgery patients at our institution. METHODS: We identified pediatric patients (ages below 18 y old) who presented to our institution for operating room intervention from May 24, 2021, to December 13, 2021. Patient demographics and opioid prescription volume were recorded. Parents and guardians were surveyed by paper "opioid diary" or phone interview between postoperative days 10 to 15, assessing pain level, opioid use, and plans for remaining opioid doses. Wilcoxon rank-sum test, Independent t test, and Pearson correlation were used for the analysis of continuous variables. Multivariable logistic regression was used to control for patient demographic variables while analyzing opioid usage relationships. RESULTS: Prescription volume information was collected for 280 patients during the study period. We were able to collect utilization information for 102 patients (Group 1), whereas the remaining 178 patients contributed only prescription volume data (Group 2). Patients with upper extremity fractures received significantly fewer opioid doses at discharge compared with other procedure types ( P =0.036). Higher BMI was positively correlated with more prescribed opioid doses ( R2 =0.647, P <0.001). The mean opioid utilization rate was 22.37%. A total of 50.6% of patients prescribed opioids at discharge used zero doses. A total of 96.2% of patients used opioids for 5 days or less. Most families had not disposed of excess medication by postoperative day 10. CONCLUSIONS: We found significant differences in opioid prescribing practices based on patient and procedure-specific variables. In addition, although our pediatric orthopaedic surgery patients had low overall rates of postoperative opioid utilization, there was significant variation in opioid use among procedure types. These results provide insights that can guide opioid prescribing practices for pediatric orthopaedic patients and promote patient education to ensure safe opioid disposal.
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Trastornos Relacionados con Opioides , Procedimientos Ortopédicos , Ortopedia , Adulto , Niño , Humanos , Analgésicos Opioides/uso terapéutico , Prescripciones de Medicamentos , Dolor Postoperatorio/tratamiento farmacológico , Pautas de la Práctica en MedicinaRESUMEN
An efficient design method for a compact and ultra-wideband multi-stage Wilkinson power divider in a parallel stripline (PSL) is proposed. To enhance the frequency bandwidth of the proposed power divider while reducing its size, the isolation branch is modified; that is, two capacitors are connected to both sides of a resistor at each isolation branch. For an efficient design process, the PSL power divider is equivalently represented by two microstrip power dividers, and the design equations are derived. Based on the design equations, an in-house algorithm is utilized to optimally determine the design parameters, including the line impedance, resistance, and capacitance of each stage. For example, a three-stage PSL power divider is designed with three λ/4 transmission lines at a base frequency of 5 GHz. To verify the accuracy of the design procedure, 3D EM simulations and measurements are performed, and the results show good agreement. Compared with the conventional three-stage Wilkinson power divider, the proposed PSL power divider achieves a wider frequency bandwidth of 1.16 to 6.51 GHz (139.5%) and a 23% shorter transmission line length of 207°, while exhibiting an insertion loss of 0.7 to 1.4 dB.
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A design method for an ultra-wideband coplanar-stripline-based vertical transition that can be used for ultra-high-speed digital interfaces is proposed. A conventional via structure, based on a differential line (DL), inherently possesses performance limitations (<10 GHz) due to difficulties in maintaining constant line impedance and smooth electric field transformation, in addition to the effects of signal skews, FR4 fiber weave, and unbalanced EM interferences. DL-based digital interfaces may not meet the demands of ultra-high-speed digital data transmission required for the upcoming 6G communications. The use of a coplanar stripline (CPS), a type of planar balanced line (BL), for the vertical transition, along with the ultra-wideband DL-to-CPS transition, mostly removes the inherent and unfavorable issues of the DL and enables ultra-high-speed digital data transmission. The design process of the transition is simplified using the analytical design formulas, derived using the conformal mapping method, of the transition. The characteristic line impedances of the transition are calculated and found to be in close agreement with the results obtained from EM simulations. Utilizing these results, the CPS-based vertical transition, maintaining the characteristic line impedance of 100 Ω, is designed and fabricated. The measured results confirm its ultra-wideband characteristics, with a maximum of 1.6 dB insertion loss and more than 10 dB return loss in the frequency range of DC to 30 GHz. Therefore, the proposed CPS-based vertical transition offers a significantly wider frequency bandwidth, i.e., more than three times that of conventional DL-based via structures.