The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFκB ...and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro-reconstitution studies suggested that RIPK1 displays distinct kinase activity-dependent and -independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1(-/-) mice, which die shortly after birth, Ripk1(D138N/D138N) mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid-induced necroptosis in vitro, and Ripk1(D138N/D138N) mice are protected from TNF-induced shock in vivo. Moreover, Ripk1(D138N/D138N) mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis.
Objectives/Hypothesis
To evaluate the voice and speech outcomes after tubed supraglottic laryngeal closure (TSLC) surgery to treat chronic aspiration after radiotherapy for head and neck cancer.
...Study Design
A retrospective case‐control study.
Methods
The data of patients who underwent radiotherapy for head and neck cancer and who later required total laryngectomy or TSLC for chronic aspiration between 2004 and 2017 were retrieved from a dysphagia clinic. Preoperative and postoperative voice and speech were assessed by the GRBAS and INFVo rating scales. Control subjects who underwent radiotherapy alone or total laryngectomy with a tracheoesophageal prosthesis for other indications were recruited for comparison.
Results
Of 15 patients who underwent a TSLC with a mean age of 57.3 years (45–75 years), 13 were male and 2 female. All patients had a history of nasopharyngeal carcinoma. The success rate of speech production using their own larynx following an intact TSLC was 64%. There was no statistically significant difference in voice and speech ratings between preoperative and TSLC subjects on the GRBAS (P = .32) and INFVo scales (P = .57), although the quality of voice appeared to deteriorate after TSLC. However, the INFVo scale for impression, intelligibility and unsteadiness of the voice after TSLC was statistically significantly better than for laryngectomy with tracheoesophageal speech.
Conclusions
A tubed supraglottic laryngeal closure controls chronic aspiration while preserving the larynx for phonation, and results in a better voice and speech quality than a laryngectomy with a voice prosthesis.
Level of Evidence
4 Laryngoscope, 131:E1616–E1623, 2021
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively ...differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced-MR imaging as potential discriminative tools.
We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced-MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADC
and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations.
The enhancing component of primary CNS lymphoma was found to have significantly lower ADC
(1.1 × 10
versus 1.4 × 10
;
< .001) and relative ADC
(1.5 versus 1.9;
< .001) and relative 90th percentile values for plasma volume (3.7 versus 5.0;
< .05) than the enhancing component of glioblastoma, but not significantly different relative 90th percentile values for the permeability transfer constant (5.4 versus 4.4;
= .83). The nonenhancing portions of glioblastoma and primary CNS lymphoma did not differ in these parameters. On the basis of receiver operating characteristic analysis, mean ADC provided the best threshold (area under the curve = 0.83) to distinguish primary CNS lymphoma from glioblastoma, which was not improved with normalized ADC or the addition of perfusion parameters.
ADC was superior to dynamic contrast-enhanced-MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma.
Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals in many Asian countries. Recent emergence of community-associated (CA) MRSA worldwide has added another serious ...concern to the epidemiology of S. aureus infections. To understand the changing epidemiology of S. aureus infections in Asian countries, we performed a prospective, multinational surveillance study with molecular typing analysis.
We evaluated the prevalence of methicillin resistance in S. aureus isolates in CA and healthcare-associated (HA) infections, and performed molecular characterization and antimicrobial susceptibility tests of MRSA isolates.
MRSA accounted for 25.5% of CA S. aureus infections and 67.4% of HA infections. Predominant clones of CA-MRSA isolates were ST59-MRSA-SCCmec type IV-spa type t437, ST30-MRSA-SCCmec type IV-spa type t019 and ST72-MRSA-SCCmec type IV-spa type t324. Previously established nosocomial MRSA strains including sequence type (ST) 239 and ST5 clones were found among CA-MRSA isolates from patients without any risk factors for HA-MRSA infection. CA-MRSA clones such as ST59, ST30 and ST72 were also isolated from patients with HA infections.
Our findings confirmed that MRSA infections in the community have been increasing in Asian countries. Data also suggest that various MRSA clones have spread between the community and hospitals as well as between countries.
Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health ...(NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.
Abstract There has been a dramatic rise in gene×environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer ...promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene–environment interactions across development in humans.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically ...diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Tricuspid regurgitation (TR) is a common and important comorbidity in patients with postoperative right ventricular outflow tract (RVOT) obstruction or pulmonary regurgitation ...(PR). Transcatheter pulmonary valve replacement (TPVR) has become a useful tool in the management of postoperative RVOT obstruction and PR, but it is unknown whether relief of the right ventricular volume and/or pressure overload by TPVR will have a beneficial effect on TR, as is often seen with surgical pulmonary valve replacement. Objectives This study sought to assess the prevalence of and factors associated with significant TR in patients undergoing TPVR for RVOT obstruction or PR. Methods Data were combined from 3 prospective multicenter trials of patients referred for TPVR. Follow-up data through 5 years post-implantation were analyzed. Results Of 300 patients studied, 77 (25.6%) had moderate or severe TR at baseline. After TPVR, TR severity was improved in 65% of those patients, and more than one-half had mild TR or less TR at discharge. Of 13 patients with severe TR pre-implantation, only 1 had severe TR at 1-year follow-up and beyond. Moderate or severe baseline TR was associated with shorter freedom from RVOT reintervention after TPVR. Conclusions In this prospective multicenter study of post-operative patients with RVOT obstruction and/or PR, TR was common. In patients with significant baseline TR, TPVR resulted in clinically relevant acute reductions in TR that persisted over at least 5 years of follow-up. These observations support the application of TPVR therapy in patients with RVOT obstruction or PR who are anatomically suitable, even in the setting of significant concomitant TR.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
To investigate a novel velopharyngeal squeeze maneuver (VPSM) and novel endoscopic pharyngeal contraction grade (EPCG) scale for the evaluation of pharyngeal motor function.
Methods
During ...endoscopic examination of 77 post‐irradiated nasopharyngeal carcinoma patients and control subjects, VPSM was rated and lateral pharyngeal wall movement graded with EPCG scale during swallowing. Pharyngeal constriction ratio (PCR) measured by videofluoroscopy was used for correlation.
Results
VPSM and EPCG scale showed almost perfect intra‐rater and inter‐rater reliability (Kappa: >0.90). VPSM was present in 61% of patients suggesting good pharyngeal motor function. VPSM was predictive of EPCG scale (Wald statistic = 29.99, p < 0.001). EPCG scale also correlated strongly with PCR (r: 0.812) and was predictive for aspiration (odds ratio: 22.14 95% CI 5.01–97.89, p < 0.001).
Conclusions
VPSM and EPCG scale are two novel tools to assess pharyngeal motor function, and both correlate well with pharyngeal contractility and aspiration.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Molecular statics and dynamics simulations were performed to investigate the mechanical properties of a monolayer graphene sheet using an efficient energy method and strain-fluctuation method. Using ...the energy method, we observed that the mechanical properties of an infinite graphene sheet are isotropic, whereas for a finite sheet, they are anisotropic. This work is the first to report the temperature-dependent elastic constants of graphene between 100 and 1000 K using the strain-fluctuation method. We found that the out-of-plane thermal excursions in a graphene membrane lead to strong anharmonic behavior, which allows large deviations from isotropic elasticity. The computed Young's modulus and Poisson's ratio of a sheet with an infinite spatial extent are 0.939 TPa and 0.223, respectively. We also found that graphene sheets with both finite and infinite spatial extent satisfy the Born elastic stability conditions. We extracted the variation in bending modulus with the system size at zero kelvin (0.83 eV) using a formula derived from the Foppl-von Karman approach. When the temperature increases, the Young's modulus of the sample decreases, which effectively reduces the longitudinal and shear wave velocities.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
PDF
