Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells ...predominantly express the CD8α coreceptor (CD8⁺), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8α represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8⁺ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORγt/T-bet ratio, and express less IFN-γ and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8⁺ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8⁺ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8⁺ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8⁺ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship.
Spontaneous swallowing frequency has been described as an index of dysphagia in various health conditions. This study evaluated the potential of spontaneous swallow frequency analysis as a screening ...protocol for dysphagia in acute stroke.
In a cohort of 63 acute stroke cases, swallow frequency rates (swallows per minute SPM) were compared with stroke and swallow severity indices, age, time from stroke to assessment, and consciousness level. Mean differences in SPM were compared between patients with versus without clinically significant dysphagia. Receiver operating characteristic curve analysis was used to identify the optimal threshold in SPM, which was compared with a validated clinical dysphagia examination for identification of dysphagia cases. Time series analysis was used to identify the minimally adequate time period to complete spontaneous swallow frequency analysis.
SPM correlated significantly with stroke and swallow severity indices but not with age, time from stroke onset, or consciousness level. Patients with dysphagia demonstrated significantly lower SPM rates. SPM differed by dysphagia severity. Receiver operating characteristic curve analysis yielded a threshold of SPM≤0.40 that identified dysphagia (per the criterion referent) with 0.96 sensitivity, 0.68 specificity, and 0.96 negative predictive value. Time series analysis indicated that a 5- to 10-minute sampling window was sufficient to calculate spontaneous swallow frequency to identify dysphagia cases in acute stroke.
Spontaneous swallowing frequency presents high potential to screen for dysphagia in acute stroke without the need for trained, available personnel.
Background
Pharyngeal swallowing power (PSP) is a novel measure of pharyngeal bolus‐driving function derived from fluid dynamics principles. This study examined the impact of bolus volume and ...viscosity on PSP to determine bolus effects on pharyngeal bolus dynamics. The impact of bolus accommodation and physical characteristics of boluses were also explored.
Methods
Thirty‐four healthy subjects swallowed materials consisting of two bolus volumes (10 and 20 mL) and four bolus viscosities (thin liquid, nectar‐thick liquid, honey‐thick liquid and pudding). High‐resolution impedance manometry was used for data collection. The pharyngeal swallowing mechanism was conceptualized as a hydraulic power system with the UES as a conduit, and PSP was calculated as the product of bolus pressure and flow across the UES. The impact of bolus characteristics on PSP was evaluated using a mixed model approach.
Key Results
Both bolus volume (F1,32.8 = 412.73, P < 0.0001) and viscosity (F3,84.7 = 28.94, P < 0.0001) were significant predictors of PSP. PSP for 20 mL bolus volume was greater than for 10 mL bolus volume. PSP was lowest in the thin liquid bolus condition and highest in the pudding bolus. All pairwise comparisons among bolus viscosities were significant except between thin liquid and nectar‐thick liquid bolus viscosities. Test of linear trend across bolus viscosities was significant (F1,97.2 = 77.25, P < 0.0001).
Conclusions & Inferences
Pharyngeal swallowing power variation across bolus conditions illustrates bolus‐related changes in bolus dynamics. Bolus effects on PSP likely result from physiological bolus accommodation combined with physical characteristics of boluses.
This study examined the impact of bolus volume and viscosity on pharyngeal swallowing power (PSP) to determine bolus effects on pharyngeal bolus dynamics. PSP variation across bolus conditions illustrates bolus‐related changes in bolus dynamics. Bolus effects on PSP likely result from physiological bolus accommodation combined with physical characteristics of boluses.
To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, ...progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction.
Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared.
We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09–1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04–1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00–3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00–1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups.
In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities.
Clintrials.gov: NCT00011986
•Age ≥ 70 years was associated with an increased risk of both cancer-related and non-cancer related death.•Carboplatin and paclitaxel administration is well tolerated regardless of age.•Older age was associated with higher rates of grade 2 or higher peripheral neuropathy.•Risks of other chemotherapy related toxicities were equal between older compared to younger patients.
The COVID-19 pandemic has highlighted and amplified family caregiving obligations for many clinical investigators and other biomedical researchers. Unpredictable access to daycare, schools, assisted ...living facilities, informal networks, and other sources of care of children, older adults, or those with special needs has been harrowing. The National Academies of Science, Engineering, and Medicine emphasized such challenges will impair the vitality of the scientific workforce, calling for research and action to bolster resources for those facing family caregiving responsibilities as they pursue careers in fields that include academic medicine. In the US, where social policies addressing needs of workers with families are less robust than elsewhere in the world, engagement in demanding professional pursuits was challenging before the pandemic. Lack of family-friendly policies has a disparate impact on single parents and women, who are more likely to shoulder family caregiving responsibilities due to persistent gendered societal norms and expectations; the result is limited access of professions like medicine to the full talent pool.
This paper demonstrates a methodology for micromixing that is sufficiently simple that it can be used in portable microfluidic devices. It illustrates the use of the micromixer by incorporating it ...into an elementary, portable microfluidic system that includes sample introduction, sample filtration, and valving. This system has the following characteristics: (i) it is powered with a single hand-operated source of vacuum, (ii) it allows samples to be loaded easily by depositing them into prefabricated wells, (iii) the samples are filtered in situ to prevent clogging of the microchannels, (iv) the structure of the channels ensure mixing of the laminar streams by interaction with bubbles of gas introduced into the channels, (v) the device is prepared in a single-step soft-lithographic process, and (vi) the device can be prepared to be resistant to the adsorption of proteins, and can be used with or without surface-active agents.
Objective
This study compared the immediate impact of different transcutaneous electrical stimulation (TES) amplitudes on physiological swallowing effort in healthy older adults versus young adults.
...Background
Swallowing physiology changes with age. Reduced physiological swallowing effort in older adults including lower lingua‐palatal and pharyngeal pressures may increase risk for swallowing dysfunction (i.e. dysphagia). Transcutaneous electrical stimulation (TES) has been advocated as an adjunctive modality to enhance outcomes in exercise‐based therapy for individuals with dysphagia. However, significant variation in how TES is applied during therapy remains and the physiological swallowing response to TES is poorly studied, especially in older adults.
Materials and methods
Physiological change in swallowing associated with no stimulation, sensory stimulation and motor stimulation was compared in 20 young adults versus 14 older adults. Lingua‐palatal and pharyngeal manometric pressures assessed physiological swallowing effort.
Results
Multivariate analyses identified interactions between age and stimulation amplitude on lingual and pharyngeal functions. Motor stimulation reduced anterior tongue pressure in both age groups but selectively reduced posterior lingua‐palatal pressures in young adults only. Sensory stimulation increased base of tongue (BOT) pressures in older adults but decreased BOT pressures in young adults. Motor stimulation increased hypopharyngeal pressures in both groups.
Conclusion
Age and TES level interact in determining immediate physiological responses on swallow performance. A one‐size‐fit‐all approach to TES in dysphagia rehabilitation may be misdirected.
Excessive nuclear or mitochondrial DNA damage can lead to mitochondrial dysfunction, decreased energy production, and increased generation of reactive oxygen species (ROS). Although numerous cell ...signaling pathways are activated when cells are injured, the ataxia telangiectasia mutant (ATM) protein has emerged as a major regulator of the response to both mitochondrial dysfunction and nuclear DNA double-strand breaks (DSBs). Because mitochondrial dysfunction is often a response to excessive DNA damage, it has been difficult to determine whether nuclear and/or mitochondrial DNA DSBs activate ATM independent of mitochondrial dysfunction. In this study, mitochondrial and nuclear DNA DSBs were generated in the A549 human lung adenocarcinoma cell line by infecting with retroviruses expressing the restriction endonuclease PstI fused to a mitochondrial targeting sequence (MTS) or nuclear localization sequence (NLS) and a hemagglutinin antigen epitope tag (HA). Expression of MTS-PstI-HA or NLS-PstI-HA activated the DNA damage response defined by phosphorylation of ATM, the tumor suppressor protein p53 (TP53), KRAB-associated protein (KAP)-1, and structural maintenance of chromosomes (SMC)-1. Phosphorylated ATM and SMC1 were detected in nuclear fractions, whereas phosphorylated TP53 and KAP1 were detected in both mitochondrial and nuclear fractions. PstI also enhanced expression of the cyclin-dependent kinase inhibitor p21 and inhibited cell growth. This response to DNA damage occurred in the absence of detectable mitochondrial dysfunction and excess production of ROS. These findings reveal that DNA DSBs are sufficient to activate ATM independent of mitochondrial dysfunction and suggest that the activated form of ATM and some of its substrates are restricted to the nuclear compartment, regardless of the site of DNA damage.
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•Expression of PstI endonuclease created DNA double-strand breaks in mitochondrial and nuclear DNA of A549 cells.•PstI stimulated the DNA damage response defined by phosphorylation of ATM and TP53 and cell cycle arrest.•DNA double-strand breaks did not affect mitochondrial oxygen consumption or production of ROS.•DNA damage can activate ATM signaling independent of mitochondrial dysfunction.
Background
The primary function of the pharyngeal swallowing mechanism is to drive ingested materials into the esophagus. Currently, a definitive measure of pharyngeal bolus‐driving function that ...accounts for bolus movement remains lacking. The primary objectives of this study were to describe the derivation of a novel biofluid dynamics measure of deglutition—that is, pharyngeal swallowing power (PSP)—and to demonstrate the consistency of PSP in normal swallowing.
Methods
The pharyngeal swallowing mechanism was conceptualized as a hydraulic power system with the upper esophageal sphincter (UES) as a conduit. PSP was calculated as the product of bolus pressure and flow across the UES. Thirty‐four young healthy subjects swallowed materials consisting of two bolus volumes (10, 20 mL) and four bolus viscosities (thin liquid, nectar‐thick liquid, honey‐thick liquid, pudding). High‐resolution impedance manometry was used for data collection. The consistency of PSP across specific bolus conditions was evaluated using standardized Cronbach's coefficient alpha.
Key Results
Standardized Cronbach's coefficient alphas in specific bolus conditions ranged between 0.85 and 0.93. Fisher weighted mean Cronbach's coefficient alphas for swallow trials across bolus volumes and across bolus viscosities ranged from 0.86 to 0.90. Fisher weighted mean Cronbach's coefficient alpha for overall consistency of PSP across all swallow trials was 0.88.
Conclusions and Inferences
PSP estimates the output power of the pharyngeal bolus‐driving mechanism during deglutition. PSP's high consistency indicates that it can be a useful biofluid dynamics measure of pharyngeal bolus‐driving function. Current results also demonstrate that consistency in pharyngeal bolus propulsion is an important physiological target for the pharyngeal swallowing mechanism.
Pharyngeal swallowing power (PSP) estimates the output power of the pharyngeal bolus‐driving mechanism during deglutition. PSP's high consistency indicates that it can be a useful biofluid dynamics measure of pharyngeal bolus‐driving function. Current results also demonstrate that consistency in pharyngeal bolus propulsion is an important physiological target for the pharyngeal swallowing mechanism.
Background The aim of this study was to compare spontaneous swallow frequency analysis (SFA) with clinical screening protocols for identification of dysphagia in acute stroke. Methods In all, 62 ...patients with acute stroke were evaluated for spontaneous swallow frequency rates using a validated acoustic analysis technique. Independent of SFA, these same patients received a routine nurse-administered clinical dysphagia screening as part of standard stroke care. Both screening tools were compared against a validated clinical assessment of dysphagia for acute stroke. In addition, psychometric properties of SFA were compared against published, validated clinical screening protocols. Results Spontaneous SFA differentiates patients with versus without dysphagia after acute stroke. Using a previously identified cut point based on swallows per minute, spontaneous SFA demonstrated superior ability to identify dysphagia cases compared with a nurse-administered clinical screening tool. In addition, spontaneous SFA demonstrated equal or superior psychometric properties to 4 validated, published clinical dysphagia screening tools. Conclusions Spontaneous SFA has high potential to identify dysphagia in acute stroke with psychometric properties equal or superior to clinical screening protocols.
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