Predicting the Activation States of the Muscles Governing Upper Esophageal Sphincter Relaxation and Opening

Copyright © 2016 the American Physiological SocietyThe swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation and deactivation of neural inputs to these muscles, including the intrinsic cricopharyngeus (CP) and extrinsic submental (SM) muscles, results in their mechanical activation or deactivation, which changes the diameter of the lumen, alters the intraluminal pressure, and ultimately reduces or promotes flow of content. By measuring the changes in diameter, using intraluminal impedance, and the concurrent changes in intraluminal pressure, it is possible to determine when the muscles are passively or actively relaxing or contracting. From these “mechanical states” of the muscle, the neural inputs driving the specific motor behaviors of the UES can be inferred. In this study we compared predictions of UES mechanical states directly with the activity measured by electromyography (EMG). In eight subjects, pharyngeal pressure and impedance were recorded in parallel with CP- and SM-EMG activity. UES pressure and impedance swallow profiles correlated with the CP-EMG and SM-EMG recordings, respectively. Eight UES muscle states were determined by using the gradient of pressure and impedance with respect to time. Guided by the level and gradient change of EMG activity, mechanical states successfully predicted the activity of the CP muscle and SM muscle independently. Mechanical state predictions revealed patterns consistent with the known neural inputs activating the different muscles during swallowing. Derivation of “activation state” maps may allow better physiological and pathophysiological interpretations of UES function

Polarimetric Properties of the Crab Pulsar between 1.4 and 8.4 GHz

New polarimetric observations of the Crab pulsar at frequencies between 1.4 and 8.4 GHz are presented. Additional pulse components discovered in earlier observations (Moffett & Hankins 1996, astro-ph/9604163) are found to have high levels of linear polarization, even at 8.4 GHz. No abrupt sweeps in position angle are found within pulse components; however, the position angle and rotational phase of the interpulse do change dramatically between 1.4 and 4.9 GHz. The multi-frequency profile morphology and polarization properties indicate a non-standard origin of the emission. Several emission geometries are discussed, but the one favored locates sites of emission both near the pulsar surface and in the outer magnetosphere.Comment: 20 pages, 7 postscript figures, uses aaspp4 Latex style. To appear in Volume 522 of The Astrophysical Journa

Hydrogen-Based Activity Enhancement in Sediment Cultures and Intact Sediments

The potential for hydrogen gas to stimulate microbial respiratory activity in sediments was investigated. Cell elutions from Passaic River (NJ), San Diego Bay (CA), and Marine Harbor sediments were amended with hydrogen gas to evaluate its impact on microbial activity measured by intracellular reduction of 5-cyano-2,3-ditolyl tetrazolium chloride (CTC). The transferability of this approach to sediment slurries and static sediment columns was evaluated based on microbial activity enhancement in Marine Harbor sediments. Results indicate that microbial activity can be increased by a factor of 2–3 at a threshold hydrogen concentration range (0.5 to 1.5 μM). Terminal restriction fragment (T-RF) length polymorphism analysis indicated that the community response to hydrogen resulted in the emergence of previously recessive populations. The causal relationship between hydrogen amendment and an increase in CTC-active cells was most likely due to community structure shifts, as evidenced by the emergence of new T-RFs (19% of total) at hydrogen concentrations above 1.5 μM. No RF was dominant within this emergent group, and no chlororespirers were detected within this group, the latter probably due to the lack of enrichment of halogenated compounds. Nevertheless, the transferability of the observed relationship between hydrogen gas amendment and microbial activity to complex sediment samples suggests a promising remedial strategy for in place contaminated estuarine sediments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63230/1/ees.2006.0078.pd

Acute Declines in Estimated Glomerular Filtration Rate in Patients Treated With Benazepril and Hydrochlorothiazide Versus Amlodipine and Risk of Cardiovascular Outcomes.

BACKGROUND: Acute declines in estimated glomerular filtration rate (eGFR) occur commonly after starting angiotensin-converting enzyme inhibitors. Whether declines in eGFR that occur after simultaneously starting angiotensin-converting enzyme inhibitors with other antihypertensive agents modifies the benefits of these agents on cardiovascular outcomes is unclear. METHODS AND RESULTS: We identified predictors of acute declines in eGFR (>15% over 3 months) during randomization to benazepril plus amlodipine versus benazepril plus hydrochlorothiazide in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial. We then determined the relation between declines in eGFR (treated as a binary variable, ≤15% versus >15% and separately, as a restricted spline variable) and the composite risk of fatal and nonfatal cardiovascular events using Cox proportional hazards models. We included 10 714 participants (median age 68 years [Q1 63, Q3 73]), of whom 1024 reached the trial end point over median follow-up of 2.8 years. Predictors of acute declines in eGFR>15% over 3 months included assignment to hydrochlorothiazide (versus amlodipine) and higher baseline albuminuria. Overall, declines in eGFR ≥15% (versus <15%) were associated with a 26% higher hazard of cardiovascular outcomes (95% CI, 1.07-1.48). In spline-based analysis, risk for cardiovascular outcomes was higher in the hydrochlorothiazide arm at every level of decline in eGFR compared with the same magnitude of eGFR decline in the amlodipine arm. CONCLUSION: Combined use of benazepril and amlodipine remains superior to benazepril and hydrochlorothiazide for cardiovascular outcomes, regardless of the magnitude of the decline in eGFR that occurred with initiation of therapy

Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

The immune checkpoint TIGIT is upregulated on T cells during bacterial infection and is a potential target for immunotherapy

Antibiotic resistance is a major public health threat, and alternatives to antibiotic therapy are urgently needed. Immunotherapy, particularly the blockade of inhibitory immune checkpoints, is a leading treatment option in cancer and autoimmunity. In this study, we used a murine model of Salmonella Typhimurium infection to investigate whether immune checkpoint blockade could be applied to bacterial infection. We found that the immune checkpoint T-cell immunoglobulin and ITIM domain (TIGIT) was significantly upregulated on lymphocytes during infection, particularly on CD4+ T cells, drastically limiting their proinflammatory function. Blockade of TIGIT in vivo using monoclonal antibodies was able to enhance immunity and improve bacterial clearance. The efficacy of anti-TIGIT was dependent on the capacity of the antibody to bind to Fc (fragment crystallizable) receptors, giving important insights into the mechanism of anti-TIGIT therapy. This research suggests that targeting immune checkpoints, such as TIGIT, has the potential to enhance immune responses toward bacteria and restore antibacterial treatment options in the face of antibiotic resistance

Modulation of Upper Esophageal Sphincter (UES) Relaxation and Opening During Volume Swallowing

“The final publication is available at Springer via http://dx.doi.org/10.1007/s00455-016-9744-4". This author accepted manuscript is made available following 12 month embargo from date of publication (17 Aug 2016) in accordance with the publisher's copyright policy.UES opening occurs following cricopharyngeus deactivation and submental muscle contraction causing hyolaryngeal elevation and UES distraction. During impedance manometry, the inverse of impedance (admittance) can be used to measure bolus presence and infer UES opening. We hypothesized that the temporal relationship between UES relaxation, opening and hyolaryngeal elevation would change with increasing bolus volume. Simultaneous intramuscular cricopharyngeal (CP) electromyography (EMG), surface submental EMG (SM-EMG), and high-resolution impedance manometry were recorded in eight (aged 27 ± 7 years, 5 M) healthy volunteers, while swallowing 0.9 % saline boluses of 2, 5, 10, and 20 ml. Data were exported and analyzed via Matlab. Statistical analysis comprised repeated measures one-way ANOVA and Pearson correlation. A P value of <0.05 was considered significant. Duration of CP deactivation increased at 20 ml volume (P < 0.001). UES relaxation and opening increased with increasing bolus volume (P < 0.001); however, overall duration of SM activation did not change. As UES opening occurs progressively earlier with increasing volumes, peak SM-EMG activity occurs relatively later (P < 0.001) and shifts from occurring before to following peak UES distention. During healthy swallowing, there is sensory modulation of cricopharyngeal and submental muscle activity. Intrabolus pressures, transmitted from the tongue base and pharynx, play a progressively more important role in sphincter opening with increasing volume. The findings may explain why some healthy elderly and patients with oropharyngeal dysphagia have difficulty swallowing larger while tolerating smaller bolus volumes

Proteinuric kidney disease in children at Queen Elizabeth Central Hospital, Malawi

Background: There is a paucity of data on paediatric kidney disease in developing countries such as Malawi. Descriptive research on kidney disease is essential to improving patient outcomes. Methods: We conducted a cross-sectional study at a tertiary hospital in Malawi from 2012 to 2013. Children under 14 years with proteinuric kidney disease were enrolled from paediatric wards and outpatient clinics at Queen Elizabeth Central Hospital (QECH). Demographic, clinical and laboratory data were collected from patients at enrolment and at 3 months review at which point clinical status and disease outcome were ascertained. Results: Thirty-four (22 male) patients were studied, mean age 8.54 (SD = 3.62 years). Glomerular disease (n = 25, 68%) was the most common presumed renal lesion at presentation. Nephritic syndrome (10) was characterised by a lower baseline complement C3 than nephrotic syndrome (p = 0.0027). Seven (47%) cases of nephrotic syndrome achieved complete remission. Eight (80%) cases of nephritic syndrome improved with supportive therapy. Nineteen (56%) patients presented with clinically significant renal damage with eGFR< 60 ml/min/1.73m2 . Six patients presented in chronic kidney disease (CKD) stage 5 of unclear aetiology, five (83%) died. Three (9%) patients had impaired kidney function and obstructive uropathy demonstrated on ultrasound, two recovered after surgery and one died. Eight (24%) patients had acute kidney injury (AKI) due to primary kidney disease, three of these patients progressed to CKD stage G3a. Seven (21%) patients were lost to follow up. Conclusion: Kidney disease is a significant cause of mortality and morbidity in children at QECH. Less than half of Nephrotic syndrome cases achieved complete remission. Mortality is highest in children with CKD of unclear cause. Some patients with AKI secondary to primary renal disease progressed to CKD. Understanding the aetiology of paediatric kidney disease and improving patient outcomes by developing enhanced diagnostic and clinical services are priorities at QECH and within Malawi

Survey of Telemedicine by Pediatric Nephrologists During the COVID-19 Pandemic

INTRODUCTION: The slow increase in use of telemedicine began to expand rapidly, along with reimbursement changes, during the coronavirus disease-2019 (COVID-19) pandemic. Standardized protocols for these services are lacking but are needed for effective and equitable health care. In this study, we queried pediatric nephrologists and their patients about their telemedicine experiences during the pandemic. METHODS: Surveys that were in compliance with the Health Insurance Portability and Accountability Act were deployed online to patients and physicians. RESULTS: We collected survey responses from 400 patients and 197 pediatric nephrologists. Patients reported positive experiences with telemedicine visits as it was logistically easier than in-person visits. Patients also felt that the quality of their visits were equivalent to what they would receive in person. Physicians used a wide variety of online systems to conduct synchronous telemedicine with Zoom (23%), EPIC (9%), Doxy.me (7%), services not specified (37%), or a mix of local or smaller services (24%). Most physicians' concerns were related to technological issues and the ability to procure physical exams and/or laboratory results. CONCLUSIONS: There is a paucity of published trials on telemedicine services in pediatric nephrology. Virtual care was feasible and acceptable for patients, caregivers, and providers during the COVID-19 pandemic