Characterizing Biomarkers of Continuous Peristalsis and Bolus Transit during Oral Feeding in Infants at pH-Impedance Evaluation: Clinical and Research Implications.

OBJECTIVE: To examine the biomarkers of pharyngoesophageal swallowing during oral feeding sessions in infants undergoing pH-impedance testing and determine if swallow frequencies are distinct between oral- and partially oral-fed infants. STUDY DESIGN: One oral feeding session was performed in 40 infants during pH-impedance studies and measurements included swallowing frequency, multiple swallow rate, air and liquid swallow rates, esophageal swallow clearance time (ESCT), and gastroesophageal reflux (GER) characteristics. Linear and mixed statistical models were applied to examine the swallowing markers and outcomes. RESULTS: Infants (30.2 ± 4.4 weeks birth gestation) were evaluated at 41.2 ± 0.4 weeks postmenstrual age (PMA). Overall, 10,675 swallows were analyzed during the oral feeding sessions (19.3 ± 5.4 min per infant) and GER events were noted (2.5 ± 0.3 per study). Twenty-four-hour acid reflux index (ARI) was 9.5 ± 2.0%. Differences were noted in oral- and partially oral-fed infants for: volume consumption (p<0.01), consumption rate (p<0.01), and length of hospital stay in days (p<0.01). Infants with ARI >7% had greater frequency of swallows (p=0.01). The oral-fed group had greater ARI (12.7 ± 3.3%, p=0.05). CONCLUSIONS: Oropharyngeal swallowing regulatory characteristics decrease over the feeding duration and were different between ARI >7% vs ≤7%. Although GER is less in infants who are partially oral-fed, the neonates with increased acid exposure achieved greater oral intakes and shorter hospitalizations, despite the presence of comorbidities. Pharyngoesophageal stimulation as during consistent feeding or GER events can activate peristaltic responses and rhythms, which may be contributory to the findings.

The Irritable Infant in the Neonatal Intensive Care Unit: Risk Factors and Biomarkers of Gastroesophageal Reflux Disease.

OBJECTIVES: To determine risk factors for arching/irritability in high-risk infants and examine the significance of comorbidity and gastroesophageal reflux (GER) characteristics. STUDY DESIGN: Retrospective analysis of 24-hour pH-impedance studies of symptomatic infants in a neonatal intensive care unit (ICU) (n = 516, 30.1 ± 4.5 weeks of gestation, evaluated at 41.7 ± 3.2 weeks postmenstrual age) was conducted. Comparisons were made between infants with >72 vs ≤72 arching/irritability events per day. We characterized risk factors for arching/irritability along with clinical, pH-impedance, and outcome correlates. RESULTS: Of 39 973 arching/irritability events and 42 155 GER events, the averages per day were 77.6 ± 41.0 and 81.7 ± 48.2, respectively. Acid reflux and impedance bolus characteristics were not significantly different between infants with >72 and ≤72 arching/irritability events (P ≥ .05). The odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for postmenstrual age and weight at evaluation were significant for risk factors of preterm birth (2.3 [1.2-4.4]), moderate or severe neuropathology (2.0 [1.1-3.6]), and presence of oral feeding at testing (1.57 [1.07-2.30]). CONCLUSIONS: Acid GER disease is unlikely the primary cause of arching/irritability and empiric treatment should not be used when arching/irritability is present. Prematurity and neurologic impairment may be more likely the cause of the arching/irritability. Arching/irritability may not be a concern in orally fed infants.

Trajectories of Daily Postconcussion Symptoms in Children.

OBJECTIVES: To identify trajectories of daily postconcussion symptoms (PCS) from the acute postinjury period to symptom resolution among concussed children and examine demographic factors and acute PCS associated with the identified symptom trajectories. SETTING AND PARTICIPANTS: Seventy-nine participants with a concussion were enrolled within 72 hours of injury and completed a daily survey that assessed PCS from enrollment until symptom resolution. DESIGN: This was a prospective cohort study among concussed children aged 11-17 years. MAIN MEASURES: Children rated their concussion symptoms daily using the Post-Concussion Symptom Scale. Symptom duration was assessed using participants' date of symptom resolution and coded as a dichotomous variable: (1) PCS duration 14 days or less or (2) PCS duration longer than 14 days. RESULTS: Of the 79 participants, most were male ( n = 53, 67%), injured during a sporting activity ( n = 67, 85%), or had PCS that persisted for more than 14 days post-injury ( n = 41, 52%). Group-based trajectory modeling yielded 4 trajectory groups: (1) low acute/resolved PCS ( n = 39, 49%), (2) moderate/persistent PCS ( n = 19, 24%), (3) high acute/persistent PCS ( n = 13, 16%), and (4) high acute/resolved PCS ( n = 8, 10%). No significant associations were found between demographic factors and the trajectory group. A higher symptom burden at injury was associated with an increased odds of being in the high acute/resolved or high acute/persistent recovery groups than being in the low acute/resolved group (odds ratio [OR] 1.39, 95% CI = 1.11-1.74; OR = 1.33, 95% CI = 1.11-1.60, respectively), as was a higher symptom severity at injury (OR = 1.09, 95% CI = 1.03-1.15; OR = 1.06, 95% CI = 1.02-1.11, respectively). CONCLUSION: Our findings may help clinicians identify concussed children on slower recovery trajectories, and implement early, individualized treatment plans that foster optimal recovery for concussed children.

Exploring the association between cognitive activity and symptom resolution following concussion in adolescents aged 11-17 years.

OBJECTIVE: As opposed to postconcussion physical activity, the potential influence of cognitive activity on concussion recovery is not well characterised. This study evaluated the intensity and duration of daily cognitive activity reported by adolescents following concussion and examined the associations between these daily cognitive activities and postconcussion symptom duration. METHODS: This study prospectively enrolled adolescents aged 11-17 years with a physician-confirmed concussion diagnosis within 72 hours of injury from the emergency department and affiliated concussion clinics. Participants were followed daily until symptom resolution or a maximum of 45 days postinjury to record their daily cognitive activity (intensity and duration) and postconcussion symptom scores. RESULTS: Participants (n=83) sustained their concussion mostly during sports (84%), had a mean age of 14.2 years, and were primarily male (65%) and white (72%). Participants reported an average of 191 (SD=148), 166 (SD=151) and 38 (SD=61) minutes of low-intensity, moderate-intensity and high-intensity daily cognitive activity postconcussion while still being symptomatic. Every 10 standardised minutes per hour increase in moderate-intensity or high-intensity cognitive activities postconcussion was associated with a 22% greater rate of symptom resolution (adjusted hazard ratio (aHR) 1.22, 95% CI 1.01 to 1.47). Additionally, each extra day's delay in returning to school postconcussion was associated with an 8% lower rate of symptom resolution (aHR 0.92, 95% CI 0.85 to 0.99). CONCLUSION: In adolescents with concussion, more moderate-high intensity cognitive activity is associated with faster symptom resolution, and a delayed return to school is associated with slower symptom resolution. However, these relationships may be bidirectional and do not necessarily imply causality. Randomised controlled trials are needed to determine if exposure to early cognitive activity can promote concussion recovery in adolescents.

Change in health-related quality of life and functional disability over time post-concussion in youth.

PURPOSE: Concussions can have detrimental on children's cognitive, emotional, behavioral, and/or social functioning. We sought to examine changes in health-related quality of life (HRQOL) and functional disability from pre-injury to 1-week post-concussion, and to symptom resolution among youth ages 11-17 with a concussion. METHODS: In this prospective, longitudinal cohort study, 83 concussed youth, ages 11-17, self-reported post-concussion symptoms daily as well as HRQOL and functional disability at baseline (pre-injury, retrospective), 1-week post-concussion, and symptom resolution. We modeled changes in overall and sub-scale HRQOL and functional disability scores over time from pre-injury to 1-week post-concussion and from 1-week post-concussion to symptom resolution using a piecewise linear mixed model, adjusting for potential covariables. Estimated fixed effects with a corresponding adjusted coefficient (beta), along with their 95% confidence intervals are presented. RESULTS: Overall HRQOL worsened from pre-injury to 1-week post-injury (ß = - 5.40, 95%CI - 9.22, - 1.58) but did not change from 1-week post-injury to symptom resolution. Physical HRQOL worsened from pre-injury to 1-week post-injury (ß = - 9.90, 95%CI - 14.65, - 5.14) but improved from 1-week post-injury to symptom resolution (ß = 1.64, 95%CI 0.50, 2.78), while psychosocial HRQOL showed no change over time. Functional disability worsened from pre-injury to 1-week post-injury (ß = 8.36, 95%CI 5.93, 10.79) but with no change from 1-week post-injury to symptom resolution. Youth with symptom duration > 14 days reported worse HRQOL and functional disability than those who recovered in ≤ 14 days and greater daily post-concussion symptom scores were associated with worse HRQOL and functional disability. CONCLUSION: Concussions have a negative impact on overall and physical HRQOL and functional disability in youth acutely post-injury. Ratings of HRQOL could be used to inform clinical treatment decisions to assist with the recovery process.

Comparison of direct effects of rice-thickened formula vs routine feeds on symptoms and gastroesophageal reflux indices: A crossover cohort study.

BACKGROUND: We compared the direct effects of routine vs rice-thickened formula on 24-h pH-impedance and symptom characteristics and then examined if dietary effects were modified by acid reflux index severity in infants. METHODS: Forty infants under consideration for gastroesophageal reflux disease and therapies were evaluated at 43 ± 1 weeks postmenstrual age. Each infant was equally fed routine diet and thickened formula during evaluations. Postprandial sessions were analyzed for acid reflux index, reflux events, clearance times, distal baseline impedance, and symptoms. RESULTS: Thickened formula has no effect (P ≥ 0.05) on acid reflux events' characteristics or overall symptom frequency. However, refluxate height and frequency of weakly acidic events and cough were decreased (P < 0.05). Prolonged bolus clearance and a decrease in distal baseline impedance were noted with thickened feeds (vs routine feeds) when acid reflux index was >7 (P < 0.05). CONCLUSION: Our pH-impedance testing protocol identifies direct effects of potential therapies at the point of care. Acutely, thickened formula does not impact acid-specific reflux indices but decreases full-column reflux and cough reflexes. In those with an acid reflux index of >7, thickened formula prolongs the distal esophageal bolus clearance (the mechanisms of which are uncertain). Clinical trials are needed to clarify objective indications and therapeutic use of thickened formulas for infants with gastroesophageal reflux disease, along with short- and long-term side effects.

Visual Function and Driving Performance Under Different Lighting Conditions in Older Drivers: Preliminary Results From an Observational Study.

BACKGROUND: Age-related vision changes significantly contribute to fatal crashes at night among older drivers. However, the effects of lighting conditions on age-related vision changes and associated driving performance remain unclear. OBJECTIVE: This pilot study examined the associations between visual function and driving performance assessed by a high-fidelity driving simulator among drivers 60 and older across 3 lighting conditions: daytime (photopic), nighttime (mesopic), and nighttime with glare. METHODS: Active drivers aged 60 years or older participated in visual function assessments and simulated driving on a high-fidelity driving simulator. Visual acuity (VA), contrast sensitivity function (CSF), and visual field map (VFM) were measured using quantitative VA, quantitative CSF, and quantitative VFM procedures under photopic and mesopic conditions. VA and CSF were also obtained in the presence of glare in the mesopic condition. Two summary metrics, the area under the log CSF (AULCSF) and volume under the surface of VFM (VUSVFM), quantified CSF and VFM. Driving performance measures (average speed, SD of speed [SDspeed], SD of lane position (SDLP), and reaction time) were assessed under daytime, nighttime, and nighttime with glare conditions. Pearson correlations determined the associations between visual function and driving performance across the 3 lighting conditions. RESULTS: Of the 20 drivers included, the average age was 70.3 years; 55% were male. Poor photopic VA was significantly correlated with greater SDspeed (r=0.26; P<.001) and greater SDLP (r=0.31; P<.001). Poor photopic AULCSF was correlated with greater SDLP (r=-0.22; P=.01). Poor mesopic VUSFVM was significantly correlated with slower average speed (r=-0.24; P=.007), larger SDspeed (r=-0.19; P=.04), greater SDLP (r=-0.22; P=.007), and longer reaction times (r=-0.22; P=.04) while driving at night. For functional vision in the mesopic condition with glare, poor VA was significantly correlated with longer reaction times (r=0.21; P=.046) while driving at night with glare; poor AULCSF was significantly correlated with slower speed (r=-0.32; P<.001), greater SDLP (r=-0.26; P=.001) and longer reaction times (r=-0.2; P=.04) while driving at night with glare. No other significant correlations were observed between visual function and driving performance under the same lighting conditions. CONCLUSIONS: Visual functions differentially affect driving performance in different lighting conditions among older drivers, with more substantial impacts on driving during nighttime, especially in glare. Additional research with larger sample sizes is needed to confirm these results.

A decade of evidence: standardized feeding initiative targeting feeding milestones and predicting NICU stays in premature infants in an all-referral level IV NICU.

OBJECTIVE: Ten-year data from the simplified, individualized, milestone-targeted, pragmatic, longitudinal and educational (SIMPLE) feeding initiative were examined by gestational age (GA) category to characterize the feeding milestones, length of hospital stays (LOHS), annual variability and predictive models for LOHS. STUDY DESIGN: Preterm infants (≤32 weeks GA, N = 434) in level-IV NICU had milestone-targeted feeding plans. Continuous data were analyzed for outcomes. RESULTS: Over 93% successfully attained full oral feedings. Earlier acquisition of feeding milestones correlated with earlier discharge (P < 0.05). Year-wise analysis showed sustained maintenance of milestones (P < 0.05). Milestones and outcomes (P < 0.001) were significantly correlated with different GA categories. Prediction models for LOHS were derived using GA, BPD, age at full enteral, postmenstrual age (PMA) at 1st and full oral feeds. CONCLUSIONS: The SIMPLE feeding program minimized variability and promoted acquisition of feeding milestones consistently. LOHS is predictable using feeding milestones, co-morbidities, GA, and PMA at feeding milestones.

Impact of esophageal mucosal permeability markers on provocation-induced esophageal reflexes in high-risk infants.

Esophageal distal baseline impedance (DBI) is an indicator of mucosal integrity; lower values suggest increased permeability. Aims were to characterize the (1) effect of DBI category (<900 Ω, 900-2000 Ω, and >2000 Ω) on sensory-motor characteristics of mid-esophageal provocation-induced motility reflexes, and (2) clinical outcomes among high-risk human infants evaluated for gastroesophageal reflux disease. Symptomatic infants (N = 49, 41 ± 3 weeks postmenstrual age) underwent pH-impedance testing to characterize acid reflux index (ARI) and DBI, and pharyngo-esophageal manometry to examine upper esophageal sphincter (UES), peristaltic, and lower esophageal sphincter (LES) functions. Sensory-motor response characteristics included response threshold (ml), occurrence (%), latency (s), duration (s), and magnitude (mmHg) upon mid-esophageal stimulations (0.1-2.0 ml of air, water, and apple juice). Motility and clinical outcomes were compared among DBI groups. In infants with DBI <900 Ω and 900-2000 Ω (vs. >2000 Ω): (a) Long-term feeding milestones did not differ (p > 0.05); (b) complete peristaltic propagation decreased in 900-2000 Ω (p < 0.05), polymorphic waveforms increased in <900 Ω and 900-2000 Ω (p < 0.05); (c) media effects were noted with liquids (vs. air) wherein UES and esophageal contractility were prolonged in <900 Ω and 900-2000 Ω (p < 0.05), and esophageal sensitivity heightened for <900 Ω with water and for 900-2000 Ω with air (both p < 0.05). ARI was not correlated with DBI in infants with chronic lung disease (r = 0.05, p = 0.82). We conclude that pharyngo-esophageal motility sensory-motor characteristics in infants are modified by DBI category. These preliminary findings pave-the-way for further physiological testing in convalescing high-risk infants to ascertain potential mechanisms of airway-digestive reflex interactions and symptom generation, which may lead to targeted therapies.

Salivary miRNA Expression in Children With Persistent Post-concussive Symptoms.

Background: Up to one-third of concussed children develop persistent post-concussive symptoms (PPCS). The identification of biomarkers such as salivary miRNAs that detect concussed children at increased risk of PPCS has received growing attention in recent years. However, whether and how salivary miRNA expression levels differ over time between concussed children with and without PPCS is unknown. Aim: To identify salivary MicroRNAs (miRNAs) whose expression levels differ over time post-concussion in children with vs. without PPCS. Methods: We conducted a prospective cohort study with saliva collection at up to three timepoints: (1) within one week of injury; (2) one to two weeks post-injury; and (3) 4-weeks post-injury. Participants were children (ages 11 to 17 years) with a physician-diagnosed concussion from a single hospital center. We collected participants' daily post-concussion symptom ratings throughout their enrollment using the Post-concussion Symptom Scale, and defined PPCS as a total symptom score of ≥ 5 at 28 days post-concussion. We extracted salivary RNA from the saliva samples and measured expression levels of 827 salivary miRNAs. We then compared the longitudinal expression levels of salivary miRNAs in children with vs. without PPCS using linear models with repeated measures. Results: A total of 135 saliva samples were collected from 60 children. Of the 827 miRNAs analyzed, 91 had expression levels above the calculated background threshold and were included in the differential gene expression analyses. Of these 91 miRNAs, 13 had expression levels that differed significantly across the three timepoints post-concussion between children with and without PPCS (i.e., hsa-miR-95-3p, hsa-miR-301a-5p, hsa-miR-626, hsa-miR-548y, hsa-miR-203a-5p, hsa-miR-548e-5p, hsa-miR-585-3p, hsa-miR-378h, hsa-miR-1323, hsa-miR-183-5p, hsa-miR-200a-3p, hsa-miR-888-5p, hsa-miR-199a-3p+hsa-miR-199b-3p). Among these 13 miRNAs, one (i.e., hsa-miR-203a-5p) was also identified in a prior study, with significantly different expression levels between children with and without PPCS. Conclusion: Our results from the longitudinal assessment of miRNAs indicate that the expression levels of 13 salivary miRNAs differ over time post-injury in concussed children with vs. without PPCS. Salivary miRNAs may be a promising biomarker for PPCS in children, although replication studies are needed.

Redefining spirometry hesitating start criteria based on the ratio of extrapolated volume to timed FEVs.

BACKGROUND: The primary purpose of this study was to investigate alternative hesitating start criteria for spirometry maneuvers that do not achieve an acceptable plateau. The current hesitating start criterion that has been in use for 30 years is based on clinical opinion from expert users; it was not established based on information from peer-reviewed scientific studies. METHODS: A total of 1,719 workers met the eligibility criteria for this study and contributed 24,945 trials. The fitted lines obtained from linear regressions of each dependent variable, volume of air calculated at time zero using the back extrapolation method (extrapolated volume [EV])/FEV(1), EV/FEV in 3 s (FEV(3)), and EV/FEV in 6 s (FEV(6)) on EV/FVC were determined. The 95th percentile of the prediction interval of each dependent variable corresponding to EV/FVC = 5% was calculated. RESULTS: The values for EV/FEV(1), EV/FEV(3), and EV/FEV(6) corresponding to the 5% EV/FVC value were determined to be 6.62%, 5.59%, and 5.25%, respectively. CONCLUSIONS: A new hesitating start criterion using EV/FEV(6) of 5.25% is recommended for tracings that do not achieve a plateau or when an FEV(6) is performed. An EV/FEV(3) of 5.59% could be incorporated into spirometry software as an early warning signal that could help operators identify trials with potential hesitating starts.

von Hippel-Lindau-dependent patterns of RNA polymerase II hydroxylation in human renal clear cell carcinomas.

PURPOSE: We have previously shown that von Hippel-Lindau (VHL) regulates ubiquitylation and proline 1465 hydroxylation of the large subunit of RNA polymerase II, Rpb1, in human renal clear cell carcinoma (RCC) cell lines. Here, our goal was to determine the effect of this VHL function and the status of P1465 hydroxylation in human RCC tumors. EXPERIMENTAL DESIGN: Primary human tumors and matched normal kidney samples were probed for expression levels of the large subunit of RNA polymerase II (Rpb1), Rpb1 hydroxylated on P1465 [Rpb1(OH)], Rpb1 phosphorylated on Ser5 [Rpb1(S5P)], and proline hydroxylases PHD1, PHD2, and PHD3. Results from RCC tumors were categorized according to the status of VHL gene. Mechanistic analysis was performed in orthotopic xenograft model using 786-O RCC cells with wild-type (WT) VHL and knockdown of PHD2, characterized by high levels of Rpb1(OH) and PHD1. RESULTS: Levels of Rpb1(OH), PHD1, and PHD2 were significantly higher in RCC tumors compared with normal kidneys. RCC tumors with WT VHL had higher levels of Rpb1(OH) and PHD1 and lower levels of PHD2 than tumors with VHL gene alterations. Levels of Rpb1(OH) significantly correlated with levels of PHD1 in tumors and normal kidneys. Knockdown of PHD2 in 786-O VHL(+) cells resulted in a more malignant phenotype in orthotopic xenografts and higher expression of specific cell cycle regulators (CDC25A, cyclin-dependent kinase 2, CCNA2) compared with VHL(-) RCC cells. CONCLUSIONS: Elevated PHD1 concomitant with decreased PHD2 are causatively related to Rpb1 hydroxylation and oncogenesis in human RCC tumors with WT VHL gene. Thus, P1465-hydroxylated Rpb1 and PHD1 represent attractive drug targets for new RCC treatments.