Novel Use of Impedance Technology Shows That Esophageal Air Events Can Be Temporally Associated With Gastroesophageal Reflux Disease-like Symptoms.

A few studies have shown that esophageal air events (EAEs), such as air-swallows, may be associated with symptoms that have historically been associated with gastroesophageal reflux disease (GERD). To objectively test a hypothesis that all EAE types (air-swallows, supragastric belches and gastric belches) can be associated with GERD-like symptoms, we removed the impedance "tags" from the GER episodes (placed during autoscan) and instead tagged either air-swallows, supragastric belches or gastric belches in each of 3 copies of the 24-hour impedance tracing for 2 infant patients who presented with symptoms suggestive of GER as an etiology. Impedance system software (MMS) analyses revealed that, in both infants, all EAE types were significantly associated (SAP >95%) with 1 or more of the GERD-like symptom types (cough, pain/crying, back-arching, and gagging). These data underscore the importance of considering other diagnoses when developing management strategies for treating GERD-like symptoms in infants.

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

BACKGROUND: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF. METHODS: Seventy-seven children with CF <10 years of age (35 infants <1 year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed. RESULTS: Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D2 (PGD2) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD2 and increased methicillin-resistant Staphylococcus aureus survival in human CF macrophages. CONCLUSIONS: Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.

Effects of Esophageal Acidification on Troublesome Symptoms: An Approach to Characterize True Acid GERD in Dysphagic Neonates.

To quantify and compare maximal extent (height) of acid reflux events (AREs) on symptom generation in dysphagic neonates. Dysphagic neonates (N = 53), born at 30 ± 5.3 weeks gestation, underwent 24-hour pH-impedance study for the evaluation of troublesome symptoms purported to be due to gastroesophageal reflux disease (GERD). AREs (pH < 4 for >4 s) detected by impedance (Z) were categorized by maximal extent as refluxate reaching distal (Z6, Z5), middle (Z4, Z3), or proximal (Z2, Z1) impedance channels. AREs reaching the pH sensor only were categorized as distal. Symptom correlation (%, symptom index, symptom sensitivity index, and symptom associated probability) and temporal characteristics (clearance times) of AREs were analyzed using linear mixed and GEE models comparing height categories presented as mean ± SEM, median (IQR), and OR (95% CI). Of the 2003 AREs, 1) distal extent AREs (n = 1642) had increased frequency (p < 0.05), decreased ACT (p < 0.05), and decreased acidity (p < 0.05); 2) in middle and proximal AREs, acid clearance was longer than bolus clearance, (p < 0.01); and 3) the odds of having cardiorespiratory (cough or sneeze) symptoms are increased with proximal and middle AREs (p < 0.05). Most proximal ascent of AREs into middle or proximal esophagus likely activates protective aerodigestive reflexes (peristalsis) or vigilant states to facilitate bolus and chemical clearance. Heightened esophageal sensitivity, acid neutralization delays, or clearance mechanism delays may accentuate multi-systemic troublesome symptoms.

Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

BACKGROUND: Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. AIMS: To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. RESULTS: Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). CONCLUSIONS: Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

Chemical clearance in infants and children with Acid reflux in the physiologic range.

BACKGROUND AND AIM: We reported that chemical clearance (CC) of acid gastroesophageal reflux (AGER) is relatively prolonged in children with cystic fibrosis (CF). Disparity in CC values within our CF cohort sparked curiosity as to what CC looks like in infants and children with AGER in the physiologic range. The aim of the study was to assess CC in infants and children with normal AGER. METHODS: Impedance-pH tracings from our database for infants (≤ 12 months) and children (>12 months-18 years) were manually scanned for 2-phase AGER episodes. Tracings were excluded for patients who had AGER Indices >3% (children) or >6% (infants), had positive GER-symptom associations, were on antireflux medications, had a fundoplication, or had impedance studies shorter than 18 hour. In addition to medians (25%-75% interquartile range), we calculated the 95th percentile for the CC duration and the fifth percentile for the CC rate. RESULTS: Two-phase AGER episodes were detected in 44 infants and 60 children. The median CC duration was 64.3 seconds (51.0-91.6 seconds) for infants and 37.5 seconds (27.7-52.4 seconds) for children. The median CC rate was 0.0622 pH units/second (PU/second) (0.0354-0.0946 PU/second) for infants and 0.0928 PU/second (0.0631-0.2057 PU/second) for children. The CC duration at the 95th percentile was 148.5 seconds for infants and 114.4 seconds for children. The CC rate at the fifth percentile was 0.0088 PU/second for infants and 0.0465 PU/second for children. CONCLUSIONS: We report reference values for CC in infants and children who have normal acid reflux. These values should not be used as "cutoff values" because they were derived from infant and children cohorts that did not include individuals with intermediate AGER.

Survival in Patients with Advanced Non-cystic Fibrosis Bronchiectasis Versus Cystic Fibrosis on the Waitlist for Lung Transplantation.

BACKGROUND: Survival in non-cystic fibrosis (CF) bronchiectasis is not well studied. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to compare survival in adult patients with non-CF bronchiectasis to patients with CF listed for lung transplantation (LTx). Each subject was tracked from waitlist entry date until death or censoring to determine survival differences between the two groups. RESULTS: Of 2112 listed lung transplant candidates with bronchiectasis (180 non-CF, 1932 CF), 1617 were used for univariate Cox and Kaplan-Meier survival function analysis, 1173 for multivariate Cox models, and 182 for matched-pairs analysis based on propensity scores. Compared to CF, patients with non-CF bronchiectasis had a significantly lower mortality by univariate Cox analysis (HR 0.565; 95 % CI 0.424, 0.754; p < 0.001). Adjusting for potential confounders, multivariate Cox models identified a significant reduction in risk for death associated with non-CF bronchiectasis who were lung transplant candidates (HR 0.684; 95 % CI 0.475, 0.985; p = 0.041). Results were consistent in multivariate models adjusting for pulmonary hypertension and forced expiratory volume in one second. CONCLUSIONS: Non-CF bronchiectasis with advanced lung disease was associated with significantly lower mortality hazard compared to CF bronchiectasis on the waitlist for LTx. Separate referral and listing criteria for LTx in non-CF and CF populations should be considered.

Combined multichannel intraluminal impedance-pH (MII-pH): multicenter report of normal values from 117 children.

Although combined multichannel intraluminal impedance/esophageal pH monitoring (MII-pH) has replaced prolonged pH monitoring alone for assessing gastroesophageal reflux (GER) in the pediatric population, it does so in the absence of reference values for non-acid GER (NAGER). The purpose of this study was to identify a normal range of NAGER impedance values for infants and children. We evaluated EPM/MII tracings for patients referred for GER assessment to Nationwide Children's Hospital (Columbus, OH), Inova Children's Hospital, and Hospital Italiano (Buenos Aires, Argentina). We excluded tracings from patients who had AGER indices greater than 50 % of the upper end of normal (i.e., >3 % for children >12 months and >6 % for infants ≤ 12 months), had a positive temporal association of GER with symptoms, were on anti-reflux medications at the time of the study, and/or had a fundoplication prior to the study. We also excluded studies with durations shorter than 20 h. Values for NAGER percent time, NAGER episode frequency, frequency of proximal NAGER, and mean NAGER duration were calculated for upright position, recumbent, and total. Study population consisted of 46 infants (20 female [F]/26 male [M], median age 4.8 months [range 3 weeks-11.9 months]) with a median AGER index of 2.2 % (range 0.0-5.9 %) and 71 children (22 F/49 M, median age 7.2 years [range 1.3-17 years]) with a median AGER index of 1.1 % (range 0-3.0 %). Data are presented in tables in the text. The results of this study provide a range of values characteristic of infants and children with normal AGER indices and no positive temporal associations of GER with symptoms. These values may be used as references for comparison to identify infants and/or children who may be at risk of developing serious clinical manifestations due to abnormal patterns of GER.

Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis.

OBJECTIVES: Few studies compare gastroesophageal reflux (GER) parameters of cystic fibrosis (CF) children and symptomatic non-CF children. We aimed to compare the impedance-pH (IMP-pH) parameters for these two groups and to test the hypothesis that prolonged acid exposure in CF patients is due to delayed chemical clearance (CC). METHODS: IMP-pH tracings from 16 CF children (median 8.2 years) and 16 symptomatic non-CF children (median 8.3 years) were analyzed. Software was used to generate IMP-pH reports and parameter data were extracted. IMP-pH was used to calculate the mean CC for each patient. RESULTS: pH studies showed no difference in acid GER (AGER) frequency (p = 0.587); however, mean AGER duration, duration of longest AGER, AGER index, and DeMeester scores were all significantly higher for CF patients. IMP showed no difference in GER frequency [neither acidic (p = 0.918) nor non-acidic (p = 0.277)], but total bolus clearance was more efficient in CF patients (p = 0.049). A larger percentage of total GER reached the proximal esophagus in non-CF children (p = 0.039). Analyses of two-phase AGER episodes showed that these events were more acidic (p = 0.003) and the CC phase was significantly prolonged in the CF cohort (p = 0.001). CONCLUSIONS: Compared to symptomatic non-CF children, CF children do not have more frequent reflux. Actually, they have better bolus clearance efficiency following reflux and may even have better control over the number of GER episodes that reach the proximal esophagus. CC of AGER, however, is significantly prolonged in the CF cohort, likely due to hyperacidity of refluxed gastric contents.

Executing and facilitating the successful combined multichannel intraluminal impedance and pH monitoring study.

Successful multichannel intraluminal impedance and pH monitoring (MII-pHM) studies rely on constant attendants (CAs) or family members (and sometimes the patients themselves) to assist in the execution and facilitation of the MII-pHM study. While "pushing buttons" [corresponding to specific symptoms, body position (upright versus recumbent), and meal start and stop times] on the MII-pHM system recording box is indeed a big part of MII-pHM study execution and facilitation, there are other concerns and duties that are equally as important. This paper outlines some of the important duties of the study facilitator (or patient) during a MII-pHM study. When provided with the proper training, study facilitators invigilating the MII-pHM study will be better able to contribute to the data collection process and ultimately to produce data that when analyzed will lead to better interpretations, clinical recommendations, and good clinical outcomes. When executed properly, MII-pHM studies have the potential to assess diurnal exposure of the esophageal mucosa to gastric/duodenal contents, provide insight regarding the proximal extent of gastroesophageal reflux (GER), provide a measurement of the mean esophageal pH, and assess mucosal integrity and temporal relationship between GER and the symptoms of interest. While several groups have offered recommendations for proper execution of the MII-pHM study, to our knowledge, there have not been publications wherein recommendations were compiled to form a single source document.

Gastroesophageal reflux causing sleep interruptions in infants.

BACKGROUND AND AIM: Little is known about the relation between gastroesophageal reflux (GER) episodes and sleep interruptions in infants. The aim of the study was to evaluate the relationship between GER and the incidence of sleep interruptions in infants. METHODS: Study patients included 24 infants (younger than 1 year) referred for multichannel intraluminal impedance and esophageal pH monitoring with simultaneous polysomnography. Exclusion criteria were a previous fundoplication and studies lasting <20 hours. Tests were clinically indicated to investigate suspicion of GER-related apnea (17, 70.8%), stridor (6, 25%), noisy breathing (2, 8.3%), and cyanotic spells (1, 4.2%). Most patients presented with significant comorbidities (19, 79.2%). RESULTS: The number of nonacid GER (NAGER) per hour was greater during sleep time than during daytime and awakening following sleep onset (median 0.27 vs 1.85 and 1.45, P<0.01). A total of 1204 (range 7-86 per infant) arousals in 24 infants was detected, 165 (13.7%) that followed GER episodes, and 43 (3.6%) that preceded GER episodes. Seven patients presented with a positive symptom association probability for arousals; 5 were exclusively because of NAGER. A positive symptom association probability for awakenings was detected in 9 patients; 4 were because of NAGER, 4 were because of AGER, and 1 was because of both NAGER and GER. Patients with awakenings related to GER presented longer mean clearance time of AGER during sleep (165.5 vs 92.8 seconds, P=0.03). CONCLUSIONS: GER was a frequent cause of interrupting sleep among our infant patients, and NAGER proved to be equally important as AGER for causing arousals and awakenings in infants.

Gastroesophageal reflux in cystic fibrosis: current understandings of mechanisms and management.

Cystic fibrosis (CF) is an inherited disease that affects both the lungs and the digestive system in children and adults. Thick mucus fills the gut and blocks lumens of the pancreas and hepatobiliary systems, creating insufficient pancreas function and liver disease. Chronic gastrointestinal (GI) complications, including intestinal obstruction, occur in neonates, and poor digestion and gastroesophageal reflux disease (GERD) in children. Although GI symptoms tend to improve with age, CF and associated GERD eventually create respiratory insufficiency; the only available treatment option at this stage is a bilateral lung transplant, which carries considerable morbidity and mortality. While GERD may reoccur as a complication of lung transplantation, GERD symptoms are often reduced following a fundoplication.

Significant Temporal Association of Esophageal Air Events (Supragastric Belches, Air Swallows, and Gastric Belches) With Hiccups: A Case Study in an Adolescent.

We previously reported our ability to objectively assess the strength of temporal relationships between gastroesophageal reflux (GER) disease-like symptoms with esophageal air events (EAEs) (air swallows, gastric belching, and supragastric belching) using impedance-pH monitoring. Recently, we similarly evaluated an adolescent female who presented to our clinic with symptoms of recurrent hiccups and with what appeared to be numerous EAEs. Hiccups were associated with GER (symptom association probability [SAP] = 100%), air swallows (SAP = 99.7%), supragastric belches (SAP = 100%), and gastric belches (SAP = 100%), with almost twice as many of the supragastric belches preceding a hiccup than any of the other 3 esophageal disturbance types (EDs) (P < 0.00001). Our data showing a significant temporal association between EAEs and hiccups support a previous report in which belching was suspected of being associated with hiccups in an adult male. Reports such as this underscore the importance of considering the assessment of temporal relationships between extra-esophageal symptoms and EDs that include not only GER, but also EAEs, such as air swallows, gastric belches and supragastric belches, when devising strategies for clinical management of patients with hiccups.

Sweat metabolomics before and after intravenous antibiotics for pulmonary exacerbation in people with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PWCF) suffer from acute unpredictable reductions in pulmonary function associated with a pulmonary exacerbation (PEx) that may require hospitalization. PEx symptoms vary between PWCF without universal diagnostic criteria for diagnosis and response to treatment. RESEARCH QUESTION: We characterized sweat metabolomes before and after intravenous (IV) antibiotics in PWCF hospitalized for PEx to determine feasibility and define biological alterations by IV antibiotics for PEx. STUDY DESIGN AND METHODS: PWCF with PEx requiring hospitalization for IV antibiotics were recruited from clinic. Sweat samples were collected using the Macroduct® Sweat Collection System at admission prior to initiation of IV antibiotics and after completion prior to discharge. Samples were analyzed for metabolite changes using ultra-high-performance liquid chromatography/tandem accurate mass spectrometry. RESULTS: Twenty-six of 29 hospitalized PWCF completed the entire study. A total of 326 compounds of known identity were detected in sweat samples. Of detected metabolites, 147 were significantly different between pre-initiation and post-completion of IV antibiotics for PEx (average treatment 14 days). Global sweat metabolomes changed from before and after IV antibiotic treatment. We discovered specific metabolite profiles predictive of PEx status as well as enriched biologic pathways associated with PEx. However, metabolomic changes were similar in PWCF who failed to return to baseline pulmonary function and those who did not. INTERPRETATION: Our findings demonstrate the feasibility of non-invasive sweat metabolomic profiling in PWCF and the potential for sweat metabolomics as a prospective diagnostic and research tool to further advance our understanding of PEx in PWCF.

Hypnosis to Reduce Distress in Children Undergoing Anorectal Manometry: A Randomized Controlled Pilot Trial.

Background/Aims: To assess the effectiveness and feasibility of a brief session of hypnosis to reduce distress in children with functional constipation undergoing anorectal manometry (ARM). Methods: A partially-blinded randomized controlled pilot trial was conducted in children 4-18 years old scheduled for ARM. Children were randomized to receive a brief session of hypnosis prior to ARM or standard care. Non-blinded and blinded observers rated the child's level of distress using the Observation Scale of Behavioral Distress and a 4-point-Likert scale, respectively. Differences between groups were analyzed using Fisher's exact test or Mann-Whitney U test as appropriate. Results: Data from 32 children (15 hypnosis and 17 standard care) were analyzed. Prior to insertion of the catheter, the observed mean levels of distress were lower in the hypnosis group according to both the non-blinded observer (median 0.0 [interquartile range {IQR} 0.0-0.3] vs 1.4 [IQR 0.3-2.4]; P = 0.009) and the blinded observer (median 0.0 [IQR 0.0-0.0] vs 0.5 [IQR 0.0-1.0]; P = 0.044). During ARM, observed and reported levels of distress did not differ significantly. In the hypnosis group, 92.9% of parents and children reported that hypnosis helped the child to relax. There were no significant differences in resting pressure, squeeze pressure, or duration of the procedure between both groups. Conclusion: A brief session of hypnosis for children before ARM is an easily incorporable intervention that lowers distress levels prior to the procedure and is positively perceived by children and parents.

Esophageal impedance monitoring for gastroesophageal reflux.

Dual pH-multichannel intraluminal impedance (pH-MII) is a sensitive tool for evaluating overall gastroesophageal reflux disease, and particularly for permitting detection of nonacid reflux events. pH-MII technology is especially useful in the postprandial period or at other times when gastric contents are nonacidic.pH-MII was recently recognized by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as being superior to pH monitoring alone for evaluation of the temporal relation between symptoms and gastroesophageal reflux. In children, pH-MII is useful to correlate symptoms with reflux (particularly nonacid reflux), to quantify reflux during tube feedings and the postprandial period, and to assess efficacy of antireflux therapy. This clinical review is simply an evidence-based overview addressing the indications, limitations, and recommended protocol for the clinical use of pH-MII in children.

"pH-Only" acid reflux events in infants during later phases of the feeding cycle are less acidic and cleared more efficiently than classic 2-phase acid reflux events.

BACKGROUND: Gastroesophageal acid exposure in infants is a function of 4 acid gastroesophageal reflux (AGER) types: classic 2-phase, single-phase, and pH-only events (POEs), as well as rereflux episodes. In symptomatic infants, classic 2-phase events and POEs make up the majority of total AGER events and AGER events lasting 5 minutes or longer, and are responsible for the majority of total gastroesophageal acid exposure. Also, in symptomatic infants, chemical clearance efficiency of classic 2-phase events has been shown to be influenced by feeding. Pathogenicity of AGER involves variables that include frequency, duration, and pH of AGER events. The purpose of this investigation was to compare classic 2-phase episodes and POEs on the basis of these variables during discrete periods related to feeding. PATIENTS AND METHODS: Impedance/pH tracings from 12 symptomatic infants (median age 20 weeks) were examined. Mean frequencies, durations, and nadir pH values were calculated during feeding, the first hour postprandial (1stPP), the second hour postprandial (2ndPP), and fasting. RESULTS: Compared with classic 2-phase events, POEs were cleared significantly more efficiently during 1stPP (3-fold, P = 0.02), 2ndPP (3-fold, P = 0.0001), and fasting (4.5-fold, P < 0.0001), and were less acidic during 2ndPP (1.9 +/- 0.15 vs 2.6 +/- 0.07, P = 0.0005) and fasting (1.5 +/- 0.12 vs 2.9 +/- 0.07, P < 0.0001). Whereas clearance of classic 2-phase events became increasingly less efficient, clearance of POEs did not fluctuate significantly during the course of the feeding cycle. CONCLUSIONS: The lower acidity and more rapid clearance during 2ndPP and fasting suggest that POEs are likely to have a different clinical impact (compared with classic 2-phase AGER events) during later phases of the feeding cycle.

Acid gastroesophageal reflux in symptomatic infants is primarily a function of classic 2-phase and pH-only acid reflux event types.

BACKGROUND: Combined esophageal pH monitoring (EPM) and multichannel intraluminal impedance (MII) reveal 4 unique acid gastroesophageal reflux (AGER) types in infants: classic 2-phase, single-phase, pH-only events (POEs), and re-reflux episodes. The extent to which different AGER event types contribute to AGER frequency, acid reflux exposure time (ARET), and the number of episodes lasting 5 minutes or longer, has never been reported. In this study, EPM/MII was used to assess AGER in symptomatic infants on the basis of these 4 AGER types. MATERIALS AND METHODS: EPM/MII tracings from 12 symptomatic infants (<12 months old) were examined. Mean frequencies and durations of each AGER type, percentages of total ARET due to each AGER type, and percentages of different AGER types lasting 5 minutes or longer, were measured. RESULTS: Of 926 total AGER events, 23.1%, 6.3%, 69.2%, and 1.5% were classic 2-phase, single-phase, POEs, and re-reflux episodes, respectively. In 20.2 hours of combined ARET, 52.3%, 2.3%, 42.4%, and 3.0% occurred during classic 2-phase, single-phase, POEs, and re-reflux episodes, respectively. Classic 2-phase and POE events were both more frequent than single-phase (P = 0.002 and P < 0.0001) and re-reflux (P = 0.002 and P < 0.0001) episodes, respectively. Increasing numbers of AGER episodes were strongly correlated with POEs (P = 0.0001). Of the 35 total AGER episodes that lasted 5 minutes or longer, 94% were classic 2-phase episodes or POEs (57% and 37%, respectively). CONCLUSIONS: In symptomatic infants, total AGER episodes, total ARET, and AGER episodes lasting 5 minutes or longer are largely a function of classic 2-phase and pH-only AGER types.