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\begin{document}

\title{The Key Timing of Pharyngeal Reflux in Patients with Laryngopharyngeal
Reflux}



\author[1]{Jeong Wook Kang}%
\author[2]{Young Chan Lee}%
\author[3]{Seong-Gyu Ko}%
\author[2]{Young Gyu Eun}%
\affil[1]{Kyung Hee University Hospital}%
\affil[2]{Kyung Hee univesity Hospital}%
\affil[3]{College of Korean Medicine, Kyung Hee University}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives: To analyze the incidence of pharyngeal reflux in
laryngopharyngeal reflux patients over a 24-hour period and find out the
key timing of pharyngeal reflux. Design: Retrospective descriptive
analysis Setting: Single institution. Participants: Sixty-nine patients
with LPR and twenty-six normal controls Methods: We reviewed 69 patients
who visited our clinic with LPR-related symptoms and were proven to have
pharyngeal reflux via 24-hour multichannel intraluminal impedance-pH
(24hr MII-pH) monitoring. Quantitative analysis was conducted for the
LPR profiles, such as the acidity of reflux, nighttime reflux, and
positional reflux. The time series of pharyngeal reflux episodes and
mealtimes were analyzed over a 24-hour period. Also, we recruited 26
normal controls. We compared the timing of pharyngeal reflux between LPR
patients and asymptomatic controls. Results: The quantitative analysis
revealed that pharyngeal reflux occurred 4.88 \selectlanguage{ngerman}± 4.59 times over 24
hours. Weakly acidic pharyngeal reflux was more abundant than acidic or
weakly alkaline reflux. Pharyngeal reflux occurred mainly during daytime
in the upright position. The most frequent timing of pharyngeal reflux
episodes was within 2 hours after meals. Additionally, there was no
significant difference of the timing of post-prandial reflux between LPR
patients and asymptomatic controls. Conclusion: The key timing of
pharyngeal reflux in patients with LPR was post-prandial 2 hours.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{The Key Timing of Pharyngeal Reflux in Patients with
Laryngopharyngeal Reflux}

\textbf{Abstract}

\emph{Objectives}\textbf{:} To analyze the incidence of pharyngeal
reflux in laryngopharyngeal reflux patients over a 24-hour period and
find out the key timing of pharyngeal reflux.

\emph{Design}\textbf{:} Retrospective descriptive analysis

Setting : Single institution.

\textbf{Participants} : Sixty-nine patients with LPR and twenty-six
normal controls

\emph{Methods}\textbf{:} We reviewed 69 patients who visited our clinic
with LPR-related symptoms and were proven to have pharyngeal reflux via
24-hour multichannel intraluminal impedance-pH (24hr MII-pH) monitoring.
Quantitative analysis was conducted for the LPR profiles, such as the
acidity of reflux, nighttime reflux, and positional reflux. The time
series of pharyngeal reflux episodes and mealtimes were analyzed over a
24-hour period. Also, we recruited 26 normal controls. We compared the
timing of pharyngeal reflux between LPR patients and asymptomatic
controls.

\emph{Results}\textbf{:} The quantitative analysis revealed that
pharyngeal reflux occurred 4.88 \selectlanguage{ngerman}± 4.59 times over 24 hours. Weakly
acidic pharyngeal reflux was more abundant than acidic or weakly
alkaline reflux. Pharyngeal reflux occurred mainly during daytime in the
upright position. The most frequent timing of pharyngeal reflux episodes
was within 2 hours after meals. Additionally, there was no significant
difference of the timing of post-prandial reflux between LPR patients
and asymptomatic controls.

\emph{Conclusion}\textbf{:} The key timing of pharyngeal reflux in
patients with LPR was post-prandial 2 hours.

\emph{Keywords}\textbf{.} Laryngopharyngeal Reflux; 24-Hour Multichannel
Intraluminal Impedance pH Monitoring; Reflux Type

\textbf{Keypoints}

\begin{itemize}
\tightlist
\item
  Pharyngeal reflux episodes of laryngopharyngeal reflux (LPR) patients
  dominantly occur in daytime.
\item
  Most pharyngeal reflux of LPR patients occurs during upright position.
\item
  Pharyngeal reflux of LPR patients frequently occurs within 2 hours
  after mealtime.
\item
  Acidities of post-prandial pharyngeal reflux were weakly acid and
  weakly alkaline.
\item
  The fundamental timing of post-prandial pharyngeal reflux in LPR
  patients does not differ from normal controls.
\end{itemize}

\textbf{Introduction}

Laryngopharyngeal reflux (LPR) is defined as extra-esophageal reflux of
gastroduodenal content to the laryngopharynx, affecting the upper
aerodigestive tract.\textsuperscript{1} LPR is similar to
gastroesophageal reflux disease (GERD), in which gastric acid rises up
the esophagus. Because of their similarities, gastroenterologists manage
LPR patients as a subtype of GERD.\textsuperscript{2} However,
otolaryngologists consider LPR as a new disease entity because many
patients with LPR-related symptoms have no GERD-associated
symptoms.\textsuperscript{3} Moreover, non-acid reflux or even gas
reflux can be a disease etiology of LPR, owing to its multifactorial
nature.\textsuperscript{4}

The gastroesophageal junction consists of a lower esophageal sphincter
(LES), diaphragm, and phrenoesophageal ligament.\textsuperscript{5} The
primary LES function is to allow food transit during swallowing and
prevents the reflux of gastroduodenal contents back into the esophagus.
Transient lower esophageal sphincter relaxation (TLESR) is defined as
spontaneous LES relaxation without swallowing. The TLESR exists
physiologically to prevent the swallowing of air. However, TLESR also
allows gastroesophageal reflux to occur.\textsuperscript{6} TLESR can be
triggered by gastric distension after meals.\textsuperscript{7} Since
TLESR mainly occurs after meals, it has been considered as a major cause
of post-prandial GERD-related symptoms.\textsuperscript{8} A
meta\selectlanguage{english}-analysis reported that baclofen, which inhibits TLESR, decreases
the number of reflux episodes in GERD patients.\textsuperscript{9}

`Laryngopharyngeal Reflux Study Group of Young Otolaryngologists of the
International Federation of Otorhinolaryngological Societies' indicated
that 24\selectlanguage{english}-hour multichannel intraluminal impedance\selectlanguage{english}-pH (24hr MII\selectlanguage{english}-pH)
monitoring is the best way to diagnose LPR based on
hypopharyngeal-esophageal reflux episodes
(HREs).\textsuperscript{10}However, to the best of our knowledge, there
has been no study specifically showing whether HREs occurring in LPR
actually occur frequently after meals, as shown in the TLESR phenomenon
in GERD. Therefore, in this study, we tried to investigate the
antecedent relationship between diet and HREs in LPR patients through
diachronic analysis of 24hr MII-pH monitoring.

\textbf{Materials and Methods}

\textbf{Subjects and study design}

In this study, we retrospectively reviewed patients diagnosed with LPR
via 24hr MII-pH monitoring. Examiners advised to all patients to keep
their common diet during 24hr MII-pH monitoring. Patients with typical
reflux symptoms and \selectlanguage{english}[?] 1 objective pharyngeal reflux episode were
classified as LPR patients.\textsuperscript{11} LPR symptoms were
assessed using the reflux symptom index (RSI).\textsuperscript{12} The
objective pharyngeal reflux episode was assessed using 24hr MII-pH
monitoring.\textsuperscript{13} Finally, we enrolled 69 LPR patients
whose test time of 24-hour MII-pH monitoring could be estimated, and raw
recording files could be accessible. Additionally, we recruited normal
controls without reflux-related symptom. 24hr MII-pH monitoring was
performed on the healthy controls. The time of pharyngeal reflux
episodes in the healthy controls was analyzed and compared with the LPR
patients. This study was approved by Institutional Review Board of OOO.

\selectlanguage{english}\textbf{24-hour multichannel intraluminal impedance-pH monitoring}

All subjects underwent 24hr MII\selectlanguage{english}-pH monitoring using a multi-channel
probe catheter for LPR (Sandhill Scientific, Inc., Highlands Ranch, CO,
ZAI-BL-54, 55, 56, ComforTEC Z/PH single-use 2.3-mm-diameter probe). The
catheter has four pairs of esophageal impedance electrodes, two pairs of
pharyngeal impedance electrodes, and two proximal-distal-pH sensors. We
placed the most proximal pharyngeal impedance electrodes 1 cm above the
upper esophageal sphincter. We checked the number of pharyngeal reflux
events, specific event time by 24-hour notation, and acidity of reflux
contents. Mealtimes were excluded from analysis. The pharyngeal reflux
was defined as any reflux episode reaching proximally to 1 cm above the
upper border of UES.\textsuperscript{14} The pharyngeal reflux includes
liquid reflux, and mixed reflux.\textsuperscript{15} Liquid reflux
retrograde 50\% decrease in impedance starting distally and propagating
at least to the next 2 or more proximal impedance measuring segments.
Mixed reflux was defined as a combination of the gas reflux and liquid
reflux patterns. The number of pharyngeal reflux was manually analyzed
by an otolaryngology specialist after automated pre-analysis with
autoscan software (Bioview Analysis, Sandhill Scientific). We defined
daytime as 06:00--18:00 and nighttime as 18:00--06:00. Pre- and
post-prandial periods were defined as 2 h immediately before and after
mealtime, respectively. The cut-off values of acidity classification
were acid (pH \textless{} 4), weakly acidic (7 \textgreater{} pH
\textgreater{} 4), and weakly alkaline (pH \textgreater{} 7).

\textbf{Statistical analysis}

Paired t-test and Wilcoxon signed rank test were used to compare
pre-prandial and post-prandial pharyngeal reflux according to whether
they were parametric or not. Statistical analysis was performed using
the R software (https://www.R-project.org, ver. 4.1.0).

\textbf{Results}

A total of 69 patients were enrolled in the study. Demographic
parameters and baseline reflux symptoms are summarized in \textbf{Table
1} . The male-to-female ratio was 25/43. The mean value of Age, BMI, and
RSI were 55.93 +- 13.02, 24.8 +- 2.71, and 12.28 +- 6.19. The most severe
reflux symptom was globus, with a mean value of 3.77 +- 1.7.

The 24hr MII-pH monitoring revealed the characteristics of pharyngeal
reflux patterns. \textbf{Table 2} shows the properties of pharyngeal
reflux depending on acidity, event time, and body position. The number
of weakly acidic pharyngeal reflux was high (3.41 +- 3.27), while acidic
and weakly alkaline reflux were 0.93 +- 2.34 and 0.55 +- 1.02,
respectively. The hourly incidence of daytime reflux, 0.229 +- 0.282, was
statistically more frequent than that of nighttime reflux (0.097 +- 0.13;
p \textless{} 0.001). The reason for using hourly incidence, and not the
total number of reflux, is for even statistical comparison over the same
observation time. In the analysis according to body position, the hourly
incidence of pharyngeal reflux was statistically higher in the upright
position (0.327 +- 0.339) than during the recumbent position (0.064 +-
0.117; p \textless{} 0.001).

We sought to evaluate the relationship between reflux episodes and
mealtimes. The common mealtimes of enrolled patients were concentrated
at 9:00--10:00 and 16:00--18:00 out of 24 hours (\textbf{Figure 1A} ).
The high incidence of pharyngeal reflux was recorded at 10:00--11:00 and
19:00--20:00 out of 24 h (\textbf{Figure 1B} ). We found that the
incidence of pharyngeal reflux increased after mealtime (\textbf{Figure
1C} ). Therefore, we compared the number of pharyngeal reflux episodes
for 2 h before and after mealtime (\textbf{Table 3} , \textbf{Figure 2}
).\textbf{Table 3} shows the comparison between pre- and post-prandial
pharyngeal reflux frequency within 2 h around mealtime. All
post-prandial reflux episodes (1.256 +- 0.878) were statistically more
frequent than all pre-prandial reflux episodes (0.632 +- 0.548, p
\textless{} 0.001). In classification according to acidity, the number
of weakly acidic post-prandial reflux (0.853 +- 0.665) was significantly
higher than that of pre-prandial weakly acidic reflux (0.433 +- 0.447, p
\textless{} 0.001). The numbers of post-prandial acid reflux and
pre-prandial acid reflux were 0.212 +- 0.420 and 0.134 +- 0.375,
respectively (p = 0.11). The numbers of post-prandial weakly alkaline
reflux and pre-prandial weakly alkaline reflux were 0.191 +- 0.390 and
0.065 +- 0.180 (p = 0.012), respectively. \textbf{Figure 2} shows the
frequency of pharyngeal reflux for all participants based on the center
zero, which represented the mealtime. The number of post-prandial
pharyngeal reflux was relatively larger than that of pre-prandial
pharyngeal reflux.

Twenty-six patients were recruited as a normal control group, and
pharyngeal reflux episodes were found in 5 patients on 24hr-MII-pH
monitoring. The mean number of pharyngeal reflux episodes in the 5
patients was 1.4 times. \textbf{Table 4} reveals whether there was a
difference in the timing of post-prandial pharyngeal reflux between
normal controls and LPR patients. Analyzing the time relationship
between mealtime and pharyngeal reflux episodes, the timing of
post-prandial reflux was 58.2 +- 61.8 minutes in the LPR patient group
and 38.4 +- 34.2 minutes in the normal control group, with no statistical
difference (p = 0.322).

\textbf{Discussion}

Since Koufman's double-probe pH monitoring study for gastroesophageal
reflux disease, several studies have improved our understanding of
LPR.\textsuperscript{16} However, because 24hr MII-pH monitoring is an
uncomfortable test that patients are reluctant to do, we may shorten the
test time if we know when pharyngeal reflux occurs frequently. Moreover,
it will be helpful in establishing an appropriate treatment strategy by
adjusting the timing of drug administration, it also may improve the
accuracy of the analysis of the test outcome. Our research may
contribute to the diagnosis and treatment of LPR. In a recent study, it
was reported that automated analysis overestimates the number of reflux
episodes compared to manual analysis.\textsuperscript{17} In our study,
the hourly number of pharyngeal reflux episodes was meaningful because
it was based on manual analysis by a skilled otolaryngologist.

In GERD, esophageal reflux typically occurs during the night and is
called nocturnal reflux. GERD reflux usually occurs in a recumbent
position. Contrasting results were obtained in this study as well (Table
2). The daytime incidence was more than two times higher than the
nighttime incidence, and the frequency of pharyngeal reflux was five
times higher in the upright position. Our study provides clues as to
whether shortening the 24-hour monitoring period is appropriate.
However, careful consideration is required in this regard because other
studies have reported that nocturnal reflux is associated with disease
severity.\textsuperscript{10} Additionally, our findings lead us to
rethink the usefulness of twice-daily proton-pump inhibitors (PPIs) for
all LPR patients. A prospective cohort study on western patients showed
that twice-daily PPIs is more efficient than once-daily
PPIs.\textsuperscript{18} However, recent another prospective cohort
study on Asian patients fails to show the therapeutic advantage of
twice-daily PPIs.\textsuperscript{19} If patients have no nighttime
reflux event, the second dose of PPIs may not useful.

We confirmed that pharyngeal reflux increased after meals compared to
before meals (Table 3). This is similar to the esophageal reflux pattern
induced by TLESR in GERD. TLESR occurs frequently in the post-prandial
period, especially within 15 minutes after meals.\textsuperscript{20} It
is correlated that the distal esophageal reflux episodes in GERD
typically occur in the post-prandial 1 h.\textsuperscript{20} Since an
acid pocket has formed near the cardia at that time, TLESR can increase
gastric acid up to the esophagus and cause heartburn symptoms in GERD
patients.\textsuperscript{21} The incidence of TLESR in GERD patients is
more than two times higher than that of normal healthy
controls.\textsuperscript{22} An esophago-pharyngeal regurgitation
process is required to induce the laryngopharyngeal symptoms in LPR. A
previous study found that transient upper esophageal sphincter (UES)
relaxation was related to pharyngeal reflux in post-prandial 3
h.\textsuperscript{23} The UES relaxation was not related to swallowing
activity and was considered transient spontaneous relaxation. Our study
also showed a doubling incidence of pharyngeal reflux in the 2 h
post-prandial period compared to the pre-prandial 2 h (\textbf{Figure 2}
). If post-prandial pharyngeal reflux plays an important role in the
physiology of LPR, the 24-hour monitoring time could be reduced. In
fact, there have been attempts to reduce the study time for GERD. A GERD
study reported that post-prandial 3 h MII-pH monitoring could be used as
a predictor of gastroesophageal reflux disease.\textsuperscript{24}

Merati et al. reported that pharyngeal reflux episodes were detected in
0-33\% of normal subjects in their
meta-analysis.\textsuperscript{25}Looking at the studies included in
their meta-analysis, the mean number of pharyngeal reflux episodes found
in normal subjects was 1-3 times. The pharyngeal reflux pattern of
normal subjects involved in those study was similar to that of normal
controls of this study. In this study, pharyngeal reflux episodes were
detected in 19\% of normal controls, and the mean numbers of their
pharyngeal reflux episodes were 1.4. There was no study that revealed
the timing of pharyngeal reflux in normal subjects. However, the fact
that TLESR occurs mainly after meals in normal subjects is comparable to
that pharyngeal reflux occurs mainly after meals in normal controls of
this study.\textsuperscript{6,7} There was not statistical difference in
the major timing of pharyngeal reflux episodes in LPR patients and
normal controls, but the difference in frequency was clear. This
suggests the importance of reducing the frequency of post-prandial
pharyngeal reflux episode in the treatment of LPR patients.

Some potential shortcomings of this study were its retrospective design.
Some patients were inevitably excluded from this study. The causes of
exclusion were as follows: (1) unclear start time of 24hr MII-pH
monitoring and (2) no raw data files for analysis. The dropout rate of
the subjects can cause selection bias. In this study, the mealtimes of
the enrolled 69 patients appeared to have a double peak shape
(\textbf{Figure 1} ). This could mean that patients skipped breakfast
among three meals per day despite our education to keep common diet To
prevent vomiting during the 24hr MII-ph probe insertion process, the
insertion was performed in a fasting state. However, skipping breakfast
may have resulted in a few failures in monitoring the routine 24 hours
of LPR patients. Eight patients had medical history of GERD among
enrolled 69 patients. Even if it is assumed that all eight patients have
GERD, we thought that it was a small fraction compared to the total
number of patients.

\textbf{Conclusions}

In conclusion, the results of this study indicate that 2 hours after
meals is a very important pharyngeal reflux timing in LPR patients.
Therefore, in the future, we need to think about ways to reduce
pharyngeal reflux episodes that occur after meals in LPR patients.



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\textbf{Table 1.} Baseline characteristics of 69 enrolled subjects with
laryngopharyngeal reflux\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Parameter & Baseline\tabularnewline
\midrule
\endhead
Patient, n & 69\tabularnewline
Male & 26\tabularnewline
Female & 43\tabularnewline
Age, y & 55.93 \selectlanguage{ngerman}± 13.02\tabularnewline
Height, cm & 163.13 \selectlanguage{ngerman}± 9.71\tabularnewline
BW, kg & 65.58 \selectlanguage{ngerman}± 12.16\tabularnewline
BMI, kg/m\textsuperscript{2} & 24.8 \selectlanguage{ngerman}± 2.71\tabularnewline
RSI &\tabularnewline
Voice & 1.38 \selectlanguage{ngerman}± 1.55\tabularnewline
Throat & 2.62 \selectlanguage{ngerman}± 2.02\tabularnewline
PND & 0.42 \selectlanguage{ngerman}± 1.14\tabularnewline
Swallow & 0.31 \selectlanguage{ngerman}± 0.74\tabularnewline
Cough-supine & 0.19 \selectlanguage{ngerman}± 0.69\tabularnewline
Dyspnea & 0.58 \selectlanguage{ngerman}± 1.33\tabularnewline
Cough & 0.58 \selectlanguage{ngerman}± 1.21\tabularnewline
Globus & 3.77 \selectlanguage{ngerman}± 1.7\tabularnewline
Heartburn & 1.65 \selectlanguage{ngerman}± 1.7\tabularnewline
Total & 12.28 \selectlanguage{ngerman}± 6.19\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

Data are shown as mean ± SD; BW, body weight; BMI, body mass index; RSI,
reflux symptom index; PND, post-nasal drip.

\textbf{Table 2.} Characteristics of pharyngeal reflux of 24-hour
multichannel intraluminal impedance-pH monitoring.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Pharyngeal reflux & p-value\tabularnewline
\midrule
\endhead
Acidity, n & &\tabularnewline
Acid & 0.93 \selectlanguage{ngerman}± 2.34 &\tabularnewline
Weakly acidic & 3.41 \selectlanguage{ngerman}± 3.27 &\tabularnewline
Weakly alkaline & 0.55 \selectlanguage{ngerman}± 1.02 &\tabularnewline
All reflux & 4.88 \selectlanguage{ngerman}± 4.59 &\tabularnewline
Time, REs/h & & \textless{} 0.001\tabularnewline
Daytime & 0.229 \selectlanguage{ngerman}± 0.282 &\tabularnewline
Nighttime & 0.097 \selectlanguage{ngerman}± 0.13 &\tabularnewline
Body position, REs/h & & \textless{} 0.001\tabularnewline
Upright & 0.327 \selectlanguage{ngerman}± 0.339 &\tabularnewline
Recumbent & 0.064 \selectlanguage{ngerman}± 0.117 &\tabularnewline
\bottomrule
\end{longtable}

Data are shown as mean \selectlanguage{ngerman}± SD; RE, reflux event; Daytime, 6:00 AM--6:00
PM; Nighttime, 6:00 PM--6:00 AM

\textbf{Table 3.} Comparison between pre- and post-prandial pharyngeal
reflux within 2 hours according to acidity in 24-hour multichannel
intraluminal impedance-pH monitoring.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Pharyngeal Reflux & Pharyngeal Reflux & P-value\tabularnewline
\midrule
\endhead
& Pre-prandial & Post-prandial &\tabularnewline
Within 2 hours, n & & &\tabularnewline
Acid & 0.134 \selectlanguage{ngerman}± 0.375 & 0.212 \selectlanguage{ngerman}± 0.420 & 0.110\tabularnewline
Weakly acidic & 0.433 \selectlanguage{ngerman}± 0.447 & 0.853 \selectlanguage{ngerman}± 0.665 & \textless{}
0.001*\tabularnewline
Weakly alkaline & 0.065 \selectlanguage{ngerman}± 0.180 & 0.191 \selectlanguage{ngerman}± 0.390 & 0.012*\tabularnewline
All reflux & 0.632 \selectlanguage{ngerman}± 0.548 & 1.256 \selectlanguage{ngerman}± 0.878 & \textless{}
0.001*\tabularnewline
\bottomrule
\end{longtable}

Data are shown as mean \selectlanguage{ngerman}± SD.

\textbf{Table 4.} Comparison between patients with laryngopharyngeal
reflux and normal controls.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
LPR patients (N = 69)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Normal controls (N = 26)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (y)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
55.93 \selectlanguage{ngerman}± 13.02\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
44.23 \selectlanguage{ngerman}± 13.87\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Male : Female (n)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26:43\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6:20\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Positive of pharyngeal reflux (n)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69/69 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5/26 (19\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Timing of post-prandial reflux (min)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58.2 \selectlanguage{ngerman}± 61.8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38.4 \selectlanguage{ngerman}± 34.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.322\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data are shown as mean \selectlanguage{ngerman}± SD.

\textbf{FIGURE LEGENDS}

\textbf{Figure 1.} Cumulative distribution of meal and pharyngeal reflux
episodes in total 69 enrolled subjects. (A) Histogram of meal; (B)
Histogram of pharyngeal reflux; (C) Probability density plot of
pharyngeal reflux episodes over 24 h.

\textbf{Figure 2.} Histogram of pharyngeal reflux episodes from
pre-prandial 2 hours to post-prandial 2 hours in a total of 69 enrolled
subjects. The x-axis means the relative time from mealtime represented
as zero.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

