Clinical impact of lipid injectable emulsion in internal medicine inpatients exclusively receiving parenteral nutrition: a propensity score matching analysis from a Japanese medical claims database - BMC Medicine - BMC Medicine

Background

Although guidelines urge lipid injectable emulsions (ILEs) beryllium utilized arsenic a portion of parenteral nutrition, galore patients successful Japan person lipid-free parenteral nutrition. Furthermore, small is known astir the effect of ILEs connected objective outcomes successful aesculapian inpatients managed with parenteral nutrition. The purpose of this survey was to analyse the objective interaction of ILEs connected interior medicine inpatients receiving parenteral nutrition.

Methods

A propensity people matching (PSM) investigation was performed utilizing a aesculapian claims database covering 451 hospitals successful Japan. Participants included the pursuing interior medicine inpatients, ages ≥ 18 years, fasting > 10 days, and receiving exclusively parenteral nutrition, betwixt 2011 and 2020. Participants were divided into 2 groups: those who did and did not person ILEs. The superior endpoint was in-hospital mortality. The secondary endpoints included intravenous catheter infection, activities of regular surviving (ADL), infirmary magnitude of enactment (LOS), and full aesculapian costs. To set for vigor doses, logistic oregon aggregate regression analyses were performed utilizing vigor dose arsenic an further explanatory variable.

Results

After PSM, 19,602 matched pairs were formed retired of 61,437 patients. The ILE radical had importantly little incidences than the non-ILE radical of in-hospital mortality (20.3% vs. 26.9%; likelihood ratio [OR], 0.69; 95% assurance interval [CI], 0.66–0.72; p < 0.001), deteriorated ADL (10.8% vs. 12.5%; OR, 0.85; 95% CI, 0.79–0.92; p < 0.001), and shorter LOS (regression coefficient, − 0.8; 95% CI, − 1.6–0.0; p = 0.045). After adjusting for vigor dose, these ORs oregon regression coefficients demonstrated the aforesaid tendencies and statistical significance. The mean full aesculapian costs were $21,009 successful the ILE radical and $21,402 successful the non-ILE radical (p = 0.08), and the adjusted regression coefficient for the ILE vs. the non-ILE radical was − $860 (95% CI, − $1252 to − $47).

Conclusions

ILE usage was associated with improved objective outcomes, including little in-hospital mortality, successful interior medicine inpatients receiving parenteral nutrition.

Lipid injectable emulsions (ILEs) service arsenic a root of indispensable fatty acids and energy-dense non-protein calories, arsenic good arsenic a main portion of parenteral nutrition [1, 2]. Nutritional enactment has been associated with improved objective outcomes successful hospitalized patients [3, 4]. Recent American Society for Parenteral and Enteral Nutrition (ASPEN) recommendations person advocated for the usage of ILEs for those patients who necessitate parenteral nutrition [5]. This proposal is based connected the imaginable objective and biochemical benefits of the summation of ILEs to parenteral nutrition, which see modulation of inflammatory responses and simplification of immune suppression.

The worth of utilizing ILEs arsenic portion of parenteral nutrition for surgical and critically sick patients has been good established, with circumstantial ILEs demonstrating some therapeutic and adverse effects [6]. On the different hand, caller retrospective surveys utilizing aesculapian claims databases [7, 8] person suggested that ILEs are not being wide utilized arsenic portion of parenteral nutrition successful the existent objective signifier successful Japan, though this is not the lawsuit globally. Moreover, small is known astir the effects of ILEs connected interior medicine inpatients who are being managed with parenteral nutrition. In particular, real-world information connected the existent interaction of ILEs connected objective outcomes successful interior medicine inpatients being managed with parenteral nutrition are lacking, and determination person been nary studies that person investigated the cost-effectiveness of utilizing ILEs for these patients.

Clarifying the interaction of ILEs connected objective outcomes successful interior medicine inpatients whitethorn assistance beforehand the much due absorption of parenteral nutrition successful this diligent population. The intent of this survey was to analyse the interaction of the usage of ILEs connected objective outcomes (i.e., mortality, activities of regular living, and complications) and aesculapian costs successful big interior medicine inpatients receiving parenteral nutrition, utilizing a aesculapian claims database.

Design and information source

A retrospective investigation was performed utilizing information that was extracted from a aesculapian claims database which included 451 hospitals and managed by the Medical Data Vision Co., Ltd. (MDV; Tokyo, Japan). The database uses the diagnosis process combination/per-diem outgo strategy (DPC/PDPS), successful which supplier reimbursement is calculated connected a flat-rate per-diem interest based connected the diagnosis group. The survey protocol was approved by the Ethics Committees of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (No. 2108-041) and the Kurume University Graduate School of Medicine (No. 21139) and registered astatine the University Hospital Medical Information Network Clinical Trial Registry (UMIN000044962). Informed consent was not required, due to the fact that each idiosyncratic accusation utilized successful this survey was anonymized.

The database included accusation connected dates of infirmary admittance and discharge, property astatine admission, sex, height, assemblage weight, assemblage wide scale (BMI), fig of beds successful admittance hospital, twelvemonth and benignant of admission, superior diseases (coded utilizing the International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10]), comorbidities (used to find the Charlson Comorbidity Index [CCI]) [9], activities of regular surviving (ADL) based connected the Barthel Index (BI) [10], levels of consciousness based connected the Japan Coma Scale (JCS) [11], malnutrition defined arsenic having mediocre oral intake of astatine slightest 10 days and debased assemblage wide scale according to the Global Leadership Initiative connected Malnutrition (GLIM) criteria [12], aesculapian treatments during hospitalization (using Japan-specific aesculapian claims codes), and discharge result status, arsenic good arsenic different accusation not utilized successful our study. The full regular doses of parenteral energy, amino acids, and ILE prescribed were calculated utilizing the parenteral nutrition infusion merchandise names and compositions on with the prescribed quantities of those products, arsenic they appeared successful the database. When signaling these doses, time 1 was regarded arsenic the time fasting started, time 2 arsenic the 2nd time aft fasting started, and truthful on.

Patient population

This survey included hospitalized big patients ages 18 years oregon older who were fasting (receiving nary oral oregon enteral nutrition) for much than 10 consecutive days and were managed with parenteral nutrition, betwixt January 2011 and September 2020. Patients were excluded from the survey who underwent country oregon entered the intensive attraction portion betwixt the time of admittance and the commencement of fasting, were suspected to beryllium successful the terminal illness signifier (defined arsenic prescribed mean vigor doses < 10 kcal/kg oregon mean amino acerb doses < 0.5 g/kg connected days 4 done 10), oregon were considered to beryllium overfed (which we based connected prescribed mean vigor doses ≥ 30 kcal/kg connected days 4 done 10). The rationale for the usage of days 4 done 10 was that the medication of parenteral nutrition usually involves a gradual summation successful dose implicit the archetypal 3 to 4 days earlier reaching the afloat people dose [7, 8].

Clinical outcomes

The superior endpoint was in-hospital mortality. The secondary endpoints included intravenous catheter corruption during hospitalization, deteriorated ADL astatine discharge, magnitude of enactment (LOS), readmission, and full aesculapian costs. ADL astatine discharge, LOS, and readmission were recorded for lone those patients who were discharged alive, whereas different information were recorded for each patients. Medical costs were calculated based connected Japanese yen and were past converted to US dollar (US$) utilizing the yearly speech complaint of 2020 reported by the Organization for Economic Cooperation and Development (OECD) (US$1 = 107 Japanese yen) [13]. Patients were considered to person deteriorated ADL erstwhile their full BI scores were little astatine the clip of discharge than astatine the clip of admission. Readmission was defined arsenic being admitted to the aforesaid infirmary again wrong 30 days of discharge.

Variables

The variables extracted from the database were categorized arsenic follows: property astatine admittance (18–59, 60–69, 70–79, 80–89, oregon ≥ 90 years), BMI (< 16.0, 16.0–18.5, 18.5–22.5, 22.5–25.0, oregon ≥ 25.0), fig of beds admittance infirmary (< 200, 200–500, oregon ≥ 500), twelvemonth of admittance (2011–2012, 2013–2014, 2015–2016, 2017–2018, oregon 2019–2020), benignant of admittance (elective oregon emergency), superior illness (by ICD-10 code), comorbidities (CCI of 0, 1, 2, oregon ≥ 3), ADL (BI of 0, 5–20, 25–40, 45–60, 65–95, oregon 100), levels of consciousness (JCS of 0 [alert], 1–3 [awake], 10–30 [arousable], oregon 100–300 [coma]), and nutritional presumption (malnutrition defined arsenic BMI < 18.5 if < 70 years aged oregon BMI < 20 if > 70 years old). Information astir aesculapian treatments (e.g., albumin infusion, humor transfusion, respirator use, dialysis, nutrition enactment team, and rehabilitation) ordered betwixt the time of admittance and time 10 was extracted from the database for each patient. Missing values for the benignant of admission, BI, and JCS were placed successful an “unknown” category.

Prescribed doses of parenteral nutrition

The prescribed mean regular doses of energy, amino acids, and ILE for days 4 to 10 aft the commencement of fasting were calculated for each diligent based connected the parenteral nutrition infusion merchandise creation and prescribed quantity of that infusion and were based connected the presumption that nutrient doses often instrumentality until time 4 to scope 100% of their people [14]. Prescribed regular doses of vigor and amino acids were calculated arsenic kilocalories (kcal) and grams (g), respectively, and reported per kilogram (kg) of assemblage value and prescribed regular doses of ILE were calculated and reported arsenic some grams and the caloric percent (%) of the full non-protein vigor administered that day.

Statistical analysis

The information absorption and statistical investigation were performed by an autarkic 3rd enactment (A2 Healthcare Corporation; Tokyo, Japan) successful bid to destruct arbitrariness and guarantee transparency. Categorical variables were summarized arsenic numbers and percentages, and continuous variables were summarized arsenic means and modular deviations (SD). Missing values were not included. First, patients eligible for the survey were divided into 2 groups: the ILE group, who were prescribed ILEs during days 4 done 10, and the non-ILE group, who were not prescribed ILEs during days 4 done 10. Next, propensity people matching (PSM) was utilized to set for confounding factors [15]. The propensity people was estimated by multivariable logistic regression investigation with the ILE radical arsenic the nonsubjective adaptable and diligent characteristics arsenic the explanatory variables. PSM was conducted utilizing a one-to-one nearest neighbour method and utilizing the caliper width. The caliper worth was 0.2, and matching was performed wrong the caliper values. To corroborate the covariate equilibrium betwixt the groups, standardized differences were calculated earlier and aft PSM. A standardized quality little than 10% was considered to correspond a balanced covariate [16].

To comparison the 2 groups for each outcome, some earlier and aft PSM, the Student t-test was utilized for continuous variables and the chi-square trial was utilized for categorical variables. To set for the differences successful the prescribed mean regular parenteral vigor doses betwixt the 2 groups, adjacent aft PSM, multivariable logistic oregon aggregate regression analyses, arsenic appropriate, were performed, with the mean regular vigor dose prescribed for days 4 done 10 added arsenic an explanatory variable. In these analyses, likelihood ratios (ORs) oregon regression coefficients, arsenic appropriate, on with 95% assurance intervals (CIs), were calculated, some earlier and aft the accommodation for energy.

For in-hospital mortality, endurance curves were generated for the 2 groups utilizing the Kaplan-Meier method, and a log-rank trial was performed. In addition, the Cox proportional hazard exemplary was utilized to cipher a hazard ratio (HR), on with a 95% CI, of the ILE radical to the non-ILE group, for in-hospital mortality. For these calculations, the patients who were discharged live were censored connected the time of discharge, and the inpatients who survived for 180 days oregon longer were censored connected time 180. All statistical analyses were performed utilizing SAS mentation 9.4 (SAS Institute Inc., Cary, NC, USA), with a two-sided value level of 5%.

Sensitivity analysis

Before modeling, the variance ostentation factors (VIFs) of diligent characteristics and prescribed mean regular parenteral nutrition doses were calculated to corroborate that determination was nary multicollinearity betwixt variables based connected aggregate regression investigation oregon multivariable logistic regression investigation [17].

To corroborate the robustness of PSM, confounding factors were adjusted by multivariable logistic regression investigation oregon aggregate regression analysis, and an accommodation investigation consisting of 2 explanatory adaptable groups (model 1, exemplary 2) was performed. In exemplary 1, the explanatory variables were the 2 groups and the diligent characteristics. In exemplary 2, the explanatory variables were those included successful exemplary 1 arsenic good arsenic the prescribed mean regular parenteral vigor during days 4 to 10. Either ORs oregon regression coefficients, on with 95% CIs, were calculated for each model.

Patient characteristics

Following the screening of 295,464 aesculapian inpatients, a full of 61,437 patients were eligible for the survey (Fig. 1). Based connected the GLIM criteria, malnutrition was recovered successful 28,097 (45.7%) of the survey patients (Table 1). Among each patients, 19,618 (31.9%) were successful the ILE radical and 41,819 (68.1%) were successful the non-ILE group, and the mean (SD) parenteral nutrition duration for each patients was 24.4 (28.5) days. After PSM, 19,602 matched pairs of patients were formed. Of the 19,602 patients successful the ILE group, 16,191 (82.6%) were 60 years oregon older, and 11,439 (58.4%) were males; successful addition, the astir communal superior illness was digestive strategy malignancy successful 6723 (34.3%) patients, followed by digestive strategy illness successful 4865 (24.8%) patients.

Fig. 1

Flowchart of diligent disposition successful the study. ^aSome patients had much than 1 crushed for exclusion. ^bDay 1 is regarded arsenic the time fasting started. Abbreviations: ILE, lipid injectable emulsion (soybean oil-based); ICU, intensive attraction unit; PSM, propensity people matching

Before PSM, the standardized differences betwixt the 2 groups were greater than 10% for sex, BI, JCS, and aesculapian treatments of albumin infusion and nutrition enactment squad (Table 1). After PSM, determination were nary variables with standardized differences greater than 10%.

Mean regular nutrition doses for days 4 to 10

The prescribed mean regular doses of parenteral nutrition for days 4 to 10 were calculated for some groups, some earlier and aft PSM (Table 2). In the ILE group, some earlier and aft PSM, the mean (SD) non-protein calorie ratio of ILEs was 14.3 (11.5) %, and the mean dose of ILEs was 14.2 (10.9) g. After PSM, the mean (SD) vigor dose was 16.5 (4.8) kcal/kg successful the non-ILE radical and 18.8 (5.1) kcal/kg successful the ILE group, and this represented a important quality (p < 0.001). Also aft PSM, the mean (SD) regular dose of amino acids was 0.73 (0.17) g/kg successful some the non-ILE and ILE groups.

Clinical outcomes

The results for superior and secondary endpoints, earlier and aft PSM, arsenic good arsenic the ORs oregon regression coefficients earlier and aft the accommodation for energy, are depicted successful Table 3. Clinical result results reported beneath are those obtained aft PSM, unless noted otherwise.

Primary endpoint

The unadjusted likelihood of in-hospital mortality were importantly little for the ILE radical than for the non-ILE radical (OR, 0.69; 95% CI, 0.66–0.72; p < 0.001). After adjusting for the vigor variable, the OR for in-hospital mortality showed the aforesaid inclination (OR, 0.71; 95% CI, 0.68–0.75). The Kaplan-Meier curves demonstrated a importantly little hazard for in-hospital mortality for the ILE radical vs. the non-ILE radical (HR, 0.76; 95% CI, 0.73–0.79; p < 0.001) (Fig. 2).

Fig. 2

Kaplan-Meier endurance curves for in-hospital mortality of interior medicine inpatients aged 18 years oregon older and fasting for much than 10 days successful Japan, January 2011 to September 2020, aft propensity people matching. The results expressed arsenic the hazard ratio (95% assurance interval) of in-hospital mortality for the ILE radical compared to the non-ILE group. Curves show a importantly little hazard for in-hospital mortality for the ILE radical vs. the non-ILE radical (HR, 0.76; 95% CI, 0.73–0.79; p < 0.001). Abbreviations: ILE, lipid injectable emulsion (soybean oil-based)

Secondary endpoints

There was nary important quality betwixt the 2 groups successful presumption of intravenous catheter infections (1.1% successful the ILE radical vs. 0.9% successful the non-ILE group; unadjusted OR, 1.20; 95% CI, 0.98–1.46; p = 0.08). The unadjusted likelihood of deteriorated ADL successful the patients who were discharged live were importantly little for the ILE radical than for the non-ILE radical (OR, 0.85; 95% CI, 0.79–0.92; p < 0.001). The unadjusted regression coefficient for LOS successful the ILE vs. the non-ILE radical was − 0.8 (95% CI, − 1.6–0.0; p = 0.045), and the coefficient adjusted for the mean regular vigor dose adaptable was − 1.80 (95% CI, − 2.6 to − 1.0).

The mean (SD) full aesculapian costs were $21,009 ($18,439) successful the ILE radical and $21,402 ($24,981) successful the non-ILE radical (p = 0.08), with the ILE radical vs. non-ILE radical unadjusted regression coefficient of − $393 (95% CI, − $822–$48). However, aft accommodation for the prescribed mean regular vigor dose connected days 4 to 10, the regression coefficient of full aesculapian costs was − 860 (95% CI, − $1252 to − $47).

Sensitivity analysis

The VIFs of diligent characteristics and mean regular parenteral nutrition doses were each beneath 2.5, confirming that determination was nary multicollinearity betwixt the variables (Additional record 1: Table S1). The ORs of in-hospital mortality and deteriorated ADL, aft accommodation for diligent characteristics (model 1), were 0.65 (95% CI, 0.62–0.68) and 0.77 (95% CI, 0.71–0.83), respectively (Additional record 1: Table S2). The regression coefficients for LOS were − 1.2 (95% CI, 2.0 to − 0.5) days successful exemplary 1 and − 2.1 (95% CI, − 2.8 to − 1.3) days aft adding the accommodation for mean regular vigor dose for days 4 to 10 successful exemplary 2, confirming the important differences betwixt the ILE radical and non-ILE radical successful some models. As successful the PSM analysis, determination were nary important differences betwixt the 2 groups successful intravenous catheter infections and readmissions. Finally, the regression coefficients for full aesculapian costs were − 411 (95% CI, − $776 to − $47) successful exemplary 1 and − $1244 (95% CI, − $1598 to − $850) successful exemplary 2, confirming that aesculapian costs were importantly little for the ILE radical than for the non-ILE group.

To the champion of our knowledge, this is the archetypal large-scale cohort survey investigating the interaction of parenteral ILE usage connected objective outcomes successful a colonisation of fasting interior medicine inpatients. In this study, we recovered that the patients successful this colonisation who were prescribed parenteral ILEs had importantly little likelihood of in-hospital mortality and of deteriorated ADL than those who were not prescribed ILEs. In addition, the ILE radical had a importantly shorter LOS than the non-ILE group. In contrast, the likelihood of having intravenous catheter infections did not disagree importantly betwixt the groups. Finally, aft accommodation for the vigor dose, the mean full aesculapian costs for the ILE radical were $860 little than for the non-ILE group.

Lipids are 1 of 3 indispensable macronutrients, on with carbohydrates and proteins. The inclusion of ILEs successful parenteral nutrition has been recommended successful respective guidelines [5, 18]. Despite this, this survey confirmed that ILEs are not being utilized consistently arsenic portion of parenteral nutrition successful Japan, arsenic has been antecedently reported [7, 8]. In fact, we observed that doubly arsenic galore patients received parenteral nutrition without ILEs arsenic patients who received it with ILEs successful Japan. There are respective imaginable reasons wherefore ILEs are often not portion of the parenteral nutrition fixed successful Japan. First, the lone commercially disposable ILEs successful Japan travel successful the signifier of soybean oil-derived products. However, these products whitethorn beforehand inflammatory reactions due to the fact that they incorporate precocious levels of n-6 polyunsaturated fatty acids [19], and they whitethorn pb to a deterioration successful immune relation and an accrued hazard of infectious complications due to the fact that of their inhibitory effect connected phagocytosis [20]. Also, whereas 3-in-1 oregon full nutrient admixtures are utilized arsenic the modular globally [21], nary merchandise containing each 3 macronutrients is commercially disposable successful Japan. Given these merchandise limitations, the complexity of adding ILEs separately to parenteral nutrition, and the anticipation of insufficient grooming related to ILE use, clinicians successful Japan whitethorn person been hindered successful their prescribing of ILEs arsenic portion of parenteral nutrition.

We judge that the results of this survey should promote much clinicians successful Japan to prescribe ILEs and frankincense beforehand the enlargement of the marketplace for ILEs. Moreover, important gaps successful ILE medication comparative to published recommendations person been reported successful different countries, including the USA [22]. On apical of that, determination has been a deficiency of studies investigating the prevalence and objective interaction of ILE usage and involving real-world databases. Accordingly, further large-scale investigations should beryllium performed to heighten the knowing of ILE usage successful ample groups of patients and successful real-world settings.

The results of this survey person suggested that the usage of ILEs during parenteral nutrition tin person a affirmative interaction connected objective outcomes, including reducing in-hospital mortality, deterioration of ADLs, and infirmary LOS, and the results suggest this tin beryllium accomplished without expanding the hazard of intravenous catheter infections. Taken together, these findings should rise consciousness that galore fasting infirmary inpatients successful Japan are not being prescribed ILEs during parenteral nutrition and that determination are important benefits to adding ILEs to parenteral nutrition successful hospital-based objective practice. There are imaginable explanations for however the summation of ILEs to parenteral nutrition whitethorn person contributed to the affirmative objective outcomes successful our study. First, the indispensable fatty acids contained successful ILEs are important components of the compartment membrane and are known to play an important portion successful maintaining biologic and physiological functions and arsenic precursors of physiologically progressive substances [18]. Second, astir patients who are fasting and necessitate parenteral nutrition person impaired glucose tolerance, and ILEs tin service arsenic effectual alternate sources of vigor arsenic good arsenic substances that exert protein-sparing effects [23, 24]. This protein-sparing effect of ILEs has been indirectly associated with improved objective outcomes successful fasting aesculapian patients [25].

PSM was utilized successful this survey to mitigate the imaginable confounding by different variables erstwhile investigating the interaction of the summation ILEs connected objective outcomes. The prescribed mean regular parenteral vigor dose was not included arsenic 1 of the covariates successful the archetypal propensity people estimation, due to the fact that it was anticipated that the full vigor doses prescribed would beryllium higher successful the patients who received ILEs than successful those who did not (simply based connected the other calories from the ILEs). Indeed, the ILE radical did person a higher prescribed mean regular vigor dose than the non-ILE group, and this was the lawsuit adjacent aft PSM was applied. Therefore, further multivariate logistic regression and aggregate regression analyses were performed, utilizing the prescribed mean regular vigor dose connected days 4 to 10 arsenic an further explanatory variable, and past PSM was applied again to reassess the interaction of the summation of ILEs connected objective outcomes. After this accommodation for the prescribed mean regular vigor dose, the resulting ORs and regression coefficients for the objective outcomes showed the aforesaid tendencies and statistical significance. Importantly, these results suggested the earlier findings and demonstrated that the summation of parenteral ILEs, autarkic of their publication to higher vigor doses, had important beneficial effects connected in-hospital mortality, deterioration of ADLs, and infirmary LOS.

Activities of regular living

Barthel Index

Body wide index

Charlson Comorbidity Index

Confidence interval

Hazard ratio

Lipid injectable emulsion

Japan Coma Scale

Length of stay

Odds ratio

Propensity people matching

Standard deviations

Variance ostentation factor

References

Authors and Affiliations

1. Department of Gastroenterological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

   Kosei Takagi

2. Biostatistics Center, Kurume University, Kurume, Japan

   Kenta Murotani

3. Medical Affairs Department, Research and Development Center, Otsuka Pharmaceutical Factory, Inc, Tokyo, Japan

   Satoru Kamoshita

4. Research and Development Center, Otsuka Pharmaceutical Factory, Inc, Tokyo, Japan

   Akiyoshi Kuroda

Contributions

The authors’ responsibilities were arsenic follows—all authors: conception and plan of the study, acquisition, investigation oregon mentation of the data, had afloat entree to each of the data, and instrumentality work for the integrity of the information and the accuracy of the information analysis; KT and SK: drafting of the manuscript; KM: statistical analysis; SK: administrative, technical, oregon worldly support; AK: supervision. The authors work and approved the last manuscript.

Corresponding author

Correspondence to Kosei Takagi.

Ethics support and consent to participate

The survey protocol was approved by the Ethics Committees of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (No. 2108-041) and the Kurume University Graduate School of Medicine (No. 21139) and registered astatine the University Hospital Medical Information Network Clinical Trial Registry (UMIN000044962). Informed consent was not required, due to the fact that each idiosyncratic accusation utilized successful this survey was anonymized.

Consent for publication

Not applicable.

Competing interests

Dr. Takagi and Dr. Murotani study grants from Otsuka Pharmaceutical Factory, Inc. during the behaviour of the study. Satoru Kamoshita and Akiyoshi Kuroda are employees of Otsuka Pharmaceutical Factory, Inc. and clasp stocks of Otsuka Holdings Co., Ltd.

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