Effect of holiday admission for acute aortic dissection on in-hospital mortality in Japan: A nationwide study.

BACKGROUND: Patients admitted on weekends have higher mortality than those admitted on weekdays. However, whether the "weekend effect" results in a higher mortality after admission for acute aortic dissection (AAD),-classified according to Stanford types-remains unclear. This study aimed to examine the association between admission day and in-hospital mortality in AAD Type A and B.
METHODS: We used data from the Japanese registry of all Cardiac and Vascular Diseases Diagnostic Procedure Combination, a nationwide claim-based database with data from 953 certified hospitals, and enrolled in-patients with AAD admitted between April 1, 2012, and March 31, 2016. Based on the admission day, we stratified patients into groups (Weekdays, Saturdays, and Sundays/holidays). The influence of the admission day on in-hospital mortality was assessed via multi-level logistic regression analysis. We also performed a Stanford type-based stratified analysis.
RESULTS: Among the included 25,641 patients, in-hospital mortality was 16.0%. The prevalence of patients admitted with AAD was relatively higher on weekdays. After adjustment for covariates, patients admitted on a Sunday/holiday showed an increased risk of in-hospital mortality (odds ratio [OR] 1.20; 95% confidence interval [CI] 1.07-1.33, p<0.001) than patients admitted on weekdays. Among patients admitted on a Sunday/holiday, only the subgroup of Stanford Type A showed a significantly increased risk of in-hospital mortality. (Stanford Type A, non-surgery vs. surgery groups: 95% CI 1.06-1.48 vs. 1.17-1.68, p<0.001 for both groups, OR 1.25 vs. 1.41, respectively, Stanford Type B, non-surgery vs. surgery groups: 95% CI 0.64-1.09 vs. 0.40-2.10; p = 0.182 vs. 0.846; OR 0.84 vs. 0.92).
CONCLUSIONS: In conclusion, patients with AAD Type A admitted on a Sunday/holiday may have an increased in-hospital mortality risk.

Introduction

Acute aortic dissection (AAD), a medical emergency, is a highly lethal condition. Its incidence rate is lower than that of other cardiovascular diseases, such as acute coronary syndrome; therefore, epidemiological studies regarding AAD remain insufficient [1].

The association between weekend admissions and an increased risk of mortality, the “weekend effect” has received much attention over the last two decades [2]. The findings of studies on the “weekend effect” included various acute phase disease management measures such as emergency and intensive care admissions, as well as urgent surgeries; however, none of the studies attributed these measures to the “weekend effect” [2-5]. The “weekend effect” seems to be influenced by the characteristics of the disease or medical systems [6]. Under such circumstances, only a few studies have reported associations between weekend admissions and mortality in AAD [7-9], and the findings regarding the “weekend effect” in AAD were also inconsistent. Kumar et al. [8] and Gallerani et al. [7], in cohort studies in the United States and Italy, respectively, have reported that admission for AAD on a weekend is associated with a significantly higher mortality rate than admission on a weekday. In contrast, Gokalp et al. reported that there was no statistically significant difference between patients with Type A AAD who underwent surgery during daytime working hours and those who underwent surgery during overtime hours in Turkey [10]. Furthermore, Ahlsson et al. reported that while there was no “weekend effect,” nighttime surgery was a risk factor for mortality according to an analysis of European registry data [9]. Moreover, no nationwide studies have been reported the weekend effect in patients with AAD classified by Stanford type, although the natural history, complications, and treatment of AAD differ between Stanford Type A and B patients [11].

Therefore, using the nationwide claim-based database from The Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination (JROAD-DPC), we investigated associations between day-wise variations in admissions for AAD and patient prognosis in a large cohort.

Methods

Study setting and patient selection

This study analyzed data between April 2012 and March 2016, from the JROAD-DPC database, a nationwide, claim-based registry from nearly all teaching Japanese hospitals with beds reserved for cardiovascular patients. The JROAD-DPC database has been described in detail previously [12, 13], and can be briefly described as follows: the JROAD-DPC database established by the Japanese Circulation Society comprises data from teaching hospitals with cardiovascular beds and the Japanese DPC/Per Diem Payment System. This database contain patients’ demographic and disease-specific data. The validity of the diagnoses contained therein has been reported [14].

Using the International Classification of Disease (ICD)-10 diagnosis codes for AAD (I70-0) as a means of identification, the data of adult patients (age >18 years) who were admitted to the hospital with AAD and patients who were admitted for emergencies were extracted from the JROAD-DPC. In addition, the diagnosis, recorded in Japanese, was used to increase the accuracy of the diagnoses; for example, patients with ruptured aortic aneurysms, secondary to trauma, sub-acute or chronic status of AAD, or dissection of peripheral arteries suspicion were excluded. The type of surgery and whether the presence or absence of surgery was related to AAD, recorded in Japanese, were also used to increase accuracy. Using the diagnosis, recorded in Japanese, the Stanford type was determined. A Stanford Type A dissection was defined as any dissection that involved the ascending aorta, whereas a Type B dissection was defined as one that involved the descending aorta. All patients were categorized into seven 1-day-of the week periods. In Japan, we have approximately 17 days of non-weekend holidays annually, considered as national holidays. For the weekday analyses, patients were grouped according to their day of admission into the following groups: weekday (Monday to Friday), Saturdays, and Sunday/holiday groups, and a group for each of the seven days. Saturdays and the Sunday/holiday groups were considered as separate groups, given that not all Japanese hospitals closed on Saturdays.

Patients’ hospitalization dates included the same days between 0:00 am and 11:59 pm.

Between April 2012 and March 2016, a total of 3,626,656 patients were registered in the database. According to the specified ICD-10 codes, 51,608 patients were diagnosed with AAD. The data of 25,641 patients were finally analyzed in this study. The flowchart of the patient selection process is shown in Fig 1.

Fig 1

Flow chart of the patient selection process.

JROAD-DPC, Japanese Registry of all Cardiac and Vascular Diseases Diagnostic Procedure Combination; ICD-10, 10th revision of the International Classification of Disease.

Ethical considerations

Our study protocol was approved by the Ethics Committee of the Nippon Medical School, Japan (approval number 30–03). The requirement for written informed consent was waived because of the anonymized nature of the data.

Measurement

The primary outcome was in-hospital mortality. The secondary outcome was in-hospital mortality by Stanford type. Our database contained data of patients who were brought to the hospital for cardiac arrest and were diagnosed with AAD during their hospital stay. The death of such patients was considered as in-hospital mortality. Contrastingly, the death of patients who were in a dying state and discharged before death upon family request was not considered as in-hospital mortality.

Statistical analysis

Patient characteristics and outcomes in terms of the patients’ sex and Stanford type were expressed as means ± standard deviations (SD), medians (interquartile range), or numbers (percentage of total), as appropriate. The correlation between baseline characteristics and each group was compared using one-way analysis of variance (ANOVA), the Kruskal–Wallis test, or X2 test, as appropriate. Regarding the frequency analysis, the average number of patients admitted per day was compared among the groups (weekdays vs. Saturdays vs. Sundays/holidays and each of the seven- day groups) using ANOVA with post-hoc Bonferroni correction. The influence of the day of admission on in-hospital mortality was assessed using a multi-level logistic regression analysis with the institute as a random intercept adjusting for possible confounders such as sex, age, Stanford type, and surgery. We compared the day of admission among weeks (weekdays [used as a reference], Saturdays vs. Sundays/holidays and groups for each of the seven days [Sundays/holidays was used as a reference]). We also performed a stratified analysis according to the Stanford type and presence or absence of surgery. Statistical analysis was performed using STATA software, version 16.0 (StataCorp, College Station, Texas, USA). Statistical significance was based on a two-tailed test and defined as a p-value of less than 0.05.

Results

Characteristics of the study population

The baseline characteristics of patients according to admission day, Stanford type, and sex are shown in Tables 1 and 2, and S1 Table. Of the 33,706 patients, 56.5% were of the male sex. The mean age ± SD was 67 ±13, and 75 ± 12 years old for men and women, respectively. The prevalence of current smoking was significantly higher (men: 72. 2%, women: 30.4%) than that of the average Japanese population [15]. Type A AAD and Type B AAD were present in 49.9% and 50.1% of patients, respectively. More than half of patients with Type A AAD underwent surgery (58.2%). The in-hospital mortality was 12.8% and 20.4%, in men and women, respectively. In contrast, the in-hospital mortality was 27.6% and 4.5% in patients with Type A and Type B AAD, respectively.

Table 1

Characteristics of patients with acute aortic dissection according to admission day.

	Weekdays	Saturdays	Sunday/Holidays	p-value
Number	18,301	3,268	4,072
Men (%)a	10,486 (57.3)	1,905 (58.3)	2,339 (57.4)	0.57
Ageb	70 ± 13	70 ± 14	70 ± 13	0.077
Current smoking (%)a	9,931 (56.5)	1,783 (54.6)	2,238 (55.0)	0.71
Comorbidity
Hypertension	12,28 (67.9)	2,203 (67.4)	2,715 (66.7)	0.30
Diabetes mellitus	1,695 (9.3)	282 (8.6)	367 (9.0)	0.49
Dyslipidemia	3306 (18.1)	547 (16.7)	684 (16.8)	0.049
Heart failure	3439 (18.8)	616 (18.8)	763 (18.7)	0.99
Myocardial infarction	644 (3.5)	111 (3.4)	131 (3.2)	0.62
Cerebrovascular disease	1575 (8.6)	258 (7.9)	383 (9.4)	0.069
Renal disease	864 (4.7)	153 (4.7)	197 (4.8)	0.94
Cancer	610 (3.3)	105 (3.2)	125 (3.1)	0.68
Stanford type A	9076 (49.6)	1,645 (50.3)	2,077 (51.0)	0.23
Surgery (%)a	5,936 (32.4)	1,064 (32.6)	1,329 (32.6)	0.86
Endovascular	471 (7.9)	71 (6.7)	95 (7.1)	0.27
Open Surgery	5,465 (92.1)	993 (93.3)	1,234 (92.9)
Hospitalization days	25 ± 21	25 ± 20	25 ± 22	0.002
In-hospital mortality (%)a	2,841 (15.5)	547 (16.7)	723 (17.8)	< 0.001

a, b Data are expressed as number (%), or mean ± standard deviation.

Table 2

Characteristics of patients with acute aortic dissection according to Stanford type.

	Stanford A	Stanford B	p-value
Number	12,798	12,843
Men (%)a	5,869 (45.9)	8,861 (69.0)	< 0.001
Ageb	71 ± 14	70± 13	0.001
Current smoking (%)a	6,197 (48.4)	7,755 (60.4)	< 0.001
Comorbidity
Hypertension	6,970 (54.5)	10,376 (80.8)	< 0.001
Diabetes mellitus	1,042 (8.1)	1,302 (10.1)	< 0.001
Dyslipidemia	1,471 (11.5)	3,066 (23.9)	< 0.001
Heart failure	2,612 (20.4)	2,206 (17.2)	< 0.001
Myocardial infarction	542 (4.2)	344 (2.7)	< 0.001
Cerebrovascular disease	1,399 (10.9)	817 (6.4)	< 0.001
Renal disease	477 (3.7)	737 (5.7)	< 0.001
Cancer	327 (2.6)	513 (4.0)	< 0.001
Surgery (%)a	7,453 (58.2)	876 (6.8)	< 0.001
Endovascular	88 (1.2)	549 (62.7)	< 0.001
Open Surgery	7,365 (98.8)	327 (37.3)
Hospitalization days	25 ± 24	24 ± 16	< 0.001
In-hospital mortality (%)a	3,528 (27.6)	583 (4.5)	< 0.001

a, b Data are expressed as number (%), or mean ± standard deviation.

Weekly variations in the frequency of AAD

Weekly variations in the frequency of AAD admissions are shown in Fig 2. The frequency of AAD admission was significantly greater on weekdays (18.5±7.9, admissions/day, ANOVA p<0.001) than Saturdays (16.3 ±6.9 admissions/day) or Sundays/holidays (15.1 ±6.5 admissions/day) (Fig 2A and 2B).

Fig 2

Frequency of admission of acute aortic dissection during weekdays, Saturdays, or Sunday/holiday (A), seven days of the week (B). The vertical line shows the average number of admitted patients per day. ANOVA, analysis of variance with post hoc Bonferroni correction. * p <0.001 vs. Sunday/holiday, † p <0.05 vs. Sunday/holiday.

Logistic regression analyses

After adjusting for sex, age, Stanford type, and surgery, patients admitted on Sundays/holidays were shown to have an increased risk of in-hospital mortality (odds ratio (OR) 1.20; 95% confidence interval [CI] 1.07–1.33, p = 0.001) compared with patients admitted on weekdays (reference) (Table 3). Patients in the Stanford type A AAD group admitted on Sundays/holidays showed a significantly increased risk of in-hospital mortality (non-surgery vs. surgery groups: 95% CI 1.06–1.48 vs. 1.17–1.68; p<0.001 for both groups, OR 1.25 vs. 1.41, respectively) compared with those who were admitted on weekdays. Conversely, those in the Stanford Type B AAD group admitted on Sundays/holidays did not show an increased risk of in-hospital mortality (non-surgery vs. surgery: 95% CI 0.64–1.09 vs. 0.40–2. 10; p = 0.182 vs. 0.846; OR 0.84 vs. 0.92). Patients who were admitted with AAD on Saturdays did not show an increased risk of in-hospital mortality (OR 1.12; 95% CI 0.99–1.25, p = 0.066).

Table 3

In-hospital mortality per weekday, Saturday, Sunday/holiday.

		Odds ratio	95% CI	P
Total	Weekdays	1.00 (reference)
N = 25,641	Saturday	1.12	0.99–1.25	0.066
	Sunday/holiday	1.20	1.07–1.33	0.001
Stanford A	Weekdays	1.00 (reference)
non-surgery	Saturday	1.18	0.99–1.41	0.072
N = 5,435	Sunday/holiday	1.25	1.06–1.48	0.007
Stanford A	Weekdays	1.00 (reference)
surgery	Saturday	1.03	0.83–1.28	0.787
N = 7,453	Sunday/holiday	1.41	1.17–1.68	< 0.001
Stanford B	Weekdays	1.00 (reference)
non-surgery	Saturday	1.13	0.87–1.47	0.358
N = 11,967	Sunday/holiday	0.84	0.64–1.09	0.182
Stanford B	Weekdays	1.00 (reference)
surgery	Saturday	0.98	0.41–2.34	0.959
N = 876	Sunday/holiday	0.92	0.40–2.10	0.846

CI, confidence interval.

In the same manner, analyses of the seven days group also showed higher in-hospital mortality on Sunday/holiday admissions than weekday admissions (Table 4). In the stratified analysis, a higher in-hospital mortality on Sunday/holiday admissions of Type A AAD was observed, while there was no significant difference in the in-hospital mortality between Sundays/holidays and weekdays in Type B AAD.

Table 4

In-hospital mortality per 7 days.

		Odds ratio	95% CI	P
Total N = 25,641	Sunday/holiday	1.00 (reference)
	Monday	0.83	0.72–0.96	0.010
	Tuesday	0.88	0.77–1.01	0.071
	Wednesday	0.78	0.68–0.90	0.001
	Thursday	0.97	0.84–1.11	0.623
	Friday	0.74	0.64–0.85	<0.001
	Saturday	0.93	0.81–1.08	0.338
Stanford A non-surgery N = 5,345	Sunday/holiday	1.00 (reference)
	Monday	0.76	0.61–0.95	0.014
	Tuesday	0.86	0.69–1.07	0.176
	Wednesday	0.81	0.65–1.00	0.055
	Thursday	0.91	0.73–1.14	0.422
	Friday	0.69	0.55–0.85	0.001
	Saturday	0.94	0.75–1.18	0.605
Stanford A surgery N = 7,453	Sunday/holiday	1.00 (reference)
	Monday	0.78	0.61–1.00	0.054
	Tuesday	0.72	0.56–0.93	0.010
	Wednesday	0.62	0.48–0.81	<0.001
	Thursday	0.81	0.64–1.04	0.099
	Friday	0.63	0.49–0.81	<0.001
	Saturday	0.73	0.57–0.95	0.017
Stanford B non-surgery N = 11,967	Sunday/holiday	1.00 (reference)
	Monday	1.12	0.80–1.58	0.505
	Tuesday	1.26	0.90–1.76	0.180
	Wednesday	1.11	0.79–1.57	0.543
	Thursday	1.37	0.99–1.90	0.058
	Friday	1.11	0.80–1.56	0.529
	Saturday	1.35	0.96–1.90	0.081
Stanford B surgery N = 876	Sunday/holiday	1.00 (reference)
	Monday	1.05	0.37–2.97	0.922
	Tuesday	1.56	0.59–4.12	0.372
	Wednesday	0.43	0.12–1.53	0.193
	Thursday	1.28	0.46–3.55	0.637
	Friday	1.20	0.42–3.40	0.736
	Saturday	1.05	0.35–3.19	0.925

CI, confidence interval.

Discussion

This large Japanese nationwide study revealed that the prevalence of AAD admission is more frequent on weekdays Furthermore, those admitted on Sundays/holidays and classified as Type A AAD had a significantly increased risk of in-hospital mortality.

The findings of the present study are congruous with those of Kumar et al. and Gallerani et al. This study also demonstrated that patients with Type A AAD rather than Type B AAD patients, admitted on a Sunday/holiday showed a significantly increased risk of in-hospital mortality when compared with weekday admissions. In contrast, the “weekend effect” was not observed in studies by Gokalp et al. and Ahlsson et al. The reasons for the differences in results remain unclear. However, the differences may be attributable to the relatively small sample sizes of the two studies (Gokalp et al., 206 patients; Ahlsson et al., 1,159 patients) when compared with that of the present study. Moreover, medical systems differ across regions and different time periods; thus, considering the results of the present study, the “weekend effect” may have become apparent in recent years in patients with Type A AAD, in Japan.

There have been speculations regarding the reasons for the occurrence of the “weekend effect.” Firstly, the “weekend effect” is partly responsible for the number of severely ill patients admitted to hospitals during the weekends [16, 17]. Sun et al. reported that the “weekend effect” was not significant if adjusted by illness severity [16]. The reason for the increased numbers of severely affected patients admitted during weekends may be the many referrals from general practitioners and direct admission to teaching hospitals during weekends. This study did not adjust for severity of illness except for the Stanford Type; however, weekend admissions had a smaller proportion of referred patients than those admitted on weekdays [44.1%, 39.3%, 35.2% on weekdays, Saturdays, Sundays/holidays, respectively]. It is conceivable that many patients with AAD were admitted directly to hospitals after the disease onset; therefore, a small selection bias may exist.

Secondly, differences in the staffing and resources of hospitals between weekdays and weekends need to be considered. Fewer people work in hospitals during the weekends/holidays than on weekdays. Inadequate staffing resources [18] and staffing levels [19] may have influenced the increase in mortality. In addition, weekend on-call teams of surgeons may have less expertise and experience in working together as compared to the weekday teams [4]. Moreover, many doctors who work on weekends may have had an excessive workload, which in turn, may have an influence on mortality rates. Fatigue in medical teams fatigue is associated with worse patient outcomes [20]. Further studies should explore the reasons underlying the “weekend effect” on AAD in-hospital mortality.

The results of the present study have shown that only patients with Type A AAD who were admitted on a Sunday/holiday, especially the surgery group, showed a significantly increased risk of in-hospital mortality when compared with weekday admissions. We speculate that the differences between Type A and Type B AAD are due to the lack of complications in Type B AAD. In the absence of malperfusion or signs of (early) disease progression, these patients can be stabilized safely using medical therapy alone to control pain and blood pressure [11], whereas in patients with Type A AAD, surgery is the treatment choice. Therefore, Type B AAD seems to be less influenced by the differences in staff or resources between weekday and weekend admissions.

This study has several limitations. First, this was a comparative analysis of observational data; therefore, risk of misdiagnosis may exist despite our careful selection of patients and surgical procedures. Second, we did not have detailed data regarding the precise time of onset of AAD, and thus we could not analyze circadian patterns. We also did not have individual information regarding the disease severity, laboratory data, presence of comorbidities, past medical history, family history, socioeconomic status, and in-hospital mortality cause. Third, as mentioned previously, the quality of medical-care systems and available resources, as well as the “weekend effect,” may differ between countries; therefore, caution should be exercised before extrapolating our results to other countries.

Despite these limitations, our study provides noteworthy information regarding the “weekend effect,” as data of several patients with AAD have not been previously analyzed. In conclusion, this Japanese nationwide observational study showed that there are more frequent AAD admissions during weekdays. Moreover, patients with Stanford Type A AAD admitted on a Sunday/holiday have an increased risk of in-hospital mortality. Further studies are required to investigate whether uniform diagnosis and therapeutic models used throughout the week can prevent worse outcomes in weekend- admission patients.

Characteristics of patients with acute aortic dissection according to sex.

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6 Jul 2021

PONE-D-21-14016

Effect of weekend admission for acute aortic dissection on in-hospital mortality in Japan : a nationwide study

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Reviewer #1: This is a retrospective observational study in which 33706 patients admitted for acute aortic dissection in 953 certified Japanese hospital were analysed in order to find a correlation between admission day and in-hospital mortality. The patients were categorized according to the day of hospital admission and the analysis was performed comparing the patients that were admitted in the hospital and treated (surgically or medically) on weekdays, Saturdays and Sundays/Holidays. Thereafter, the analysis was carried out by each day of the week. The study showed that the patients with acute type A aortic dissection admitted on Sunday/holiday had a significantly increased risk of in-hospital mortality. In contrast, the patients admitted for acute type B aortic dissection didn’t show a difference in terms of in-hospital mortality according to the day of admission to the hospital.

The topic of this study is very interesting and the potentialities of the analysis, including a large cohort of patients, are higher.

The manuscript is well written, with proper English.

However, there are some points of discussion:

1. The abstract should be divided in the appropriate sections.

2. The method of categorization of patients used to perform the analysis was described in the section “Data definition”. It should be moved in the section “Study setting and patients selection”.

3. In the section “Measurement”, it was described only the primary outcome of the study. This item should be improved.

4. The information regarding the patient’s selection and the definition of population analysed in the study, in association with the flow-chart of the patient selection process, were reported in the section “Results”. It should be moved in the “Methods” section.

5. The Table 1 and Table 2 showed the characteristics of the patients according to sex and to Stanford type. The variables analysed are few. In particular, many pre-operative variables, including cardiovascular risk factors, that could help to understand the risk profile of patients are not analysed.

6. In Table 2, they reported that 8065 patients (23.9%) of the overall population were “Unknown”. This group of patients should be removed from the analysis.

7. In Table 2, the authors reported that 58.2% of acute type A aortic dissection were treated surgically. How were the remaining patients treated?

8. The type of aortic surgery performed is not reported.

9. The post-operative complications of patients underwent aortic arch surgery should be added.

10. The authors reported in the limitation of the study the lack of the pre-operative, intra-operative and post-operative information, but these data are important to comprehend the risk profile of the patients and the results of the study.

11. The Table 3 reported the logistic regression analysis for in-hospital mortality for weekday, Saturday, Sunday/holiday and for every 7 days of the week. The two different analysis are reported in two different tables that should be numbered separately. Moreover, in these tables the results are difficult to understand.

12. Among acute type B aortic dissection, both surgically and medically treated patients were included. These two types of patient population could not be considered in the same group. The patients with acute type B aortic dissection surgically treated have anatomic and hemodynamic instability requiring urgent surgical/endovascular treatment. Instead, patients medically treated are stable and had lower risk of morbidity and mortality.

13. In order to find a correlation between admission day and in-hospital mortality, it may be more interesting to analyse in detail the single population of patients admitted in the hospital for acute type A aortic dissection and treated with emergent surgical operation. In fact, as the authors of this study also report, the acute Type A aortic dissection seems more vulnerable to “weekend effect” than the acute Type B aortic dissection medically treated.

Reviewer #2: Congratulations for selecting one of the most important diseases in CTS.

Methods

As far as I can tell, you have used ANOVA for comparing weekdays vs weekends.

Have you performed ad hoc analysis in order to determine where the significant results peak? Or pairwise testing with P-value correction.

You use frequently stratified analysis term: make describe it under statistical analysis

Results

Table 2 lacks a statistical test between Type A and B.

In both logistic regression analysis your weekdays vs sunday/holiday is containing saturday?

In stratified analysis p-value and CI reporting there is discordance: if CI contains 1 results can not be significant, please do revisit your analysis

From table make clear comparing groups with its p values

I truly and honestly think there is something else, only week day can not explain the complexity of the AAD mortality.

It could be interesting to understand time of admission (morning shift or evening shift), shortage of professionals, ect.

Please do share your depersonalized data.

Reviewer #3: 1. Aortic dissection type-A and type B have very different severities and they are very distinct disease entities: most A need big open surgery and most B need only endovascular or non-surgical treatments. They should not be mixed in the same article. If it does, please make sure to discuss them separately.

2. Here the grouping was defined as "admission date". Please specify in more detail. Was it referred to actual clock time or admin time? Was your date starting from 8:01 am or 0:01 am? For example, was 1 am on Monday classified as Monday or Sunday? By admin time, Monday starts from 8am Monday but manpower at 1 am Monday still belongs to Sunday. Please clarify. This confusion will cause a huge misclassification.

3. Here in the Title "weekends" always include Saturdays. But in your manuscript, Saturdays were not treated the same as Sunday or holidays. If your major grouping was Sundays/holidays vs weekdays/non-holidays, please revise your Title accordingly--it's not "weekend" effect! Revised to "holiday" effect or maybe some other better term. Please clarify.

4. What are the non-weekend holidays in Japan? Please specify. Also, was there any holidays celebrated differently in different parts in Japan--namely, was there any holiday off in some parts but non-off in other parts in Japan? In this nationwide study, this geographical holiday variations must be considered if any.

5. The outcome of "in-hospital mortality" needs more clarification. In Asian culture, some family prefer the patients to die at home What if the dying patient, alive when leaving hospital, was transferred home to die naturally. Was it "in-hospital mortality"? Also, how about the OHCA cases? If they were resuscitated and able to be diagnosed as aortic dissection, were they included or excluded in the study cohort? If these OHCA aortic dissection cases were supported by ECMO throughout the course until withdrawal, were they (dead before arrival to hospital) considered "in-hospital death"?

There are some confusions requiring clarification in the manuscript. Please address them properly.

Reviewer #4: the study sounds interesting but difference between groups (weekend and weekday) are missing and the final results should be adjuasted for differences. Table 1 reports difference according to gender which is not the issue under evaluation. Without a correct adjustment no conclusions can be traced

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Robert J. Chen, MD, MPH

Reviewer #4: No

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15 Sep 2021

RESPONSE TO THE REVIEWERS

On behalf of all the authors, I would like to thank the Reviewers for their valuable suggestions, which have helped us to revise and improve our manuscript. I would also like to thank the Editor for the kind remarks.

RESPONSE TO REVIEWER:

Reviewer #1:

1. The abstract should be divided in the appropriate sections.

Thank you for pointing this out. We have divided the Abstract sections: Background, Methods, Results, and Conclusion.

2. The method of categorization of patients used to perform the analysis was described in the section “Data definition”. It should be moved in the section “Study setting and patients selection”.

Thank you for pointing this out. We have moved these sentences to the “Study setting and patients selection” section.

3. In the section “Measurement”, it was described only the primary outcome of the study. This item should be improved.

Based on your comment, we have added information on the secondary outcome and variables that may be controversial, such as in-hospital mortality.

4. The information regarding the patient’s selection and the definition of population analysed in the study, in association with the flow-chart of the patient selection process, were reported in the section “Results”. It should be moved in the “Methods” section.

Based on your comment, we have moved the said sentences to the “patients’ selection process” in the Methods.

5. The Table 1 and Table 2 showed the characteristics of the patients according to sex and to Stanford type. The variables analysed are few. In particular, many pre-operative variables, including cardiovascular risk factors, that could help to understand the risk profile of patients are not analysed.

Thank you for pointing this out. We have added data of patients’ comorbidities (i.e. hypertension, diabetes, dyslipidemia, congestive heart failure, myocardial infarction, cerebrovascular disease, renal disease, and cancer).

6. In Table 2, they reported that 8065 patients (23.9%) of the overall population were “Unknown”. This group of patients should be removed from the analysis.

We have removed the “Unknown” group of Stanford type patients from the analysis. As a result, we reanalyzed our data and reported the results accordingly.

7. In Table 2, the authors reported that 58.2% of acute type A aortic dissection were treated surgically. How were the remaining patients treated?

Within this database, we could not know the detailed treatment progression of each patient. The remaining patients were medically treated.

8. The type of aortic surgery performed is not reported.

We have added the type of surgical intervention (endovascular or open surgery) in the Tables. Open surgery was performed in 98.8% of the Stanford type A group. On the other hand, endovascular repair was performed in 62.7% of the Stanford type B group.

9. The post-operative complications of patients underwent aortic arch surgery should be added.

Unfortunately, this database does not contain information about post-operative complications. We mentioned this as one of the study limitations (lack of postoperative date in the database).

10. The authors reported in the limitation of the study the lack of the pre-operative, intra-operative and post-operative information, but these data are important to comprehend the risk profile of the patients and the results of the study.

We acknowledge the importance of this information in this study. However, the database does not contain information about post-operative complications.

11. The Table 3 reported the logistic regression analysis for in-hospital mortality for weekday, Saturday, Sunday/holiday and for every 7 days of the week. The two different analysis are reported in two different tables that should be numbered separately. Moreover, in these tables the results are difficult to understand.

Based on your comment, we have separated these two tables (Table 3 and Table 4).

12. Among acute type B aortic dissection, both surgically and medically treated patients were included. These two types of patient population could not be considered in the same group. The patients with acute type B aortic dissection surgically treated have anatomic and hemodynamic instability requiring urgent surgical/endovascular treatment. Instead, patients medically treated are stable and had lower risk of morbidity and mortality.

Based on your suggestion, we divided the patients into the four groups (Stanford type A and surgical intervention (-), Stanford type A and surgical intervention (+), Stanford type B and surgical intervention (-), and Stanford type B and surgical intervention (+)) in the stratified analysis. In the present analysis, only 6.8% of patients with Stanford type B had surgical intervention. In the stratified analysis, in-hospital mortality of patients with Stanford type B admitted on　Sunday/holiday in both the surgical intervention (-) and (+) group was not significantly different from those admitted during the weekdays.

13. In order to find a correlation between admission day and in-hospital mortality, it may be more interesting to analyse in detail the single population of patients admitted in the hospital for acute type A aortic dissection and treated with emergent surgical operation. In fact, as the authors of this study also report, the acute Type A aortic dissection seems more vulnerable to “weekend effect” than the acute Type B aortic dissection medically treated.

Based on your suggestion, we divided patients with Stanford type A according to presence or absence of surgical intervention. In the stratified analysis, patients with Stanford type A and presence of surgical intervention seemed more vulnerable to the “weekend effect” than absence of surgical intervention.

Reviewer #2:

Methods

14. As far as I can tell, you have used ANOVA for comparing weekdays vs weekends.　Have you performed ad hoc analysis in order to determine where the significant results peak? Or pairwise testing with P-value correction.

Given that this study did not aim at knowing the differences between the particular days, we did not perform an ad hoc analysis. This study rather focused on investigating the difference between the presence or absence.

15. You use frequently stratified analysis term: make describe it under statistical analysis

Thank you for pointing this out. We have improved the statistical analysis section.

Results

16. Table 2 lacks a statistical test between Type A and B.

Based on your comment, we added the statistical test used in comparing between Type A and B groups.

17. In both logistic regression analysis your weekdays vs sunday/holiday is containing saturday?

Saturday was included in both logistic analyses.

18. In stratified analysis p-value and CI reporting there is discordance: if CI contains 1 results can not be significant, please do revisit your analysis

Based on your suggestion, we performed a re-analysis and provided the CIs where available, to justify the significant differences.

19. From table make clear comparing groups with its p values

Thank you for pointing this out. We have included the p values in the tables and added more information on the statistical test used in the Method.

20. I truly and honestly think there is something else, only week day can not explain the complexity of the AAD mortality. It could be interesting to understand time of admission (morning shift or evening shift), shortage of professionals, ect. Please do share your depersonalized data.

As your righty commented, the factors influening AAD mortality are complex. The weekend effect involves several factors; however, our database did not contain the exact time of admission.

Reviewer #3:

21. Aortic dissection type-A and type B have very different severities and they are very distinct disease entities: most A need big open surgery and most B need only endovascular or non-surgical treatments. They should not be mixed in the same article. If it does, please make sure to discuss them separately.

Thank you for pointing this out. We stratified our data according to the presence/absence of surgical intervention and presented the results accordingly. Furthermore, we discussed the findings in the Discussion section.

22. Here the grouping was defined as "admission date". Please specify in more detail. Was it referred to actual clock time or admin time? Was your date starting from 8:01 am or 0:01 am? For example, was 1 am on Monday classified as Monday or Sunday? By admin time, Monday starts from 8am Monday but manpower at 1 am Monday still belongs to Sunday. Please clarify. This confusion will cause a huge misclassification.

Thank you for pointing this out. The time range for admissions in our study was 00:00 am–11:59 pm. 　The patients’ real admission time reflected the admission day.

23. Here in the Title "weekends" always include Saturdays. But in your manuscript, Saturdays were not treated the same as Sunday or holidays. If your major grouping was Sundays/holidays vs weekdays/non-holidays, please revise your Title accordingly--it's not "weekend" effect! Revised to "holiday" effect or maybe some other better term. Please clarify.

Thank you for pointing this out. We have changed the title from “weekend admission” to “holiday admission.”

24. What are the non-weekend holidays in Japan? Please specify. Also, was there any holidays celebrated differently in different parts in Japan--namely, was there any holiday off in some parts but non-off in other parts in Japan? In this nationwide study, this geographical holiday variations must be considered if any.

Non-weekend holidays (i.e., national holidays) are same in all parts of Japan. We have added information in the methods to clarify this issue.

25. The outcome of "in-hospital mortality" needs more clarification. In Asian culture, some family prefer the patients to die at home What if the dying patient, alive when leaving hospital, was transferred home to die naturally. Was it "in-hospital mortality"? Also, how about the OHCA cases? If they were resuscitated and able to be diagnosed as aortic dissection, were they included or excluded in the study cohort? If these OHCA aortic dissection cases were supported by ECMO throughout the course until withdrawal, were they (dead before arrival to hospital) considered "in-hospital death"? There are some confusions requiring clarification in the manuscript. Please address them properly.

Thank you for pointing these out. Patients who were in a dying state upon discharge (left to die naturally at home) or patients supported by ECMO throughout the course until withdrawal were not considered as “in-hospital mortality.” It is true that, some patients and their families in Japan prefer to die at home, however, very few patients in dying state with emergency conditions were left to go home. Furthermore, our database contained data of patients who were brought to the hospital for cardiac arrest state and were diagnosed with AAD. Such patients’ deaths were considered in-hospital mortality.

Reviewer #4:

26. Difference between groups (weekend and weekday) are missing and the final results should be adjuasted for differences. Table 1 reports difference according to gender which is not the issue under evaluation. Without a correct adjustment no conclusions can be traced

We have changed Table 1 from the difference between men and women to difference between weekend and weekday groups. The table according to sex has been considered as Supplementary Table1.

Submitted filename: responsetothereviewers20210902.docx

Click here for additional data file.

11 Oct 2021

PONE-D-21-14016R1Effect of holiday admission for acute aortic dissection on in-hospital mortality in Japan : a nationwide studyPLOS ONE

Dear Dr. Kato

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Additional Editor Comments (if provided):

Dear Author, in my opinion the manuscript presents all the criteria for a publication, however before proceeding I kindly ask you to address the last and minor issue pointed out by Reviewer 2.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors modified the paper based on the suggested changes.

In particular:

1. The abstract was divided in the appropriate sections.

2. The information regarding the patient’s selection and the definition of population analysed in the study were included in the appropriate paragraph.

3. In the section “Measurement”, it was described exhaustively all the outcomes of the study.

4. In the Table 1 and Table 2 the pre-operative variables, including cardiovascular risk factors, were added.

5. The 8065 patients (23.9%) included in the “Unknown” section were removed from the analysis.

6. The type of aortic surgery performed and the post-operative complications of patients underwent aortic arch surgery were not added to the analysis. However, the authors explain that these types of information were not available in the database and this problem was mentioned as one of the study limitations.

7. The authors divided the patients into four groups (Stanford type A and surgical intervention (-), Stanford type A and surgical intervention (+), Stanford type B and surgical intervention (-), and Stanford type B and surgical intervention (+)) in the stratified analysis, as suggested. Thus, the readers could better understand which kind of patient’s population is more vulnerable to the “weekend effect”.

Reviewer #2: Methods

Not clear what stands for surgical intervention (-) or (+), make clearer statements.

Results

In all tables in caption or footnote the specific test has been used for comparison.

In Figure 2 try to use different types of plot, for example boxplot! And provide an ad hoc test for better weekday separation and significance.

Reviewer #3: The revision addressed the concerns and issues I uncovered in my previous reviews. The issues of time definition and potential selection bias were addressed or acknowledged.

Reviewer #4: I have no more comment. The authors adequately addressed all the comments. The manuscript is now improved

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Marianna Berardi

Reviewer #2: Yes: Rafik Margaryan MD, PhD

Reviewer #3: Yes: Robert Jeenchen Chen, MD, MPH

Reviewer #4: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Oct 2021

RESPONSE TO THE REVIEWERS

On behalf of all the authors, I would like to thank the Reviewers for their valuable suggestions, which have helped us to revise and improve our manuscript. I would also like to thank the Editor for the kind remarks.

RESPONSE TO REVIEWER:

Reviewer #2: Methods

Not clear what stands for surgical intervention (-) or (+), make clearer statements.

Response: Thank you for raising this point. We have revised the　descriptions to ensure clarity and avoid any confusion.

Results

In all tables in caption or footnote the specific test has been used for comparison.

In Figure 2 try to use different types of plot, for example boxplot! And provide an ad hoc test for better weekday separation and significance.

Response: Thank you for your suggestion. We have changed Figure 2 to a boxplot and performed an additional ad hoc test.

Submitted filename: responsetothereviewers20211026.docx

Click here for additional data file.

4 Nov 2021

Effect of holiday admission for acute aortic dissection on in-hospital mortality in Japan : a nationwide study

PONE-D-21-14016R2

Dear Dr. Kato,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors, Im pleased to inform you that the manuscript, after final revision, can be finally accepted.

Reviewers' comments:

9 Nov 2021

PONE-D-21-14016R2

Effect of holiday admission for acute aortic dissection on in-hospital mortality in Japan: a nationwide study

Dear Dr. Kato:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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