Minimally invasive management of acute ureteral obstruction and severe infection caused by upper urinary tract calculi

Abstract

PURPOSE

To evaluate therapeutic efficacy of two minimally invasive surgical methods in managing acute ureteral obstruction and severe infection caused by upper urinary tract calculi (UUTC).

PATIENTS AND METHODS

Data of 47 patients diagnosed with acute upper urinary tract obstruction and severe infection caused by ureteral calculus using X-ray CT between September 2014 and January 2019 were retrospectively analyzed. All patients were treated with immediate renal drainage and, after infection and ureteral obstruction were relieved, UUTC removal. Renal drainage was performed by ultrasound-guided percutaneous nephrostomy and retrograde ureteral catheterization was performed using cystoscopy. Kidney and ureteral stones were removed; renal function and the urinary tract were examined by X-ray during follow-up.

RESULTS

Percutaneous nephrostomy was performed in 29 patients in a critical condition including intolerance to surgery, high-grade hydronephrosis, or failure of retrograde ureteric stent placement. In other 18 patients diagnosed with small stones (≤10 mm) and low-grade hydronephrosis, indwelling double-J ureteral stents were temporally installed by a cystoscope. Acute infection and ureteral obstruction were relieved; white blood cell counts returned to normal values within 3 to 7 days after drainage in all patients. In the second-stage treatment, percutaneous nephrolithotomy (PCNL), ureteroscopic lithotripsy, extracorporeal shock wave lithotripsy and nephrectomy were performed in 24, 10, 8 and 5 patients, respectively. No patients developed severe complication after stone removal surgery. All patients were followed up for 3 months to 4.5 years. Renal function was significantly recovered; 17/29 (59%) patients with elevated serum creatinine returned to normal and serum creatinine in 12/29 (41%) patients improved significantly after drainage, with a pre-operation level of 285±169μM vs 203±91μM post-operation (P = 0.014). Five patients were lost during follow-up.

CONCLUSION

This study demonstrated an optimal approach for relieving upper urinary tract obstruction and acute infection in which percutaneous nephrostomy drainage is preferred for patients with severe pyonephrosis, large stones (>10 mm) with high-grade hydronephrosis, steinstrasse, or failure in retrograde ureteric stent placement, while retrograde ureteral catheterization using cystoscopy is suitable for patients diagnosed with small stones (≤10 mm) and low-grade hydronephrosis.

Keywords

Urolithiasis upper urinary tract calculi (UUTC)pyonephrosis percutaneous treatment

1 Introduction

Ureteric obstruction is most commonly caused by urolithiasis, tumors, infections, post-traumatic stenosis, congenital anomalies, or surgical operations. The obstructed infected kidney is a urological emergency. Urinary tract obstruction in the presence of pyelonephritis may lead to the collection of bacteria and debris in the collecting system, which may subsequently result in pyonephrosis [1]. Pyonephrosis is a serious complication of ureteric obstruction, often associated with renal parenchymal destruction, deteriorating function, and septic complications [2].

Upper urinary tract calculi (UUTC) can cause urinary tract obstruction, often associated with urinary tract infection (UTI). A UTI can be fatal, especially in a complicated UTI with potential urinary tract disease or systemic disease related to the immune system, including diabetes mellitus, and during chemoradiotherapy [3]. Acute obstruction increases intrapelvic pressure, bacteria or toxins enter the blood circulation through various reflux pathways, and the release of various inflammatory factors causes systemic inflammatory response syndrome, which can lead to multiple organ dysfunction and can result in severe systemic poisoning symptoms or shock, while pyonephritis deteriorates renal function [4].

Pyonephrosis, an infection of the kidneys’ collecting system, is one of the most serious complications of UUTC. Pus collects in the renal pelvis and causes the distension of the kidney. It can cause kidney failure and even death [5]. Although antibiotics are commonly used to treat this infectious disease, drugs are less effective when the upper urinary tract is filled up with infected urine. Therefore, immediate drainage is key to avoid severe morbidity and even mortality in the management of pyonephrosis induced by UUTC.

Currently, there are 2 ways for urgent decompression of obstructed collecting systems: retrograde ureteral catheterization and percutaneous placement of a nephrostomy tube. The choice of drainage method remains a controversial issue [2 , 6]. We present a retrospective clinical study of the outcomes of percutaneous nephrostomy and retrograde ureteral catheterization for the treatment of acute ureteral obstruction and severe pyonephrosis caused by UUTC in patients treated at the Department of Urology of Shenzhen Longhua District Central Hospital.

2 Patients and methods

2.1 Patients

Between September 2014 and January 2019, 47 patients (17 males and 30 females, aged 21 to 84 years [median 41.2 years]) were diagnosed with pyonephrosis and obstruction by lithangiuria, needing hospitalization and urine drainage; 28 patients presented with sepsis due to an obstructive stone and 19 patients had hydronephrosis due to an obstructive stone without overt sepsis. Patients were treated with percutaneous nephrostomy or retrograde ureteral catheterization by the same surgical team. In 4 patients retrograde ureteric stent placement failed, and percutaneous nephrostomy was chosen. Data were collected regarding patient demographics, stone parameters, and clinical outcomes. History, symptoms, laboratory values, imaging results, and therapy were included in the review. 8(17%) patients had diabetes mellitus and 14 (30%) patients had 2 or more comorbidities. The main symptoms were flank abdominal pain (94%) and fever (83%). Table 1 shows the main symptoms and the laboratory results, including fever, flank abdominal pain, voiding symptoms, leukocytosis, elevated serum creatinine, and pyuria. The Chi-square test was used for statistical analysis of qualitative data, and P < 0.05 was considered statistically significant.

Table 1
Main clinical symptoms and laboratory values in 47 patients with UUTC

Symptom No. of patients (%)

Flank abdominal pain 44 94%

Fever>38.5°C 39 83%

Frequent urination 21 45%

Macrohematuria 18 38%

Leukocytosis (WBC > 10×10⁹/l) 31 66%

Pyuria (WBC > 20/hpf) 47 100%

Elevated creatinine (serum creatinine values men > 111μM, women > 73μM) 29 62%

Symptom	No. of patients	(%)
Flank abdominal pain	44	94%
Fever>38.5°C	39	83%
Frequent urination	21	45%
Macrohematuria	18	38%
Leukocytosis (WBC > 10×10⁹/l)	31	66%
Pyuria (WBC > 20/hpf)	47	100%
Elevated creatinine (serum creatinine values men > 111μM, women > 73μM)	29	62%

Ultrasound or computed tomography (CT) examination showed lithangiuria in the affected side. CT examination showed inflammatory changes around the kidney on the affected side (Fig. 1). The diameter of the calculi was 5–32 mm. Stones were located in the ureter (n = 12, 26%), in both the ureter and the kidney (n = 28, 60%), or in the kidney (n = 7, 14%). All patients received intravenous broad-spectrum antibiotics before surgery, which were subsequently tailored to microbiology results along with the clinical and biochemical response. Also, blood and urine samples were collected for microbiological examination. Bladder urine cultures were obtained from either clean-voided or catheter specimens from all 47 patients. Renal urine cultures were collected from the nephrostomy drainage tube under sterile conditions from 29 patients. Blood culture specimens were obtained in 21 patients during febrile episodes (≥38.5°).

Fig.1

Inflammatory changes around the left kidney.

2.2 Percutaneous nephrostomy

Briefly, the patients were placed in a prone position under local anesthesia. A 16G coaxial needle was used to initially puncture a major calyx under ultrasound guidance (BK Ultrasound System, Denmark). The irrigation solution was discharged through the puncture needle tube, proving the puncture was successful. The guidewire was inserted through the puncture needle channel. The skin incision (about 5 mm) was made from the puncture site, the puncture needle was pulled out, and the F8 dilatation tube was slowly pushed into the target calyx along the guidewire by rotation. Next, the dilated sheath was used sequentially from 10 Fr to 18 Fr to expand muscle and fascial layers. The dilatation sheath was withdrawn, 14F to 16F nephrostomy tubes were inserted along the guidewire into the renal pelvis, the guidewire was removed, and the tube was fixed.

2.3 Retrograde ureteral catheterization

Briefly, patients were placed in the lithotomy position under surface anesthesia. Some patients were sensitive to pain and could not tolerate it, so we used general or spinal anesthesia. Under video surveillance, saline was continuously irrigated using a peristaltic pump. A 6/7.8 Fr Wolf rigid ureteroscope was used, and the guidewire was retrogradely inserted into the ureter. If the guidewire could smoothly go up about 25–27 cm, an F5/6 open-ended ureteral stent was placed through the guidewire. If the guidewire could not pass due to the stone obstruction, percutaneous nephrostomy was carried out instead. Retrograde ureteric stent placement failed in 4 cases.

3 Results

Original pre-operative radiographic reports were reviewed. Sites of renal obstruction were determined from radiographic data. Kidney– ureter– bladder (KUB) radiography, intravenous pyelography sonograms, a color Doppler ultrasound, and a plain CT scan of the uropoietic system showed the size and location of calculi and different degrees of hydronephrosis; 32 cases were complicated with perirenal infection, hydronephrosis, or renal insufficiency. The pre-operative creatinine level was 285±169μM; 31 cases were complicated with different stages of renal insufficiency, and of the 39 cases of unilateral calculi, the contralateral renal function was normal in 34 cases. Five cases suffered from pre-operative contralateral renal insufficiency (Fig. 1). Staghorn calculi were found in 9 of 47 cases, steinstrasse was found in 7 of 47 cases. The sites of obstruction were calices (3 of 47), renal pelvis (17 of 47), proximal ureter (10 of 47), mid-ureter (8 of 47), and distal ureter (9 of 47). The perioperative data are presented in Table 2.

Table 2
Patients’ perioperative data

Variable Value

Median age (mean±SD, years) 41.2 (54.2±23.5)

Male-to-Female Ratio 17 : 30

Side of stone (left/right/bilateral) 24/15/8

Median stone burden (range, mm) 35.4±17.1 (9–32)

Type of stone

Virgin stones 40

Steinstrasse 7

Stone site

Renal pelvis 22

Proximal ureter 8

Middle ureter 8

Distal ureter 9

Hydronephrosis

Grade I 9

Grade II 15

Grade III 17

Grade IV 6

Creatinine level on presentation (mean±SD, μM) 285±169

Creatinine level after surgery (mean±SD, μM) 203±91

Variable	Value
Median age (mean±SD, years)	41.2 (54.2±23.5)
Male-to-Female Ratio	17 : 30
Side of stone (left/right/bilateral)	24/15/8
Median stone burden (range, mm)	35.4±17.1 (9–32)
Type of stone
Virgin stones	40
Steinstrasse	7
Stone site
Renal pelvis	22
Proximal ureter	8
Middle ureter	8
Distal ureter	9
Hydronephrosis
Grade I	9
Grade II	15
Grade III	17
Grade IV	6
Creatinine level on presentation (mean±SD, μM)	285±169
Creatinine level after surgery (mean±SD, μM)	203±91

We divided the ureter into the upper, middle, and lower segment [7]. Stone size is usually given in 1 or 2 dimensions and stratified into≤10 mm, 10–20 mm, and≥20 mm (largest diameter). We graded hydronephrosis based on diuretic urography using a 4-grade system scale [8]. Like in the work of Van Cangh et al. [9], 9 patients were classified as grade 1, 15 as grade 2, 17 as grade 3, and 6 as grade 4.

Microbiological culture results obtained with samples from the bladder, midstream urine, renal urine, and blood are shown in Table 3. Of 47 bladder urine samples, 1 case was clear, 8 cases were yellow, 25 cases were chocolate color, 11 cases were dark, and 2 cases were fresh red. Of 29 renal drainage urine samples, 4 cases were yellow, 19 cases were chocolate color, and 6 cases were dark. Organisms were cultured in 27 of 47 bladder cultures, 16 of 29 renal cultures, and 8 of 28 blood cultures obtained. Multiple organisms were obtained in 2 of 19 bladder samples and 3 of 21 of renal urine specimens. In 18 of 23 patients, either the bladder or the renal urine sample showed infection. Renal urine cultures showed organisms different from those from bladder urine in 2 of 29 patients when both were obtained. Escherichia coli was the most frequent uropathogen identified in bladder urine, renal urine, and blood cultures.

Table 3

Microbiology of pyonephrosis in the clean-voided urine and drained urine samples from renal pelvis

	Bladder urine samples (n = 47 in total)	Urine samples from renal drainage (n = 29 in total)	Blood samples (n = 24 in total)
Organism
Escherichia coli	7	5	3
Proteus mirabilis	4	3	0
Enterococcus faecalis	3	2	1
Pseudomonas aeruginosa	3	1	1
Klebsiella pneumoniae	3	1	1
Acinetobacter baumannii	2	1	1
Streptococcus agalactiae	2	0	0
Enterobacter	1	1	1
Candida	1	2	0
Miscellaneous	1	0	0
Urine color
Clear	1	0
Yellow	8	4
Chocolate color	25	19
Dark	11	6
Fresh red	2	0

Most patients had a history of UTI and/or UUTC; 1 patient with calyceal diverticulum had a renal stone with sepsis. A total of 14 of 47 patients were treated previously by extracorporeal shock wave lithotripsy (ESWL) or endourological procedures such as ureteroscopic lithotripsy or percutaneous nephrostolithotomy.

During the operations, purulent urine spurted out from the drainage tube in 17 patients. The procedures were performed and/or supervised by 2 experienced endourologists. In all patients, the body temperature and blood white blood cell (WBC) counts returned to normal values within 3 to 7 days after drainage. Two patients developed septic shock and were sent to the intensive care unit (ICU) even after percutaneous nephrostomy. Two patients’ blood pressure fluctuated between 68–79/48–57 mmHg during the operations; they were given blood pressure increasing drugs and sent to the ICU for septic shock treatment. When the infection was under control, percutaneous nephrostolithotomy. (PCNL) was performed to remove the stones (Figs. 2, 3). Hospitalization time ranged from 5 to 23 days (median 9 days). None of the patients developed a pneumothorax, urinary extravasation, perirenal hematoma, or abdominal organ injuries. In all patients, acute symptoms and blood WBC counts returned to normal values within 3 to 7 days after drainage.

Fig.2

Pyonephrosis caused by calculi at the ureteropelvic junction.

Fig.3

In the second stage, the stone was removed (the same patient as in Fig. 2).

The therapies used after drainage of pyonephrosis are shown in Table 4. Eight cases were treated with ESWL, 10 received ureteroscopic lithotripsy, and 24 underwent PCNL; nephrectomy was used in 5 cases due to a nonfunctional kidney. Asymptomatic stones with a diameter of less than 3 mm are usually considered clinically insignificant residual fragments (CIRFs). Patients without stones or with only CIRFs were considered successful cases. The stone-free rate was 87% after all secondary procedures. Post-operactive renal function varied among patients; 17/29 (59%) patients with elevated serum creatinine levels returned to normal, 12/29 (41%) patients with elevated serum creatinine levels improved significantly after drainage; the pre-operative level was 285±169μM vs 203±91μM post-operatively (P = 0.014) (Table 2). No deaths due to pyonephrosis were recorded during the follow-up period. Stone analysis results of 31 (66%) patients are available; mixed urolith was found in 24 (77%), calcium oxalate stones were found in 22 (71%), magnesium ammonium phosphate was found in 13 (42%), and carbonate apatite was found in 9 (29%) patients. During the follow-up period of 3 months to 4.5 years, 5 patients were lost; 11/39 patients (28%) showed recurrent UTI, and in 4/39 patients (10%) pyonephrosis recurred.

Table 4

The definitive treatment after drainage of pyonephrosis

Treatment approach	ESWL	PCNL	Nephrectomy	Ureteroscopic lithotripsy
No. of patients	8	24	5	10
Pyonephrosis	2	5	0	3
Severe hydronephrosis	0	20	5	1
Percutaneous nephrostomy drainage	3	24	5	0
Retrograde ureteral catheterization	4	0	0	10

Abbreviations: ESWL, extracorporeal shock wave lithotripsy; PCNL, percutaneous nephrolithotomy.

4 Discussion

Pyonephrosis is defined as infected hydronephrosis associated with suppurative destruction of the parenchyma of the kidney. The obstructed kidney with UTI is a urological emergency. Infection can aggravate obstruction and endanger renal function and the life of the patient. Decompression is often urgently necessary to prevent further complications in infected hydronephrosis secondary to (unilateral or bilateral) stone-induced renal obstruction.

The principal treatment strategy of urinary tract obstruction is to remove obstruction as soon as possible and to protect renal function. The traditional method is percutaneous drainage or ureteral indwelling catheter drainage under cystoscopy to relieve the obstruction. Retrograde ureteral catheterization is used in patients with small stones (≤10 mm) and hydronephrosis grade 1 or 2. The method is to place the double J catheter through the stone site using a cystoscope or ureteroscope. Percutaneous nephropuncture drainage is used in patients in a critical condition, with unstable vital signs, and with intolerance to surgery, as well as in patients with large stones (>10 mm) and hydronephrosis grade 3 or 4 or in patients where retrograde ureteric stent placement failed [10].

The use of antibiotics may inhibit bladder urine culture growth despite significant infection in an obstructed kidney. However, renal urine should be sent for culture and sensitivity analysis even after antibiotic therapy has started because of the frequent discrepancy between urine and aspirate results due to the slow-rising antibiotic level [11, 12]. In our study, E. coli was the most frequently identified uropathogen in bacterial culture analysis. The presence of E. coli and Proteus mirabilis may be chronic and may be associated with calculi. Bacteria that are more difficult to treat, such as Pseudomonas aeruginosa, may cause treatment failure. With the widespread use of broad-spectrum antibiotics, renal dysfunction may contribute to the emergence of drug-resistant strains [2].

In our study, women were more likely to have infected urolithiasis and pyelonephritis (17/30), as well as sepsis with organ dysfunction. These results are similar to those reported by Sammon et al. [13] and may reflect the higher prevalence of UTI in women [14]. This may be related to the anatomical structure of women, who often have asymptomatic bacteriuria. Retrograde ureteral catheterization and percutaneous placement of a nephrostomy tube should be performed immediately to decompress the obstructed collecting systems after the initial empiric antibiotic treatment [15]. Timely drainage increases renal perfusion and delivery of antibiotics to both parenchyma and urine [16, 17].

Percutaneous nephrostomy and retrograde ureteral catheterization are compared in Table 5. Both methods are equally effective [18, 19]. In our study, percutaneous nephrostomy drainage is shown to be an effective and safe procedure; only 1 operative complication occurred, i.e., a perinephric hematoma. Percutaneous drainage offers many advantages over retrograde ureteral stent placement. It is quick and allows for the placement of a large-caliber drainage tube, and compared with retrograde ureteral stent placement, it is easier to control urinary output and discharge large volumes of pus from the pelvis. Nephrostomy can usually be performed under local anesthesia and only requires ultrasound guidance. The collecting system and ureter can be well visualized during antegrade nephrostography, and antegrade internalization of nephrostomy tubes can often be accomplished in the second stage. Moreover, nephrostomy cultures provide a higher microbiological detection rate than bladder urine cultures [15, 20]. However, the procedural time is often longer [21], and potential disadvantages are leakage, displacement of the tube, and bleeding, particularly in coagulopathic patients. Retrograde techniques, however, are sometimes difficult to execute due to enlarged obstructive prostates, urinary diversions, impassable ureteric obstructions, unidentifiable ureteric orifices, and lithotomy positioning [22]. Ureteral stenting often needs to be performed in the operating room under general or spinal anesthesia. In addition, the risk of perforating the ureter exists when stenting. Furthermore, sepsis may flare up under the pressure of the irrigation fluid. Therefore, our team generally prefers nephrostomy over ureteral stenting.

Table 5
Comparison of percutaneous nephrostomy and retrograde ureteral catheterization

Percutaneous nephrostomy Retrograde ureteral catheterization

Indications – High-grade hydronephrosis – Small stones (≤10 mm)

– Severe pyonephrosis – Low-grade hydronephrosis

– Steinstrasse – No pyonephrosis

– Failed retrograde ureteric stent placement

Anesthesia – Local anesthesia – General anesthesia/spinal anesthesia/surface anesthesia

Advantage – Quick – Noninvasive

– Excellent visualization

– Effectively drain urine

– Offers unique bacteriological information

– Provides access for second-stage surgery

Potential risks - Hemorrhage – Failed catheterization

– Urine leakage - Flare up sepsis

– Perinephric haematoma – Perforating the ureter

– Displacement of the tube

– Longer procedural time

(>2 weeks)

	Percutaneous nephrostomy	Retrograde ureteral catheterization
Indications	– High-grade hydronephrosis	– Small stones (≤10 mm)
	– Severe pyonephrosis	– Low-grade hydronephrosis
	– Steinstrasse	– No pyonephrosis
	– Failed retrograde ureteric stent placement
Anesthesia	– Local anesthesia	– General anesthesia/spinal anesthesia/surface anesthesia
Advantage	– Quick	– Noninvasive
	– Excellent visualization
	– Effectively drain urine
	– Offers unique bacteriological information
	– Provides access for second-stage surgery
Potential risks	- Hemorrhage	– Failed catheterization
	– Urine leakage	- Flare up sepsis
	– Perinephric haematoma	– Perforating the ureter
	– Displacement of the tube
	– Longer procedural time
	(>2 weeks)

In our study, 2 patients were sent to the ICU after percutaneous nephrostomy for septic shock. Septic shock is dangerous and progresses rapidly, as well as can cause kidney failure and death in a short time. Percutaneous nephrostomy not only allows for the effective drainage of urine, but also provides access for second-stage surgery [18, 19]. The definitive therapy of 5 patients with grade 4 hydronephrosis, who had a renal function of less than 10% according to the renal ECT scan after drainage and who had recurrent UTI and/or persistent renal pain, was nephrectomy [23]. When the infection was under control, PCNL was performed to remove the stones in the percutaneous nephrostomy group through the original channel. Ureteroscopic lithotripsy and ESWL were carried out in all patients in the retrograde ureteral catheterization group (Table 4).

Several imaging examinations were used in the diagnosis of obstructive pyelonephritis (Table 6). Ultrasound was used as the primary diagnostic imaging tool. It is safe, repeatable, and inexpensive. It can determine the location of stones, as well as upper urinary tract dilatation [24, 25]. The sensitivity and specificity of X-ray plain film KUB radiography is 44–77% [26, 27]. KUB radiography should not be used if non-contrast-enhanced CT is considered [28, 29]. However, KUB is helpful in differentiating between radiolucent and radiopaque stones and should be used for comparison during follow-up. KUB radiography and ultrasound are important assisting methods in the diagnosis of renal insufficiency and pyonephrosis caused by urinary calculi.

Table 6

Advantages and disadvantages of diagnostic methods for obstructive pyelonephritis

	Advantages	Disadvantages
Ultrasound	– Safe (no risk of radiation)	– Limitation in accuracy
	– Reproducible
	– Inexpensive
Kidney– ureter– bladder (KUB) radiography	– Simple	– Low sensitivity and specificity
	– Noninvasive
	– Inexpensive
Intravenous pyelography	– Relatively high accuracy	– Poor sensitivity and specificity
		– Prudence in renal function insufficiency
Computed tomography (CT)	– High sensitivity and specificity	– The requirement of multiple slider images

CT is a safe and accurate method for the diagnosis of negative stones, and non-contrast-enhanced CT allows for the determination of stone diameter and density. In evaluating patients with suspected acute urolithiasis, non-contrast-enhanced CT is significantly more accurate than intravenous urography [30]. CT allows for rapid acquisition of 3D data and information on stone size and density, skin-to-stone distance, and surrounding anatomy, but at the cost of increased radiation exposure.

Intravenous urography can provide information about renal function, the anatomy of the collecting system, and the level of obstruction. It is recommended when CT scanning is not possible, and it may show reduced inflow of contrast media or reveal a silent kidney. Care needs to be taken not to give contrast media to renal insufficiency patients.

5 Conclusion

Percutaneous nephrostomy and retrograde ureteral catheterization are equally effective in emergency drainage for patients with acute pyonephrosis. Percutaneous nephrostomy drainage is preferred for patients with severe pyonephrosis, large stones with high-grade hydronephrosis, or steinstrasse, or when retrograde ureteric stent placement failed. Retrograde ureteral catheterization using cystoscopy is suitable for patients with small stones (≤10 mm) and low-grade hydronephrosis. Compared with the retrograde ureteral stent, percutaneous nephrostomy not only effectively drains urine, but also provides access for second-stage surgery, provides unique bacteriological information and management advantages, and results in few complications. Moreover, percutaneous nephrostomy is the first choice for patients with severe urolithiasis who cannot tolerate epidural or general anesthesia. Only percutaneous nephrostomy should be performed in the first stage. Definitive treatment of the stone(s) should be delayed until sepsis is resolved, so lithotripsy should be performed at the second stage to avoid excessive bleeding or sepsis. Percutaneous nephrostomy is especially suitable for basic-level hospitals with poor medical conditions.

Conflict of interest

None of the contributing authors have any financial or personal relationships with people or organizations that could inappropriately influence work on this article.

Footnotes

Acknowledgments

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

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