Sarah Gauthier
email: gauthiersarah21@gmail.com

Pierre Tattevin

Louis Soulat

Jacques Bouget

Sandra Abergel

Juliette Hascoet

Romain Mathieu

Luc Beuzit

Didier Myhie

Mathieu Revest

Karim Bensalah

Benoit Peyronnet

Intensité de la douleur et imagerie à la phase initiale d'une pyélonéphrite aiguë Pain intensity and imaging at the initial phase of acute pyelonephritis

Keywords: imagerie, échographie, scanner, pyélonéphrite, douleur imaging, ultrasound, CT scan, pyelonephritis, pain ACCEPTED

Objectif. Rechercher l'existence de facteurs prédictifs de complication urologique à l'imagerie en cas de pyélonéphrite aiguë de la femme de 18-65 ans.

Méthode

. Nous avons réalisé une étude monocentrique, observationnelle et rétrospective. Les patientes consultant dans un service d'urgences entre 2010 et 2015 pour une pyélonéphrite aiguë ont été incluses. Le critère d'exclusion était l'absence d'imagerie des voies urinaires aux urgences. Le critère de jugement principal était la présence d'une complication urologique à l'imagerie. Le critère de jugement secondaire était la modification thérapeutique après diagnostic par imagerie. Résultats. 193 patientes ont été incluses : 88 (45,6 %) présentaient une complication urologique à l'imagerie. En analyse multivariée dans cette cohorte globale, l'antécédent de calcul urinaire (OR=2,41 ; p=0,01) et le caractère morphino-requérant de la douleur (OR=5,29 ; p=0,009) étaient associés à la découverte d'une complication urologique à l'imagerie. Parmi les 120 patientes avec pyélonéphrite simple ayant eu une imagerie, 45 % avaient une complication urologique, avec modification de la prise en charge thérapeutique chez 36,7 % d'entre elles. En analyse multivariée, l'âge > 40 ans (OR=4,58 ; p=0,02) et le caractère morphino-requérant de la douleur (OR=3,78 ; p=0,02) étaient significativement associés à la découverte d'une complication urologique à l'imagerie et à une modification de la prise en charge (OR=6,76 ; p=0,005 et OR=4,19 ; p=0,01 respectivement).

Conclusion.

Le caractère morphino-requérant de la douleur, l'âge et l'antécédent de calcul des voies urinaires étaient associés au risque de complication urologique à l'imagerie chez les patientes atteintes d'une pyélonéphrite aiguë.

Introduction

Urinary tract infection (UTI) is one of the most common disease in primary care. It is the second cause of antibiotic prescription in France [START_REF] Elkharrat | Épidémiologie de l'infection urinaire communautaire de l'adulte en France[END_REF] and worldwide [START_REF] Geerlings | Clinical Presentations and Epidemiology of Urinary Tract Infections[END_REF]. UTI is more prevalent in women because of the female genitourinary anatomy [START_REF] Sabih | Urinary Tract Infections, Complicated[END_REF], with up to one-third of sexually active women affected [START_REF] Foxman | Epidemiology of urinary tract infections: incidence, morbidity, and economic costs[END_REF]. Pyelonephritis is an upper urinary tract infection, with clinical presentation involving fever and sometimes lower back pain and lower urinary tract symptoms.

There are two types of complicated UTIs: severe pyelonephritis with sepsis signs and obstructive pyelonephritis [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF][START_REF] Kalra | Approach to a Patient with Urosepsis[END_REF]. Imaging (computed tomography [CT] scan or ultrasound) aimed at ruling out a complicated presentation of UTI, is recommended by urological societies during the diagnostic evaluation of all pyelonephritis patients [START_REF] Grabe | Guidelines on Urological infections [Internet[END_REF][START_REF] Bruyère | Pyélonéphrites aiguës[END_REF]. Conversely, some primary care societies only recommend imaging study in selected cases such as lack of improvement after treatment or relapse [START_REF] Colgan | Diagnosis and Treatment of Acute Pyelonephritis in Women[END_REF].

The 2015 French multidisciplinary guidelines only recommend an imaging studypreferentially an ultrasound -in case of "pyelonephritis with hyperalgesia" [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF]. While the idea makes sense, there is currently no data in the scientific literature to support this statement. Some studies suggest an association between clinical criteria (fever, duration of symptoms, flank pain, comorbidities), biological criteria (inflammatory syndrome), and renal abscess, which could encourage their use to select patients requiring initial imaging study [START_REF] Huang | Acute bacterial nephritis: a clinicoradiologic correlation based on computed tomography[END_REF][START_REF] Campos-Franco | Acute focal bacterial nephritis in a cohort of hospitalized adult patients with acute pyelonephritis. Assessment of risk factors and a predictive model[END_REF][START_REF] Yen | Renal abscess: Early diagnosis and treatment[END_REF][START_REF] Chen | The role of emergency ultrasound for evaluating acute pyelonephritis in the ED[END_REF][START_REF] Sørensen | The role of imaging of the urinary tract in patients with urosepsis[END_REF][START_REF] Wang | The use of ultrasonography in evaluating adults with febrile urinary tract infection[END_REF][START_REF] Kim | Usefulness of Blood Cultures and Radiologic Imaging Studies in the Management of Patients with Community-Acquired Acute Pyelonephritis[END_REF]. Other studies did not report any risk factor for renal abscess, with authors pleading for systematic initial imaging to detect complications [START_REF] Rollino | Acute pyelonephritis: analysis of 52 cases[END_REF][START_REF] Rollino | Acute pyelonephritis in adults: a case series of 223 patients[END_REF].

The aim of this study was to assess predictive factors of urological complication on imaging findings (obstruction in the urinary tract, abscess) in women aged 18 to 65 years diagnosed with pyelonephritis in the emergency department.

Patients and methods

Study design

We conducted a single center retrospective chart review in the Hospital of Rennes, France.

The medical records of all women aged 18 to 65 years who presented at the emergency department for acute pyelonephritis between January 2010 and January 2015 were analyzed.

Inclusion criteria were: female gender, age between 18 and 65 years, final diagnosis of acute pyelonephritis. The exclusion criterion was the absence of imaging study performed in the emergency department (ultrasound, enhanced or unenhanced CT scan, or urinary tract CT scan).

We obtained the list of patients from the French hospital discharge database (French acronym PMSI), using the following ICD 10 codes: N10 (acute tubulointerstitial nephritis), N11.0 (nonobstructive reflux-associated chronic pyelonephritis), N110 (pyelonephritis with reflux), N11.1 (chronic obstructive pyelonephritis), N11.8 (other chronic tubulointerstitial nephritis), N119 (chronic tubulointerstitial nephritis, unspecified), N12 (tubulointerstitial nephritis), O23.0 (infections of kidney in pregnancy), and N13.6 (pyonephrosis). We also queried our emergency department software (Résurgences®) looking for medical records with the ICD 10 code N10 as a final diagnosis (acute tubulointerstitial nephritis).

The following data was extracted from the charts and then entered in a digital spreadsheet: age, comorbidities, history of urolithiasis, history of urinary tract abnormality, history of urological procedures, neurogenic lower urinary tract dysfunction, and clinical signs. Other data was included such as clinical data (spontaneous pain and localization, flank pain at palpation, fever and highest temperature, chills, vomiting, macroscopic or microscopic hematuria, urinary signs, deterioration of general status, loss of consciousness, other general signs, pain intensity according to a visual analogue scale from 1 to 10, duration of symptoms), blood tests (CRP level [mg/L], leukocyte level and platelet count [Giga/L], creatinine level [µmol/L]), type of imaging study (unenhanced or contrast-enhanced CT scan, ultrasound), microbiological findings (results of blood cultures and cytobacteriological testing of urine), type of antibiotics used and duration, and infection outcomes (pain requiring morphine use, septic shock, use of catecholamines, hospitalization and duration, recurrence of urinary infection).

Uncomplicated pyelonephritis was defined as per the French infectious diseases society's (French acronym SPILF) guidelines [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF] as pyelonephritis in women aged ˂65 years, without ACCEPTED MANUSCRIPT -CLEAN COPY ongoing pregnancy, without anatomical abnormality of the urinary tract, without immunodeficiency, and without severe chronic kidney disease.

Protocol for the management of pyelonephritis in the emergency department over the study period

A standardized protocol was used for all pyelonephritis cases diagnosed over the study period, with an initial clinical evaluation (abdominal pain, flank pain, lower urinary tract symptoms, and other signs). Biological assessment was performed (creatinine, urea, blood count, CRP). A urine dipstick test and a urine culture were also performed. Blood cultures were performed in case of sepsis signs. The urologist's advice was sought if patients had a history of urological disorder or in case of complicated presentations of pyelonephritis. No stringent protocol was implemented regarding the use of morphine, which was left at the physician's discretion. An imaging study was performed in the emergency department when the SPILF's criteria for uncomplicated pyelonephritis were not met, or in case of persistent symptoms despite antibiotic treatment, or at the physician's discretion. Outpatient imaging study was always prescribed to patients who did not undergo an imaging study in the emergency department. Patients were admitted to hospital if they had a complicated presentation of pyelonephritis, if they required intravenous treatment, or if they had abscess or comorbidities. The antibiotic treatment was chosen as per the SPILF's guidelines [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF].

The type of imaging study was chosen according to clinical signs and symptoms after discussion between the emergency physician and the on-call radiologist [START_REF] Demertzis | State of the art: imaging of renal infections[END_REF][START_REF] Hyzy | Evidence-Based Critical Care: A Case Study Approach[END_REF]. Evaluation of the upper urinary tract by ultrasound was preferred in young women to avoid radiations, allowing to easily diagnose hydronephrosis and pyonephrosis. However, this imaging technique heavily depends on the radiologist's skills and is poorly reliable in overweight patients. Additional CT scan was performed when no diagnosis could be made by ultrasound.

CT scan is irradiating but more accurate, especially to detect urinary stones. The choice to perform unenhanced or contrast-enhanced CT scan was left at the physician/radiologist's discretion.

The primary endpoint was the identification of one or more of the following urological complication(s) on imaging findings: stones in the urinary tract, hydronephrosis, and renal abscess. The secondary endpoint was a treatment change after imaging diagnosis.

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Statistical analyses

Statistical analyses were performed using the JMP v.12.0 ® software (SAS Institute Inc, Cary, NC, USA). Continuous quantitative variables were expressed as means and standard deviations, and qualitative variables as numbers and percentages. Quantitative variables were compared with Fisher's exact test or the chi-square test, and continuous quantitative variables were compared using the Mann-Whitney test. Predictive factors of urological complication on imaging findings and of imaging findings leading to treatment changes were looked for with univariate and multivariate logistic regression analyses. Only covariates with p<0.2 were included in the multivariate model. When significant statistical association was observed between a continuous variable and the primary endpoint, these variables were dichotomized around the median to identify an "at risk" cut-off. Statistical significance was set at p<0.05.

Results

Characteristics of patients

A total of 193 patients were included for analysis as 46 patients were excluded because they did not undergo imaging study in the emergency department (Figure 1). The mean age was 37.7 years (±14.5), 26.9% of patients (n=52) had a history of urolithiasis, 19.2% (n=37) had a history of urinary tract abnormality, 10.4% (n=20) had a neurogenic bladder, 7.3% (n=14) underwent kidney transplantation, and 6.7% (n=13) had diabetes (Table 1). The mean pain intensity according to a visual analogue scale (VAS) was 5.8/10 (±2.9), 82.9% (n=159) had fever >38.5°C, and the mean time since symptom onset was 3.5 days (±3.9). The mean Creactive protein level was 136.9 mg/L (±110.8) and the mean serum creatinine level was 143.4 µmol/L (±120.6).

All 193 patients underwent imaging study: renal ultrasound for 37% (n=71), contrastenhanced CT scan with excretory urography for 27.5% (n=53), unenhanced CT scan for 20.8% (n=40), and contrast-enhanced CT scan without excretory urography for 14.6% (n=28).

Urological complication(s) on imaging findings and impact on the patient's management

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Eighty-eight (n=45, 6%) of the 193 patients had a urological complication on imaging findings (Table 2): 10 patients had renal abscesses (5.2%), 42 patients had a stone in the upper urinary tract ipsilateral to the flank pain (21.8%), 10 patients had another cause of obstruction in the upper urinary tract (5.2%), and 26 patients had hydronephrosis ipsilateral to the flank pain (13.5%).

Treatment was changed based on imaging findings in 68 patients (35.2%), with a surgical treatment (emergency or planned surgery) for 62 patients (32.1%); 58 patients had emergency urinary diversion (30.1%) (including nine patients with nephrostomy tube and 49 patients with a double-J ureteral stent), three patients (1.6%) had a longer duration of antibiotic therapy, two patients (1%) had a follow-up imaging study scheduled, two patients (1%) had diagnostic ureteroscopy, three patients (1.6%) had another specialized management (drainage of digestive abscess, gynecological procedure, etc.).

Seventy-one patients (36.8%) underwent renal ultrasound and 122 patients (63.2%) CT scan.

Patients who underwent CT scan were more often diagnosed with urological complications than those who underwent ultrasound (56.2% versus 26.8%, p<0.001). Treatment changes (39.7% vs 26.8%, p=0.004), pyelonephritis signs on imaging findings (66.9% vs 30.3%, p<0.001), and incidental differential diagnoses (31.4% vs 10.1%, p=0.005) were more frequently associated with patients who underwent CT scans. Differential diagnosis was observed on imaging findings for 45 patients (23.3%): eight patients (4.1%) had a renal mass (cyst, tumor, etc.), four patients (2.1%) had a gynecological abnormality, 14 patients (7.3%) had a congenital abnormality of the urinary tract, and one patient (0.6%) had emphysematous pyelonephritis and other various diagnoses.

Predictive factors of urological complications on imaging findings

The univariate analysis revealed that age (OR=4.09, p=0.004), history of urolithiasis (OR=3.85, p<0.001), CRP level at the time of hospital admission (OR=6.94, p=0.02), and pain requiring morphine use (OR=3.15, p=0.01) were associated with urological complications on imaging findings (Table 3).

The multivariate analysis revealed that history of urolithiasis (OR=2.41, p=0.01) and pain requiring morphine use (OR=5.29, p=0.009) remained the only two variables significantly associated with urological complications on imaging findings.

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The univariate analysis revealed that age (OR=2.82, p=0.04), pain requiring morphine use (OR=3.40, p=0.007), and history of urolithiasis (OR=2.63, p=0.004) were significantly associated with treatment change based on imaging findings. Pain requiring morphine use (OR=6.35, p=0.002) remained the only significant predictor of treatment change based on imaging findings in the multivariate analysis.

Analysis in the uncomplicated pyelonephritis subgroup

A total of 154 patients had uncomplicated pyelonephritis, of whom 120 patients had an imaging study performed in the emergency department and were included in the study (Figure 2). Characteristics of these patients are detailed in Table 4.

A urological complication was diagnosed on imaging findings in 54 patients (45%): renal abscess in seven patients (5.8%), hydronephrosis in 37 patients (30.8%), a stone in the upper urinary tract ipsilateral to the flank pain for 33 patients (27.5%), and another cause of upper urinary tract obstruction in seven patients (5.8%). Treatment was changed based on imaging findings in 44 patients (36.7% of the subgroup of uncomplicated pyelonephritis patients).

The univariate analysis revealed that age (OR=4.82, p=0.01), history of urolithiasis (OR=2.80, p=0.02), systemic symptoms (OR=2.17, p=0.048), and pain requiring morphine use (OR=3.19, p=0.04) were significantly associated with urological complication on imaging findings. The multivariate analysis revealed that age (OR=4.58, p=0.02), and pain requiring morphine use (OR=3.78, p=0.02) were still significantly associated with urological complication on imaging findings (Table 5).

The univariate analysis revealed that age (OR=4.87, p=0.01), pain requiring morphine use (OR=3.53, p=0.02), and history of urolithiasis (OR=2.51, p=0.04) were significantly associated with treatment change based on imaging findings. Age (OR=6.76, p=0.005) and pain requiring morphine use (OR=4.19, p=0.01) remained the only statistically significant predictors of treatment change based on imaging findings in the multivariate analysis.

The percentage of urological complications on imaging findings observed in patients with pain requiring morphine use was 69%, and 62.5% of patients underwent treatment change based on the imaging findings (Figure 3).

The percentage of urological complications based on imaging findings in patients aged ≥40 years was 57.7%, and 46.2% of these patients had a treatment change (Figure 4).

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The percentage of urological complications based on imaging findings in patients with a history of urolithiasis was 64.3%, and 53.6% of these patients had a treatment change (Figure 5).

Discussion

Our study identified three predictive factors of urological complication on imaging findings in women aged 18-65 years presenting with pyelonephritis: history of urolithiasis, pain requiring morphine use, and age (linear association between urological complications on imaging findings).

To our knowledge our study is the first to report the association between pain intensity and the risk of urological complication on imaging findings. However, other predictive factors of urinary tract obstruction have already been reported: inflammation on blood test, fever intensity [START_REF] Huang | Acute bacterial nephritis: a clinicoradiologic correlation based on computed tomography[END_REF], or low blood pressure [START_REF] Campos-Franco | Acute focal bacterial nephritis in a cohort of hospitalized adult patients with acute pyelonephritis. Assessment of risk factors and a predictive model[END_REF]. Only the SPILF's guidelines [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF] mention the need for imaging studies in case of hyperalgesia in patients with acute pyelonephritis, but they do not clearly define hyperalgesia. We did not observe any association between pain intensity as assessed by VAS and the risk of urological complication, but we observed a significant association with pain requiring morphine use. Hence our work could be regarded as a posthoc validation of the SPILF's guidelines statement regarding the need for immediate imaging studies in this population with pain requiring morphine use. Our findings also evidenced the lack of association between pain intensity as assessed by VAS and morphine prescription in our emergency department.

In our study, as in previous series [START_REF] Demertzis | State of the art: imaging of renal infections[END_REF][START_REF] Venkatesh | Acute Pyelonephritis -Correlation of Clinical Parameter with Radiological Imaging Abnormalities[END_REF][START_REF] Kawashima | Radiologic evaluation of patients with renal infections[END_REF], urological complications were more frequently diagnosed by CT scan than ultrasound. This might be due to a selection bias because patients with severe presentations of pyelonephritis could be more likely to have a CT scan than an ultrasound; we were thus more likely to detect complications. However, the better sensitivity of the CT scan in detecting urinary complications of pyelonephritis has already been reported in literature. The impact of radiations on young women should be accounted for when choosing the imaging modality as well as the risk of allergy to gadolinium contrast agent [START_REF] Hyzy | Evidence-Based Critical Care: A Case Study Approach[END_REF]. The use of first-line CT scan should thus be restricted to specific patients: severe clinical presentation, additional imaging study when the ultrasound does not provide a diagnosis.

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Initial assessment of patients by ultrasound in the emergency department has been increasingly used over the past decade [START_REF]Emergency Ultrasound Guidelines[END_REF][START_REF] Scalea | Focused Assessment with Sonography for Trauma (FAST): results from an international consensus conference[END_REF]. Initially used for multiple traumatic injuries (Focused Assessment with Sonography for Trauma, FAST), the ultrasound is now used in many other indications. According to the recent French emergency society guidelines, emergency physicians should "be able to diagnose hydronephrosis by ultrasound" [START_REF] Sfmu | Premier niveau de compétence pour l'échographie clinique en médecine d'urgence[END_REF]. Little data is available in the literature [START_REF] Yen | Renal abscess: Early diagnosis and treatment[END_REF], but initial ultrasound performed in the emergency department in patients presenting with acute pyelonephritis could contribute to identifying patients requiring further imaging study by radiologists (either CT scan or ultrasound). Using FAST ultrasound might minimize the risk of missing urological complications during the initial assessment and may improve the cost-effectiveness of these patients' management [START_REF] Kameda | Overview of point-of-care abdominal ultrasound in emergency and critical care[END_REF].

We observed an association between a history of urolithiasis and a risk of urological complications on imaging findings. To our knowledge this variable has rarely been investigated as a potential risk factor for urological complications [START_REF] Spilf | Mise au point -Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte[END_REF][START_REF] Grabe | Guidelines on Urological infections [Internet[END_REF]. Risk factors for complications are indeed usually limited to "abnormalities of the urinary tract", without past history of urolithiasis. The statistical association we demonstrated might be explained by the high risk of recurrence of urolithiasis (up to 50% at 5 years) [START_REF] Gálvez | Diagnosis and radiological follow up of urinary lithiasis[END_REF][START_REF] Ljunghall | A Prospective Study of Renal Stone Recurrences[END_REF]. Similar to previous series [START_REF] Yen | Renal abscess: Early diagnosis and treatment[END_REF][START_REF] Chen | The role of emergency ultrasound for evaluating acute pyelonephritis in the ED[END_REF][START_REF] Sørensen | The role of imaging of the urinary tract in patients with urosepsis[END_REF][START_REF] Wang | The use of ultrasonography in evaluating adults with febrile urinary tract infection[END_REF][START_REF] Van Nieuwkoop | Predicting the Need for Radiologic Imaging in Adults with Febrile Urinary Tract Infection[END_REF], our findings emphasize the importance of this criterion. It should therefore be included in the decision-making process to select patients for initial imaging assessment.

Our study has several limitations, such as its retrospective and single-center design.

Moreover, the relatively small sample size and inherent lack of statistical power might explain the lack of statistical significance for some variables (e.g., systemic symptoms).

Inclusions were made based on our local information system with ICD 10 codes allowing us to only identify patients with a final diagnosis of pyelonephritis. It would have been relevant to include in our analysis all patients with a clinical presentation compatible with pyelonephritis, to assess the role of imaging study in detecting differential diagnoses. As the choice of imaging study may impact diagnosis, one may think than complications were not diagnosed in patients who underwent ultrasonography versus those who had a CT scan performed. There was also a selection bias as selecting patients in the emergency department does not properly reflect the population of patients consulting in primary care settings. Patients included in our study and those consulting in community settings probably do not share the same characteristics, especially as some of our patients had been referred ACCEPTED MANUSCRIPT -CLEAN COPY to the emergency department by their family physician. This selection bias could explain the similar rates of complications on imaging findings in patients presenting with uncomplicated pyelonephritis and in the whole cohort (all pyelonephritis cases). Hence, no conclusion could be drawn from our work on the management of patients in a primary care setting.

Conclusion

Pain intensity as assessed by visual analogue scale was not associated with the risk of urological complications on imaging findings or with treatment change based on imaging findings, either in the whole cohort (including pyelonephritis at high risk of complications) or in the selected population of patients without comorbidities. However, pain requiring morphine use was significantly associated with a risk of urological complications on imaging findings, which supports the role of initial imaging study in patients presenting with such clinical signs and symptoms. Age and history of urolithiasis highly increased the likelihood of urological complications on imaging findings. These clinical criteria could help detect good candidates for initial imaging study among patients with uncomplicated pyelonephritis.

Nevertheless, the high rate (45%) of urological complications on imaging findings in patients with uncomplicated pyelonephritis consulting at the emergency department would argue in favor of systematic initial imaging study in these patients.

Figure 1 .Figure 1 .Figure 2 .Figure 2 .Figure 3 .Figure 3 .Figure 4 .Figure 4 .

 11223344 Figure 1. Flow chart -acute pyelonephri s

Figure 5 .Figure 5 .

 55 Figure 5. Complications urologiques et modifications du traitement selon l'existence ou non d'un antécédent de calcul urinaire Figure 5. Urological complication and treatment changes according to a past history of urolithiasis

Table 1 .

 1 Characteristics of patients

	Tableau 1. Caractéristiques des patientes
		Characteristics of patients
		N=193
	Mean age (years)	37.7 (± 14.5)
	Comorbidities and history of urological disorders
	Diabetes
		13 (6.7%)
	Kidney transplantation
		14 (7.3%)
	Neurogenic bladder
		20 (10.4%)
	Urinary tract abnormality
		37 (19.2%)
	History of urolithiasis
		52 (26.9%)
	Fever >38.5°C	159 (82.8%)
	Systemic symptoms (fainting, deterioration of general status, etc.)	60 (31.3%)
	Pain intensity assessed by visual analogue scale (/10)	5.8 (± 2.9)
	Mean CRP level at admission (mg/l)	136.9 (± 110 .8)
	Mean serum creatinine level at admission (µmol/l)	143.3 (± 120.6)

CT: computed tomography ACCEPTED MANUSCRIPT -CLEAN COPY

Table 2 .

 2 Urological complications on imaging findings

	Tableau 2. Complications à l'imagerie
		Patients with imaging
	Type of urological	study
	complications
		n=193
	Renal abscess	10

Stone in the upper urinary tract ipsilateral to the flank pain 42 Another cause of obstruction in the upper urinary tract (hematoma, tumor, fecaloma, etc.) 10 Hydronephrosis ipsilateral to the flank painTable 3 .

 3 Prognostic factors of urological complication on imaging findings in univariate and Tableau 4. Caractéristiques des patientes du sous-groupe pyélonéphrites simples sans signes de gravité

	multivariate analyses
	Tableau 3. Facteurs prédictifs de complication urologique à l'imagerie en analyses
	univariées et multivariées
				Urological complication on imaging findings
	Variables		Univariate analysis			Multivariate analysis
			95% confidence			95% confidence
		Odds ratio	interval Lowest Highest	p value	Odds ratio	interval Lowest Highest	p value
			limit	limit			limit	limit
	Age	4.09	1.97	6.24	0.004*	2.53	0.86	4.32	0.19
	Past history of urolithiasis	3.85	1.98	7.77	<0.001*	2.41	0.94	6.45	0.01*
	Neurogenic bladder	0.62	0.22	1.57	0.31	-	-	-	-
	Past history of upper urinary tract surgery	0.88	0.43	1.82	0.75	-	-	-	-
	Diabetes	1.02	0.32	3.20	0.97	-	-	-	-
	Systemic symptoms	1.76	0.96	3.29	0.07	1.79	0.75	4.34	0.19
	CRP level at admission	6.94	1.72	9.89	0.02*	4.07	0.81	3.93	0.16
	Pain requiring morphine use	3.15	1.28	8.58	0.01*	5.29	1.51	22.07	0.009*

Table 4 .

 4 Characteristics of patients included in the uncomplicated pyelonephritis, without severe signs, subgroup

	Characteristics of patients
	n=120

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Table 5 .

 5 Prognostic factors of urological complications on imaging findings, in univariate and multivariate analyses in patients with uncomplicated pyelonephritis Tableau 5. Facteurs prédictifs de complication urologique à l'imagerie en analyses univariées et multivariées chez les patients ayant un tableau de pyélonéphrite simple

				Urological complications on imaging findings
	Variables		Univariate analysis			Multivariate analysis
			95% confidence			95% confidence
		Odds ratio	interval Lowest Highest	p value	Odds ratio	interval Lowest Highest	p value
			limit	limit			limit	limit
	Age	4.82	2.61	6.57	0.01*	4.58	2.44	6.36	0.02*
	Past history of urolithiasis	2.80	1.18	6.96	0.02*	2.42	0.95	6.48	0.06
	Systemic symptoms	2.17	1.01	5.14	0.048*	2.34	0.97	5.83	0.06
	CRP level	2.71	0.27	7.88	0.28	-	-	-	-
	Pain requiring morphine use	3.19	1.08	10.76	0.04*	3.78	1.18	13.72	0.02*
	Visual analogue pain
		1.01	0.25	3.91	0.99	-	-	-	-
	Highest pain
	Mean time since symptom onset	1.34	0.08	6.77	0.78	-	-	-	-

Visual analogue scale


Niels Dehio

Yuquan Wang

Abderrahmane Kheddar

Dual-arm Box Grabbing with Impact-aware MPC utilizing soft deformable End-effector Pads

Keywords:

Safely generating impacts is challenging due to subsequent discontinuous velocity jumps and high impact forces. For this reason, state-of-the-art multi-robot controllers performing collaborative object manipulation typically approach contacts with low relative velocities. We instead aim for highspeed bi-manual impact-aware swift grabbing tasks, generating intentionally maximum feasible impacts. Therefore, we propose that the robot end-effector tips be equipped with deformable soft pads. The hardware modification partially absorbs the shock and enables us to control the deformation state during the prolonged impact duration. Mapping the robot's structural hardware constraints from the high-dimensional configuration-space to the low-dimensional contact-space enables us to model the bounded deformation dynamics explicitly. Exploiting constrained modelpredictive control (MPC), we maximize the impact velocity within the feasible limits for dual-arm setups with deformable endeffector tips. Our control paradigm is assessed with real-robot experiments on two redundant Panda manipulators, demonstrating high pre-impact velocities for boxes with varying weights and size. The approach also applies to grabbing soft objects with rigid end-effectors.

I. INTRODUCTION

W E aim at enabling robotic fast grabbing and tossing of bulky box objects in automated industrial sorting chains 1 . Collaborative dual-arm manipulation -and more generally, multi-arm manipulation -has a long history in robotic research, dating back to the late 1980s with early works reported in [START_REF] Hayati | Hybrid position/force control of multi-arm cooperating robots[END_REF], [START_REF] Lee | Dual redundant arm configuration optimization with taskoriented dual arm manipulability[END_REF]. Bi-manual object manipulation allows us to overcome the payload limit of a single manipulator [START_REF] Dehio | Modeling and Control of Multi-Arm and Multi-Leg Robots: Compensating for Object Dynamics during Grasping[END_REF] and is a by-design choice for humanoid robots when lifting heavy weights [START_REF] Henze | Passivity-based whole-body balancing for torque-controlled humanoid robots in multi-contact scenarios[END_REF], [START_REF] Arisumi | Dynamic lifting motion of humanoid robots[END_REF]. Classical research topics comprise optimization of contact locations and contact forces, manipulability optimization, identification of object dynamics, and many more. However, few studied high-speed contact transitions for swiftly grabbing rigid objects bi-manually.

We want to maximize feasible end-effector velocities for the contact grabbing, prior to lifting, inherent in bi-manual tasks Manuscript received September 29, 2021; Revised January 16, 2022; Accepted February 21, 2022. This paper was recommended for publication by Editor Markus Vincze upon evaluation of the Associate Editor and Reviewers' comments. This work is in part supported by the Research Project I.AM. through the European Union H2020 program (GA 871899).

1 N. Dehio, Y. Wang and A. Kheddar are with the CNRS-University of Montpellier LIRMM Interactive Digital Humans group, Montpellier, France. niels.dehio,yuquan.wang,kheddar@lirmm.fr 2 A. Kheddar is also with the CNRS-AIST Joint Robotics Laboratory, IRL, Tsukuba, Japan.

Digital Object Identifier (DOI): see top of this page. 1 Refer to Impact-Aware Manipulation https://i-am-project.eu Fig. 1: Schematic illustration of impact forces for a given mass and pre-impact velocity with a rigid (left) and soft (right) contacts.

Fig. 2: Two Panda manipulators with soft, deformable pads attached to the end-effectors. We initiate contacts for swift box grabbing with pre-impact velocities of 0.61 m/s. The video is available at: https://youtu.be/dPLNfl7knF8 without damaging the robot arms and the grabbed objects. This is a non-trivial challenge w.r.t the maximum impact that gearboxes and torque sensors can handle. We propose utilizing soft, deformable end-effector pads for dual-arm grabbing tasks. The softness will absorb a large part of the kinetic energy, allowing for higher impact velocities compared to rigid end-effectors. Figure 1 illustrates the shape of the contact force at impact: the same mass and contact velocity leads to a significant force peak in the rigid case, whereas in a soft case the force curve is flattened. Consequently, a soft pad at end-effectors increases the set of physically possible robot movements when it comes to contact with rigid objects. Yet, trajectory planning and control requires material's softness modeling in order to fully exploit deformable end-effector pads.

Our main contribution is the derivation of bounded deformation dynamics for a dual-arm system with deformable end-effector pads. These constrained deformation dynamics provide the basis for a model predictive control (MPC) scheme [START_REF] Sheridan | Three models of preview control[END_REF], [START_REF] Nakamura | Multi-preview configuration control for predictive behavior of redundant manipulator[END_REF], [START_REF] Lee | Mpc-based hierarchical task space control of underactuated and constrained robots for execution of multiple tasks[END_REF], generalized from single-arm poking [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF] to dual-arm grabbing. The MPC optimizes the deformation trajectory, which is to be initiated with the highest possible end-effector velocities. Our formulation maps structural hardware limits of two potentially redundant robot arms2 onto the low-dimensional contact-space. Including these inequality constraints into the deformation dynamics ensures safe operation over a sufficiently long preview-horizon. Compared to existing works, the novelty of our approach lies in the explicit computation of the maximum feasible contact velocity for a dual-arm robot setup to swiftly grab a rigid object bi-manually.

We assessed our impact-aware controller with various objects grabbing experiments with two Panda manipulators, see Fig. 2 and shown in the accompanying video available at https://youtu.be/dPLNfl7knF8. We could successfully achieve high impact velocities without violating hardware limitations. Executing the rigid box grabbing task without soft pads and similar (to soft) contact velocities would trigger the robot's safety reflex, resulting in a freeze-stop and potential hardware damage. On the other hand, our approach also applies to grabbing known soft objects with rigid end-effectors.

II. RELATED WORKS

It is difficult to predict accurately contact forces (in this case, impulses) or stress induced from two-impacting bodies [START_REF] Faik | Modeling of impact dynamics: A literature survey[END_REF]. Conventional contact mechanics, e.g., the Hertz theory, predict contact forces for spherical contact surfaces [START_REF] Pashah | Prediction of structural response for low velocity impact[END_REF]. So far, the latter is limited to non-articulated objects and is not applicable for actuated robots with complex kinematic chains. This explains, in part, that related works on collaborative multi-arm robots establish contacts with relatively low endeffector velocities to grab objects [START_REF] Murooka | Global planning of whole-body manipulation by humanoid robot based on transition graph of object motion and contact switching[END_REF], [START_REF] Yan | Dual-arm coordinated motion planning and compliance control for capturing moving objects with large momentum[END_REF], [START_REF] Gienger | Human-robot cooperative object manipulation with contact changes[END_REF].

Our pilot experiments confirm that an impact with a soft material significantly reduces the peak impulsive force and increases the overall impact duration, see the schematic illustration in Fig. 1. The approach for joint object manipulation in [START_REF] Dehio | Modeling and Control of Multi-Arm and Multi-Leg Robots: Compensating for Object Dynamics during Grasping[END_REF] uses deformable rubber elements attached on top of the rigid end-effector to mitigate the risk inherent to high peak impacts. Yet, the material softness and the actual deformations were not considered within the model-based torque-controller. Few works focused on modeling deformable robotic fingertips [START_REF] Watanabe | Softness effects on manipulability and grasp stability[END_REF] and virtual spring-damper systems [START_REF] Wimböck | Comparison of object-level grasp controllers for dynamic dexterous manipulation[END_REF] for grasping scenarios, though, without discussing the resulting contact transitions. Contact forces arising from penetrating soft material have been precisely modeled in [START_REF] Azad | Model estimation and control of compliant contact normal force[END_REF]. In [START_REF] Smoljkic | Constraint-based interaction control of robots featuring large compliance and deformation[END_REF] a deformable end-effector tip is modeled at the quasi-static level neglecting dynamic effects. The finite element method (FEM) is usually used in various continuum mechanics problems. It has been adopted in robotics to simulate material deformations, e.g., [START_REF] Bouyarmane | FEM-based static posture planning for a humanoid robot on deformable contact support[END_REF], [START_REF] De Magistris | Humanoid walking with compliant soles using a deformation estimator[END_REF], [START_REF] Coevoet | Soft robots locomotion and manipulation control using FEM simulation and quadratic programming[END_REF]; so far not in high-speed contact transitions with actuated robots.

The robot's structural hardware limits defined in the jointspace implicitly result in bounds in the contact-space. These bounds need to be fulfilled when intentionally generating impacts. Besides switching joint-space reference trajectories, where such limits are accounted in the off-line planned trajectories [START_REF] Rijnen | Control of humanoid robot motions with impacts: Numerical experiments with reference spreading control[END_REF], to our best knowledge, only a few related works on task-space impact-aware control take these hardware limits into account. The prediction of impact-induced state jumps caused by rigid contacts is formulated in [START_REF] Wang | Impact-friendly robust control design with task-space quadratic optimization[END_REF] to limit the end-effector speed prior to making contact. For impacting soft contacts with a manipulator, we inferred in [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF] the configuration-dependent maximum feasible impact velocity. This upper velocity bound can be tracked with the robot arm before making contact, guaranteeing the robot's hardware limits during the following deformation phase.

An initial attempt towards impact-aware multi-arm box grabbing has been made in [START_REF] Wang | Impact-aware task-space quadratic-programming control[END_REF] with a humanoid and rigid contacts, lifting a lightweight, empty box. However, we are not aware of any study on swift dual-arm grabbing employing deformable material. In this paper, we explicitly model soft pads attached to two end-effectors in a dual-arm setup and devise a constrained impact-aware MPC in the contact-space, thereby extending and enhancing previous works.

III. MAPPING HARDWARE LIMITS TO CONTACT-SPACE

Let us elaborate further the mapping of the manipulator's structural hardware limits onto the contact-space, initially described in [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF] and inspired by [START_REF] Samy | Post-impact adaptive compliance for humanoid falls using predictive control of a reduced model[END_REF], [START_REF] Orsolino | Feasible region: An actuation-aware extension of the support region[END_REF]. This configurationdependent mapping is not trivial when dealing with redundant robots. Considering the full Cartesian contact-space, the mapping procedure is computationally demanding and hence unsuitable for real-time control. Fortunately, the mapping simplifies, and a real-time solution exists when restricting the end-effector motion along the contact normal.

A. Constrained Robot State

Let us model the rigid-body dynamics for a fixed-base manipulator with N actuated joints in contact situation by

τ + J T 1 f = Mq + h , (1)
where τ ∈ R N are the joint torques, f ∈ R is the scalar force along the contact normal, M ∈ R N ×N denotes the joint-space inertia, q ∈ R N are the joint accelerations, and h ∈ R N comprises gravity, Coriolis and centrifugal forces. The end-effector Jacobian J ∈ R 6×N consisting of six rows is decomposed as

J 1 = o T 1 J and J 2..6 = o T 2..6 J with the orthonormal base O = [o 1 , o 2.
.6 ] ∈ R 6×6 and the vector o 1 ∈ R 6 corresponding to the contact normal. We assume a full-rank Jacobian J in this letter.

We represent the robot state (generalized coordinates) by the vector q T , qT , qT , f T T ∈ R 3N +1 , which implicitly includes the joint torques τ through [START_REF] Hayati | Hybrid position/force control of multi-arm cooperating robots[END_REF]. The robot state is feasible at a given time instance when satisfying the structural hardware limits provided by the robot manufacturer 3 . These limits form a convex, high-dimensional polytope where symbols ¯ , ¯ denote lower and upper limits of , respectively. The particular hardware limits relate to the resilience of gearboxes and torque sensors, and to the maximum force a wrist-mounted force-torque sensor can afford. When planning a discretized robot trajectory, the robot state must fulfill (2) at each time instance.

      q q q f τ -h       ≤       I, 0, 0, 0 0, I, 0, 0 0, 0, I, 0 0, 0, 0, I 0, 0, M, -J T 1           q q q f     ≤       q q q f τ -h       , (2)
In the following, we focus on an established contact situation with a deformable material, as indicated in Fig. 3. It is irrelevant for the analysis if the soft material is part of the environment or the robot. The scalar contact-space velocity ż = J 1 q ∈ R and acceleration z = J 1 q + J1 q ∈ R in contact normal direction are generally non-zero. Besides, let us enforce zero end-effector velocity 0 = ẋ = J 2..6 q ∈ R 5 and zero acceleration 0 = ẍ = J 2..6 q + J2..6 q ∈ R 5 (i.e., no tangential contact velocity). These relationships are gathered in matrix form as

    J 1 , 0, -I, 0 J 2..6 , 0, 0, 0 J1 , J 1 , 0, -I J2..6 , J 2..6 , 0, 0         q q ż z    =     0 0 0 0     , (3)
To represent motion in the contact-space (along the contact normal), we define the low-dimensional deformation state z T , żT , zT , f T T ∈ R 4 , which is implicitly bounded by the hardware limits described above. The configuration-dependent contact-space bounds are explicitly derived in the following subsections by combining (2) and (3). In other words, we map the high-dimensional polytope onto the low-dimensional space, see also [START_REF] Bretl | Testing static equilibrium for legged robots[END_REF].

B. Contact-Space Bounds on Velocity

The lower bound on the contact-space velocity ż yields ż = min q J 1 q (4) s. t. J 2..6 q = 0 q ≤ q ≤ q due to the block-structure in (2) and (3). The upper velocity bound ż is obtained by negating the objective function.

C. Contact-Space Bounds on Acceleration and Force

Due to the structure of (2), the bounds on contact-space acceleration z and force f are coupled and cannot be treated separately. Geometrically, the set of feasible z and f is represented by a two-dimensional convex polytope (= polygon). Its convex hull consists of multiple vertices. Such a vertex can be obtained by solving the linear program (for J q 0, refer to the explanation in Sec. IV-A)

arg min q,f ,z z v 1 + f v 2 (5) s. t. J 1 , 0, -I J 2..6 , 0, 0   q f z  = 0 0   q f τ -h   ≤   I, 0, 0 0, I, 0 M,-J T 1 , 0     q f z  ≤   q f τ -h  
The scalar weights v 1 , v 2 ∈ R can be geometrically interpreted as a two-dimensional ray pointing in a particular search direction. By solving (5) multiple times for different rays, a list of vertices is collected, approximating the convex hull of feasible z and f . Refer to [START_REF] Bretl | Testing static equilibrium for legged robots[END_REF] and [START_REF] Roux | Control of humanoid in multiple fixed and moving unilateral contacts[END_REF] for an efficient algorithm to select meaningful search directions (rays), such that the convex hull is well covered after few iterations. The vertex representation is converted into an equivalent halfspace representation, where matrix P = [P z, P f ] determines halfplanes, and vectors p, p denote offsets

p ≤ P zz + P f f ≤ p . (6)

D. Contact-Space Bounds on Deformation Position

We assume an unilateral contact, implying that the soft material cannot be stretched by pulling. Further, the material has a maximum penetration depth depending on its thickness and the elastic deformation domain. Hence, the scalar contact deformation z ∈ R (related to the initial contact point and the absolute end-effector position along the contact normal) satisfies lower and upper bounds z, z to be within the deformation domain.

E. Constrained Deformation State

Summarizing the previous derivation, the low-dimensional deformation state z T , żT , zT , f T T is feasible at a given time instance when satisfying the bounds

  z ż p  ≤   I, 0, 0, 0 0, I, 0, 0 0, 0, P z P f       z ż z f     ≤   z ż p  . (7)
It is important to note that a feasible deformation state also guarantees the existence of an associated feasible robot state q T , qT , qT , f T T . When planning a discretized deformation trajectory, the deformation state must achieve [START_REF] Nakamura | Multi-preview configuration control for predictive behavior of redundant manipulator[END_REF] at each time instance.

F. Illustrative Example

Consider a planar manipulator with two rotational joints. The link lengths are l 1 = 0.5 m, l 2 = 0.3 m, link masses are m 1 = 3 kg, m 2 = 2 kg, and the center-of-mass is located in each link center. The upper hardware limits are given by q = [2, 3] T rad/s, q = [10, 20] T rad/s 2 , τ = [25, 10] T Nm, f = 100 N, and the lower limits are their negative values.

Let us analyze the specific posture q = [ π /3, -π /3] rad, assuming the end-effector established a soft, deformable contact. The end-effector is pointing along the vector [1, 0] T , also treated as the contact normal. Given (2) and (3), we extract the individual constraints w.r.t. velocities q ≤ q ≤ q , (7a)

ż = J 1 q , (7b) ẋ = J 2 q , (7c) 0 = ẋ = J 2 q , ( 7d
)
and w.r.t. the coupled acceleration and force q ≤ q ≤ q , (7e)

f ≤ f ≤ f , (7f) τ -h ≤ Mq -J T 1 f ≤ τ -h , (7g) z = J 1 q + J1 q , (7h) ẍ = J 2 q + J2 q , (7i) 0 = ẍ = J 2 q + J2 q . ( 7j
)
The blue 2D-polytopes (i.e., polygons) in Fig. 4 show the feasible set in terms of joint velocities q1 , q2 (top part)

X 1 = q ∈ R 2 | (7a) , and (8a)
its mapping onto end-effector velocities ż, ẋ (bottom part)

X 2 = ż ∈ R, ẋ ∈ R, q ∈ R 2 | (7a) -(7c) . (8b)
The red 1D-polytope (line segment with scalar upper/lower bounds) indicates how these feasible sets shrink when additionally enforcing (7d) to avoid a tangential contact velocity.

Y 1 = q ∈ R 2 , f ∈ R| (7e) -(7f) , (8a) Y 2 = q ∈ R 2 , f ∈ R| (7e) -(7g) , (8b) Y 3 = z ∈ R, ẍ ∈ R, q ∈ R 2 , f ∈ R| (7e) -(7i) , (8c) Y 4 = z ∈ R, ẍ ∈ R, q ∈ R 2 , f ∈ R| (7e) -(7j) . ( 8d
)
IV. APPROACH Our proposed impact-aware dual-arm grabbing controller is provided, as input, with the preferred contacting points for each category of objects. These pair of contact points are collinear line to opposite contact normal directions and parallel tangent to contact normal planes. Because we aim at swiftly grabbing (not grasping) and conformably with industrial recommendations, contacts on objects are chosen so as to not generate rotational torque during the grabbing phase. There is no restriction on their shape; a deforming pad allows casting locally the object's surface at the contacting spots.

While approaching the object to be grabbed with two soft end-effectors, in each cycle, the controller expects that both contact events will happen in the next iteration. With this expectation, the controller repeatedly recomputes and tracks the maximum feasible (configuration-dependent) pre-impact velocities. By doing so, the controller is robust to object's width uncertainties and to exact contact timing and localization (along the normal). Our approach generates intentional impacts for swift dual-arm grabbing without violating hardware limits during the deformation phase.

In the following, we derive a bounded deformation dynamics model; formulate a constrained optimization problem for planning and controlling a feasible dual-arm penetration trajectory; explain how our controller handles light asynchronous contact events; and provide a comparison to our previous work on impact-aware single-arm soft poking.

A. Bounded Dual-Arm Deformation Dynamics

In [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF], we proposed the bounded deformation dynamics model for poking soft material with a single robot, cf. Fig. 6 left. Here, we generalize our prior work for dual-arm grabbing scenarios. Consider a fixed-base dual-arm robot system grabbing a rigid object with soft deformable pads attached to both end-effectors, cf. Fig. 6 right. We utilize the indexes ( o ), ( l ), ( r ) to indicate the object, left and right manipulator, respectively, and chose the notation ( l|r ) for indicating the left or right manipulator.

Let us model the interaction with the soft material as a mass-spring-damper system at each end-effector (also known as Kelvin-Voigt model [START_REF] Flügge | Viscoelasticity[END_REF]) with the material's constant, finite stiffness k l|r > 0 and damping p l|r > 0 ∈ R. Denote the relative deformation position of both end-effectors as z l ∈ R, z r ∈ R, and the object's relative position as z o ∈ R, as indicated in Fig. 6 right. Based on Newton's laws, we derive the three equations of motion

m l zl = -f l + k l (z o -z l ) =fspring-left + p l (ż o -żl ) =fdamper-left , (9)
m r zr = -k r (z r -z o ) =fspring-right -p r (ż r -żo ) =fdamper-right + f r , (10)
m o zo = -k l (z o -z l ) =fspring-left -p l (ż o -żl ) =fdamper-left + k r (z r -z o ) =fspring-right + p r (ż r -żo ) =fdamper-right , (11)
with effective mass

m l|r = o T 1 J l|r M -1 l|r J T l|r o 1 -1
> 0 [30] and with f l|r as a function of the applied joint torques τ l|r based on (1). These three equations can be gathered as

M   zl zr zo   = K   z l z r z o   + P   żl żr żo   +   -f l f r 0   , (12)
or,

  zl zr zo   = M -1 K   z l z r z o   + M -1 P   żl żr żo   + M -1   -f l f r 0   (13)
with

M =   m l 0 0 0 m r 0 0 0 m o   , M -1 =   1 m l 0 0 0 1 mr 0 0 0 1 mo   ∈ R 3×3 (14)
and

K =   -k l 0 k l 0 -k r k r k l k r (-k l -k r )   , P =   -p l 0 p l 0 -p r p r p l p r (-p l -p r )   . (15)
Let us introduce the deformation-dependent system state

s = [z T l , z T r , z T o , żT l , żT r , żT o ] T ∈ R 6 ( 16
)
and the control input

u = -1 m l f l 1 mr f r ∈ R 2 . ( 17
)
Reformulating the second-order differential equation ( 13) yields the continuous-time state-space representation

ṡ = A c s + B c u (18)
with

A c = 0 3×3 I 3×3 M -1 K M -1 P ∈ R 6×6 , B c =   0 3×2 I 2×2 0 1×2   ∈ R 6×2 . ( 19
)
We assume small changes in the robot configuration due to relatively small indentations, implying constant inertia M, constant Jacobian J, zero Jacobian derivative J. Accordingly, there is a negligible change in the effective masses m l|r and in the mass matrix M, resulting in constant A c . Discretization of ( 18) yields the discrete-time state-space representation with

A d ∈ R 6×6 , B d ∈ R 6×2
, where subscript i denotes steps at time t = i∆t utilizing the sample time ∆t

s i+1 = A d s i + B d u i . ( 20
)
Note that the resulting discretized acceleration zi is linear in terms of state s i and control input u i . Refer to appendix -A for the derivation of matrices C and

D zi = Cs i + Du i . (21)
We can also predict the future forces imposed by the deformed left and right end-effector pads through

f i = 1 0 0 0 1 0 K P s i . (22)
This unbounded deformation dynamics model described so far in [START_REF] De Magistris | Humanoid walking with compliant soles using a deformation estimator[END_REF] is parameterized by the object mass m o , the configuration-dependent effective masses m l|r , and the soft material properties k l|r , p l|r . In reality, however, the system behavior is bounded. The actual contact-space bounds correlate with the particular penetrating robot hardware limits specified in high-dimensional configuration-space. The previous section showed how to map the structural hardware limits onto contact-space bounds for a single manipulator, which applies here identically for both robot arms. Due to these constraints, not all possible deformation trajectories (i.e., acceleration profiles) are physically achievable with particular robot hardware, which is an often-ignored fact for dynamic deformation control.

Given an initial grabbing deformation state s 1 , and a series of future control inputs u 1 , u 2 , . . . we can now predict the following deformation states s 2 , s 3 , . . . via [START_REF] De Magistris | Humanoid walking with compliant soles using a deformation estimator[END_REF]. Indirectly, we are also obtaining the predicted accelerations z1 , z2 , . . . via [START_REF] Coevoet | Soft robots locomotion and manipulation control using FEM simulation and quadratic programming[END_REF], and the contact forces f 1 , f 2 , . . . via [START_REF] Rijnen | Control of humanoid robot motions with impacts: Numerical experiments with reference spreading control[END_REF]. We can then confirm with [START_REF] Nakamura | Multi-preview configuration control for predictive behavior of redundant manipulator[END_REF] if this particular series of control inputs results in feasible deformation states that correspond to feasible robot states. Accordingly, knowledge of the bounded deformation dynamics is of utmost importance for the constrained modelpreview proposed in the following.

B. Impact-Aware Model Predictive Control

Always considering that the contacts will happen right after the current control cycle, we formulate an optimization problem that plans a feasible dual-arm penetration trajectory in the contact-space over a preview horizon of h steps, starting from the exact moment of the contact transition with z 1 l = z 1r = z 1o = 0 and ż1o = 0. The decision variables consist of the initial pre-impact velocities ż1 l , ż1r , which are to be optimized, and the subsequent control inputs u 1 , . . . , u h . We propose the linear problem:

min ż1 l , ż1r ,u T 1 ,...,u T h ż1r -ż1 l (23)
subject to

s 1 = 0 ż1 , s i = z i żi s i+1 = A d s i + B d u i ż1o = 0 and żh l|r = 0 z ≤ z i = [I, 0] s i ≤ z ż ≤ żi = [0, I] s i ≤ ż p ≤ P z zi + P f f i ≤ p
This contact-space MPC problem can be solved efficiently in each control cycle and requires k l|r , p l|r , m l|r , m o and h.

The upper and lower bounds on z enforce the penetration and ensure that the minimization of ż1r -ż1 l is unique 4 . However, due to the linear objective to be optimized, a set of infinite trajectories may exist that are all optimal. In order to select a unique series of control inputs u 1 , . . . , u h , a secondary low-weight prioritized quadratic objective may be added to the optimization problem. For example, in Fig. 8, we minimize the quadratic error between desired and predicted forces in the nullspace of the primary objective. Note that this does not affect the maximum impact velocities.

In practice, we recompute [START_REF] Wang | Impact-friendly robust control design with task-space quadratic optimization[END_REF] in each control cycle. We are interested only in the optimized pre-impact velocities ż1 l , ż1r , which are tracked with velocity controllers by the endeffectors. Consequently, this control scheme does not require knowledge of the contact location and the box width, as it operates the manipulators within the feasible impact limits that are updated in each control cycle.

Note that this control scheme does not distinguish whether the soft material is attached to the end-effectors or to the object. Consequently, the proposed approach also generalizes to swiftly grabbing soft objects with rigid end-effectors.

C. Asynchronous Contact Transitions

Encountering asynchronous contact transitions with a delay of few iterations is not surprising, since we do not explicitly plan the contact time and roughly assume the object is placed approximately in the center of the two end-effectors. We observe these two contact events by monitoring the endeffector forces, either via wrist-mounted sensors or via external joint torque measurements mapped onto the end-effector. For example, after making contact with the right (resp. left) soft pad, the object could start moving to the left (resp. right) while compressing the right (resp. left) pad. Inferring the objects relative position and velocity as well as the compression is straightforward given the known model of the pad and the measured force. The MPC ( 23) is then initialized with the systems current state, continuing to assume the other contact event to occur after the current control cycle, etc. Hence, the above formulation is slightly adapted with z 1r = 0, z 1 l = 0 (resp. z 1r = 0, z 1 l = 0) and with z 1o = 0, ż1o = 0 according to the measurements. The MPC formulation automatically accounts for the worst case and computes an optimum contact velocity for the left (resp. right) end-effector that is tracked. Now, if the second contact event is not detected after few iterations, the controller switches to the handling recovery procedure for such cases.

D. Comparison with Prior Work and Discussion

Our prior work [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF], models the system dynamics for a single-arm soft poking scenario, cf. Fig. 6 left. Note that the dual-arm model proposed in this paper (cf. Fig. 6 right) is more general. This is easy to see in [START_REF] Smoljkic | Constraint-based interaction control of robots featuring large compliance and deformation[END_REF] when treating the object and the right manipulator (with zero joints) as part of the rigid environment. Basically, there are no equations of motion for the rigid environment. We obtain the single-arm model described in [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF], with

K = -k ∈ R, P = -p ∈ R, M = m ∈ R, s = [z, ż] T ∈ R 2 , u = -1 m f ∈ R, resulting in A c = 0 1×1 I 1×1 M -1 K M -1 P ∈ R 2×2 , B c = 0 1×1 I 1×1 ∈ R 2×1 . ( 24
)
Note that the proposed approach can seamlessly control a heterogeneous dual-arm plattform, consisting of manipulators from two different manufacturers. Applying instead the singlearm method [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF] independently for each arm would either cause grabbing failures or result in more conservative behavior. Such a naive approach is missing the fact that the object may swing between the two end-effectors. This aspect becomes relevant when operating robot arms with different kinematic/dynamic properties, resulting in different contact velocities and different effective masses for both end-effectors. Moreover, the benefits of having a centralized multi-robot control w.r.t a controller per arm, is thoroughly explained in [START_REF] Bouyarmane | Quadratic programming for multirobot and task-space force control[END_REF].

V. REAL-ROBOT EXPERIMENT

The experimental platform is a dual-arm setup composed of two Panda manipulators from FrankaEmika with each 7 DOF, utilizing 3D-printed plastic end-effectors equipped with two identical soft pads (0.1 m × 0.1 m contact surface and 0.05 m depth). The dual-robot platform is controlled based on our existing multi-objective QP-control framework [START_REF] Bouyarmane | Quadratic programming for multirobot and task-space force control[END_REF]. We implemented a new extension (available open-source 5 ) to synchronize the two Panda manipulators, a feature that the manufacturer does not officially support. Our experiments are made according to representative objects and simplified scenarios provided by industrial use-cases.

In a preliminary study, we evaluated the contact force profile for the chosen soft pad. Therefore, a single panda robot repeatedly impacts an ATI-mini45 force-torque sensor with an end-effector velocity of 0.18 m/s, showing consistent behavior in Fig. 7. The force sensor data is acquired with a frequency of 25 kHz, that is sufficient enough to capture such impact dynamics. The overall impact lasts 0.13 s, and the maximum force is about 25 N. The soft impact is considerably longer and significantly less forceful than our similar experiments with a rigid end-effector, see data in [START_REF] Wang | On inverse inertia matrix and contact-force model for robotic manipulators at normal impacts[END_REF].

We identified the model parameters of the soft material offline with the procedure described in [START_REF] Dehio | Robot-safe impacts with soft contacts based on learned deformations[END_REF], [START_REF] Azad | Model estimation and control of compliant contact normal force[END_REF]. Employing the stabiliplus library6 , ( 5) is solved in every control cycle. The optimization problem ( 23) is parameterized with h = 15 steps and the discretization sample time ∆t = 25 ms, resulting in the preview horizon of 0.375 s. We solve it utilizing the COPRA library7 . The optimization result constitutes an upper bound on the pre-impact velocities and should be as up-to-date as possible. Primary end-effector velocity tasks track the maximum possible pre-impact velocities with both manipulators. Besides, secondary tasks minimize the joint accelerations to account for the redundancy, thereby avoiding elbow self-motion to maintain the effective masses. The controller switches to an admittance task [START_REF] Bouyarmane | Quadratic programming for multirobot and task-space force control[END_REF] upon contact detection. The admittance controller incorporates the robot's force sensor signals, thereby accounting for material model inaccuracies. It tracks the reference force 60 N (depending on the object's mass) more accurately in practice than following the previously planned deformation trajectory. More research is needed to include the actual force measurements into the state-space representation for the MPC [START_REF] Smoljkic | Constraint-based interaction control of robots featuring large compliance and deformation[END_REF].

We here discuss only one object experiment due to space limitations -please refer to the video for the other objects. The box to be grabbed weights 4 kg, is 0.38 m wide (not known by the controller), and is placed initially in the center between the two end-effectors 8 . Analyzing the logged data, all hardware limits are satisfied. After moving 0.24 m within 0.12 s, the end-effectors detect the contact with a relative pre-impact velocity of ±0.61 m/s, refer to Fig. 8. The box lift-up motion is triggered upon ending both contact phases. Steady-state forcetracking is reached after approximately 0.3 s of deformation and partial restitution, confirming the chosen preview duration. The final measured force is close to the reference force; Fig. 8 also shows the planned deformation trajectory at the contact event. As discussed above, this prediction is not necessarily unique because the linear program (23) may yield an infinite set of solutions in terms of different sequences of control inputs.

VI. CONCLUSION AND FUTURE WORK

Intentionally generated impacts accelerate contact transitions and speed-up the manipulation of objects by collaborative multi-robot teams in industrial automation sorting processes. Equipping the robot end-effector tips with deformable soft pads extends the system's motion capabilities, allowing larger impact velocities. Utilizing the deformable contact force model, we plan (at runtime) and execute constrained deformation trajectories for powerful intentional impact-aware grabbing: Our approach to bi-manual object manipulation swiftly grabs and lifts bulky box objects without compromising the robot's structural hardware limitations.

Extension to multi-arm systems [START_REF] Dehio | Enabling impedance-based physical humanmultirobot collaboration: Experiments with four torque-controlled manipulators[END_REF] requires to adapt grasp quality measures proposed for rigid contacts [START_REF] Roa | Grasp quality measures: review and performance[END_REF] to deformable contacts. Future work will tackle the planning of pre-impact null-space postures, influencing the end-effector's effective mass [START_REF] Mansfeld | Improving the performance of biomechanically safe velocity control for redundant robots through reflected mass minimization[END_REF]. We are also interested in swiftly grabbing moving objects that would require considering friction and tangential relative motions. Finally we are also investigating other possible soft materials. Fig. 8: Impact-aware bi-manually grabbing a 4 kg box with maximum configuration-dependent contact velocities ±0.61 m/s. The absolute measurements along the contact normal are indicated by solid red and blue lines for the two manipulators. Planned trajectories for the deformation phase (shaded area) are plotted as dotted purple and cyan lines when detecting the contact at 0.12 s. The green curve shows the maximum feasible pre-impact velocity at a given time step that is tracked (before making contact) and black the reference contact force of 60 N (after making contact).

Accordingly, we can reformulate [START_REF] Sheridan | Three models of preview control[END_REF]

Fig. 3 :

 3 Fig.3: A manipulator penetrating a deformable contact. The deformation velocity, acceleration, and force are bounded and depend on the particular robotic hardware limits.

Figure 5

 5 highlights the coupling between acceleration and force. The four sub-figures from top to bottom show the four 3D-polytopes Y 1 , Y 2 , Y 3 , Y 4 utilizing a triangularization technique for visualization, where the last one (Y 4 ) shrinks to 2D due to additionally enforcing (7j)

Fig. 4 :

 4 Fig. 4: Top: feasible set (8a). Bottom: (8b).

Fig. 5 :

 5 Fig. 5: Top to bottom: feasible sets (8a)-(8d).

Fig. 6 :

 6 Fig. 6: Left: Soft pad modeled as a mass-spring-damper system attached to the end-effector. Right: Bi-manually grasping a rigid object with soft pads attached to both end-effectors. Important parameters are stiffness k, damping p, and effective mass m. The deformation position is z.

Fig. 7 :

 7 Fig. 7: Recorded data of nine impacts with the Panda. The end-effector softpad moves horizontally with 0.18 m/s, bumps orthogonally into a force sensor mounted to a wall, and pulls back upon contact detection.

1 : 3 , 1 : 3 A 1 : 3 , 4 : 6 A 4 : 6 , 1 : 3 A 4 : 6 , 4 : 6 and B d = B 1 : 3 , 1 : 2 B 4 : 6 , 1 : 2 Reformulate ( 20 )

 13131346461346461312461220 APPENDIXA. Deformation acceleration zi reformulated w.r.t. s i and u i Let us denote the matrix elements of matrices A d , B d asA d = A with z = [z T l , z T r , z T o ] T , ż = [ż T l , żT r , żT o ] T żi+1 = A 4:6,1:3 z i + A 4:6,4:6 żi + B 4:6,1:2 u iThe acceleration zi is linear in terms of deformation state s i and control input u i 6,1:3 z i + A 4:6,4:6 -I żi + B 4:6,1:2 u i = 1 ∆t A 4:6,1:3 , A 4:6,4:6 -I z i żi + 1 ∆t B 4:6,1:2 u i = Cs i + Du i 8 Object dynamics and friction coefficient are only required for selecting the minimum needed reference squeezing force. The object width can be inferred upon contact detection.

  in terms of deformation state s i and control input u i by substituting[START_REF] Rijnen | Control of humanoid robot motions with impacts: Numerical experiments with reference spreading control[END_REF]

	P zi f i	= P	Cs i + Du i [K, P] s i	= P	C [K, P]	s i +P	D 0	u i

The dual-arm system may be composed of redundant manipulators with different kinematic / dynamic properties from two different manufacturers.

For example, find the limits for the Panda manipulator from FrankaEmika: https://frankaemika.github.io/docs/control parameters.html#constants

In Fig.6right, the left arm is constrained by zl = 0 and the right arm by zr = 0. Consequently, ż1 l > 0 and ż1r < 0 is enforced.

See https://github.com/jrl-umi3218/mc franka

See https://github.com/JulienRo7/stabiliplus

See https://github.com/jrl-umi3218/copra

ACKNOWLEDGMENT

The authors thank Dr. Pierre Gergondet for his support and Julien Roux for providing a C++ implementation of [28].


Rikke Stausholm

Charlotte Ernstsen

Severine Mazuad-Guittot

David Møbjerg Kristensen

Intrauterine exposure to drugs and reproduction -still reasons for concern!

Keywords: Pregnancy, drugs Pregnancy, drugs, reproduction, thalidomide, diethylstilbestrol, mild analgesics

The last decades have seen an increasing use of pharmaceutical drugs worldwide and the chemical compounds have become ever more intertwined in lifestyles across the globe. Alone in the US, statistics show that half of the population has taken at least one prescription drug within the last month. The high use of pharmaceutical compounds is not without consequence and the last century has shown that especially the combination of drugs and pregnancy can result in severe outcomes. In this commentary, we will cover two of these examples, respectively thalidomide and diethylstilbestrol, and couple this evidence with the emerging concern that intrauterine exposure to widely used mild analgesics may also result in subtle by adverse effects. These include reproductive congenital malformations that have been coupled with subsequent reproductive defects later in life.

Introduction

In the last decades, xenobiotic compounds including pharmaceutical drugs have become ever more intertwined in everyday life across the world. Simultaneously, evidence show that infertility affects approximately 10-15% of the population in developed countries [START_REF] Ombelet | Global Access to Infertility Care in Developing Countries: A Case of Human Rights, Equity and Social Justice[END_REF][START_REF] Rutstein | Infecundity, Infertility, and Childlessness in Developing Countries[END_REF]. This increase in infertility is suggested to have many causes including genetic differences, fetal exposures, recreational drug or alcohol abuse, dietary issues, environmental or occupational exposure to reprotoxicological agents, and pharmaceutical drugs [START_REF] Skakkebaek | Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility[END_REF]. Due to these multiple factors underlying infertility, it is hard to understand the etiology of the disorder and whether it is due to a specific exposure from drugs. However, it remains that drug use is high across the world. This is evident in the US, where in a period from 2011-2014, approximately half of the U.S. population (48.9%) had taken a prescription drug in the last 30 days, with 23.1% of the population having taken three or more prescription drugs during the last month (National Center of Health Statistics 2017). This is likely an underestimation, as the data does not include nonprescription drugs and over-the-counter drugs like mild analgesics consisting of non-steroid antiinflammatory drugs (NSAIDs) and N-acetyl-para-aminophenol (paracetamol/acetaminophen (APAP)). The increase in exposure to drugs is exemplified by the increase in number of patients placed on long-term medication regimens at a young age (including potential mothers) due to e.g. diabetes, chronic migraine, epilepsy or clinical depression [START_REF] Samplaski | Adverse Effects of Common Medications on Male Fertility[END_REF][START_REF] Westergaard | Medication-Overuse Headache: A Perspective Review[END_REF][START_REF] Lindsay | Metformin Use in Pregnancy: Promises and Uncertainties[END_REF]. This results in a substantial number being at risk of experiencing a decrease in fertility due to side effects of maternal drug treatment. The last 50 years have shown that this risk is not negligible, as drugs have been shown to disrupt reproduction through prenatal and adult exposures by hormonal and non-hormonal mechanisms.

Thalidomide

The disastrous implications after maternal use of thalidomide during pregnancy is a solemn reminder that the intrauterine period is a time of high vulnerability. Thalidomide (α-phthalimidoglutarimide) is an immunomodulatory drug and the prototype of the thalidomide class of drugs [START_REF] Foster | Immunomodulatory Drugs: IMiDs in Acute Myeloid Leukemia (AML)[END_REF][START_REF] Nooka | Mechanism of Action and Novel IMiD-Based Compounds and Combinations in Multiple Myeloma[END_REF]. Today, it is mainly used as a treatment of cancers (e.g. multiple myeloma) due to its anti-angiogenesis effects. During 1957During -1961, this , this anti-cancer drug was sold in most European countries as a nonbarbiturate hypnotic sedative which was able to produce deep sleep without hangover or risk of dependency or overdoses. In addition to this, the secondary anti-emetic effect made it popular among pregnant women suffering from morning sickness. This resulted in a tragedy as thalidomide was developed and introduced prior to formal testing for harmful effects. The maternal use resulted in an increased rate of miscarriages in the pregnant women and among the newborn, more than 10,000 were born with a range of severe and debilitating malformations [START_REF] Vargesson | Thalidomide-Induced Teratogenesis: History and Mechanisms[END_REF][START_REF] Smithells | Recognition of Thalidomide Defects[END_REF]. Some of these defects included severe malformations of upper and lower limbs and abnormalities of the ear and eye [START_REF] Smithells | Recognition of Thalidomide Defects[END_REF]. Furthermore, genital defects were observed such as small or complete absent testes, mal-descended testes (cryptorchidism), and midline fusion defect of the male ventral urethra resulting in misplaced urethra opening (hypospadias) in the newborn males and defects of reproductive tracts and malformations of the uterus in the females [START_REF] Mani | EEndocrine Disrupting Chemicals: A Challenge to Child Health[END_REF][START_REF] Vargesson | Thalidomide-Induced Teratogenesis: History and Mechanisms[END_REF].

As thalidomide has multiple effects on body homeostasis, the specific mechanisms remain debated. It has been suggested that thalidomide disrupts the early mesodermal differentiation by damaging undifferentiated cells [START_REF] Tachikawa | Thalidomide Induces Apoptosis during Early Mesodermal Differentiation of Human Induced Pluripotent Stem Cells[END_REF] as well as resulting in anti-angiogenesis, evasion of apoptosis and inhibition of pro-inflammatory innate responses [START_REF] Paravar | Thalidomide: Mechanisms of Action[END_REF][START_REF] Hideshima | Thalidomide and Its Analogs Overcome Drug Resistance of Human Multiple Myeloma Cells to Conventional Therapy[END_REF][START_REF] Du | Thalidomide Inhibits Growth of Tumors through COX-2 Degradation Independent of Antiangiogenesis[END_REF]. Furthermore, thalidomide can bind as an antagonist to the androgen receptor (AR) [START_REF] Capitosti | Thalidomide Analogues Demonstrate Dual Inhibition of Both Angiogenesis and Prostate Cancer[END_REF]) and hence inhibit different androgens like testosterone which have a pivotal impact during development of male secondary sex characteristics and reproductive tissues. The antagonistic mechanisms on AR may account for some of the milder malformations like cryptorchidism and hypospadias, while the complete absent of testis are more likely associated with the anti-angiogenesis effects. Hence, the defects observed after prenatal thalidomide exposure are likely results of both reduced or blocked hormonal actions and non-hormonal effects.

Diethylstilbestrol

A decade after the initial reports showing effects of thalidomide and prenatal exposure to a hormonal active compound, the synthetic nonsteroidal estrogen diethylstilbestrol (DES), was shown to be associated with reproductive developmental disruption and subsequent congenital malformations [START_REF] Swan | Intrauterine Exposure to Diethylstilbestrol: Long-term Effects in Humans[END_REF][START_REF] Palmer | Urogenital Abnormalities in Men Exposed to Diethylstilbestrol in Utero: A Cohort Study[END_REF]. During a period of close to 40 years from the 1940s and into the 1970s, DES was prescribed for pregnant women in the belief that it was preventing spontaneous abortion and premature births [START_REF] Swan | Intrauterine Exposure to Diethylstilbestrol: Long-term Effects in Humans[END_REF][START_REF] Johansson | Environmental Influences on Ovarian Dysgenesis -Developmental Windows Sensitive to Chemical Exposures[END_REF]. DES was finally banned from use during pregnancy in 1971 after numerous adverse effects being described including different pregnancy-related problems like spontaneous abortion, preterm delivery and ectopic pregnancy together with abnormalities of the reproductive tract [START_REF] Jishi | Current Perspective of Diethylstilbestrol (DES) Exposure in Mothers and Offspring[END_REF][START_REF] Adam | Adverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol[END_REF][START_REF] Gill | Association of Diethylstilbestrol Exposure in Utero With Cryptorchidism, Testicular Hypoplasia and Semen Abnormalities[END_REF]). Among abnormalities which remain controversial to this day, it was suggested that DES was associated with in increased risk of vaginal/cervical clear cell adenocarcinoma (CCA) among exposed girls and testicular cancer, cryptorchidism, and hypospadias in boys [START_REF] Swan | Intrauterine Exposure to Diethylstilbestrol: Long-term Effects in Humans[END_REF][START_REF] Johansson | Environmental Influences on Ovarian Dysgenesis -Developmental Windows Sensitive to Chemical Exposures[END_REF][START_REF] Jishi | Current Perspective of Diethylstilbestrol (DES) Exposure in Mothers and Offspring[END_REF][START_REF] Adam | Adverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol[END_REF][START_REF] Newbold | Increased Tumors but Uncompromised Fertility in the Female Descendants of Mice Exposed Developmentally to Diethylstilbestrol[END_REF]. Recent data have suggested that some of these increased risks may be passed on to the third generation (grandchildren) that never been directly exposed to the synthetic estrogen [START_REF] Jishi | Current Perspective of Diethylstilbestrol (DES) Exposure in Mothers and Offspring[END_REF][START_REF] Newbold | Increased Tumors but Uncompromised Fertility in the Female Descendants of Mice Exposed Developmentally to Diethylstilbestrol[END_REF][START_REF] Newbold | Adverse Effects of the Model Environmental Estrogen Diethylstilbestrol Are Transmitted to Subsequent Generations[END_REF]Newbold 2008). Still controversial, this would suggest that DES may disrupt endocrinology through transgenerational epigenetic changes established during the intrauterine exposure of their parents [START_REF] Walker | Intensity of Multigenerational Carcinogenesis from Diethylstilbestrol in Mice[END_REF][START_REF] Ho | Environmental Factors, Epigenetics, and Developmental Origin of Reproductive Disorders[END_REF].

Still need for concern!

Although the effects of DES remain disputed, the studies conducted in order to understand the effects of this estrogen have proven long lasting as they contributed to laying the foundation for the development of the field of endocrine disruption. The estrogenic effects of DES made it clear that hormonal active compounds can disturb the delicate reproductive development. This realization in turn was instrumental for the development of the estrogen hypothesis in the early 1990s, proposing that prenatal exposure to multiple hormonal active xenobiotics may disrupt reproductive development [START_REF] Sharpe | Falling Reproductive[END_REF].

In recent years, several drugs types have been associated with prenatal problems. Of these, especially the mild analgesics (from now on analgesics) used to relieve pain, fever and malaise during pregnancy have received increasing attention [START_REF] Kristensen | Analgesic Use-Prevalence, Biomonitoring and Endocrine and Reproductive Effects[END_REF]). Rodent studies have showed analgesic-induced endocrine disruptions of fetal gonadal development (both testis and ovaries) resulting in infertility and premature ovarian insufficiency [START_REF] Leverrier-Penna | Ibuprofen Is Deleterious for the Development of First Trimester Human Fetal Ovary Ex Vivo[END_REF]. Like thalidomide and DES, several of the analgesic drugs were developed prior to formal testing and have been on the market for many decades. Acetylsalicylic acid (ASA, aspirin) was developed in the 19 th century and has been marketed >100 years, while APAP and isobutylphenylpropionic acid (IBP, ibuprofen) have been marketed for ~60 and ~50 years, respectively. Moreover, sales of analgesics have been steadily increasing over the past 20 years and are now the most commonly used over-the-counter drugs worldwide. Of concern is the generally high use of analgesics during pregnancy, especially for APAP, with women using well above 50% across the world, as it is used without the need to consult a physician or pharmacist [START_REF] Kristensen | Analgesic Use-Prevalence, Biomonitoring and Endocrine and Reproductive Effects[END_REF]. This concern has increased after intrauterine exposure to analgesics was suggested to increase the risk of congenital cryptorchidism in two studies in 2010 [START_REF] Kristensen | Analgesic Use-Prevalence, Biomonitoring and Endocrine and Reproductive Effects[END_REF]). An epidemiological study, using hospital registry data for cryptorchidism, reported that exposure to APAP for 4 weeks was associated with an increased risk [START_REF] Jensen | Maternal Use of Acetaminophen, Ibuprofen, and Acetylsalicylic Acid during Pregnancy and Risk of Cryptorchidism[END_REF], while a second study using a standardized assessment of cryptorchidism combined with experimental rodent approaches showed that use of analgesics during especially the second trimester increased the risk of cryptorchidism through anti-androgenic mechanisms. The latter study also showed that this risk remained significant when IBP and ASA were examined separately, and a tendency was seen for APAP. The risk was amplified if the exposure was >2 weeks with similar results found in separate analyses for APAP and ASA. The risk was highest among the few mothers who used more than one compound simultaneously for >2 weeks, suggesting an additive cocktail effect [START_REF] Kristensen | Intrauterine Exposure to Mild Analgesics Is a Risk Factor for Development of Male Reproductive Disorders in Human and Rat[END_REF]. Subsequent studies have found similar associations to both cryptorchidism and hypospadias together with reductions in anogenital distance among infants supporting the potential antiandrogenic effects of analgesics [START_REF] Fisher | Prenatal Paracetamol Exposure Is Associated with Shorter Anogenital Distance in Male Infants[END_REF][START_REF] Lind | Maternal Use of Mild Analgesics during Pregnancy Associated with Reduced Anogenital Distance in Sons: A Cohort Study of 1027 Mother-Child Pairs[END_REF].

Although a subsequent meta-analysis of analgesic use during pregnancy and risk of cryptorchidism was inconclusive [START_REF] Gurney | Analgesia Use during Pregnancy and Risk of Cryptorchidism: A Systematic Review and Meta-Analysis[END_REF], studies using human abortion material have subsequently strongly supported a direct effect of analgesics on the fetal testis [START_REF] Maamar | Ibuprofen Results in Alterations of Human Fetal Testis Development[END_REF][START_REF] Driesche | Prolonged Exposure to Acetaminophen Reduces Testosterone Production by the Human Fetal Testis in a Xenograft Model[END_REF]. Concern about the effects on the female reproductive development has similarly been increasing after three rodent studies showed disrupted ovary development and subfertility in female offspring after analgesic exposure [START_REF] Holm | Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility[END_REF][START_REF] Dean | Analgesic Exposure in Pregnant Rats Affects Fetal Germ Cell Development with Inter-Generational Reproductive Consequences[END_REF][START_REF] Johansson | Perinatal Exposure to Mixtures of Endocrine Disrupting Chemicals Reduces Female Rat Follicle Reserves and Accelerates Reproductive Aging[END_REF]. These data may suggest that APAP in the animals reduced the migration of primordial germ cells or proliferation of the oogonia. This in turn lead to a decreased germ pools (reduced by approximately 50%), resulting in reduced fertility in the adult rodent dams and premature ovarian insufficiency (Arendrup et al. 2018).

The rodent data has subsequently been supported from studies using human fetal gonadal explants that have been exposed to IBP and APAP (Leverrier-Penna et al. 2018;Arendrup et al. 2018). These data show e.g. that exposure during the first trimester to IBP diminished ovarian germ cells though a cytotoxic effect induced already after two days of exposure [START_REF] Leverrier-Penna | Ibuprofen Is Deleterious for the Development of First Trimester Human Fetal Ovary Ex Vivo[END_REF]. In male rats there has been observed a postnatal compensation of fetal germ cell reduction because germ cell proliferation resumes after birth [START_REF] Dean | Analgesic Exposure in Pregnant Rats Affects Fetal Germ Cell Development with Inter-Generational Reproductive Consequences[END_REF]), a mechanism that likely could also happen in human males. However, in human females, proliferation of germ cells in the ovaries is restricted by the meiosis happening from week 11 of gestation, so any fetal germ cell loss is irreversible and could therefore potentially have long-term consequences for oocyte reserves and fertility (Arendrup et al. 2018). As mentioned above, the latter has been shown in both mice and rats where in utero exposure to APAP resulted in a reduction in germ cells in both sexes but only persisted into adulthood in the female and not male offspring (Arendrup et al. 2018).

It is still too early to be giving a precise explanation of the actions of analgesics, resulting in congenital malformations. However, it is obvious that the effects of prenatal analgesic exposure are much less severe and more subtle than the effects of thalidomide and DES. It is therefore likely that analgesics, unlike thalidomide and DES, will continue to play a vital role in the clinic for pregnant women in many years to come. It is also clear that thalidomide, DES, and analgesics all share the fact that they are drugs developed in the 19 th and the first of half of the 20 th century prior to the thorough testing seen today. Other compounds belonging to this category of drugs, valproate and metformin, have recently been associated with reproductive problems after prenatal exposure as well [START_REF] Bertoldo | Impact of Metformin on Reproductive Tissues: An Overview from Gametogenesis to Gestation[END_REF][START_REF] Veroniki | Comparative Safety of Anti-Epileptic Drugs during Pregnancy: A Systematic Review and Network Meta-Analysis of Congenital Malformations and Prenatal Outcomes[END_REF]. Especially valproate used for neurological diseases such as epilepsy and migraine has caused increased concern after several studies have showed increased risk of numerous congenital malformations including cryptorchidism and hypospadias together with fetal loss [START_REF] Rodríguez-Pinilla | Risk of Hypospadias in Newborn Infants Exposed to Valproic Acid During the First Trimester of Pregnancy[END_REF][START_REF] Raghavan | Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias: A Review[END_REF][START_REF] Veroniki | Comparative Safety of Anti-Epileptic Drugs during Pregnancy: A Systematic Review and Network Meta-Analysis of Congenital Malformations and Prenatal Outcomes[END_REF]. It is therefore likely that the next years will see data supporting the disruptive effects of this early generation of drugs on reproduction after prenatal exposure, emphasizing the need to further caution the use among the pregnant. [START_REF] Vargesson | Thalidomide-Induced Teratogenesis: History and Mechanisms[END_REF][START_REF] Mani | EEndocrine Disrupting Chemicals: A Challenge to Child Health[END_REF]

Table 1

 1

	337	:
	338
		Prenatal	Timing	Reported Reproductive	Mechanisms
		Exposure	Window	Effects
		Thalidomide	Throughout	Absent or malformed testes
			gestation but	(infertility)
			increased
			sensitivity in
			the first
			trimester

Cryptorchidism (Vargesson 2015;Mani et al. 2017) Hypospadias (Vargesson 2015;Mani et al. 2017) Miscarriages (Vargesson 2015;Smithells and Newman 1992) Defects of the female reproductive tracts (Vargesson 2015;Mani et al. 2017) Malformations of the uterus (Vargesson 2015;Mani, Danasekaran, and Annadurai 2017) Multiple mechanisms incl. anti-angiogenesis, antagonism of the androgen receptor and disruption of early mesodermal differentiation (Tachikawa et al. 2018; Paravar and Lee 2008; Hideshima et al. 2000; Du et al. 2005; Capitosti et al. 2004) Diethylstilbestrol (DES) First trimester Cryptorchidism (Swan 2001; Jishi and Sergi 2017; Johansson et al. 2017) Hypospadias (Swan 2001; Jishi and Sergi 2017; Johansson et al. 2017) Increased risk of clear cell adenocarcinoma in females and testicular cancer in males (Swan 2001; Johansson et al. 2017; Jishi and Sergi 2017; Adam et al. 2011;Troisi et al. 2007;Newbold et al. 1998) Abnormalities in female Estrogenic

Funding for carrying out this review was kindly provided by The Candys Foundation. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.