Human Aortic Stenotic Valve-Derived Extracellular Vesicles Induce Endothelial Dysfunction and Thrombogenicity Through AT1R/NADPH Oxidases/SGLT2 Pro-Oxidant Pathway.

Pathological tissues release a variety of factors, including extracellular vesicles (EVs) shed by activated or apoptotic cells. EVs trapped within the native pathological valves may act as key mediators of valve thrombosis. Human aortic stenosis EVs promote activation of valvular endothelial cells, leading to endothelial dysfunction, and proadhesive and procoagulant responses.

External validation of and improvement upon a model for the prediction of placenta accreta spectrum severity using prospectively collected multicenter ultrasound data.

INTRODUCTION: This study aimed to validate the Sargent risk stratification algorithm for the prediction of placenta accreta spectrum (PAS) severity using data collected from multiple centers and using the multicenter data to improve the model. MATERIAL AND METHODS: We conducted a multicenter analysis using data collected for the IS-PAS database. The Sargent model's effectiveness in distinguishing between abnormally adherent placenta (FIGO grade 1) and abnormally invasive placenta (FIGO grades 2 and 3) was evaluated. A new model was developed using multicenter data from the IS-PAS database. RESULTS: The database included 315 cases of suspected PAS, of which 226 had fully documented standardized ultrasound signs. The final diagnosis was normal placentation in 5, abnormally adherent placenta/FIGO grade 1 in 43, and abnormally invasive placenta/FIGO grades 2 and 3 in 178. The external validation of the Sargent model revealed moderate predictive accuracy in a multicenter setting (C-index 0.68), compared to its higher accuracy in a single-center context (C-index 0.90). The newly developed model achieved a C-index of 0.74. CONCLUSIONS: The study underscores the difficulty in developing universally applicable PAS prediction models. While models like that of Sargent et al. show promise, their reproducibility varies across settings, likely due to the interpretation of the ultrasound signs. The findings support the need for updating the current ultrasound descriptors and for the development of any new predictive models to use data collected by different operators in multiple clinical settings.

Left atrial remodeling and voltage-guided ablation outcome in persistent atrial fibrillation patients according to CHA2DS2-VASc score.

BACKGROUND: CHA2DS2-VASc score-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. There are currently no data on the efficacy of low voltage zone (LVZ)-guided ablation in persistent AF patients according to CHA2DS2-VASc score. We assessed in a cohort of persistent AF patients the extent of LVZ, the regional distribution of LA voltage and the outcome of LA voltage-guided substrate ablation in addition to PVI according to CHA2DS2-VASc score. METHODS: 138 consecutive persistent AF patients undergoing a first voltage-guided catheter ablation were enrolled. 58 patients with CHAD2DS2-VASc score ≥ 3 and 80 patients with CHAD2DS2-VASc score ≤ 2 were included. LA voltage maps were obtained using 3D-electroanatomical mapping system in sinus rhythm. LVZ was defined as < 0.5 mV. RESULTS: In the high CHAD2DS2-VASc score group, LA voltage was lower (1.5 [1.1-2.5] vs. 2.3 [1.5-2.8] mV, p = 0.02) and LVZs were more frequently identified (40% vs. 18%), p < 0.01). Female with CHA2DS2-VASc score ≥ 3 (p = 0.031), LA indexed volume (p = 0.009) and P-wave duration ≥ 150 ms (p = 0.001) were predictors of LVZ. After a 36-month follow-up, atrial arrhythmia-free survival was similar between the two groups (logrank test, P = 0.676). CONCLUSIONS: AF patients with CHAD2DS2-VASc score ≥ 3 display more LA substrate remodeling with lower voltage and more LVZs compared with those with CHAD2DS2-VASc score ≤ 2. Despite this atrial remodeling, they had similar and favorable 36 months results after one single procedure. Unlike male with CHAD2DS2-VASc score ≥ 3, female with CHAD2DS2-VASc score ≥ 3 was predictor of LVZ occurrence.

Prevalence of fetal anomalies, stillbirth, neonatal morbidity, or mortality in pregnancies complicated by placenta accreta spectrum disorders.

INTRODUCTION: Placenta accreta spectrum disorders (PAS) lead to major complications in pregnancy. While the maternal morbidity associated with PAS is well known, there is less information regarding neonatal morbidity in this setting. The aim of this study is to describe the neonatal outcomes (fetal malformations, neonatal morbidity, twin births, stillbirth, and neonatal death), using an international multicenter database of PAS cases. MATERIAL AND METHODS: This was a prospective, multicenter cohort study based on prospectively collected cases, using the international multicenter database of the International Society for PAS, carried out between January 2020 and June 2022 by 23 centers with experience in PAS care. All PAS cases were included, regardless of whether singleton or multiple pregnancies and were managed in each center according to their own protocols. Data were collected via chart review. Local Ethical Committee approval and Data Use Agreements were obtained according to local policies. RESULTS: There were 315 pregnancies eligible for inclusion, with 12 twin pregnancies, comprising 329 fetuses/newborns; 2 cases were excluded due to inconsistency of data regarding fetal abnormalities. For the calculation of neonatal morbidity and mortality, all elective pregnancy terminations were excluded, hence 311 pregnancies with 323 newborns were analyzed. In our cohort, 3 neonates (0.93%) were stillborn; of the 320 newborns delivered, there were 10 cases (3.13%) of neonatal death. The prevalence of major congenital malformations was 4.64% (15/323 newborns), most commonly, cardiovascular, central nervous system, and gastrointestinal tract malformations. The overall prevalence of major neonatal morbidity in pregnancies complicated by PAS was 47/311 (15.1%). There were no stillbirths, neonatal deaths, or fetal malformations in reported twin gestations. CONCLUSIONS: Although some outcomes may be too rare to detect within our cohort and data should be interpreted with caution, our observational data supports reassuring neonatal outcomes for women with PAS.

Universal screening of postpartum depression with Edinburgh Postpartum Depression Scale: A prospective observational study.

OBJECTIVES: To assess the feasibility of universal screening of postpartum depression (PPD), using the Edinburgh Postpartum Depression Scale (EPDS) in the general population. To investigate the proportion of women identified as being at risk of PPD and with confirmed PPD or other mental disorders after a psychiatric consultation. METHODS: A multicenter prospective cohort study in four French maternities conducted between 2020 and 2023. All women aged over 18 years, who delivered following a singleton pregnancy after 37 weeks of gestation were eligible for inclusion. The exclusion criteria were pre-existing psychiatric disorders such as depressive syndrome. The EPDS was completed at 8 weeks postpartum via an online self-administered questionnaire. If the response to the questionnaire suggested a mental disorder, a psychiatric consultation was proposed to the women concerned. The endpoints were the proportion of women completing the EPDS, the EPDS score, the proportion of women at risk of PPD, the proportion of psychiatric consultation, and the subsequent diagnosis. RESULTS: The study included 923 women, of whom 55.0% (508/923) completed the EPDS. Among them, 28.1% (143/508) had an EPDS score of 10 or more, and 11.2% (57/508) received a psychiatric consultation. PPD was confirmed in 8.8% (5/57) of women. Other disorders detected were mood disorders, disorders specifically associated with stress, and anxiety/fear-related disorders, in 33.3%, 28.1%, and 14.0% of the women, respectively. CONCLUSIONS: Screening with self-administered EPDS is feasible, with a good response rate, making it possible to suspect mental disorders, including PPD, and to offer psychological support when needed.

Is the rabbit a natural model of fetal growth restriction? Morphological and functional characterization study using diffusion-weighted MRI and stereology.

INTRODUCTION: Rabbits are routinely used as a natural model of fetal growth restriction (FGR); however, no studies have confirmed that rabbits have FGR. This study aimed to characterize the fetoplacental unit (FPU) in healthy pregnant rabbits using diffusion-weighted MRI and stereology. A secondary objective of the study was to describe the associations among findings from diffusion-weighted MRI (DW-MRI), fetal weight measurement and histological analysis of the placenta. METHODS: Pregnant rabbits underwent DW-MRI under general anesthesia on embryonic day 28 of pregnancy. MR imaging was performed at 3.0 T. The apparent diffusion coefficient (ADC) values were calculated for the fetal brain, liver, and placenta. The placenta was analyzed by stereology (volume density of trophoblasts, the maternal blood space and fetal vessels). Each fetus and placenta were weighed. Two groups of fetuses were defined according to the position in the uterine horn (Cervix group versus Ovary group). RESULTS: We analyzed 20 FPUs from 5 pregnant rabbits. Fetuses and placentas were significantly lighter in the Cervix group than in the Ovary group (34.7 ± 3.7 g vs. 40.2 ± 5.4 g; p = 0.02). Volume density analysis revealed that the percentage of fetal vessels, the maternal blood space and trophoblasts was not significantly affected by the position of the fetus in the uterine horn. There was no difference in ADC values according to the position of the fetus in the uterine horn, and there was no correlation between ADC values and fetal weight. DISCUSSION: The findings of a multimodal evaluation of the placenta in a rabbit model of FGR suggested is not a natural model of fetal growth restriction.

Potential of dapagliflozin to prevent vascular remodeling in the rat carotid artery following balloon injury.

BACKGROUND AND AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms. METHODS: Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry. RESULTS: Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group. CONCLUSIONS: Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.

Passive Polarized Vision for Autonomous Vehicles: A Review.

This review article aims to address common research questions in passive polarized vision for robotics. What kind of polarization sensing can we embed into robots? Can we find our geolocation and true north heading by detecting light scattering from the sky as animals do? How should polarization images be related to the physical properties of reflecting surfaces in the context of scene understanding? This review article is divided into three main sections to address these questions, as well as to assist roboticists in identifying future directions in passive polarized vision for robotics. After an introduction, three key interconnected areas will be covered in the following sections: embedded polarization imaging; polarized vision for robotics navigation; and polarized vision for scene understanding. We will then discuss how polarized vision, a type of vision commonly used in the animal kingdom, should be implemented in robotics; this type of vision has not yet been exploited in robotics service. Passive polarized vision could be a supplemental perceptive modality of localization techniques to complement and reinforce more conventional ones.

Activated factor X stimulates atrial endothelial cells and tissues to promote remodeling responses through AT1R/NADPH oxidases/SGLT1/2.

AIMS: Atrial fibrillation (AF), the most common cardiac arrhythmia favoring ischemic stroke and heart failure involves left atrial remodeling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodeling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. METHODS AND RESULTS: AECs were from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-ß-gal) activity.In AECs, FXa increased ROS formation, senescence (SA-ß-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-ß and collagen-1/3a) and pro-remodeling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which was prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodeling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. CONCLUSIONS: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodeling and pro-fibrotic responses in AECs and in human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodeling and the progression of atrial fibrillation substrate.

Opportunities for, and barriers to, uterus-preserving surgical techniques for placenta accreta spectrum.

INTRODUCTION: Placenta accreta spectrum (PAS) can lead to major peripartum morbidity. Appropriate management approaches depend on the clinical severity, each individual's preference, and the treating team's expertise. Peripartum hysterectomy is the most frequently used treatment option. However, it can impact psychological well-being and fertility. We investigated whether conservative treatment with focal resection or leaving the placenta in situ is associated with comparable or lower maternal morbidity than hysterectomy in centers of excellence within the International Society for placenta accreta spectrum (IS-PAS). Furthermore, a survey was conducted to explore potential barriers to conservative management in antenatal counseling and intraoperative decision-making. MATERIAL AND METHODS: Confirmed PAS cases in the prospective IS-PAS database from 22 registered centers between January 2020 and June 2022 were included in the analysis. A separate online survey with 21 questions was answered by the IS-PAS center experts about indications, diagnostic criteria, patient counseling, surgical practice, changes from the preoperative treatment plan, and why conservative management may not be offered. RESULTS: A total of 234 cases were included in the analysis: 186 women received hysterectomy and 38 women were treated by focal resection, and 10 by leaving the placenta in situ. Blood loss was lower in the focal resection group and in the placenta in situ group compared to the hysterectomy group (p = 0.04). 46.4% of the women initially planned for focal resection, and 35.7% of those initially planned for leaving the placenta in situ were ultimately treated by hysterectomy. Our survey showed that the IS-PAS centers preferred hysterectomy according to a woman's wishes (64%) and when they expected less blood loss and morbidity (41%). Eighteen percent of centers did not offer focal resection at all due to a lack of experience with this technique. Reasons for not offering to leave the placenta in situ were avoidance of unexpected reoperation (36%), puerperal infection (32%), or skepticism about the method (23%). CONCLUSIONS: Uterus-preserving treatment strategies such as focal resection appear to be safe alternatives to peripartum hysterectomy. However, less than half of the IS-PAS centers perform them. Acceptance of conservative treatments could be increased by standardized criteria for their implementation and by systematic training for PAS experts.

Left atrial remodeling and voltage-guided ablation outcome in obese patients with persistent atrial fibrillation.

Background: Obesity is a risk factor for atrial fibrillation (AF). Data regarding left atrial (LA) remodeling in obese patients are scarce. Whether obesity favors AF recurrence after catheter ablation (CA) is still controversial. We assessed the distribution of epicardial atrial fat on computed tomography (CT), LA bipolar voltage, low-voltage zone (LVZ) extent, and the outcome of voltage-guided ablation of persistent AF in obese and non-obese patients. Methods: A total of 139 patients with persistent AF undergoing a first voltage-guided ablation were enrolled and divided into two groups: 74 were non-obese and 65 were obese. Epicardial adipose tissue (EAT) was assessed on a CT scanner. LA endocardial voltage maps were obtained using a 3D mapping system in sinus rhythm. LVZ was defined as a bipolar peak-to-peak voltage amplitude <0.5 mV. Results: LA volume, voltage, and EAT amount were similar in the two groups. LVZ was less frequent in obese patients [12 (18.8%) vs. 26 (35.1%), p = 0.05], particularly on the anterior wall. The posterior and lateral EATs were correlated with posterior and lateral LVZ extent, respectively, in obese patients. After 36 months of follow-up, the AF-free survival rate was similar. Lateral EAT [odds ratio (OR) 1.21, 95% confidence interval (CI) 1-1.4, p = 0.04] and P-wave duration (OR 1.03, 95% CI 1-1.05, p = 0.03), but not body mass index (BMI), were predictors of AF recurrence after CA. Conclusion: In obese patients, LVZ was less marked than in non-obese patients with similar LA volumes, voltage, and EAT amounts. In obese patients, posterior and lateral EATs were correlated with posterior and lateral LVZ extents. Obese patients had a similar and favorable 36-month outcome after AF ablation. BMI was not predictive of AF recurrence.

Impact of New-Onset Right Bundle-Branch Block After Transcatheter Aortic Valve Replacement on Permanent Pacemaker Implantation.

BACKGROUND: A delayed and recurrent complete atrioventricular block (CAVB) is a life-threatening complication of transcatheter aortic valve replacement (TAVR). Post-TAVR evaluation may be important in predicting delayed and recurrent CAVB requiring permanent pacemaker implantation (PPI). The impact of new-onset right bundle-branch block (RBBB) after TAVR on PPI remains unknown. METHODS AND RESULTS: In total, 407 patients with aortic stenosis who underwent TAVR were included in this analysis. Intraprocedural CAVB was defined as CAVB that occurred during TAVR. A 12-lead ECG was evaluated at baseline, immediately after TAVR, on postoperative days 1 and 5, and according to the need to identify new-onset bundle-branch block (BBB) and CAVB after TAVR. Forty patients (9.8%) required PPI, 17 patients (4.2%) had persistent intraprocedural CAVB, and 23 (5.7%) had delayed or recurrent CAVB after TAVR. The rates of no new-onset BBB, new-onset left BBB, and new-onset RBBB were 65.1%, 26.8%, and 4.7%, respectively. Compared with patients without new-onset BBB and those with new-onset left BBB, the rate of PPI was higher in patients with new-onset RBBB (3.4% versus 5.6% versus 44.4%, P<0.0001). On post-TAVR evaluation in patients without persistent intraprocedural CAVB, the multivariate logistic regression analysis showed that new-onset RBBB was a statistically significant predictor of PPI compared with no new-onset BBB (odds ratio [OR], 18.0 [95% CI, 5.94-54.4]) in addition to the use of a self-expanding valve (OR, 2.97 [95% CI, 1.09-8.10]). CONCLUSIONS: Patients with new-onset RBBB after TAVR are at high risk for PPI.

Risk factors for placenta accreta spectrum disorders in women with any prior cesarean and a placenta previa or low lying: a prospective population-based study.

This study aimed to identify the risk factors for placenta accreta spectrum (PAS) in women who had at least one previous cesarean delivery and a placenta previa or low-lying. The PACCRETA prospective population-based study took place in 12 regional perinatal networks from 2013 through 2015. All women with one or more prior cesareans and a placenta previa or low lying were included. Placenta accreta spectrum (PAS) was diagnosed at delivery according to standardized clinical and histological criteria. Of the 520,114 deliveries, 396 fulfilled inclusion criteria; 108 were classified with PAS at delivery. Combining the number of prior cesareans and the placental location yielded a rate ranging from 5% for one prior cesarean combined with a posterior low-lying placenta to 63% for three or more prior cesareans combined with placenta previa. The factors independently associated with PAS disorders were BMI ≥ 30, previous uterine surgery, previous postpartum hemorrhage, a higher number of prior cesareans, and a placenta previa. Finally, in this high-risk population, the rate of PAS disorders varies greatly, not only with the number of prior cesareans but also with the exact placental location and some of the women's individual characteristics. Risk stratification is thus possible in this population.

Sex disparities in cardiogenic shock: Insights from the FRENSHOCK registry.

BACKGROUND: Cardiogenic shock (CS) is the most severe form of acute heart failure. Discrepancies have been reported between sexes regarding delays, pathways and invasive strategies in CS complicating acute myocardial infarction. However, effect of sex on the prognosis of unselected CS remains controversial. OBJECTIVES: The aim was to analyze the impact of sex on aetiology, management and prognosis of CS. METHODS: The FRENSHOCK registry included all CS admitted in 49 French Intensive Care Units (ICU) and Intensive Cardiac Care Units (ICCU) between April and October 2016. RESULTS: Among the 772 CS patients included, 220 were women (28.5%). Women were older, less smokers, with less history of ischemic cardiac disease (20.5% vs 33.6%) than men. At admission, women presented less cardiac arrest (5.5 vs 12.2%), less mottling (32.5 vs 41.4%) and higher LVEF (30 ± 14 vs 25 ± 13%). Women were more often managed via emergency department while men were directly admitted at ICU/ICCU. Ischemia was the most frequent trigger irrespective of sex (36.4% in women vs 38.2%) but women had less coronary angiogram and PCI (45.9% vs 54% and 24.1 vs 31.3%, respectively). We found no major difference in medication and organ support. Thirty-day mortality (26.4 vs 26.5%), transplant or permanent assist device were similar in both sexes. CONCLUSION: Despite some more favorable parameters in initial presentation and no significant difference in medication and support, women shared similar poor prognosis than men. Further analysis is required to cover the lasting gap in knowledge regarding sex specificities to distinguish between differences and inequalities. NCT02703038.

Optimal Heart Failure Medical Therapy and Mortality in Survivors of Cardiogenic Shock: Insights From the FRENSHOCK Registry.

BACKGROUND: The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline-directed heart failure (HF) medical therapy (GDMT) and one-year survival rate in patients who are post-CS. METHODS AND RESULTS: FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in-hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P<0.001 and 29% versus 37%, P<0.001, respectively). In the overall cohort, the one-year mortality rate was 23%. Triple GDMT prescription was significantly associated with a lower one-year all-cause mortality compared with non-triple GDMT (adjusted hazard ratio 0.44 [95% CI, 0.19-0.80]; P=0.007). Similarly, 2:1 propensity score matching and inverse probability treatment weighting based on the propensity score demonstrated a lower incidence of one-year mortality in the triple GDMT group. As the number of HF drugs increased, a stepwise decrease in mortality was observed (log rank; P<0.001). CONCLUSIONS: In survivors of CS, the one-year mortality rate was significantly lower in those with triple GDMT. Therefore, this study suggests that intensive HF therapy should be considered in patients following CS.

Fostering Cardio-Endometriosis: A Call to Action for a Comprehensive Understanding of Cardiovascular Disease in Endometriosis.

Recently, a growing body of evidence has highlighted a concerning link between endometriosis and cardiovascular disease. Endometriosis, a chronic, inflammatory hormone-dependent condition affecting 5 to 10% of reproductive-aged women worldwide, has long been associated with reproductive and gynecological consequences. However, emerging research has suggested that it may also contribute to adverse cardiovascular outcomes. This paper aims to shed light on the importance of recognizing cardio-endometriosis as a new and developing sphere of research in the field of cardiology, thereby urging the medical community to address this pressing issue.