Background: Severe obesity among adolescent shows a worrisome trend in regard to its increasing prevalence and poses a great challenge for treatment. Conservative measures have modest effects on weight loss, usually fail in achieving a sustainable weight loss and resolution of comorbidities. This has led to greater utilization of bariatric surgery (BS) that offers a fast reduction in body mass index with little perioperative complications. Despite the increasing utilization of BS, data are still insufficient, regarding their long-term outcome in adolescents. We review short- and long-term effects of BS and their implications on bone health and nutritional deficiencies in adolescents. In addition, we discuss possible pharmaceutical alternatives. Summary: BS results in a substantial weight loss of roughly 37% in the first-year post-operation and is superior to conservative measures in resolution of metabolic comorbidities. BS significantly improves health-related quality of life. Longer follow-up (F/U) shows weight regain in 50% of patients. Furthermore, reduced bone mass and nutritional deficiencies were reported in up to 90% of patients. Most recently, alternative to BS became more relevant with approval of GLP-1 analogues use in adolescents. GLP-1 analogues are potent enough to induce moderate clinically meaningful weight loss and improvement of metabolic component. Key Messages: We conclude that obese adolescents without major obesity-related complications may benefit from pharmacological interventions with lifestyle modification. We advise considering BS as treatment approach in adolescents with severe obesity and major obesity-related complications with proper preoperative preparation and postoperative F/U in excellence centers.
The chronic disease of childhood obesity is a global epidemic and a major concern for public health that affects all ethnic groups and nationalities. Childhood obesity beholds greater risk for noncommunicable diseases, psychiatric morbidity, and higher mortality rate in adulthood [1-4]. Furthermore, the economic burden it poses on the health care system is substantial .
The prevalence of obesity has increased from 4% in the mid-seventies to a peak of 18% in 2016, with 124 million children worldwide defined as obese . Despite reports showing a stabilization of this trend in some countries, the prevalence of severe obesity continues to increase and poses a greater challenge for treatment [7, 8]. The definition of severe obesity includes class II and III obesity. Class II obesity is defined as body mass index (BMI) ≥120% of the 95th percentile for age and sex corresponding to a BMI ≥35 kg/m2 in adults. Class III obesity is defined as BMI ≥140% of the 95th percentile for age and sex corresponding to a BMI ≥40 kg/m2 in adults . Weight loss in childhood reverses the CVD risk in adulthood  and greatly improves quality of life (QoL) and reduces mortality [10, 11]. A weight loss of 5–10% is sufficient in preventing long-term comorbidities, specifically cardiovascular disease . Treating severe obesity with first-line therapy – modification of dietary habits, physical activity, and behavioral changes has a modest effect and renders with failure in most cases [13-15]. The sustainable weight loss is not preserved after the intervention program is over . Pharmacotherapy as adjuvant to lifestyle modification may achieve better results . In severely obese adolescents, the additive effect of orlistat and phentermine (both FDA approved for use in adolescents) in weight loss and reversal of comorbidities such as insulin resistance, hypertension, and hyperlipidemia are still minimal . Furthermore, their side effects, especially gastrointestinal symptoms when using orlistat negatively affect the adherence to therapy . Data are lacking regarding their sustainable effect on weight loss. The off-label use of metformin may has a similar minimal effect of 1.16 kg/m2 . The limited success of conservative measures in treating severely obese adolescents has increased the utilization of bariatric surgery (BS). The use of BS has increased 2.7-fold in the past decade . BS achieves fast reduction of BMI; resolution of most metabolic comorbidities alongside with few/rare perioperative complications and a strong safety profile have gained these procedures, great popularity among adolescents. Eligibility for BS differs depending on the applied guidelines [22-25]. The revised guidelines published in 2018 by the American Society for Metabolic and Bariatric Surgery Pediatric Committee recommend referring to BS, adolescents with a BMI >35 kg/m2 or >120% of the 95th percentile and any comorbidity or a BMI >40 kg/m2 or >140% of the 95th percentile  (see Table 1). Guidelines of Endocrine society differentiate between major and mild comorbidities and suggest BS in adolescents with BMI >35 kg/m2 but <40 kg/m2 only if accompanied with major comorbidity, such as type 2 diabetes mellitus (T2DM), moderate to extreme sleep apnea, pseudotumor cerebri, debilitating orthopedic problems, and nonalcoholic steatohepatitis (NASH) with advanced fibrosis or a BMI >40 kg/m2. In addition, it emphasizes the importance of adolescents attaining at least Tanner stage 4 and near final height before referring to BS . The criteria of The Interdisciplinary European Guidelines on Metabolic and Bariatric Surgery are more stringent and suggest considering BS only in adolescent with BMI >40 kg/m2 and at least one comorbidity . A shared requirement by the different guidelines is the necessity to evaluate the patient’s ability to adhere to the postoperative dietary regimen, including micronutrient administration. Most commonly used bariatric procedures in adolescents are Roux en Y Gastric Bypass (RYGB) and sleeve gastrectomy (SG). SG is a restrictive procedure that includes resection of 85% of the stomach, along its greater curvature. RYGB is a combination of malabsorptive and restrictive procedure that includes the creation of a small stomach pouch anastomosed with the mid-jejunum (The Roux limb). The remainder, bypassed portion, of the stomach is connected to the jejunum allowing passage of bile acids and pancreatic secretions to the proximal jejunum, where they mix with ingested nutrients (The common limb). Both procedures show similar reduction in BMI and reverse of comorbidities [28, 29]. SG has gained more acceptances in the past decade and is currently the most common procedure performed in adolescents. The reason for this preference is lower perioperative complications including less dumping syndrome, less iron malabsorption, and less re-operations [30, 31]. Adjustable gastric banding (AGB) is not FDA approved for adolescents and shows higher failure rate and re-operation . Despite the increasing use of bariatric procedures, data are still insufficient, regarding their long-term outcome in adolescents, weight regain, and their implication on bone health and nutritional deficiencies. In this review, we conducted a literature review of short- and long-term outcome and complications of BS.
Short-Term Implications of Bariatric Procedures Performed in Adolescence
The short-term safety of bariatric procedures performed in adolescents is similar if not superior to that of adult patients (Table 2). In patients aged 18–21 years, the 30-day reoperation and readmission rates are 1.5% and 4.1%, respectively . Of note, rates of acute and short-term (<12 months) complications are highly dependent of the procedure performed and the surgical center. For example, in Teen Labs, major complications that were defined as life-threatening and potentially capable of causing permanent harm or resulting in reoperation, occurred in 19 (8%) of all participants (RYGB 9.3%, SG 4.5%) . In contrast – in the prospective Bariatric Outcomes Longitudinal Database (BOLD) collected from 423 surgeons at 360 hospitals across the USA evaluating short-term (≤1 year after surgery) complications of adolescents who underwent RYGB or LAGB – 21.6% of patients (98 of 454) who underwent RYGB and 49% (22 of 436) who underwent LAGB within this time frame had a significant complication. The authors reported 1 case of death due to cardiac failure occurring 5 months post-op. Twenty-nine of the RYGB patients (6.4%) and 8 of the LAGB patients (1.8%) were readmitted for re-operations . Overall, bariatric procedures performed in excellence centers with a large patient volume can be considered as relatively safe .
The impact of bariatric procedures on weight loss and obesity-related comorbidity is by far superior to forms of conservative obesity management. In the AMOS study, BMI was significantly lower in adolescent undergoing RYGB than age-matched controls who were treated conservatively. RYGB in these patients led to improvements in obesity-related cardiovascular risk factors (components of the “metabolic syndrome”) such as altered glucose metabolism, plasma lipids, and systolic and diastolic blood pressure . Similar metabolic outcomes were reported for by the Pediatric Bariatric Study Group showing a major weight loss in the first year post-op (37% reduction in BMI) along with resolution of most metabolic comorbidities . Similar important improvement in the short postoperative period was also reported for QOL measures and for some but not all psychological outcomes . Thus, one can safely argue that the short-term outcome data for weight loss, metabolic comorbidity resolution, and psychological outcomes in adolescents undergoing bariatric procedures in experienced centers is favorable and highly positive.
Long-Term Implications of Bariatric Procedures Performed in Adolescence
Impact on Obesity Status and Weight Regain
The main purpose of performing bariatric procedures at any age is long-term sustainable weight loss and recovery from obesity-related comorbidity. It is important to acknowledge that BS-induced weight loss, regardless of the procedure performed, is not different from other sorts of weight loss and leads to a sustained metabolic adaptation that favors weight regain [45, 46]. Data from multiple groups indicate that the early effect of these procedures in general (with some delicate differences between them) is highly positive and that the first 12–18 months post-op are characterized by a substantial excess weight loss. The weight loss reaches a plateau at about 18 months, and Inge et al.  have elegantly shown in obese adolescents that following RYGB, the percent change in BMI is consistent regardless of baseline BMI and is roughly 37%. This introduces a major dilemma to the caregiver regarding the optimal timing for performing such procedure. Allowing a severely obese adolescent to continue to gain weight while waiting and preparing for the procedure might adversely affect the lowest degree of BMI reached . On the other hand, performing the procedure before meeting the criteria or without optimal preparation may lower the chance of achieving an optimal result .
The issue of weight regains following bariatric procedures raises significant questions regarding their utilization, specifically in adolescents. Studies from several groups have demonstrated in adults that 5 years or more following SG, the most commonly performed procedure in adolescents, there is a substantial weight regain and significant reduction in remission rates of obesity-related metabolic complications [49, 50]. Moreover – on longer follow-up (F/U) of 7 years after SG – more than half of patients have regained weight substantially . An important and significant predictor of weight regain following bariatric procedures is younger age of the patient , indicating that adolescents are probably closer to young adults in regards to their weight regain prognosis than to older obese patients. In adolescents, the presurgical weight loss of BS candidates is the best predictor of postoperative weight loss , suggesting that those who do adhere to compliance requirements and show up for visits yet fail to lose weight prior to surgery will probably gain less from the procedure in the long run. Surprisingly, despite high rates of severe obesity in caregivers of adolescents undergoing BS as well as family dysfunction, these factors are not related to the degree of weight loss success following the procedure .
It is important to mention in this context that weight regain, representing “weight cycling,” is a strong predictor of future morbidity. Significant weight cycling was shown among obese adults to relate to reduced muscle mass and strength . Moreover, weight variation has been shown in adults to significantly increase the risk of cardiac mortality  (specifically when occurring in early adulthood in females ), development of T2DM [58, 59] and hypertension . Thus, patients undergoing bariatric procedures with initial weight loss success followed by weight regain may be at increased risk for morbidity and mortality later. This issue has been studied in large populations yet not in the context of BS, thus longer F/U of surgical patients is warranted in order to draw reliable conclusions.
Impact on Metabolic Complications of Obesity
One of the main obesity-driven morbidities developing early in life is type T2DM. Indeed, diabetes is one of the significant complications that allow performing BS at lower BMI thresholds in adults and in adolescents. TEEN-LABS and the AMOS study clearly demonstrated that both RYGB and SG have a major and impressive effect on diabetes remission in obese adolescents. Specifically, at 5-year follow-up, in the AMOS study, 4 participants with T2DM at baseline were all in clinical remission at 5 years and in TEEN-LABS – the prevalence of T2DM went down from 14% at baseline (22 patients) to 2.4% at 5 years. The effect of BS on remission and metabolic control of T2DM is by far superior to any lifestyle or pharmacological intervention tested in obese adolescents. When the data regarding adolescents with T2DM were compared between the TEEN-LABS and TODAY , BS emerged as by far superior to conservative/pharmacological management in regard to metabolic control, weight loss, and remission of other comorbidities . Upon modeling future cardiovascular risk using the Framingham CVD event score – surgery reduced such risk significantly compared to medical interventions over 1 and 5 years of F/U . Similarly, presence of diabetes and obesity-related kidney disease, manifested as hyperfiltration and elevated urinary albumin excretion, improved significantly in obese adolescents with T2DM undergoing surgery compared to medical therapy . In view of the rather pessimistic results of the TODAY study , designed to test medical interventions in obese adolescents, bariatric procedures seem to be the most efficient and sustainable intervention for obese adolescents with T2DM.
Importantly, it has clearly been shown that the effects of RYGB and of SG in regard to glucose metabolism are similar  and are driven strictly by the weight loss per se and not by additional hormonal mechanisms, as previously postulated. Specifically – when a comparable weight loss (∼18%) is induced by surgery and by diet – hepatic and muscle insulin sensitivity as well as beta-cell function are equally improved . Similarly, caloric restriction in itself achieves T2DM remission as well and as fast as bariatric procedures by reducing hepatic and pancreatic lipid deposition and restoring beta-cell function . The fact that weight loss is the main driving force of T2DM remission regardless of the way it was achieved highlights the fact that BS can be spared if comparable weight loss can be achieved using more conservative measures.
Nonalcoholic fatty liver disease (NAFLD) is common among obese adolescents while NASH, the marker of a significant obesity-related complication in BS guidelines, is less frequently encountered. Recent meta-analyses have shown that clinically significant improvements in NAFLD can be detected even with modest weight loss (independent of how it was achieved) yet greater weight loss is associated with greater improvements [67, 68]. Specifically, there was a dose-response relationship of weight lost with liver inflammation, ballooning, and resolution of NAFLD or NASH but limited evidence of such relation with fibrosis or NAFLD activity score. In a study performed specifically in adult patients with NASH – BS lead to resolution of NASH in 84% of participants at 5 years of F/U showing evidence of progressive reduction of fibrosis . To put this result into perspective, a clinical trial of Semaglutide for obese adults with NASH resulted in a 13% weight loss, using the higher dose, after 72 weeks, and with 59% NASH resolution while changes in fibrosis stage were not different compared to placebo . These observations emphasize again that the determinant of NAFLD/NASH resolution is weight loss in general and not an effect of specific bariatric procedures.
Hypertension is commonly found in severely obese adolescents. Both AMOS and TEEN-LABS show very impressive remission of hypertension at 2 and 5 years of F/U. Specifically, in AMOS, 100% of bariatric patients had complete resolution of systolic and/or diastolic hypertension while in TEEN-LABS a 68% remission rate was observed. Other studies of obese adolescents undergoing bariatric procedures have shown comparable excellent remission rates of hypertension [38, 71]. Similarly, improvements in the typical dyslipidemia of obese adolescents (elevated triglycerides and low HDL-cholesterol ) are markedly improved following bariatric procedures with typical normalization occurring early post operatively yet significant recurrence over time (95% at 5-year F/U) . Of note, RYGB produces the better improvements in dyslipidemia and hypertension than other bariatric surgical procedures.
The amount of weight loss needed to improve elements of the metabolic syndrome in obese children and adolescents, such as hypertension, elevated triglycerides and low HDL-cholesterol concentrations, is 0.25–0.50 BMI SD score . This BMI SDs change translates to a BMI reduction of 1.0–2.0 kg/m2 in a 13 years old adolescent, and is associated with an improvement of all abnormal cardiovascular risk factors, except fasting blood glucose. Specifically, in obese adolescents, a 1 mg/dL increase in HDL is typically associated with a 0.74-kg weight loss, and a 1 mg/dL decrease in triglycerides is associated with a 0.1-kg weight loss . Thus, the degree of BMI change needed to improve components of the metabolic syndrome (hypertension, hypertriglyceridemia, and insulin resistance), which are the main determinants of cardiovascular morbidity in obese subjects , is well below that induced by bariatric procedures.
Impact on Bone Health and Fracture Risk
Despite the very positive effects of bariatric procedures on multiple metabolic parameters, there is increasing evidence of adverse skeletal effects related to these procedures. The mechanisms underlying the adverse effects of bariatric procedures on bone health may be due to potential vitamin D deficiency, significant mechanical unloading due to weight loss and an acute reduction in leptin concentrations . SG has been shown to reduce bone mass by reducing bone formation along with rapid demineralization, independent of the weight loss or vitamin D and calcium deficiencies . Specifically, in adults, SG has been shown to reduce hip bone mineral density (BMD) by 9.2% at 24 months F/U . Importantly, despite the fact that the majority of the weight loss following SG occurs by 24–36 months, the markers of bone turnover remain elevated well beyond that period . The clinical impact of such BMD reductions is a significant increase (hazard ratio [HR] 1.3–2.3) in fracture risk following bariatric procedures [81, 82] with some studies showing even greater risk (HR up to 5) at specific skeletal sites . The long-term fracture risk following RYGB seems to be even greater than that of SG . Based on the current literature, fracture risk appears to manifest >2 years following the surgical procedure and seems to increase in following years . The typical vulnerable site for fractures is the hip and although the absolute risk of fractures is modest, the age of fracture occurrence is much younger than expected for age-related fractures.
In obese adolescents, RYGB worsens deficiencies of micronutrients related to bone metabolism and is associated with secondary hyperparathyroidism and low BMD values . The effect of bariatric procedures in adolescents manifests as clinically significant reductions in whole-body none mineral content as well as BMD z score . Compared to obese adolescents without surgery – those who underwent SG-induced weight loss had a negative impact on areal BMD and some high-resolution peripheral quantitative computed tomography parameters . Specifically, SG had a negative effect on BMD z scores of the narrow neck and intertrochanteric regions of the hip . Despite these findings, bone strength parameters remained stable, possibly because of a decrease in cortical bone porosity and an increase in cortical volumetric BMD. It is unclear yet whether the dynamics in parameters of bone density and strength stabilizes over time or continues to decline.
Taking into consideration that peak bone mass is not attained until early adulthood, the adverse impact of bariatric procedures performed in adolescence may have an even more deleterious effect later in life. It may be somewhat reassuring that obese adolescents typically have higher BMD than their lean peers, thus their starting point prior to surgery is better. There is a significant knowledge gap regarding the long-term impact of BS on fracture risk in adulthood of those operated during adolescence.
Impact on Postoperative Nutritional Deficiencies
Adult BS candidates have been shown to have significant nutritional deficiencies prior to surgery necessitating a structured preoperative nutritional preparation [88, 89]. Moreover, presence of such deficiencies in adults prior to performance of BS is the best predictor for their presence 12 months following surgery, specifically in SG . When the F/U of patients undergoing SG is longer (4 years) – the rate of nutritional deficiencies increases with specific worsening of low vitamin D levels (86%) and presence of elevated parathyroid hormone levels (60%) .
When adherence to nutritional requirements is defined as taking the vitamin supplements at least 3 times a week – data from the AMOS study suggested that the adherence rate is 44–61% at 5 years of F/U . More than 60% had iron deficiency regardless of adherence and rates of vitamin D and vitamin B12 were, as expected, significantly lower among those not adhering to supplementation. Two years following SG performed in obese adolescents, 89% had vitamin D insufficiency and 38% had low albumin levels . In TEEN-Labs, ferritin levels decreased significantly after both procedures. Low ferritin levels were detected in 71% at 5 years after RYGB and in 45% 5 years after SG (both significantly greater rates than those observed at baseline) . The authors indicated that at least 2 nutritional deficiencies were detected by 5 years in 59% of RYGB and 27% of SG patients. These observations highlight the fact that nutritional deficiencies are common in obese adolescent prior to and following bariatric procedures. The presence of such deficiencies preoperatively and poor adherence to nutritional recommendations post operatively are strong predictors of clinically significant nutritional deficiencies on F/U.
Impact on QOL and Mental Problems
Obese children and adolescents in general and BS candidates in particular typically report reduced QOL compared to their lean and overweight peers . It is generally accepted that in adults there is an inverse association between weight changes and QOL, thus weight loss is usually associated with positive health related but not necessarily mental QOL changes . BS in adults has been shown to increase self-harm emergencies over time including suicidal ideation and suicide attempts [95, 96]. Some studies indicate an alarming adjusted HR of 2.85 (95% CI: 2.40–3.39) for attempted suicide following bariatric procedures . Importantly, the vast majority of self-harm events occurred in adults who were diagnosed with a mental health disorders within the 5 years prior to surgery.
In TEEN-Labs, joint pains, impaired physical function, and impaired health-related QOL significantly improved at 1 and 3 years of F/U [98, 99]. Similar observations have been demonstrated in the AMOS study at the 5-year F/U – yet along with major improvements in health-related QOL parameters, significant mental health problems persisted despite the substantial weight loss . Specifically, obese adolescents who underwent BS had significantly greater utilization of specialized psychiatric treatment services (that increased over time) compared to the control group that was treated conservatively. Self-esteem of patients undergoing surgery was significantly improved at 5 years compared to baseline yet overall mood was not. As shown in adults, poor mental health at baseline, prior to surgery, is a strong predictor of poor mental health on F/U, and the decline in mental health status seems to manifest after the first year post-op . Of note, the poor mental outcome was not related to the degree of weight loss in adolescents nor in adults.
Are There Valid Alternatives to BS in Obese Adolescents?
The vast majority of obese adolescents have very low motivation for participation in lifestyle intervention programs . Upon testing the long-term (at least 2 years) efficacy of such programs in >20,000 obese European adolescents treated in specialty centers, only a very modest portion of participants (7%) achieve clinically significant weight loss (at least 0.25 BMI SD score) while the vast majority are lost to F/U . Of note, not surprisingly, the highest success rate of conservative obesity management was demonstrated in highly motivated patients . The less obese participants of such programs usually respond better than their more obese counterparts, at least in regard to BMI reduction . Regardless, the positive clinically meaningful impact on BMI of conservative management in cases of severe adolescent obesity is very modest at best. As a mandatory component of any adolescent bariatric program is the 6-month preparation period, these observations emphasize the importance of defining and identifying the compliance and motivation of participants as this can serve as a predictor of the long-term success of the surgical intervention.
Until recently, the pharmacological treatment options for obesity management in adolescents were limited. The efficacy of Orlistat and Metformin is rather modest at best and the impact of classic lifestyle interventions is modest and usually unsustainable over time . The introduction of GLP-1 analogues therapy in this age-group represents a first demonstration of an agent that is potent enough to induce moderate clinically meaningful weight loss. The recently published trial for Liraglutide in obese adolescents showed a treatment effect after 1 year of 7.14% body weight loss and 0.37 SD score in BMI with 43% of the treatment group losing at least 5% in BMI and 26.1% losing >10% of BMI . These results are very similar to those shown for Liraglutide in obese adults [107, 108]. Importantly, when Liraglutide was tested in obese adolescents with T2DM, a metabolic improvement was demonstrated yet one that is much smaller than that induced by bariatric procedures without evidence of clinical remission . Exenatide administered once weekly in obese adolescents reduced SD score by 0.09 over 6 months of treatment without affecting liver fat . Of note, the effect size of GLP-1 analogues on BMI, specifically of Liraglutide, is within the range that is sufficient to improve most cardiovascular risk biomarkers such as hypertension and dyslipidemia yet is still significantly inferior in comparison to surgery. Moreover, cessation of drug administration results in weight regain, as in other pharmacological anti-obesity treatments . Altogether, the current experience with the use of GLP-1 analogues in obese adolescents shows promising results and one could argue that a significant proportion of adolescent BS candidates could potentially benefit from such agents in order to reverse and improve minor obesity-related complications as well as their degree of obesity in general.
In summary, pharmacological treatment of obesity most probably cannot substitute BS in cases where significant complications are present, such as T2DM or steatohepatitis (although this hypothesis remains to be tested in this age-group). On the other hand, in obese adolescents with uncomplicated obesity or milder obesity-related complications (such as hypertension, dyslipidemia, or gastro-esophageal reflux disease), pharmacological treatment is highly likely to lead to a significant improvement and even normalization of the comorbidity. The advantage of pharmacological treatment in this context is its reversibility (ability to withhold treatment). On the other hand, the amount of BMI change induced by such therapy is far from sufficient in cases of obese adolescents with BMIs in the 40 s and above.
Bariatric surgical procedures for obese adolescents can be considered safe and efficacious in the short term. Accumulating data of longer F/U periods raises some concerns regarding the sustainability of the weight loss achieved and the resolution of some metabolic complications along with concerns regarding bone health. For obese adolescents with severe obesity-related complications, such as T2DM, steatohepatitis, or life-threatening OSA, BS, performed with proper preoperative preparation and in excellence centers, is probably an excellent choice. Similarly, obese adolescents with BMI levels above 45 kg/m2 will probably remain obese even after surgical interventions yet may benefit in regard to their complications. Obese adolescents with lower BMIs and milder obesity-related complications (such as hypertension, dyslipidemia, reduced mobility, and QOL among others) may significantly benefit from pharmacological interventions along with a structured lifestyle modification program. Such intervention will, at best, lead to a moderate weight loss that is smaller than that achieved by surgery but will probably lead to resolution of metabolic complications and improvement of psychological measures. Obviously, a combination of a pharmacological intervention and lifestyle modification will be safer in the short and long term and allow later consideration of surgery in cases of failure. We thus suggest that obese adolescents without major obesity-related complications may deserve treatment with medications with proven efficacy that are already available prior to referral to BS.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
There are no funding sources to declare.
The followings are the authors’ contributions: Rana Halloun: writing – original draft and writing – review and editing; Ram Weiss: conceptualization, writing – review and editing, and supervision.