With the unprecedented growth of the elderly population in China, elderly-care facilities (ECFs) are in a fast expansion process. However, limited attention has been paid to the imbalance at the actual utilization level of ECFs. This research aims to reveal the spatial inequity of ECFs and to quantitatively examine the effect of accessibility and institutional service capacity on utilization. Taking Chongqing, China, as the study area, we measured the spatial accessibility of different travel modes by the Gaussian Two-Step Floating Catchment Area (G2SFCA) method and investigated distribution differences in spatial accessibility, service capacity, and utilization of ECFs by the Dagum Gini Coefficient and its decomposition. Then, the impact of spatial accessibility and service capacity on the utilization of regional ECFs was quantified by multiscale geographically weighted regression (MGWR). The study findings can be summarized as follows. (1) Walking accessibility has the most significant impact on the utilization of ECFs and shows geographic heterogeneity. Developing a pedestrian-oriented network of pathways is essential to enhance the utilization of ECFs. (2) Accessibility by driving and bus-riding does not correlate with regional ECFs utilization, and relevant studies cannot rely on them alone for assessing the equity of ECFs. (3) In the utilization of ECFs, since the inter-regional difference is more significant than the intra-regional difference, efforts to reduce the overall imbalance should be oriented toward inter-regional variation. The study’s findings will assist national policymakers in developing EFCs to enhance health indicators and quality of life for older adults by prioritizing financing for shortage areas, coordinating ECFs services, and optimizing road systems. Population aging is growing increasingly significant and has become a major social issue worldwide . AccordiThe physical condition of the elderly deteriorates with age , which iThe inequality of social service resources for disadvantaged groups has been a primary concern in sustainable urban development ,16. ReseWhat are the characteristics of the spatial distribution of ECF utilization, accessibility, and service capacity? In what areas do they exhibit significant imbalances?What are the main sources of the overall imbalance in the utilization of ECFs?How do accessibility and service capacity impact ECF utilization? What is the extent of the impact?Although some studies on the application of the equity method enhancement and assessment have been done, the existing studies still have some limitations. First, there is not only a quantitative imbalance in the supply of, and demand for, ECFs. More seriously, there is also an imbalance in space utilization , which hThe purpose of this research is to reveal the spatial inequity of ECFs in Chongqing and to quantitatively examine the effect of accessibility and institutional service capacity on utilization. Furthermore, it provides a solid foundation for national policymakers to rationalize resource allocation for ECF services and optimize the distribution of the ageing population. The research framework for this paper is shown in Chongqing, located in the southwest of China’s heartland, is the economic centre of the upper Yangtze River area. With the largest elderly population in China, Chongqing has been entering a state of deep ageing society. According to the Chongqing Statistical Yearbook 2021 , ChongqiTo obtain a more accurate spatial analysis, we used the sub-district (jiedao), a form of township-level administrative division in China, as the basic spatial unit to measure the inequity of elderly care institutions in the main urban area of Chongqing. The seventh national census collected data on the senior population in Chongqing’s 161 sub-districts . The metTo ensure consistency between geographical and demographic data, we extracted information from the Chongqing Civil Affairs Bureau about elderly institutions in 2021 . A totalThe spatial data of the road network is derived from the Gaode Map and the Open Street Map, which mainly consists of the rail transit network, bus network, and urban roads . AccordiThe traditional two-step floating catchment area method (2SFCA) treats supply and demand point interactions by dichotomy . Howeverj:m is the class type of the ECFs, j within the search threshold, j, k, k and the ECF j, and Step 1: Calculating of the ratio of beds to elderly population in the catchment area of the ECF i to the ECFs, calculated by summing the accessibility of the three types of ECFs.Step 2: calculating the spatial accessibility index We use the Dagum Gini decomposition method to measure regional differences. This method overcomes the limitations of the traditional Gini coefficient and the Thiel index, and effectively analyzes the causes of regional differences . AdditioThe overall Gini coefficient is calculated as follows:wG, i.e., the spatial differences between variable value within districts, which refers to such differences between sub-districts within nine districts in this study. (ii) Inter-regional difference nbG, i.e., the differences of variable value between districts, which refers to such differences between nine districts in this study. iii) Intensity of transvariation tG, i.e., the differences of variable value between districts, which refers to such differences between nine districts in this study, refers to the remainder of the overall Gini coefficient generated by the overlapping effects between regions. The relationship between them satisfies w + Gnb + Gt= G. The formula is as follows:j and h, j and h, j and h respectively.The overall Gini coefficient The traditional OLS is a clear and simple linear regression. However, it ignores changes in spatial variables caused by fluctuating spatial locations. Researcher have offered geographically weighted regression (GWR) as an excellent solution to the problem of geographical non-smoothness using regional regression analysis with variable parameters . Unlike The spatial accessibility of ECFs in different places shows whether older individuals have equal access to ECFs. To answer questions 1 and 2 mentioned in the introduction, we focused on two aspects: the spatial distribution characteristics of accessibility and the quantification of accessibility discrepancies.The accessibility score is the number of ECF beds available to each older adult using a specific method of transportation, and is shown by its colour: redder indicates more accessibility, while yellower indicates lower accessibility. The accessibility distribution varies greatly between modes of transportation. Accessibility to ECFs by rail transit, car, and bus is presented in wG, we identified the districts with the most uneven accessibility distributions at the sub-district level. nbG to identify districts with the greatest differences in accessibility between groups. As shown in From the perspective of inter-regional differences, we used nbG and intensity of transvariation tG. Therefore, identifying and reducing interregional differences is the first step toward ensuring equity in service capacity and spatial use in Chongqing. In addition, identifying and adjusting high imbalances within the region is also essential.wG shown in wG values greater than 0.5. Regarding spatial utilization, the utilization rate of ECFs varies significantly between sub-districts in the Yuzhong, Nan’an and Dadukou regions. The wG value is exceptionally high in Yuzhong District, which reaches 0.8  indicates that accessibility by walking and rail transit, as well as service capacity, have a direct impact on the utilization of ECFs.The MGWR model was used to analyze the overall and local effects of the factors on utilization. p-values for each element in p-values for rail transit, walking, and service capacity, with darker shades indicating statistically significant results. As shown in p-values ranging from 0.40 to 0.42  Our study’s explanatory variables included many factors . Nevertheless, income, air quality and other uncertain information, such as subjective preferences of older adults in different age groups, were not considered. In the future, these data can be supplemented and improved with government guidance, and their impact on space utilization can be further investigated by overlaying income data and air quality. (2) In addition to the number of people served to the number of beds ratio, service capacity also includes the quality of meals and the quantity of other equipment, such as televisions and air conditioners. Due to the large sample size, these data are not currently available. Future research could develop more quantitative statistics on these elements and use more comprehensive service metrics to evaluate the quality of ECF services. This will facilitate a more accurate analysis of its contribution to utilization.At the local level, sub-districts that need to be improved can be divided into two categories: without ECFs and with low ECFs utilization  Overall, walking accessibility has the most significant impact on the utilization of ECFs, and there is spatial heterogeneity in this significance. Building a pedestrian-friendly pathway system is critical for improving ECF utilization. (2) Regarding the utilization of ECFs, the inter-regional difference is significantly higher than the intra-regional difference and is the primary source of overall difference. Eliminating overall differences must consider the sensible deployment of resources across districts. (3) Accessibility by driving and bus-riding does not correlate with the utilization of ECFs. Therefore, relying on them alone to evaluate the service equity of ECFs is inadequate, and this should be avoided in future studies. We emphasize the actual utilization of ECFs as a more equitable criterion than single accessibility.As the elderly population continues to grow, it is increasingly urgent to eliminate inequalities in services for ECFs. Therefore, it is imperative to develop separate strategies for unbalanced areas, with policy and economic support. Furthermore, appropriate policies should be oriented toward inter-regional differences in order to maintain ECF sustainability through coordinated resource allocation. The findings contribute to identifying service inequities in ECFs on an overall and local level, and provide a valuable reference for planners to develop coping strategies in the urban regeneration process.


Sickle Cell Disease (SCD) is a progressive genetic disease that causes organ damage and reduces longevity. Hydroxyurea is an underutilized evidence-based medication that reduces complications and improves survival in SCD. In a multi-site clinical trial, part of the NIH-funded Sickle Cell Disease Implementation Consortium (SCDIC), we evaluate the implementation of a multi-level and multi-component mobile health  patient and provider intervention to target the determinants and context of low hydroxyurea use. Given the complexity of the intervention and contextual variability in its implementation, we combined different behavioral and implementation theories, models, and frameworks to facilitate the evaluation of the intervention implementation. In this report, we describe engagement with stakeholders, planning of the implementation process, and final analytical plan to evaluate the implementation outcomes.During 19 meetings, a 16-member multidisciplinary SCDIC implementation team created, conceived, and implemented a project that utilized Intervention Mapping to guide designing an intervention and its evaluation plan. The process included five steps: (1) needs assessment of low hydroxyurea utilization, (2) conceptual framework development, (3) intervention design process, (4) selection of models and frameworks, and (5) designing evaluation of the intervention implementation.Behavioral theories guided the needs assessment and the design of the multi-level mHealth intervention. In designing the evaluation approach, we combined two implementation frameworks to best account for the contextual complexity at the organizational, provider, and patient levels: (1) the Consolidated Framework for Implementation Research (CFIR) that details barriers and facilitators to implementing the mHealth intervention at multiple levels , and (2) the Technology Acceptance Model (TAM), a conceptual model specific for explaining the intent to use new information technology . The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) framework was used to measure the outcomes.Our research project can serve as a case study of a potential approach to combining different models/frameworks to help organize and plan the evaluation of interventions to increase medication adherence. The description of our process may serve as a blueprint for future studies developing and testing new strategies to foster evidence-based treatments for individuals living with SCD. Sickle cell disease (SCD) is a devastating genetic disease where progressive organ damage leads to premature death . Only a As the first FDA-approved evidence-based drug for SCD, daily oral hydroxyurea is a medication recommended by guidelines  and withDuring the development of the multi-level/multi-component mHealth intervention, a major challenge within the SCDIC was to construct an evaluation approach to identify how each contextual level  and intervention component  could influence implementation and effectiveness outcomes, both as individual factors and interactively. For instance, patients, providers, and institutional characteristics can influence the implementation and distal effectiveness outcomes. Still, implementation outcomes can also interact across multiple levels , modifying the effectiveness outcomes. To address this challenge, we used the intervention mapping methodology , which awhat and how contextual factors influence implementation outcomes while anticipating possible interrelationships  among the intervention components. This paper will discuss different theories, models, and frameworks and how they are optimally combined to evaluate the implementation of a multi-level/multi-component mHealth intervention to improve hydroxyurea utilization in SCD   . We descThis descriptive narrative of the process selects and blends theories, models, and frameworks to design the clinical trial evaluation that tests a new multi-level/multi-component mHealth intervention to improve hydroxyurea adherence among patients with SCD .β0-thalassemia).This multi-center study included seven SCDIC clinical sites, all academic institutions in urban, suburban, and rural areas, with some degree of organizational and population variability. All sites have experienced SCD providers  and trainees . The prevalence of eligible patient participants  ranged from 40 to 60% of the patient population at each site. Among eligible participants, approximately 70% were covered under government health plans (primarily Medicaid). Most patients were aged >25 years, although, in two sites, about half of eligible patients were adolescents. Among eligible patients, approximately 70% had a severe SCD genotype  and the SCDIC Implementation Research Committee (composed of implementation scientists) offered an additional layer of scientific input, suggested changes to the study, and voted to approve the study in its final form.Our activities began by providing level-setting knowledge about SCD and dissemination and implementation research to all members of the SCDIC. As the research team was diverse and background knowledge was often non-overlapping, much of the initial work centered on the generation of a shared vision, i.e., establishing agreement on the goals of the program and the process whereby a research question was developed and addressed. The design of the intervention components followed a comprehensive needs assessment phase examining the barriers and enablers to hydroxyurea utilization in the SCD population at multiple levels (Activity 1). Next, a conceptual model evolved using Intervention Mapping (Activity 2) to guide the development of the interventions and the planning of the implementation strategies (Activity 3), the selection of the models and frameworks (Activity 4), and the evaluation plan (Activity 5). We used an inclusive consensus approach throughout all activity phases and defined and selected priorities, designed interventions, and measured outcomes. Our study is fully accrued and is on track to complete data analysis by March 2023. Next, we will present the details of each activity.Our needs assessment focused on care redesign to improve hydroxyurea uptake and considered intervention targets, modalities, and strategy mechanisms. Barriers and enablers to hydroxyurea utilization in the SCD population were conducted through literature synthesis –22, popuInformed by the needs assessment, we developed a comprehensive conceptual model centered on Intervention Mapping. To organize the components of the intervention at both the patient and the provider levels, we used Intervention Mapping to identify specific methods and practical applications to create change in determinants, performance objectives, and behavioral change outcomes. Intervention Mapping is a protocol based on using theory and evidence for developing effective behavior change interventions . A primaSCDIC investigators noted the widespread use of technology among patients with SCD    a two-level intervention: (1) ication) , and (2)oxyurea) . User-ceoxyurea) , 39. Patrvention  40)..InChargeInCharge Health and HU Toolbox. The “train and educate stakeholders strategy” . Other implementation strategies included understanding barriers and facilitators to digital health interventions, a thorough understanding of the implementation context, and patient feedback. These strategies were prospectively tracked and documented by each participating site.A menu of implementation strategies was used to increase the implementation outcomes of both trategy” , 42 incltrategy” , 42 was Our challenge in organizing patient, provider, and clinic-level contextual factors within SCDIC included the selection of implementation frameworks that would appropriately represent the multiple dimensions of the intervention  while accounting for the complex context where the population received care and where we sought to enhance the impact of our intervention. For instance, unmet social needs can lead to health disparities  and may SCDIC investigators considered several models and frameworks to define theory-based domains associated with contextual variables and the overall robustness of the mHealth innovation. Our goal was to examine the influences of patient, provider, and clinical setting level characteristics on study outcomes and the qualitative examination of barriers and enablers of the mHealth innovation. Given that different models and frameworks identify other metrics for evaluating implementation success, the group decided to combine the Consolidated Framework for Implementation Research (CFIR)  and the In addition to CFIR and RE-AIM/RE-AIM QuEST, we also used the Technology Acceptance Model (TAM) , 49 to dInCharge Health implementation might correlate with hydroxyurea adherence and (2) how the level of HU Toolbox implementation might correlate to increases in providers' knowledge and self-efficacy in prescribing hydroxyurea. To assess outcomes within each RE-AIM domain, quantitative measures were selected with possible moderation or mediation by CFIR constructs  by overcoming the challenges of forming a functional and integrated diverse team that had first to learn how to work together, share knowledge, and develop the conceptual models, to create the interventions, select, and combine implementation frameworks, and design the evaluation plans that are appropriate for use in complex multilevel interventions. Our diverse community of scientists, government representatives, clinicians, and patient partners recognized that a proper understanding of the implementation process would require careful consideration of the multi-level factors that can influence the implementation in the SCD population. Embedded in this concept was the notion that for the group to properly function and advance the research question, developing trust, respect, and having a shared vision was essential. The research team integration followed collaboration and team science principles, which set clear expectations for sharing credit, authorship, and maintaining self-awareness . Strong Our selection of theories, models, and frameworks followed our needs assessment phase. For this project, no models were adapted to fit the study intervention or evaluations. However, for some frameworks, not all constructs were applicable. For instance, the “Mobile health care systems self-efficacy” driver within TAM was less pertinent to developing the provider-level intervention. That's because, among SCD providers, the perception that mHealth could help with the task of prescribing hydroxyurea was less of a factor when the dominant perceived ease of use and usefulness of the intervention were used . Additionally, the outer setting construct within CFIR was not examined, as implementing mHealth in clinics is mainly controlled by the local leadership and policies and generally not regulated by the existing health systems policies. We did not encounter problems aligning our outcomes and influential contextual factors to the existing domains and constructs of the frameworks used. However, the issue of problems aligning with existing domains may occur depending on the research question, and population studied. Therefore, the careful selection of models and frameworks deserves extra attention and effort from the investigators, as adaptations to existing models and frameworks may be required.why implementation might succeed or fail if used proactively and help to identify relevant modifiable factors affecting adoption, implementation, and maintenance. By understanding the why, we hope to identify mediators and moderators of the intervention and narrow down the components of the intervention that should be modified, removed, or new ones that need to be created in further adaptation while shedding light on the mechanism of interventions and identification of new implementation strategies. Finally, adding qualitative data to CFIR will allow us to map the level of influence on the CFIR constructs and domains. A qualitative design can expand quantitative data and provide new hypotheses to explain why implementation succeeds. Therefore, adding a qualitative design when using CFIR can be useful.Our work describing the process development of how to combine implementation models and frameworks to study how multi-level contextual factors optimally and comprehensively affect implementation outcomes adds to this growing literature. When models and frameworks are combined to evaluate the implementation of an intervention or practice, essential factors that caused the organization to reject or accept the intervention can be uncovered. For instance, formally appointing key stakeholders to ensure the fidelity of the intervention or gaining visible support from the system and local leaders are contextual factors that are not necessarily known as pre-conditions for optimal implementation , 54. WhiOur process to select the theories, models, and frameworks was iterative and followed matching theories and strategies to the type of intervention we sought to implement to best fit the quality gap we were trying to address, namely, low hydroxyurea utilization in SCD. Our process ensured diverse perspectives and consensus. It is possible, however, that this selection was not optimal. For example, our choice of models and frameworks preceded the publication of the RE-AIM expansion, which recognizably could represent an alternative to our approach. RE-AIM and PRISM can also be combined to investigate contextual predictors of the implementation outcomes, and an expanded version of RE-AIM has recently been published . Althougwhy. The results of our mHealth adherence-enhancing study and future research will refine the evaluation approach to create new knowledge in developing an evaluation model for multi-level interventions to increase hydroxyurea uptake among adolescents and adults with SCD.In conclusion, we report the processes of developing a multi-level, multi-component intervention to foster greater use of hydroxyurea therapy among patients with SCD and detail this multi-level intervention and our comprehensive plan for its evaluation. Careful consideration of how the multiple components of the intervention can interact with the various targets and contextual factors will facilitate the description of the implementation's how, when, what, where, and who of the implementation and the


Stress is a process that triggers various physiological, hormonal and psychological mechanisms in response to a threat, which significantly affects the health of an individual. The COVID-19 pandemic introduced a lot of social changes that required constant adaptation to unfavorable conditions. The aim of the study was to assess the impact of stress related to this pandemic on pregnant women, mothers of premature infants and their families, and on obstetric complications, particularly preterm birth. A comprehensive literature review was performed using electronic databases such as Pubmed, Science Direct and Google Scholar. Keywords such as: “prematurity”; “pregnancy”; “stress”; “COVID-19” and various combinations of the above were used. Maternal stress and anxiety increase the levels of corticotropin-releasing hormone (CRH) in the placenta, which in turn affects the incidence of preterm birth and many other related maternal and neonatal complications. In addition, it was found that SARS-CoV-2 infection may increase the risk of this phenomenon. The COVID-19 pandemic has adversely affected preterm birth rates and the mental health of mothers of preterm infants, exacerbating their negative experience of having a premature baby. More research is needed to demonstrate the long-term effects of COVID-19 stress on prematurity. The premature birth of a child, defined as birth before 37 weeks of gestation, is becoming increasingly common worldwide. More than 50% long-term morbidity and circa 75% of perinatal mortality is caused by premature birth. Survived preterm children are at increased risk of developing neurological, respiratory and gastrointestinal complications .According to the National Children’s Health Institute in Poland, every third child born before the completion of 32 weeks of gestation requires hospitalization in a neonatal intensive care unit [Data published between 2015 and 2023 by the European Centre for Disease Prevention and Control (ECDC) under the Euro-Peristant project indicates that 7.1% of all live births in European countries are premature. However, the prevalence of preterm birth varies among individual countries, with Romania having a rate of 11.1% and Iceland having a rate of only 5.5% .According to the World Health Organization (WHO), approximately 14.9 million premature babies were born worldwide in 2021, accounting for around 10.6% of all births ,5.Moreover, lockdown during the COVID-19 pandemic could have caused modifications in environmental and behavioral life, such as reduction of physical activity, employment, social support and the most common in this group, reduction of access to healthcare—especially gynecological and obstetric . HedermaThe comprehensive literature review was performed using the electronic databases: Pubmed, Science Direct and Google Scholar. Keywords such as: “prematurity”; “pregnancy”; “stress”; “COVID-19” and various combinations of the above were used. The search was limited by 2019 year for „COVID-19” and 2010 year for the others keywords. The aim of this review paper is to summarize the current state of knowledge about how experience of COVID-19 pandemic may have affected the stress of prematurity. Due to many research, the influence of COVID-19 pandemic in the adults is currently well-known. The importance of this review paper is focusing on the impact of stress caused by pandemic in the early, prenatal and postnatal (particularly premature) stage of life. Stress may affect the pregnancy course, or obstetric complications, as well as long-term maternal and offspring outcomes .Both the incidence of COVID-19 in pregnant women and the impact of this infection on pregnancy outcomes are still being investigated. Existing research suggests that SARS-CoV-2 infection may increase the risk of preterm birth and numerous pregnancy complications. There have also been reports of the potential placental transport of the virus and maternal-fetal transmission of the infection; however, the risk appears to be relatively low, and the number of reports confirming intrauterine transmission of the coronavirus is limited ,9,10.Conducted studies indicate that COVID-19 infection increases the risk of preterm birth compared to healthy women. This may be attributed to the inflammatory state resulting from the infection, which leads to the initiation of premature uterine contractions. The authors of one study conducted on a large population of pregnant women in the United States observed that COVID-19 increased the risk of preterm birth by 60% ,9.Coronavirus infection can adversely affect the overall health status of pregnant women, manifesting in various symptoms such as fever, cough, muscle aches, gastrointestinal disturbances (diarrhea and nausea), and respiratory difficulties. Pregnant women are also more susceptible to developing pneumonia and acute respiratory distress syndrome, which carries the risk of severe oxygen deprivation for both the mother and the fetus. Severe COVID-19 infection can also serve as an indication for the premature termination of pregnancy for the health of the mother and the fetus, thus warranting iatrogenic preterm delivery ,14,15,16Furthermore, COVID-19 infection increases the risk of gestational diabetes mellitus, gestational hypertension, preeclampsia, and intrauterine fetal demise .Maternal psychological stress, or prenatal stress, as well as major stressful events  during pregnancy, has been negatively associated with gestational age, weight and length of a child at birth. Furthermore maternal stress caused by psychosocial factors, such as single-parenting, food insecurity, or lack of physical activity, have been linked to lower birth weight .Fetal programming is a concept described by sensation, receivement and reaction of the fetus to the intrauterine environment. Sensitive periods of fetal programming may lead to structural and functional changes in cells, tissues and organs, and therefore, long-term consequences . CriticaIn conclusion the most common two factors, which influence on fetal programming are pregnancy nutrition and stress . HoweverThe consequences of perinatal stress, as preterm birth and low birth weight, affects also on brain development and reduction in regional brain volume, including the prefrontal cortex, the premotor cortex, the medial temporal lobe, the lateral temporal cortex and the postcentral gyrus, which are associated with a variety of cognitive functions . ThomasoMaternal stress mechanism, by excess exposure of glucocorticoids, may change in utero environment in association of adverse cardio-metabolic and cardio-vascular outcomes in their offspring, such as obesity and overweight, insulin resistance, diabetes, hypertension, hyperglycemia and metabolic syndrome . Van denMaternal stress-involved endocrine alterations may also affect maternal cognitive brain functions and behavior. Pregnancy contributes to changes in structure and function of the brain in regions involving recognition, spatial memory and stress responsivity, which persist via lifespan . MoreoveAnother major concern in the modern obstetrics, that affect maternal and fetal health, is the increase of pregnancy-related cancer prevalence. The most frequent malignant tumor diagnosed during pregnancy is breast cancer, although the occurrence of other types, such as hematological, skin, or ovarian cancer, have been reported. Medical multidisciplinary interventions, especially personalized and integrated treatment, may prevent iatrogenic pregnancy complications, such as impaired fetal growth or preterm birth. Nanotechnology, as the reaction in the structures on a molecular level, improves biocompatibility, pharmacokinetics, targeting of the tumor and reduces systemic toxicity or drug resistance. Nanomedicine, as a field of nanotechnology, offers the opportunity to safe and effective application of antiblastic agents during the pregnancy. However, fetal exposure on nanoformulation, by transplacental transport is still an issue of the debate in gynecological and obstetric profession. Hence, future research is necessary to development of rational, effective and safe treatment for pregnancy-associated cancers .Stress is a common problem among pregnant women. United States data from the Centers for Disease—Control Pregnancy Risk Assessment Monitoring showed that nearly 75% of postpartum women reported at least one major stressful event in the year prior to the birth of their child . It has The HPA axis can be overactivated by external stress-inducing factors. The consequence is an excessive release of endogenous cortisol and an increase of its concentration in the placenta, the process itself is regulated by metalloproteinase-1 (MMP-1), -2 (MMP-2), -3 (MMP-3) and -9 (MMP-9) . A case-Also remarkable is the fact that chronic and repeated acute stressors through modulation of the HPA axis can affect the epigenome and transcriptome, consequently causing changes related to receptors for glucocorticosteroids .Maternal stress as a risk factor for preterm birth remains a major cause of maternal morbidity and mortality worldwide . Beyond Due to the adverse effects of prenatal stress on pregnancy and perinatal outcomes, it is important to identify and mitigate pregnant women’s exposure to stress early in order to prevent premature births. For this purpose, routine prenatal care should include screening for behavioral health problems and potential intervention . Both unBoth the incidence of COVID-19 in pregnant women and the impact of this infection on pregnancy outcomes are still being investigated. Existing research suggests that SARS-CoV-2 infection may increase the risk of preterm birth and numerous pregnancy complications. There have also been reports of the potential placental transport of the virus and maternal-fetal transmission of the infection; however, the risk appears to be relatively low, and the number of reports confirming intrauterine transmission of the coronavirus is limited ,53,54,55Conducted studies indicate that COVID-19 infection increases the risk of preterm birth compared to women uninfected with the SARS-CoV-2 virus . The autCoronavirus infection can adversely affect the overall health status of pregnant women, manifesting in various symptoms such as fever, cough, muscle aches, gastrointestinal disturbances (diarrhea and nausea), and respiratory difficulties. Pregnant women are also more susceptible to developing pneumonia and acute respiratory distress syndrome, which carries the risk of severe oxygen deprivation for both the mother and the fetus. Pregnant women with COVID-19 are compromised and less able to cope with the disease in general, especially when it comes to the effects of delayed diagnosis and overdue referral to treatment, when compared to non-pregnant women. The main reason is that advanced pregnancy brings about physiological and metabolic changes that have an impact on the immune system, cardiovascular function and, essential in this context, respiratory system . BecauseSevere COVID-19 infection can also serve as an indication for the premature termination of pregnancy for the health of the mother and the fetus, thus warranting iatrogenic preterm delivery ,14,15,16Considering the mental health of pregnant women, depression is still at the first place among all mental illnesses in this population group . Stress The birth of a premature baby carries various consequences and implications for both the mother and the family of the preterm infant. Based on numerous scientific studies, it has been found that mothers of premature infants experience many health problems. These include infections, hypertension, increased postpartum bleeding, generalized infections, and genital tract infections. It has been demonstrated that patients who give birth before completing 37 weeks of gestation require longer hospitalization and rehabilitation ,71,72,73In addition to the physical consequences of preterm birth, it has been examined that mothers who are mothers of preterm infants experience significant and enduring emotional consequences. Numerous studies have shown that mothers experience high levels of stress and anxiety, which are associated with uncertainty about the future and the health of the child. Furthermore, the separation of the mother from the child in the neonatal unit generates strong feelings of worry and fear about their development and safety. This separation alters the experience of motherhood and poses difficulties in forming a bond with the child. The necessity of making difficult medical and ethical decisions contributes to elevated levels of anxiety and stress in mothers ,75,76,77Women who have experienced preterm birth are at increased risk of developing postpartum depression. The challenging experiences associated with traumatic preterm birth, separation from the child after birth, and the infant’s stay in the neonatal intensive care unit are factors that significantly elevate the levels of perceived stress, sadness, discouragement, and helplessness. It has been observed that mothers of preterm infants often blame themselves for the premature birth. They frequently experience negative thoughts and question whether the preterm birth could have been avoided or if something could have been done differently to prevent it. They also ask why it happened to them and their child. Feelings of guilt and uncertainty hinder the emotional adjustment process for women in the situation of preterm birth. It has been proven that preterm birth increases the risk of anxiety disorders and heightens the level of anxiety experienced by mothers. The stress associated with caring for a preterm child and the experience of anxiety are more prevalent in mothers of preterm infants compared to women who gave birth at term ,77,78,79Another factor that disrupts the emotional stability of mothers is social isolation, which results from the time spent in the hospital with their child. Devoting oneself entirely to the care of the preterm infant separates and limits the mother’s contact with family and the community.The issue of prematurity also affects other members of the family. It brings about changes in roles and responsibilities within the family. Siblings of preterm infants require increased attention and support during this time when parents focus on caring for the preterm infant. The issue of prematurity also disrupts the relationship and closeness between the father and the mother of the preterm newborn. This is a consequence of mutual blame for the preterm birth, as well as the disruption of the mother’s experience of sexuality due to the trauma of preterm birth. The family also experiences financial burdens associated with long-term medical care, including transportation to the hospital where the preterm infant is receiving care, treatment, hospitalization, and rehabilitation, which require significant financial resources. Around-the-clock care for the preterm infant, hospital visits, uncertain prognosis, and frequent stressful situations can lead to significant emotional exhaustion in the family. This has a negative impact on relationships and the well-being of the family ,81,82,83The COVID-19 pandemic has increased the risk of vitamin D deficiency among pregnant women due to reduced sunlight exposure, particularly during periods of isolation and quarantine. This article examines the association between vitamin D deficiency and the heightened risk of preterm birth. Although the link has been studied, the underlying mechanisms remain the subject of ongoing scientific research. Potential factors that closely correlate with vitamin D deficiency and may contribute to preterm birth include the impact on the immune system, hormonal regulation, inflammatory state, and vascular function. This paper also highlights recent scientific studies conducted in different regions that explore the relationship between vitamin D levels during pregnancy and the severity of COVID-19, as well as the risk of preterm birth.Vitamin D is an essential nutrient that has profound implications for human health, influencing various physiological processes, especially during pregnancy and reproductive health. However, the COVID-19 pandemic has raised concerns about vitamin D deficiency in pregnant women, mainly due to reduced exposure to sunlight as a result of isolation and quarantine measures. This deficiency has been linked to an increased risk of preterm birth, but the exact mechanisms underlying this association are yet to be fully understood and require further scientific investigation ,85.Impact on the Immune System:Vitamin D plays a pivotal role in the proper functioning and regulation of the immune system. Deficiencies in this vitamin can lead to an altered immune response, making individuals more susceptible to infections, inflammations, and conditions that heighten the risk of preterm birth. Calcitriol, the activated form of vitamin D, directly affects immune cells such as T lymphocytes, B lymphocytes, and macrophages, as these cells express vitamin D receptors on their surface. A 2021 study conducted by Turkish scientists aimed to assess the levels of vitamin D in pregnant women and its association with the severity of COVID-19. The study revealed a significant difference between vitamin D levels and the severity of COVID-19 in pregnant women, suggesting that maintaining adequate vitamin D levels may reduce the severity of inflammation caused by COVID-19 ,86,87.Regulation of Hormonal System:Vitamin D influences the production of hormones, including steroid hormones crucial for maintaining pregnancy. Insufficient vitamin D levels can disrupt hormonal processes and directly impact the uterus’s ability to sustain a pregnancy for its full term. The vitamin D pathway is intertwined with calcium and phosphorus metabolism and also influences the production and action of progesterone, a key pregnancy hormone. A study conducted in Bangladesh in May 2023 examined the impact of vitamin D deficiency on the course of pregnancy and found a potential link between low vitamin D levels and an increased risk of preterm birth .Inflammatory State:Research has extensively investigated the association between vitamin D deficiency and inflammatory conditions within the body. In response to infections and inflammation, the body produces pro-inflammatory substances like cytokines, which trigger an immune response and increase the risk of preterm birth. Chronic inflammatory states accompanying vitamin D deficiency may interfere with fetal development and uterine health, leading to an elevated risk of preterm birth. A 2022 laboratory study conducted in Turin, Italy, on a group of 160 women, explored genetic variants related to vitamin D and their potential impact on vitamin D levels during pregnancy. The study found a significant correlation between vitamin D levels and a positive result in one of the SARS-CoV-2 tests, indicating that vitamin D deficiency may influence preterm birth ,86.Impact on Vascular Function:Vitamin D influences the proper functioning of blood vessels by affecting the production of nitric oxide and endothelin. Nitric oxide relaxes blood vessels and enhances their elasticity, while endothelin constricts blood vessels. Vitamin D deficiencies can disrupt these mechanisms, affecting the vasodilation and vasoconstriction processes in blood vessels, leading to impaired uterine function and reduced capacity to maintain pregnancy. A study conducted in Spain in 2020 explored the impact of vitamin D on preeclampsia and the risk of preterm birth. The findings suggested that higher vitamin D concentrations in pregnant women might decrease the risk of preterm birth and preeclampsia .The COVID-19 pandemic has highlighted the potential impact of vitamin D deficiency on the risk of preterm birth among pregnant women. Although scientific studies have demonstrated the association between vitamin D levels and preterm birth risk, the precise underlying mechanisms necessitate further investigation. Understanding these mechanisms could aid in the development of preventive and therapeutic strategies to mitigate the risks associated with vitamin D deficiency during pregnancy, particularly during pandemics like COVID-19 ,85,86,87The COVID-19 pandemic has had a significant impact on various aspects of social life and the mental health of people worldwide. A review of studies has shown that in the case of mothers of premature infants, COVID-19 has had a significant effect on exacerbating the already challenging situation of premature birth. This is a consequence of strong emotions and anxiety related to the risk of coronavirus infection for both the mother and, most importantly, the premature baby. Based on the conducted scientific research, it has been demonstrated that the COVID-19 pandemic has contributed to an increased level of anxiety and stress.Physical and emotional stress: Mothers of premature infants experience both physical and emotional stress, resulting from the need to adapt to new requirements related to caring for a premature baby in conditions of an epidemiological threat. In a published Italian study from 2021 that focused on the impact of the COVID-19 pandemic on parental stress, breastfeeding, and lactation success among mothers of premature infants whose children were in the neonatal intensive care unit (NICU), it was found that the availability of breast milk and breastfeeding decreased drastically . However, it was noted that the rate of breastfeeding was similar before and during the pandemic after the premature baby’s discharge from the hospital. Another study conducted by the University of Liverpool and the School of Health in Australia examined experiences related to the stress of prematurity using the social media platform Twitter. A total of 3161 tweets from parents of premature infants were analyzed. It was found that the COVID-19 pandemic and the associated restrictions, which affected parents’ contact with preterm infants, imposed significant emotional burdens on the studied group ,93,94,95p > 0.05). The result of this study highlights the importance of kangaroo care for the mental health of mothers, which was often impossible or limited during the COVID-19 pandemic. According to WHO, Kangaroo mother care has been demonstrated to reduce baby mortality by as much as 40%, hypothermia by more than 70%, and severe infections by 65% in infants delivered preterm or at low birthweight [Health safety concerns: Mothers of premature infants have heightened concerns about their children’s health in the context of the pandemic. These concerns primarily revolve around the risk of coronavirus infection, especially in the case of premature babies who are more susceptible to infections. This leads to increased anxiety and fear in women who have given birth before the due date. Spanish scientists from Torrecardenas University Hospital (between 2020 and 2022) focused on assessing the kangaroo mother care method in reducing anxiety and stress in women after preterm birth in the context of the COVID-19 pandemic. A cohort study was conducted on recruited mothers whose children were in the neonatal intensive care unit and participated in kangaroo mother care, and their stress levels were measured using the Parental Stressor: Neonatal Intensive Care Unit (PSS: NICU) scale and the STAI E/R questionnaire before and after implementing kangaroo care. It was proven that mothers in the group where kangaroo care had not yet been applied obtained higher scores on the PSS: NICU scale and the STAI E/R questionnaire compared to women who practiced kangaroo care. However, no statistically significant differences were found  had to be modified to ensure the safety of both healthcare staff and patients. These changes, such as the use of personal protective equipment (PPE) and limitations on visitation, created additional challenges and emotional strain for parents, particularly mothers of premature infants ,92,93,94The main factors determining this phenomenon include:In summary, the COVID-19 pandemic has had a profound impact on mothers of premature infants, exacerbating their experiences related to premature birth. The interrelationships between stress, the COVID-19 pandemic and prematurity are presented in The physical, emotional, and practical challenges faced by these mothers have been further complicated by the pandemic, resulting in increased levels of stress and anxiety. Certainly there is a significant impact of limited access to health service, hospitalization and deferred diagnostic, treatment or rehabilitation of premature children on their future outcomes.The limitation of this study is primarily the structure of the narrative review with a more descriptive and subjective view of the topic. Another limitation is the relatively short time that has elapsed since the beginning of the COVID-19 pandemic. For this reason, the long-term consequences for mothers and their offspring of premature delivery during the pandemic are currently unknown. However, an in-depth analysis of the literature allows us to summarize the current state of knowledge in many aspects of the subject. The article characterized the general impact of the COVID-19 pandemic on maternal and fetal health during pregnancy. In addition, stress is presented as a reaction at the physiological and molecular level, its impact on the prenatal and postnatal period of children. Furthermore, the study described a possible consequence of stress and the COVID-19 pandemic, caused by, among others, vitamin D deficiency, which is premature birth and the impact of prematurity on the future development of offspring.More research is needed to investigate and observe how the stress of prematurity during the COVID-19 pandemic influences the long-term impact.


Researchers have long attempted to stimulate the immune system of cancer patients as a therapeutic strategy. During these attempts, the mechanisms of immune escape have emerged and are now better defined, thus identifying new classes of immunotherapeutic drugs as immune checkpoint inhibitors (ICIs). ICI-based immunotherapy has dramatically improved the prognosis and survival of patients with advanced cancers. However, the identification of potential biomarkers useful to identify patients most likely to benefit from immunotherapy is, presently, still flawed.The exact knowledge of the biological and molecular pathways involved in the regulation of immune response and immune escape is mandatory to understand the basis of modern immunotherapy, define the mechanisms involved in resistance, and develop new effective strategies.Cancer cells can be considered pathogens; therefore, their related pathology depends on the extent of tumor growth and the effectiveness of immune responses. The immune response against cancer can be divided into two phases based on the mechanisms that define the body’s defense capacity. The initial phase is called resistance, in which the body tries to eliminate cancer cells, and the second is called tolerance, in which the body attempts to limit the health impacts caused by cancer. During the resistance phase, the immune system recognizes the antigenic diversity of the tumor and attempts to reduce the cancer cell burden once oncogenesis is initiated. Thus, the clinical manifestations of cancer highlight the low tumor immunogenicity and reduced ability of the immune system to control tumor cell growth through escape mechanisms .Macrophages, dendritic cells, and T and B cells are the main contributors to antitumor resistance. Activation of the immune system, known as immunosurveillance, follows the classical steps of antigen recognition, antigen presentation to effector and regulatory T cells, and the physiological end of the immune response through immune checkpoint pathways. Macrophages are essential during the initial phase of the immune response because of their antineoplastic properties, capacity to synthesize cytokines, and interactions with and recruitment of helper cells and cytotoxic T lymphocytes. However, their persistent activation leads to the impairment of effective T cell responses by causing T cell exhaustion, a condition in which lymphocytes, even when activated, are nonfunctional and subsequently undergo programmed cell death, which may contribute to immunodepression and cancer immune escape. Therefore, the growth of a tumor that overcomes resistance mechanisms underlines the lack of efficacy of a specific immune response, which is followed by a macrophage-mediated chronic inflammatory response with related symptoms, the persistence of which leads to tolerance. The tolerance phase is then characterized by several symptoms, such as anemia, anorexia, and muscle wasting, which may compromise the efficacy of the immune response and immunotherapy .Therefore, the immune profile and composition of the tumor microenvironment (TME) may play a crucial role in influencing the antitumor immune response and efficacy to immunotherapy. Considering the importance of both tumor and TME immune subtypes in immunotherapy, Lai et al.  proposedTumor-derived extracellular vesicles (EVs) are among the tumor-related factors that contribute to the establishment of an immunosuppressive TME. These particles contribute to tumor immune escape in several ways: (a) by suppressing CD8+ T cell activation and proliferation; (b) by expressing ligands that bind to T cell death receptors, such as the Fas ligand; (c) by polarizing macrophages toward the M2 phenotype; and (d) by inducing the secretion of inflammatory cytokines. Moreover, EVs express checkpoint molecules on their surface, allowing tumor cells to evade immune cell attack and acquire resistance to ICIs. Additionally, tumor-derived EVs interact with lymph-node-resident lymphatic endothelial cells and induce the expression of PD-L1 on their surface, thus inducing T cell apoptosis and resulting in tumor immune escape and progression. In their review, Kiya et al.  discusseStarting with an analysis of the unique immune environment of the liver and subsequent alterations to the TME, a review by Ruff et al.  discusseUnderstanding the mechanisms of resistance to ICIs and identifying parameters to predict optimal response to treatment are cornerstones of modern immuno-oncology research. The discovery of predictive biomarkers for ICI-based immunotherapy is evolving. Programmed death ligand 1 (PD-L1) expression in tumor samples is recognized as a marker of eligibility for immunotherapy, although not univocally. Mutations in other genes, particularly those involved in mismatch repair (MMR), may predict the efficacy of immunotherapy. Mutations in MMR genes impair DNA repair, leading to microsatellite instability associated with neoantigen formation. Mutations in genes involved in DNA repair and replication have been associated with a higher mutational load and correlated with an increased response to PD-1 blockade. However, in some cases, specific mutations have been associated with immunotherapy resistance, although the underlying mechanisms remain controversial and require further investigation. For example, current evidence suggests that immunotherapy is not beneficial for patients with non-small-cell lung cancer (NSCLC) carrying EGFR mutations. Indeed, EGFR mutations have been shown to be associated with immunosuppressive TME, lower TMB, and increased PD-L1 expression, which may lead to a poor response to ICIs . MadedduBRAF oncogene and the NF1 tumor suppressor gene, indicated the use of targeted therapy with dabrafenib and trametinib, which achieved disease stabilization. This article demonstrates how the presence of coexisting mutations in these genes affects the disease course and immunotherapy efficacy and is crucial in the planning of treatment.Moreover, next-generation sequencing (NGS) may be fundamental in identifying predictive biomarkers of response/resistance to ICIs as a prelude to the development of rational treatment strategies, especially in pre-treated patients. Grenda et al.  describeNovel immunotherapeutic approaches, including the immune modulation of the TME by combining the targeted inhibition of different immune mediators and tumor proliferative pathways, could represent a potentially effective strategy in the future. Jacques et al.  reportedIn any case, when considering the mechanisms that modulate the effectiveness of immunotherapy, the evaluation of the patient’s general status is crucial. In particular, a compromised nutritional status, especially in the context of cancer cachexia, which is a complex metabolic syndrome driven by cancer-related chronic inflammation typical of advanced cancer patients, may affect the immune response and impair immunotherapy efficacy. In this regard, a recent prospective study by our group supports the evidence that cachexia, with its related changes in inflammatory, body composition, energy metabolism, and nutritional parameters, is a key prognostic and predictive factor for ICI-based immunotherapy in patients with advanced NSCLC . ConsistIn conclusion, taking the concepts mentioned above as references, we can affirm that the basis for immunotherapy and immunomodulation should require clinicians to verify: (i) the presence of an immunogenic antigen, (ii) the activation of T cells, as indicated by the increased expression of immune checkpoints (such as CTLA4 and PD-1), (iii) the integrity of effector T cell functions, (iv) the absence of an immunosuppressive TME characterized by the presence of Treg cells, immunosuppressive macrophage populations, PD-L1 expression, or cytokines with immunosuppressive actions, (v) the presence of molecular and genetic alterations that can influence the immune response, the TME profile, and the efficacy of immunotherapy, and (vi) the absence of a chronic inflammatory status typical of the tolerance phase, associated with oxidative stress, with consequent changes in energy metabolism and systemic debilitating symptoms .Our Special Issue, with three original articles and three reviews, contributes to the discussion and clarification of these issues and highlights how understanding the precise role of the immune response in specific subsets of patients in relation to the stage of disease, tumor type, molecular profile, TME composition, and general patient status is a goal that should be pursued vigorously. This merged evidence provides new insights for a more personalized and potentially effective application of immunotherapy in clinical practice.


Laparoscopic surgery for pelvic organ prolapse is a complex procedure, requiring high technical skills and great knowledge of the anatomy to perform a safe dissection and achieve the best clinical and surgical outcomes.To highlight the anatomical landmarks during dissection in this procedure and give tips for a safer and more effective performance.Surgical videos of the dissection involved in laparoscopic surgery for pelvic organ prolapse in a stepwise approach.Identification of the most important anatomical landmarks involved in the dissection of the promontory, the para-rectal space, the recto-vaginal space, and the vesico-vaginal space. Advice for acquiring better exposure and the right cleavage planes. Presentation of some difficult cases during dissection.Step-by-step overview of the different steps of dissection involved in laparoscopic surgery for pelvic organ prolapse, specifying the most important anatomical landmarks for reference and at risk of damage and presenting tips to correctly perform the dissection.Besides the great surgical technical skills required, deep knowledge of pelvic anatomy is key for performing laparoscopic surgery for pelvic organ prolapse safely, minimising complications and recurrence and improving quality of life and the overall success of surgery. As a complex surgical procedure, laparoscopic surgery for pelvic organ prolapse involves careful dissection and correct identification of the anatomical structures to prevent complications and recurrence and achieve better clinical and surgical outcomes. This video article aims to highlight the anatomical landmarks involved in the dissection during laparoscopic surgery for pelvic organ prolapse and give advice for a safer and more effective dissection.Laparoscopic surgery for pelvic organ prolapse is a complex surgical procedure, requiring advanced technical skills. The surgical dissection involved in this procedure, namely the dissection of the promontory, involves risk of damage of important structures in proximity, including vascular structures, nerves, and the right ureter. Therefore, great knowledge of the pelvic anatomy is mandatory to perform the dissection with safety, prevent immediate and late complications, minimise prolapse-related symptoms, and improve quality of life . In addiWe present a video to set forth the different steps of the surgical dissection involved in laparoscopic surgery for pelvic organ prolapse in a stepwise approach, namely the dissection of the promontory, the para-rectal space, the recto-vaginal space, and the vesico-vaginal space . We seleA step-by-step overview of the surgical dissection involved in laparoscopic surgery for pelvic organ prolapse was performed.First, we started by presenting the dissection of the promontory, which aims to reach the anterior longitudinal ligament to attach the mesh later in the procedure. We pointed out the safer area to perform this dissection, in a triangular region in proximity to the aortic bifurcation, the left common iliac vein, the middle sacral vessels, the right ureter and the right hypogastric nerve .Secondly, we presented the dissection of the para-rectal space and underlined the potential anatomical structures at risk of damage in the pelvic side wall, namely the uterine artery, the ureter, the internal iliac vein, and the right inferior hypogastric nerve.We proceeded to dissect the recto-vaginal space, drawing attention to the vagina, the rectum, the recto-vaginal ligament, the middle rectal artery and the puborectalis portion of the levator ani muscles.Finally, we presented the dissection of the vesico- vaginal space, noting the vagina, the bladder, the vesico-uterine ligaments, and the ureters.Throughout the video, the different anatomical structures in each step of the dissection are highlighted. Advice is given on how to optimise exposure to perform the dissection, by using tissue retraction systems. Dissection techniques and choosing the correct plane, utilising the champagne effect is also discussed.Laparoscopic surgery for pelvic organ prolapse, which has been performed since 1992, is one of the preferred routes of surgical treatment of prolapse, especially apical, due to being a minimally invasive and effective technique .The dissection includes a risk of potential damage to important structures, which can be minimised by appreciating the pelvic anatomy and correctly identifying the anatomical structures in each step of surgery. By avoiding lesion of the vascular structures, haemorrhage is prevented, which could be potentially life-threatening . AdditioIn terms of long-term anatomical result and recurrence, in one uni-centric study including 115 patients with apical prolapse who underwent laparoscopic nerve-sparing sacrocolpopexy, no apical prolapse was found in the 10% of the patients that presented with recurrence and all of them were asymptomatic .To the best of our knowledge, this is the first video-article pointing out the anatomical landmarks involved in all steps of dissection of laparoscopic surgery for pelvic organ prolapse, presenting, as well, tips to consider for a careful and correct dissection.The performance of laparoscopic surgery for pelvic organ prolapse requires not only great surgical technical skills, but also a deep knowledge of the pelvic anatomy. The correct dissection of the pelvic spaces and anatomical structures involved in this procedure provides greater safety, by preserving relevant anatomical structures and avoiding intraoperative and postoperative complications. Additionally, a precise dissection is essential to achieve a satisfying anatomical result and minimise the risk of recurrence. Consequently, knowing the anatomical landmarks and the right dissection technique is key to success of surgery.https://vimeo.com/786591464/d9724dc8bd


Indiscriminate drug administration may lead to drug therapy results with varying effects on patients, and the proposal of personalized medication can help patients to receive effective drug therapy. Conventional ways of personalized medication, such as pharmacogenomics and therapeutic drug monitoring (TDM), can only be implemented from a single perspective. The development of pharmacometabolomics provides a research method for the realization of precise drug administration, which integrates the environmental and genetic factors, and applies metabolomics technology to study how to predict different drug therapeutic responses of organisms based on baseline metabolic levels. The published research on pharmacometabolomics has achieved satisfactory results in predicting the pharmacokinetics, pharmacodynamics, and the discovery of biomarkers of drugs. Among them, the pharmacokinetics related to pharmacometabolomics are used to explore individual variability in drug metabolism from the level of metabolism of the drugs in vivo and the level of endogenous metabolite changes. By searching for relevant literature with the keyword “pharmacometabolomics” on the two major literature retrieval websites, PubMed and Web of Science, from 2006 to 2023, we reviewed articles in the field of pharmacometabolomics that incorporated pharmacokinetics into their research. This review explains the therapeutic effects of drugs on the body from the perspective of endogenous metabolites and pharmacokinetic principles, and reports the latest advances in pharmacometabolomics related to pharmacokinetics to provide research ideas and methods for advancing the implementation of personalized medication. The greatest difficulty encountered in drug therapy is that one drug cannot be used in a fixed dose and at the same time in an optimal regimen to treat all individuals suffering from a disease. Individual patients exhibit varying responses to the same pharmaceutical agent: some patients achieve efficacious treatment, while others show no therapeutic effects; furthermore, certain individuals may even experience adverse drug reactions (ADRs). These divergent drug responses arise as a consequence of the interplay between drug metabolism and the physiological  state of the patient. This can also be construed as the amalgamation of the body’s disposition toward the drug and the drug’s therapeutic effect on the body. The existence of such individual diversity in the course of pharmaceutical therapy not only complicates treatment for certain patients but also poses challenges to the later stages of clinical drug trials. The origins of individual diversity predominantly stem from controllable factors, such as the patient’s lifestyle , and pharmaceutical disease-related factors (the co-administration of medications and associated complications), as well as uncontrollable factors, which encompass the patient’s genetic information, age, gender, and ethnic and racial attributes . Figure In light of the swift progress in DNA sequencing and related molecular biology methodologies, the paradigm of ‘pharmacogenomics’ emerged as a concept by researchers acknowledging the potential genetic impact on drug response phenotypes . PharmacFurthermore, apart from investigating an organism’s drug disposition facilitated by endogenous substance metabolism, a comprehensive understanding of the drug’s intrametabolic processes within the organism is essential. Variables, including the drug’s physicochemical attributes, concentration, and dosage exert consequential influences on therapeutic outcomes. The conventional method of drug administration is to use a fixed dose and an undifferentiated administration method to guide patients to use drugs, ignoring the metabolic variability of drugs among individuals. Consequently, this approach may yield diverse therapeutic outcomes, including efficacy, inefficacy, and potentially adverse reactions. With the establishment of characterization methods for drugs in vivo, pharmacokinetics can effectively elucidate the dynamic transformations of drugs within an organism, and it can be used for the quantitative study of the absorption, distribution, metabolism, and excretion of drugs in the organism . PharmacTo date, there have been over 260 published research articles and reviews in the field of pharmacometabolomics, as evidenced by the results retrieved from PubMed. These publications span a range of domains, encompassing diverse drugs and diseases. The published review on pharmacometabolomics predominantly amalgamates elements of pharmacokinetics, pharmacodynamics, and the discovery of biomarkers to elucidate the relationship with precision medication. Nonetheless, specific research articles and reviews that precisely target the realm of pharmacometabolomics within the domain of pharmacokinetics have yet to be published. Building upon the foundation of metabolic regulation and drug metabolism, this review provides an overview of the evolution and utilization of pharmacometabolomics. Pharmacokinetics-related to pharmacometabolomics employs metabolomics as the analytical platform, using the baseline metabolic profile of an organism to predict inter-individual variations in drug pharmacokinetics. This approach proactively anticipates therapeutic outcomes of drugs by considering the physiological state of the organism and its environmental context. We anticipate that this approach, by synergistically considering alterations in endogenous metabolites and drug metabolism, will pave the way for novel, precision-oriented drug delivery strategies. Personalized medicine, an inevitable trajectory in future medical advancements, presents formidable implementation challenges. Confronted with diverse hurdles and lofty aspirations, alongside traditional approaches to personalized medication, there is an imperative for ongoing innovation and research endeavors. These endeavors aim to establish a robust precision drug delivery framework, enabling genuine personalization across multiple dimensions, encompassing genetics, metabolism, and pharmaceuticals. This holistic approach seeks to maximize therapeutic efficacy while mitigating the risks of adverse drug reactions and drug metabolism-related issues for patients.In a systematic manner, the series of changes that occur within a biological organism following the introduction of a drug, whether stemming from the drug’s intrinsic dynamic alterations or resulting from changes in its metabolites, are challenging to observe directly. The dynamic alterations of a drug within an organism can be categorized into four processes: absorption, distribution, metabolism, and excretion, collectively forming the field of pharmacokinetics, which quantitatively investigates these processes within the biological system . As a diThe current clinical approach to implementing personalized medication is mainly therapeutic drug monitoring (TDM), which is defined as “individualizing drug dosage by maintaining plasma or blood drug concentrations within the targeted therapeutic range or window” . As oppoEndogenous metabolites are compounds produced by the body with a molecular weight of less than 1000 Da, such as amino acids, peptides, sugars, organic acids, lipids, vitamins, growth factors, nucleosides, and nucleotides . The comWith the evolution of the field of metabolomics, coupled with advancements in its analytical techniques, significant strides have been achieved in the profiling and quantification of endogenous metabolites and metabolic mechanisms in vivo, as shown by other studies . ThroughThe formal inception of pharmacometabolomics dates back to the year 2006, marked by the pioneering work of T. Andrew Clayton and colleagues. Their seminal investigation demonstrated the composition of pre-dose urine in rats held predictive capabilities regarding the magnitude of liver injury subsequent to acetaminophen administration . The genTo steer the course of personalized drug delivery, the full integration of various technical means and data information makes different personalized medication methods complement each other and demonstrate mutuality, so as to promote the implementation of personalized medication by more accurately predicting drug reactions and monitoring drug metabolism processes. A frequently employed approach for personalized drug administration in clinical settings, TDM, predominantly concentrates on the surveillance of drug metabolism (pharmacokinetics). However, it omits consideration of inter-individual metabolic variations among patients and thus falls short in its capacity to prognosticate drug response during the drug delivery process . Pharmacmax), and the clearance rate (CL). The AUC and Cmax can reflect the absorption rate and degree of the drug in the body, while clearance is the apparent volume of distribution of the drug removed from the body per unit of time, elucidating the inherent disposition characteristics of the organism toward the administered drug. Especially for certain pharmaceuticals demanding heightened clinical scrutiny, the vigilant monitoring of these indices assumes paramount significance. Based on mass spectrometry technology, we established and validated a quantitative drug detection method, and blood samples at different time points after drug administration were collected to detect the blood drug concentration and related pharmacokinetic parameters with the established method, and the pharmacokinetic parameters and drug time profiles were obtained after statistical analysis.Here, we will describe in detail the experimental procedures of Pharmacokinetic-related pharmacometabolomics. In PK studies of pharmacometabolomics, researchers generally do not measure complete pharmacokinetic parameters, and the three most frequently used pharmacokinetic metrics in predicting the individualized PK of a drug or a specific pharmacokinetic parameter based on endogenous metabolites are the area under the drug time curve (AUC), the peak concentration of the drug (CThe metabolomics process is divided into the following steps: (a) sample collection, (b) data acquisition, (c) data processing, and statistical analysis. As shown in (a) The sample collection process here mainly includes sample selection, collection, and pre-processing. Pharmacometabolomics sample selection is usually based on drug response (good or poor), and biosamples collected for analysis are typically derived from both pre- and post-drug administration time points. Urine is usually the preferred biosample for non-invasive sample collection; not only can it be collected in large quantities, but it can also characterize drug metabolism in biological organisms . In Zhix(b) Commonly, the analytical platforms for metabolomics are MS and NMR. As previously discussed, each of these platforms possesses distinct merits and drawbacks. In the context of pharmacometabolomics research, both MS and NMR have been utilized. However, scrutiny of (c) In pharmacometabonomics experiments, variability in drug responses among patients’ post-administration can be attributed to the idiosyncrasies in their pre-administration physiological conditions, so it is typically necessary to assess the baseline metabolic profile. Raw metabolomics data obtained from analytical platforms are complex and make it difficult to acquire effective information; as such, it is necessary to use relevant analytical software to select correlated signals and reduce redundancy to generate easy-to-analyze data matrices. Taking the metabolomics data from LC-MS as an example, its pre-processing steps are generally de-noising, baseline correction, peak alignment, peak identification, and normalization . Proper After obtaining data from both pharmacokinetic and metabolomics components, we will establish a model to evaluate and analyze the correlation between pharmacokinetic parameters and differential metabolites, and identify metabolites with predictive ability. In the corpus of published literature, the preferred approach for model construction is partial least squares (PLS) analysis. PLS analysis is a multivariate statistical data analysis method, which can quickly and efficiently screen out the relevant variables and establish the correlation between the variables, and it can be used to perform regression modeling with multiple severely correlated dependent variables. It represents a statistical analytical technique that amalgamates the strengths of principal component analysis, canonical correlation analysis, and multiple linear regression. Moreover, its response matrix has a prediction function, which is an advantageous method that meets the requirements of pharmacometabolomics data analysis. In addition, the correlation analysis of pharmacokinetic and metabolomics data will also use conventional analysis methods for calculating correlation coefficients, such as Pearman correlation coefficient and Spearman correlation coefficient ,66,153. Research in pharmacokinetics related to pharmacometabolomics can be categorized into specific objectives: predicting individual PK , predicting the drug clearance rate, predicting the drug area under the curve (AUC) and maximum concentration (Cmax), and predicting drug exposure. Within these defined research objectives, a significant emphasis has been placed on the prediction of individual pharmacokinetics (PK) through the utilization of identified endogenous differential metabolites. Notably, groundbreaking research in this realm was conducted by Phapale et al.  in 2010.With the popularization of precision medicine and the increasing enthusiasm for pharmacometabolomics research, pharmacometabolomics has been widely applied to various drugs and diseases in preclinical research. However, the translation of its findings into practical clinical applications has been sluggish, impeding the effective transference of preclinical research outcomes to the realm of precision medicine. The initial purpose of drug metabolomics was to predict the outcomes of drugs, which coincided with the most urgent problem of precision medicine. Concurrently, as pharmacometabolomics proactively anticipates individualized patient responses to drug treatments by considering patient-specific factors as variables, determining how to effectively obtain and process effective information on these baseline metabolic factors is also one of the research challenges. Although preclinical research in pharmacometabolomics has great prospects, it still requires equipment support and powerful data conversion technology to transform it into clinically applicable drug response monitoring methods. With the rise of biopharmaceuticals with strong specificity, high target selectivity, and good therapeutic effects, various malignant diseases, including tumors, can be effectively treated. Current research in pharmacometabolomics mainly focuses on small-molecule chemical drugs. Due to the large molecular weight and unique pharmacokinetic characteristics of biopharmaceuticals, there are no clear guiding principles for the characterization of the body’s disposal of biopharmaceuticals. Moreover, the drug characteristics of biopharmaceuticals, such as charge, glycosylation type, patient gene polymorphisms, and individual factor differences, have unknown effects on the ADME of biopharmaceuticals. Consequently, there is an imperative need to intensify the investigative efforts within pharmacometabolomics pertaining to the domain of biopharmaceuticals. Such endeavors are essential for refining clinical drug administration guidance and fostering innovation within the biopharmaceutical sector. In the big data environment, the reasonable utilization of artificial intelligence, large databases, and machine learning holds the potential to significantly enhance the precision and efficacy of personalized drug administration significantly. In the realm of targeted personalized therapy, the deployment of artificial intelligence and machine learning algorithms can facilitate the optimization of drug dosages. In preclinical studies of pharmacometabolomics, establishing a correct prediction model and accurately predicting PK features is a key step in data transformation. By analyzing high-throughput omics data using machine learning prediction algorithms can not only discover new biomarkers to assist in patient stratification and disease diagnosis and treatment, but also gain a deeper understanding of disease mechanisms and metabolites upstream and downstream of the pathways involved.The development of pharmacometabolomics has only covered a period of less than 20 years, but it has led to exciting achievements. From the initial prediction of acetaminophen hepatotoxicity in rats to the current prediction of the drug toxicity of the COVID-19 drug remdesivir, pharmacometabolomics is constantly advancing through its own technological and theoretical innovation. Pharmacokinetics- related pharmacometabolomics monitors the therapeutic response of drugs from two aspects: drug metabolic behavior and changes in endogenous metabolites before and after administration and predicts the body’s response to drugs. This comprehensive approach facilitates the anticipation of an individual’s response to drugs, enabling the precise and efficient execution of personalized drug administration strategies Pharmacometabolomics provides new research ideas and methods for personalized drug delivery, but it still needs to combine technological innovation and development with other omics to achieve complementarity and mutual assistance between omics technologies. This synergy will enable a dynamic and stimulating trajectory for the evolution of drug metabolomics within the life sciences domain.


The Subthalamic Nucleus (STh) is a lens-shaped subcortical structure located ventrally to the thalamus, that despite being embryologically derived from the diencephalon, is functionally implicated in the basal ganglia circuits. Because of this strict structural and functional relationship with the circuits of the basal ganglia, the STh is a current target for deep brain stimulation, a neurosurgical procedure employed to alleviate symptoms in movement disorders, such as Parkinson’s disease and dystonia. However, despite the great relevance of this structure for both basal ganglia physiology and pathology, the neurochemical and molecular anatomy of the STh remains largely unknown. Few studies have specifically addressed the detection of neurotransmitter systems and their receptors within the structure, and even fewer have investigated their topographical distribution. Here, we have reviewed the scientific literature on neurotransmitters relevant in the STh function of rodents, non-human primates and humans including glutamate, GABA, dopamine, serotonin, noradrenaline with particular focus on their subcellular, cellular and topographical distribution. Inter-species differences were highlighted to provide a framework for further research priorities, particularly in humans. The Subthalamic Nucleus (STh) is a lens-shaped subcortical structure located ventrally to the thalamus, that despite being embryologically derived from the diencephalon, is functionally implicated in the basal ganglia circuits. Because of this strict structural and functional relationship with the circuits of the basal ganglia, and in particular the motor circuits mediating movement suppression, the STh is a current target for deep brain stimulation (DBS), a neurosurgical procedure employed to alleviate symptoms in movement disorders, particularly Parkinson’s disease (PD) and dystonia  in non-human primates performed by Haynes and Haber  indicateNevertheless, despite evidence indicating functional intergation of STh afferences and the presence of functional gradients as opposed to functional territories with distinct boundaries, definition of “predominantly” limbic, associative and motor areas of the STh remains crucial for DBS in treating neurological and psychiatric diseases , immunohistochemistry, immunofluorescence and autoradiography, allowing the identification of neuronal subpopulations, and thereby potential functional subdivisions within the structure. Information on receptor expression and distribution within the STh could provide significant advantages in defining functionally segregated regions, thus advancing our understanding of structure’s subdivision and circuitry.While we have previously described the morphology, topography and connectivity of the STh in humans and non-human primates  and findings in humans. The ultimate objective of this study is to further underline the need to validate and translate the findings deriving from animal models to humans, despite known methodological and technical limitations.The following paragraphs describe the main neurotransmitter systems, the ionotropic and metabotropic receptors, as well as correlated structural and functional markers that are relevant for STh physiology and pathology. For each major system, a summary table and a schematic figure and is provided for quick orientation throughout included studies.Glutamatergic system markers have been extensively investigated in rodents, non-human primates and humans, with little-to-no interspecies differences, suggesting that the glutamatergic system maintains its organization throughout phylogenesis. Studies addressing glutamatergic system markers are reported in Table Glutamatergic neurons represent the most conspicuous neuronal population in the STh. Glutamatergic STh neurons are considered type 1 projection neurons and are homogeneously distributed throughout the STh in rodents, non-human primates and humans Iwahori . SimilarGlutamatergic ionotropic receptors. Glutamatergic ionotropic receptors (iGluR) comprise AMPA, NMDA, and Kainate receptor families. In the rodent STh, AMPA and NMDA receptors (and their subunits), are predominantly localized at the level of glutamatergic and gabaergic asymmetrical synapses  are diffusely distributed throughout the STh in rodents  in rodents, non-human primates and humans  and non-human primates  neurons. Furthermore, GAD + neurons do not express calcium binding proteins, such as parvalbumin, calbindin or calretinin, which are expressed in GAD− neurons. The increasing ventrolateral gradient of GABAergic interneurons evidenced by Lévesque and Parent , coupledDopaminergic afferences to the STh derive from the substantia nigra pars compacta (SNpc)  innervation of the STh has been widely discussed in rodents, non-human primates and humans  mRNA expression was detected . In the human STh, a higher expression of calretinin following a dorsolateral-ventromedial increasing gradient has been evidenced, while parvalbumin is distributed according to a dorsolateral-ventromedial decreasing gradient (Morel et al. Calcium binding proteins have received substantial attention due to their involvement in calcium mediated signaling, often reflecting specific firing patterns in neurons. Studies on non-human primates have evidenced how specific calcium binding proteins, particularly calretinin, calbindin and parvalbumin can identify distinct neuronal populations within the brain, particularly the basal ganglia. Indeed, earlier evidence pointed towards calretinin as a distinct marker of non-motor STh neurons, being located predominantly at the level of the medial aspect of the structure (Fortin and Parent In the present review, we have assessed morphological studies examining the expression and distribution of markers for different neurotransmitter systems in the STh of rodents, non-human primates and humans. No studies assessed in this review have defined a clear anatomical segregation of any of the investigated neurotransmitter systems; rather, these studies have evidenced variable distribution gradients of neurochemical markers throughout the main axes of the STh, particularly in humans. This seems to suggest that complete segregation of functional territories within the STh, as originally hypothesized with the tripartite hypothesis, should be considered a conceptual simplification of a much more complex and variable internal organization of the STh (Alkemade and Forstmann We believe future research on the functional anatomy of the STh should be performed by considering the most recent findings on co-occurring functional segregation and integration in the STh. Numerous older studies did not account for STh variability across the three-dimensional planes, mostly because this was beyond the scope of the study itself. STh specific studies performed on serial sections (Levesqué and Parent Lastly, while Parkinson’s Disease and other synucleinopathies generally do not affect the STh, at least via evident neuropathological alterations like Lewy bodies and neurites, functional alterations are well known to occur. The abnormal firing pattern of STh neurons in Parkinson patients is most-often regarded as a consequence of broader circuit perturbations occurring due to dopamine loss and nigral degeneration; the role of direct dopaminergic modulation, via nigro-subthalamic pathways, is often neglected (Emmi et al. In conclusion, available structural data concerning the functional and neurochemical anatomy of the human STh is scarce, and studies from the literature, with few exceptions, are often descriptive in nature or do not report on the distribution of the markers within the whole extent of the structure. Moreover, there are very few studies assessing the extent of functional reorganization within the STh occurring as consequence of neurodegenerative diseases, like Parkinson’s Disease.We hope this review of literature encourages future studies on the functional and neurochemical anatomy of the human STh, and that appropriate methodological approaches will be employed to evaluate the spatial distribution of relevant markers throughout the whole nucleus.


Anisakiasis, a zoonotic disease that can lead to small intestine obstruction, has seen a significant rise in Spain. The country has become the first in Europe with an annual incidence of 8000 cases, primarily due to the popularity of consuming exotic dishes of undercooked or raw fish and the impact of climate change. The clinical presentation of anisakiasis can mimic symptoms of acute appendicitis or intestinal obstruction, leading to potential misdiagnosis. This case report describes a 37-year-old patient with no significant medical history who presented abdominal distension and intense pain in the right lower quadrant. The patient underwent surgery and received physiotherapy treatment, including therapeutic exercises and pulsed-pressure myofascial vacuum therapy, to facilitate functional recovery. The increasing incidence of anisakiasis in Spain underscores the need to consider it in the differential diagnosis of digestive diseases, given the high consumption of poorly prepared or raw fish in the region. Zoonosis is an infectious disease that can be transmitted between different species, including from animals to humans. Parasites are one of the causative agents of these diseases, and animals can act as vectors for their transmission. Fish, for instance, have been identified as one of the animal groups that can transmit parasites to humans . HoweverFurthermore, it is important to note that even though there may be a lower number of diagnosed cases, it does not diminish the potential severity and potential for fatal consequences. It is worth mentioning that, particularly in cases of parasitic nematodes, long-term control heavily relies on chemotherapeutic treatments. However, the prolonged use or incorrect dosage of these treatments can lead to the development of drug resistance ,3. DespiAnisakiasis, also known as anisakiosis, refers to the parasitic infection of humans exclusively caused by the third-stage larvae of the Anisakis simplex sensu lato parasite. It is important to distinguish anisakiasis from anisakidosis, which encompasses diseases caused by various members of the Anisakidae family . The larAnisakiasis is primarily contracted through the consumption of raw or undercooked fish that is infested with the larvae of this nematode ,8. AccorAfter the fish has died, the nematode larvae ensure their survival by migrating from the fish’s gastrointestinal tract to its muscle tissue and nearby organs . This unAmong the various methods employed for parasite inactivation, it is noteworthy to mention the use of pulsed electric fields, which have been widely utilized as a non-thermal approach to inactivate microorganisms present in liquid foods . This teThe symptoms are caused by two pathophysiological mechanisms: IGE-mediated immediate hypersensitivity allergic reaction and gastrointestinal inflammatory reaction. There are two clinical presentations based on the extent of penetration into the mucous membrane: the non-invasive luminal form  and the invasive gastrointestinal form , which is the more prevalent. The invasive form can be further classified into two distinct clinical presentations: gastroduodenal (65%) and intestinal  .The clinical manifestation of the intestinal form can sometimes lead to misleading suspicions of acute appendicitis or intestinal obstruction . IntestiWe present the case of a 37-year-old patient with no significant medical history who experienced abdominal distension for several days. In the last two days, the patient also developed acute and severe abdominal pain localized to the right lower quadrant without fever or vomiting. The patient lost consciousness; as a result, the patient sought medical attention at the emergency department, and emergency diagnostic tests were performed.During the abdominal examination, the abdomen was found to be soft and depressible. Superficial and deep palpation in the mesogastrium and right lower quadrant elicited pain. No signs of peritoneal irritation were observed. The laboratory analysis revealed only an elevated C-reactive protein level of 81 mg/L . The scan revealed the following observations: there was asymmetric mural thickening of the intestinal wall with submucosal edema, affecting a short segment of approximately 4 cm in length in the distal ileum located in the right lower quadrant  18,19].,19.18,19He presented a subocclusive picture with dilation of proximal bowel loops, as well as the presence of fluid and air-fluid levels inside. The patient presented a subocclusive condition characterized by dilation of the proximal bowel loops and the presence of fluid and air-fluid levels. These findings were accompanied by infiltration of the mesenteric fat, subcentimeter mesenteric lymphadenopathy, and a minimal amount of free fluid in the right parietocolic leak  19,20].,20.19,20The patient’s subocclusive presentation of the small intestine raised the possibility of tumor or inflammatory–infectious causes. An exploratory laparotomy was performed, which involved resecting the affected segment of the distal ileum, measuring approximately 10/15 cm in length, along with its mesentery. A mechanical side-to-side anastomosis was performed. The surgical intervention was justified by the possibility of the existence of lymphoma and, finally, due to the obstruction and ischemia of the intestinal segment ,20. The A new medical history was obtained from the patient, who reported frequent consumption of marinated raw fish in recent months. Following the surgical intervention, a physiotherapy treatment plan was implemented, which included kinesitherapy and therapeutic physical exercises during the hospital phase. The exercise regimen was continued in the outpatient phase, with the addition of the pulsed negative pressure procedure.® Vacuum Treatment device, specifically targeted scar tissue to prevent adhesions and myofascial retraction that could limit mobility .,20.18,20Additionally, it is worth noting that physiotherapy treatment plays a crucial role in achieving functional recovery following such a significant surgical intervention. Early mobilization programs have been shown to facilitate recovery after abdominal surgery ,25. ActiPrevious research on this subject coincides in pointing out the importance of exercise for therapeutic purposes to promote recovery after abdominal surgery ,28. In tAnisakiasis has significant clinical implications, and its increasing incidence in Spain, attributed to the high consumption of fish and the recent culinary trends of consuming it undercooked or raw, necessitates considering it as a potential diagnosis for digestive diseases. Due to the non-specific radiological findings associated with the intestinal form of the disease, it is advisable to include it in the differential diagnosis of inflammatory causes, with support from a thorough medical history. Surgical intervention plays a crucial role in the management of anisakiasis, and post-surgical physiotherapy treatment promotes the patient’s short- and long-term recovery, ultimately enhancing their overall quality of life.