Metastasis is the main cause of death in patients with malignant tumors worldwide. Mounting evidence suggests lipid droplet metabolism is involved in the process of metastasis. As a mechanism to selectively degrade lipid droplets, the current research on lipophagy and tumor metastasis is quite limited. This review summarizes the crosstalk among lipophagy, tumor lipid metabolism and cancer metastasis, which will provide a new reference for the development of effective targeted drugs.Obesity is a prominent risk factor for certain types of tumor progression. Adipocytes within tumor stroma contribute to reshaping tumor microenvironment (TME) and the metabolism and metastasis of tumors through the production of cytokines and adipokines. However, the crosstalk between adipocytes and tumor cells remains a major gap in this field. Known as a subtype of selective autophagy, lipophagy is thought to contribute to lipid metabolism by breaking down intracellular lipid droplets (LDs) and generating free fatty acids (FAs). The metastatic potential of cancer cells closely correlates with the lipid degradation mechanisms, which are required for energy generation, signal transduction, and biosynthesis of membranes. Here, we discuss the recent advance in the understanding of lipophagy with tumor lipid metabolism and review current studies on the roles of lipoghagy in the metastasis of certain human malignancies. Additionally, the novel candidate drugs targeting lipophagy are integrated for effective treatment strategies. Cancer metastasis is the progression of cancer cells escaping from a primary site to distant organs that they gradually colonize . Cancer Lipophagy is a source of alternative energy in times of nutrient scarcity . In a brNotably, recent studies indicate that lipophagy not only supports fuels for cancer metastasis , but alsAs a selective autophagy, the steps of lipophagy include initiation of autophagy, phagophore nucleation, expansion of phagophore, fusion of autolysosome and degradation of LDs, enjoying overlapping and special parts with autophagy .Under tumor hypoxia and nutrient shortage circumstances, elevated levels of AMP/ATP and ADP/ATP ratios inhibit the mammalian target of rapamycin complex 1 (mTORC1) signal pathway by activating the energy sensor AMP-activated kinase (AMPK) pathway . And theActing as gatekeepers of LDs, the degradation of LD surface proteins (PLINs) is a prerequisite for lipophagy to occur . ExposurMany ATGs are critical in the elongation of phagophores. During the progress, the Atg5-Atg12-Atg16 complex promotes the autophagic vesicle formation . Atg12 cTranscription factors TFEB and TFE3 are key regulators in autophagosome maturation and lysosomal biogenesis . The locAfter the formation of autolysosome, lysosomal acid lipase (LAL), localized in the lysosome originally, attacks and degrades the internal cholesterol esters (CEs) and TGs stored in LDs . The FAsOn the one hand, many hormones are involved in the regulation of lipophagy. It is proved that β-adrenergic signaling enhances the lipophagy procedure in a Rab-7-dependent manner . StimulaCross-talk between adipocytes and cancer cells in the tumor microenvironment (TME) can create a metabolic symbiosis driving cancer metastasis. Lipophagy can occur in both adipocytes and tumor cells. Lipophagy may modulate differentiation process of adipocytes from adipocyte precursor cells. Research carried out by Hahm et al. showed that the expression of LC3-II, AMPK activity and formation of acidic vesicles appeared during the normal differentiation of mouse 3T3-L1 preadipocytes . The inhKnown as energy sources and membrane constituents, FAs are required to meet the metabolic demand of cancer cells or to adapt to reduced serum-derived lipid availability in TME . A varieTumor cells can support growth by ingesting FAs obtained from extracellular lipolysis. In normal physiological state, as essential membrane glycoprotein, CD36 mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis in multiple cell types . CD36, aThe ingested FAs are then utilized by FAO, also called β-oxidation, which mainly occurs in mitochondria. The progress requires long-chain acyl-coenzyme A synthase (ACSL) to activating acyl CoA, which is then catalyzed by carnitine palmityl acyltransferase 1 (CPT1) from cytoplasm to mitochondria. Each ACSL isoform is responsible for channeling long-chain FAs to a different metabolic fate. Its deregulation has also been observed frequently in variable cancers . A miR-3As ATP citrate lyase (ACLY) converts citrate to oxaloacetate, cytosolic acetyl-CoA is generated, which serves as a major substrate for lipid synthesis. The IKKβ-USP30-ACLY axis controls lipogenesis and tumorigenesis . First cAn excess of FAs can be harmful to cells due to lipotoxicity, so cells convert FAs into TGs and CEs for storage in LDs. The final step of TG synthesis is catalyzed by diacylglycerol acyltransferase (DGAT) while cholesterol acyltransferase (CAT) is the key enzyme in the form of CEs. By the way, some extra sphingolipids and cholesteryl esters can form lipid rafts in the plasma membrane that play a role in signal transduction . As a re2) are more suitable for lipophagy [Malnutrition and stress conditions mediate LDs degradation via lipolysis and lipophagy. In colon cancer cells, overexpression of key lipase ATGL is observed in obesity-promoted colonic tumorigenesis via lipid metabolic reprograming . Meanwhiipophagy . WhetherAccording to integrative analysis of multiple omics data, it is revealed that lipid metabolism disturbances caused by lipophagy may confer pro-metastatic traits and directly impact the metastatic dissemination process . The metEMT is a cellular pathway that represents a salient property of primary tumor development and metastasis, in which cells lose their epithelial properties (characterized by the loss of membranous E-Cadherin) and acquire features of mesenchymal cells  . Higher Oxidative stress refers to a state in which the oxidative and anti-oxidative effects are unbalanced. The accumulation of reactive oxygen species (ROS) is the main cause of it . To optiLipophagy is a selective autophagic process that not only facilitates the clearance of lipid aggregates, but also provides energy for the replication of multiple pathogenic microorganisms. In the latest study, inflammatory mediators released by LDs and their surface antiviral proteins form a line of defense during microbial infection, thereby acting as a molecular switch in innate immunity . HepatitAs a result of lipophagy, excessive FAs are produced in lysosomes. Researchers recently discovered that lipid-filled lysosomes fuse with plasma membranes for extracellular export, altering systemic lipid homeostasis and intercellular communication . P53 is With the increasing understanding of the mechanism of lipophagy, scholars try to find ways to effectively control metastasis by inhibiting the lipophagy pathway. There have been recent proposals that LDs can serve as functional markers of CSCs, whose biogenesis is a multistep process involving the enzyme diacylglycerol acyltransferase 2 (DGAT2). Pretreatment with PF-06424439, an inhibitor of DGAT2, in conjunction with X-ray exposure can enhance the radiosensitivity of breast cancer cells and improve the effectiveness of radiotherapy . When usThe above summarized the crosstalk among lipophagy, tumor lipid metabolism and cancer metastasis. A better understanding of the crosstalk mechanism will lead to new and exciting therapeutic possibilities for cancer elimination. Despite the fact that the related mechanisms of lipophagy have been illustrated, as well as some proteins or genes that are key participants in lipophagy have been validated, the overall landscape of lipophagy requires further research. The researchs on the roles of lipophagy in tumor cells and tumor stromal cells including tumor-associated adipocytes, tumor-associated fibroblasts and tumor-associated macrophages are also warranted. Unfortunately, the mechanism of lipophagy related to tumor angiogenesis and immune escape is still lacking, which are closely related to the metastatic potential of tumors. With the development of new sequencing technologies and probe labels, more pivotal factors involving lipophagy and cancer metastasis will be formulated, and new personalized clinical treatment options will be developed, based on the sufficient fundamental research.


Editorial on the Research TopicDevelopments in ureteroscopic stone treatment: Key themes and remaining challenges By Becker REN, Roberts WW, Lipkin ME, Ghani KR. (2022) Front. Surg. 9: 1050285. doi: 10.3389/fsurg.2022.1050285Frontiers in Surgery collection.The 2022 edition of the Developments in Ureteroscopic Stone Treatment (DUST) symposium brought together an international group of content experts and thought leaders in Miami, Florida for a spirited discussion of recent advances and challenges in the field. The content spanned important themes from preventative management to technological advances in ureteroscopes and working instruments, choices around intraoperative parameters such as laser type, energy settings, irrigation methods, lithotripsy strategies , stenting practices, and post-operative management. Safety and efficacy outcomes remain paramount, but considerations of cost and the patient experience have also gained considerable recognition and interest. Huang et al.} and summarized by {Meng et al.}, these ureteroscopes aim to alleviate some of the challenges of reusable platforms, such as financial cost and complex sterilization. Many new designs also seek to incorporate ergonomic advances such as lighter weight and different grip positions. Single-use platforms have overall become far more affordable, even as their quality has improved to closely rival that of reusable ureteroscopes. Studies comparing safety and efficacy outcomes between single-use and reusable ureteroscopes find they perform similarly overall, and even on parameters such as overall program cost, environmental footprint, and image quality, single-use ureteroscopes are increasingly competitive with reusable platforms.One topic of intense interest at the DUST symposium was the proliferation of single-use digital ureteroscopes. As highlighted in work by {J. Lee et al.} describe several promising new designs in various stages of development. These incorporate a range of innovations from novel stent compositions and coatings to radical reconceptualization of the stent as we know it, such as suture-based stents or dissolvable material.Similarly, ureteral stent technology continues to improve with the goals of improving patient comfort while maintaining functional performance. {Lai et al.}, which maintains synchronous visualization by adapting a rigid ureteral access sheath into a controlled closed-suction fluid system, has been described in China.Other groups continue to push the field forward with novel technologies for active stone fragment evacuation. Removal of fragments and debris from the collecting system during or after laser lithotripsy may theoretically reduce the risk of steinstrasse, stone recurrence, and/or other complications. At the DUST symposium we heard that fluoroscopic-guided steerable aspiration catheters are currently being tested in US clinical trials, while the in-line system described by {Gui et al.} found in a retrospective comparison that patients undergoing mini-PCNL with the ESMS system had significantly reduced irrigant fluid absorption and blood loss, as well as improved postoperative pain scores and return-to-work time, compared to patients undergoing mini-PCNL without ESMS.A similar controlled fluid system for mini-percutaneous nephrolithotomy (PCNL) has also been developed in China , which employs inflow and outflow monitoring gauges to facilitate intraoperative calculations of irrigant fluid absorption and blood loss. {Khusid et al.}, vigilance of intrarenal pressures and the potential for pyelovenous backflow represents an emerging key strategy for preventing infectious complications. Others, which have been the focus of professional society guidelines include preoperative urine testing, evaluation of patient risk factors, and evidence-based antimicrobial prophylaxis.A secondary benefit of such regulated fluid systems is the ability to monitor and modulate intrarenal pressures and thermal dissipation. These previously underappreciated intraoperative parameters were heavily emphasized at the DUST symposium, as emerging data continue to elucidate their critical roles in determining key outcomes such as tissue injury, patient pain, and post-procedural infections. As described by {Miller & Semins} summarize many of the key considerations for those performing and assisting with ureteroscopy, including radiation safety, laser safety, and surgical ergonomics. The authors provide numerous simple, practical, and easily implemented strategies to help optimize safety for urologists and operating room staff.Recent years have also seen an improved awareness of operator and staff safety, with increased emphasis on provider wellness and career longevity. Alongside our colleagues throughout the health sciences, urologists are increasingly recognizing that we cannot take the best care of our patients, unless we also take care of ourselves. In their review, {Clark et al.}, including both medical and surgical management. A systematic review and meta-analysis by {Yi et al.} compares surgical options of flexible ureteroscopy and shockwave lithotripsy (SWL) for stone disease in patients with horseshoe kidney, finding that while both are safe with low complication rates, ureteroscopic treatment offers better stone-free rates. Rounding out the collection, {M. Lee et al.} provide an excellent review and practical guideline for workup and management of nephrolithiasis in pregnancy. This is a prime example of how technological and methodological advances in ureteroscopy have led to its adoption as a safe and successful first line treatment option in these complex patients. The evidence-based multidisciplinary consensus statements fill several important gaps in existing society guidelines, and will undoubtedly prove to be an invaluable resource for the on-call general urologist.As the field continues to work toward optimizing every aspect of the “index” ureteroscopic stone procedure, we have also accumulated better evidence to guide management of special circumstances and subpopulations. The particular challenges of cystinuria are reviewed in detail by {DUST 2022 was an expository glimpse into the future of ureteroscopic stone treatment, touching on many exciting new developments, as well as remaining controversies and challenges. For many attendees, the highlight of the meeting once again was the infamous Balloon Debate, which pitted renowned experts against one another on which is the optimal management strategy for an asymptomatic 9 mm lower pole renal stone. Perhaps by DUST 2023 we will be closer to an answer.


Salinity is considered one of the most devastating environmental stresses that drastically curtails the productivity and quality of crops across the world. More than 20% of the world’s cultivable lands are dealing with the adversity of salt stress and these salt-prone areas are continuously increasing, due to both natural and anthropogenic activities . However+).Salt stress is a major environmental stress that affects plant growth and development. Salt stress increases the intracellular osmotic pressure and can cause the accumulation of sodium to toxic levels . Like ot+ and Cl− in the foliage. This leads to reduced shoot growth coupled with reduced leaf expansion and the inhibition of lateral bud formation. In response to salt stress, plant cells accumulate compatible solutes and redistribute ions, which enables them to acclimate to a low soil water potential. Additionally, the endogenous abscisic acid (ABA) content increases, followed by changes in principle genetic expression in salt stress conditions. Moreover, increased levels of ions, such as Na+ and Cl−, trigger ionic toxicity in plants due to the disruption in ion homeostasis and the unavailability of essential nutrients, which are essential for plant growth and metabolism [2O2; singlet oxygen, 1O2; superoxide radicals, O2•−; and hydroxyl radicals, OH•, which are highly reactive and usually toxic. They are capable of disrupting different cellular components, such as proteins, lipids, and nucleic acids and destructing the structural integrity of the plants [Coupled with the abovementioned effects, salt stress produces a variety of physiological and metabolic changes in plants, seed germination behavior, photosynthesis, other biosynthetic process inhibition, and growth reduction. Different crops respond to salinity in different ways; glycophytes mostly show growth and total yield reduction, whereas halophytes can grow and reproduce easily under saline conditions. Therefore, at higher osmotic pressures in the root–soil interface, there is a slower impact caused by the build-up of Natabolism . The comtabolism . Salt-ine plants .Melissa officinalis L. Plants were subjected to salt stress treatment by the application of NaCl solutions (50 or 100 mM) to the pots. Generally, the NaCl treatments were found to inhibit the growth of plants, simultaneously enhancing the accumulation of phenolic compounds , especially at 100 mM NaCl. However, the salt stress did not disturb the accumulation of photosynthetic pigments and the proper functioning of the PS II photosystem [On contrary, NaCl may also be used as an elicitor. Hawrylak-Nowak et al.  applied tosystem .Melissa officinalis L. Plants were subjected to salt stress treatment by application of NaCl solutions  to the pots. Therefore, the proposed method of elicitation represents a convenient alternative to cell suspension or hydroponic techniques as it is easier and cheaper with a simple application in lemon balm pot cultivation. The improvement of lemon balm quality by NaCl elicitation can potentially increase the level of health-promoting phytochemicals and the bioactivity of low-processed herbal products.In nature, plants usually produce secondary metabolites as a defense mechanism against environmental stresses. Different stresses determine the chemical diversity of plant-specialized metabolism products. In this study, we applied an abiotic elicitor, i.e., NaCl, to enhance the biosynthesis and accumulation of phenolic secondary metabolites in Plants are sessile and thus have to develop suitable mechanisms to adapt to high-salt environments. Thus, in response to salt stress signals, plants adapt via various mechanisms, including regulating ion homeostasis, activating the osmotic stress pathway, mediating plant hormone signaling, and regulating cytoskeleton dynamics and cell wall composition. Unraveling the mechanisms underlying these physiological and biochemical responses to salt stress could provide valuable strategies to improve agricultural crop yields. Plants, therefore, alter physiologically to deal with this situation. In species exposed to salt stress, common responses include an increase in osmotic adjustment, changes in cell wall elasticity, and an increase in the percentage of apoplastic water, which minimizes saline effects by maintaining foliar turgidity. Several compounds that work in the osmotic regulation of plants are well known, e.g., carbohydrates , nitrogen molecules , and organic acids . Proline (Pro) and glycine betaine (GB) are the most essential and efficient compatible solutes among the organic osmolytes which minimize the salt-stress effects and improve plant growth.Mesembryanthemum crystallinum L.) during a 72 h response period following salinity stress removal and found that the presence of salinity stress is required not only for the induction of stress-dependent crassulacean acid metabolism (CAM) photosynthesis but also for maintaining its functioning. The rapid shutdown of the energy-demanding functional CAM seems to be one small component of the flexibility features. As we showed here, the metabolic flexibility of the common ice plant includes rapid and far-reaching changes [Plant metabolic plasticity is also a vital factor in regulating salt stress response in plants. Nosek et al.  analyzed changes .It is essential to carry out the necessary research on salt stress and soil pollution mitigation to increase agricultural productivity and feed the world’s growing population. As global hunger and salinity stress intensify, there is a rise in interest in ecologically sustainable solutions for salt tolerance. Apart from using freshwater for irrigation there are many other alternative approaches for developing salt-tolerant crops. Developing halophytes as alternative crops, using interspecific hybridization to improve current crop tolerance, utilizing the wide range of varieties of existing crops, the introduction of variation within existing crops through genetic approaches, or improving salt-tolerant varieties.Plant growth-promoting bacteria, phytohormones, and organic acids can also be used to promote salt tolerance in plants. Moreover, the improvement and/or alteration of some agricultural management practices will also play a vital role in the mitigation of salt stress in the first place. For example, conventional crop and pasture breeding for salt tolerance, soil reclamation, various management practices based on reducing the salt zone for seed germination and seedling establishment, pre-sowing irrigation with good quality water, appropriate use of ridges or beds for planting, and general management practices  will reduce the impact of soil salinity on crop performance.tmt transgenic line exhibited greater proline levels than WT plants, lower chlorogenic acid levels, and lower activity of catalase and peroxidases. Plants that accumulate α-TC produced more methylated proline and glycine betaines and showed greater activity of superoxide dismutase than γ-TC deficient plants [Surowka et al.  reportedt plants .Different plant hormones and genes are also associated with the signaling and antioxidant defense system to protect plants when they are exposed to salt stress. Salt-induced ROS overgeneration is one of the major reasons for hampering the morpho-physiological and biochemical activities of plants which can be largely restored by enhancing the antioxidant defense system that detoxifies ROS .RBOHD and RBOHF, varied between the halophyte and the glycophyte. The expression of these genes in E. salsugineum leaves was induced by abscisic acid (ABA) and ethephon spraying indicates that in the halophyte E. salsugineum, the maintenance of the basal activity of NOXs in leaves plays a role during acclimation responses to salt stress.Reactive oxygen species signaling is crucial in modulating stress responses in plants, and NADPH oxidases (NOXs) are an important component of signal transduction under salt stress . PilarskCombining genomics and transcriptomics is a new approach that deals with the deep understanding and knowledge of the molecular response of a plant to salinity. Modification of genetic expression in salt stress comprises a variety of ways that plants use to induce or suppress the transcription of genes.Quertani et al.  performeProteomic and metabolomic research provides an excellent tool for examining plant adaptation to salinity. Hence, these are frequently utilized to identify the molecular processes of plant response to salt stress.In mulberries, Gan et al.  performebolTLP1, a thaumatin-like protein gene that confers tolerance to salt stress in broccoli  because bolTLP1 may function by regulating phytohormone -mediated signaling pathways, hydrolase and oxidoreductase activity, sulfur compound synthesis, and the differential expression of histone variants [He et al.  identifivariants .However, more information as well as research on genetic engineering, transcriptomics, proteomics, and metabolomics research, as well as their combined responses, is required to determine the salt-tolerance mechanism of plants. Identification of rice salt-tolerance genes and their molecular mechanisms could help breeders genetically improve salt tolerance . Genome-14-3-3 family in salt stress. They identified a total of 17 potential 14-3-3 gene family members that were identified from the Chinese Spring whole-genome sequencing database. Importantly, most 14-3-3 members in wheat exhibited significantly downregulated expression in response to alkaline stress [The study of Shao et al.  providedHIOMT in apple plants induced by salinity. They found that compared with the wild type, transgenic lines indicated higher melatonin levels and showed reduced salt damage symptoms, lower relative electrolyte leakage, and less total chlorophyll loss from leaves under salt stress. Further, transgenic lines showed a lower amount of ROS due to the enhanced activity of antioxidant enzymes, downregulated the expression of the abscisic acid synthesis gene (MdNCED3), accordingly reducing the accumulation of abscisic acid under salt stress [Considering the importance of the physiological functions of melatonin, Tan et al.  studied t stress .PsnNAC036 gene and found that the overexpression of PsnNAC036 stimulated plant growth and enhanced salinity and heat tolerance in Populus simonii × P. nigra.Zhang et al.  characteBADH1 by next-generation sequencing reveals an association with salt tolerance in rice during domestication. Despite the unclear association between BADH1 and salt stress, these findings can be useful for future research development related to its gene expression [Next generation gene sequencing opens the avenue to revealing salt tolerance mechanisms more precisely. Min et al.  reportedpression .Katja et al.  detectedMillettia pinnata, MpZFP1, is a positive regulator of plant responses to salt stress due to its activation of gene expression and efficient scavenging of ROS and enhances salt tolerance in transgenic Arabidopsis. The heterologous expression of MpZFP1 in Arabidopsis increased the seeds’ germination rate, seedling survival rate, and biomass accumulation under salt stress [Yu et al.  found tht stress .The plant cytoskeleton is associated with plant salt stress responses. Therefore, the molecular mechanism underlying microtubule functions in plant salt stress response is important. Chun et al.  found thOverall, the 19 contributions in this Special Issue “Plant Responses and Tolerance to Salt Stress: Physiological and Molecular Interventions” discuss the various aspects of salt stress responses in plants. It also discusses various mechanisms and approaches to conferring salt tolerance on plants. These types of research studies provide further directions in the development of crop plants for the saline environment in the era of climate change.


Pancreatic trauma in children is rare; therefore, both scientific knowledge and clinical experience regarding its management are limited. Abdominal sonography and subsequent computed tomography (CT) imaging are the diagnostic mainstay after severe abdominal trauma in many pediatric trauma centers. However, the diagnosis of pancreatic injury is missed on the initial imaging in approximately one third of cases, with even higher numbers in young children. While conservative treatment is preferred in low-grade injuries, surgical interventions may be indicated in more severe injuries. We present a case series including four patients with high-grade pancreatic injury. Two patients were treated surgically with open laparotomy and primary suture of the head of the pancreas and pancreatico-enterostomy, one patient underwent endoscopic stenting of the pancreatic duct and one received conservative management including observation and secondary endoscopic treatment. We want to emphasize the fact that using a minimally invasive approach can be a feasible option in high-grade pancreatic injury in selected cases. Therefore, we advocate the necessity of fully staffed and equipped high-level pediatric trauma centers. Pancreatic trauma in children is rare, occurring in 3–12% of patients with abdominal injuries ,5. FrequDemographic and clinical data on four consecutive patients with severe pancreatic injury were extracted from the hospital patient data information system of a level one pediatric trauma center over an 8-year period. Data analyzed included age, gender, mechanism of injury, mode of treatment , periprocedural care and long-term outcome. Data were fully and automatically anonymized before extraction from the clinical information system; extraction was performed by a third-party database operator using clinical diagnosis codes and age cutoffs. The study was exempted from ethical review by our institution’s clinical directorate.From 2010 to 2018, four patients—aged 4 to 13 years—with blunt abdominal trauma resulting in high-grade pancreatic injury were admitted to our institution. Two of those presented with an AAST grade III injury , whereasPatient 1 was a 13-year-old male, suffering blunt abdominal trauma during a motor vehicle accident. The initial diagnosis was obtained from abdominal sonography and subsequent CT scans, revealing an AAST grade IV injury with complete proximal transection of the pancreas including the pancreatic duct. Due to the extensive injury to the pancreas, the decision was made to opt for open surgical management. Upon dissection of the pancreas, the pancreatic head and corpus were completely transected with disruption of the pancreatic duct; however, the ampulla Vateri was intact. The pancreatic head was sutured, and a Y-Roux anastomosis to reconnect the pancreatic body and tail performed. Postoperatively, the patient presented with a portal vein thrombosis with partial obstruction, which was successfully treated conservatively with anticoagulants.Patient 2 was a 7-year-old male who was referred to our center on post-accident day one with diagnosis of an incomplete rupture of the pancreas. Due to inconclusive CT imaging, ERCP with possible intervention was scheduled. However, on ERCP, complete dissection of pancreatic head and body (AAST IV) including complete rupture of the pancreatic duct was visible. Minimally invasive stenting of the pancreatic duct was unsuccessful; therefore, open surgical management was necessary. During open surgery, a rupture of the jejunum with a diameter of one centimeter was encountered and surgically sutured. Due to complete transection of the pancreas and pancreatic duct without option of surgical reconstruction, surgical management included suture of the pancreatic head and primary gastro-pancreatic anastomosis. However, it must be pointed out that internal drainage after distal pancreatectomy is only feasible in physiologically stable patients. Postoperative course of treatment was uneventful.Patient 3 was a 7-year-old female who initially presented nearly asymptomatic following a non-motorized scooter accident. Initial work-up included laboratory exams and abdominal sonography. Due to increasing pancreatic enzymes, minimal free fluid on sonography and recurrent vomiting, an MRI of the pancreas was obtained revealing AAST grade III injury to the pancreas including the pancreatic duct. Minimally invasive treatment was chosen, and the pancreatic duct was stented with a Ch 5 pigtail drainage during ERCP . Overall, 5 months after initial intervention, the pancreatic stent was successfully removed  imaging ,14. LaboIn case of inconclusive or dissonant findings between abdominal sonography and CT scans, endoscopic retrograde cholangiopancreatography (ERCP) and/or magnetic resonance cholangiopancreatography (MRCP) were shown to be the most reliable diagnostic modalities for pancreatic duct evaluation ,17. AddiPancreatic injury can be divided into five categories in accordance with the American Association for the Surgery of Trauma . Other mWhile non-operative—conservative—management is preferred in low-grade (grade I and II) injuries, the best course of treatment to manage grade III, IV and V injuries remains controversial ,26. HoweERCP is not only an effective diagnostic tool for evaluation of ductal integrity in pancreatic injury, but also affords the possibility of immediate therapeutic interventions. A minimally invasive approach can avoid laparotomy with all associated short- and long-term complications, including risk of hemorrhage, bowel and solid organ laceration, wound dehiscence, infection, prolonged pain, immobility, and intensive care admission ,14. Thern = 5) and an exacerbation in epigastric pain for up to 48 h (n = 2). Management was successful, though median length of total parenteral nutrition and hospital stay were long .However, in the last decade, more experience has been gained using ERCP in very young patients. Houben et al. reported on 15 cases of pediatric pancreatic injuries from 1999–2004, 12 of which underwent ERCP, and nine stents were placed due to ductal injury or development of symptomatic fluid collection [In a retrospective study, Rosenfeld et al. reviewed 28 children with pancreatic injury who underwent ERCP . In totaData from this case series add to the currently limited knowledge on pancreatic injuries in children. In case of inconclusive imaging, ERCP can be an essential tool to evaluate suspected pancreatic injury and assess the pancreatic duct. Favorable outcomes in both patients with pancreatic duct injury who were treated with a minimally invasive approach suggest that ERCP can be a safe and feasible alternative to conservative or an open surgical approach in selected cases. However, our cases clearly demonstrate challenges and potential serious complications following ERCP. Therefore, attempting this treatment should be reserved for centers capable of appropriate complication management. However, since incidence rates of pancreatic injuries in children are very low, the generation of highly discriminatory data will remain a challenge—multi-center registry studies might be capable of generating such conclusions.


Glaucoma is a group of optic neuropathies featured by degeneration of retinal ganglion cells and loss of their axons in the optic nerve. The only currently approved therapies focus on lowering intraocular pressure with medication and surgery. Over the previous few decades, technological advances and research progress regarding pathogenesis has brought glaucomatous gene therapy to the forefront. In this review, we discuss the three current genome editing methods and potential disease mechanisms of glaucoma. We further summarize different genome editing strategies that are being developed to target a number of glaucoma-related genes and pathways from four aspects including strategies to lower intraocular pressure, neuroprotection, RGC and optic nerve neuro-regeneration, and other strategies. In summary, genome therapy is a promising therapy for treating patients with glaucoma and has great potential to be widely applied in clinical practice. Glaucoma is a group of optic neuropathies featured by degeneration of retinal ganglion cells (RGCs) and loss of their axons in the optic nerve . By 2020Glaucoma is classified as primary glaucoma, secondary glaucoma and congenital glaucoma, based on pathogenesis, age of onset. Primary glaucoma is further classified as open-angle and angle-closure (or closed-angle) glaucoma, according to the trabecular meshwork (TM) function and iridocorneal angle. Increased cup‐disk ratio (CDR), CDR asymmetry, elevated intraocular pressure (IOP), specific genetic backgrounds, and reduced corneal thickness each raise the risk of primary glaucoma . SecondaDespite the great adverse impact of glaucoma on human health, there is still no adequate treatment for completely preventing glaucoma progression and no way currently to reverse the damage. Clinical treatments focus on lowering IOP using medication or surgery. However, risk factors beyond the elevation of IOP may aggravate glaucoma. Therefore, lowering IOP in many cases fails to halt further damage to RGCs and their axons. The extent and duration of medical and surgery therapy efficacy are limited.With recent advancements in technology and the discovery of specific disease mechanisms, there is growing possibility that future glaucoma treatment will focus more on the direct protection of RGCs and the optic nerve and neuron regeneration to reverse glaucomatous injury. This potential propels gene therapy and genome editing into the spotlight of the glaucoma field as they can be tailored to target specific disease pathways and exert lasting and effective outcomes. Of the 22 gene therapy products that had been approved worldwide as of 2019 , LuxturnGene therapy, historically defined as the transfer of genetic material to cells, has extended into three fields, gene augmentation, gene suppression, and genome editing, of which genome editing stands out for its characteristic of precise manipulation of targeted genes. Although antiviral and anti-cancer strategies account for most clinical trials of genome editing, there have been some clinical trials regarding ocular diseases see in . The eyeSince the discovery of genes being the basic genetic unit that controls biological traits, it has become an aspiration of humans to modify them in order to cure diseases fundamentally. Gene therapy is the optimal indicated approach for diseases rooted in mutated genes. The areas in which gene therapy has been most commonly applied include cancers, monogenic diseases, cardiovascular diseases, infectious diseases, neurological diseases, and ocular diseases, among others. Gene therapy to date can be characterized as the knock-down of deleterious genes and augmentation of necessary or desirable genes and has included the genetic modification of mutated genes using site-specific editing.The realization that a targeted DNA double-strand break (DSB) can stimulate endogenous DNA repair mechanisms forms the foundation of genome editing. There are two main types of DNA repair, homology-directed repair (HDR) and non-homologous end-joining (NHEJ). HDR utilizes templates from either exogenously supplied donor sequence or sister chromatid for precise DNA repair, which leads to the insertion and correction of the relevant gene/DNA. In contrast to the predictable gene-editing that results from HDR, NHEJ functions to repair DSBs in a template-independent manner through direct ligation of DNA ends. This process is error-prone and has a high possibility of introducing insertions and/or deletions (indels) at the site of the break. These indels may cause gene mutations leading to frameshifts and premature stop codons. It is possible to cause gene deletions through NHEJ with large DNA segments.To stimulate endogenous cellular DNA repair, current genome editing methods focus on various types of sequence-specific nucleases that form site-specific DSBs. For genome editing, novel nucleases are used, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9.The technology using ZFNs for genome editing was made possible with the discovery of the precise DNA-binding domain and FokI restriction endonuclease. The zinc finger protein is a type of transcription factor with the zinc finger domain forming the basis for the necessary DNA-binding specificity. The modular design of DNA-binding proteins makes it relatively easy to generate chimeric sequence-specific nucleases by replacing the FokI DNA-binding domain with a zinc finger domain.Similar to ZFNs, TALENs are programmable DNA-binding nucleases with the catalytic domain of the FokI endonuclease fused to transcription activator-like effector (TALE) repeats. Different from that of ZFNs, the highly conserved 34 amino acid TALE repeats are responsible for the DNA-binding specificities of TALENs instead of zinc finger domains. Each TALE repeat specifies a single base pair and makes it possible to target any DNA sequence of choice.in vitro modification, the CRISPR/Ca9 has been simplified to two components by fusing the crRNAs and tracrRNAs as guide RNAs (gRNAs). The CRISPR/Cas system also requires a protospacer-adjacent motif (PAM) situated immediately 3′ to the target site. Cas9 has six domains of which the PAM interacting domain specifically recognizes PAM to initiate the targeted binding to the DNA. The Rec I domain of Cas9 acts as the gRNA binding domain. Domains HNH and RuvC are nuclease domains that cut single-stranded DNA. Once Cas9 finds a specific PAM, the gRNA attempts to pair with the target DNA sequence and consequently forms a DSB. Compared with the nuclease systems discussed above, Cas9 complexed with gRNAs is free of novel chimeric nucleases. Instead, the target sites are altered by simply modifying a few base pairs of the gRNAs.CRISPR/Ca9 technology was initially derived from an adaptive immune system in bacteria that is used to defend against invading viruses. Among the main components of the technology, CRISPR RNAs (crRNAs) and trans-activating crRNAs (tracrRNAs) recognize specific DNA base pairs and the CRISPR-associated (Cas) proteins act as nucleases to perform precise cleavage of the DNA. After Scientists today have recognized the potential ability to control genetic mutations using powerful biotechnology to modify the DNA in living cells and even modify the genetic code of all species on the planet. In addition to the NHEJ and HDR strategies, many novel CRISPR strategies have been developed. Among the many gene-editing tools, the latest and possibly most effective is CRISPR-Cas9. The development, transformation, and application of gene editing tools based on the CRISPR system have shown explosive growth, which allows for precise gene editing to better serve humans. The discovery of new Cas orthologues and variants, such as VRER SpCas9, VQR SpCas9 , Cas13  and xCasCRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) are types of safe pattern reformative CRISPR systems that avoid permanent sequence mutations  see in . Gene reHowever, application of CRISPRi is limited due to the large sizes of the coding sequences of dCas9 fusion proteins. Incorporation of RNA-protein interacting systems into gRNA helps resolve the limitation by recruiting effector proteins. The recruitment of RNA-binding proteins by RNA aptamers allows for the independent regulation of multiple genes simultaneously  see in .Homology-independent targeting integration is a novel evolution of the NHEJ pathway, which directly ligates exogenous DNA fragments to DSBs. DSBs are generated in the genome targeting sequence, as well as both ends of the inserted DNA fragments, due to a pair of flanking CRISPR targeting sequences of the inserted DNA matching the genome targeting sequence .The novel genome editing approach of base editing achieves precise base mutations without creating DSBs or the need of delivering templates see in . The basA brand-new genome editing tool based on CRSIPR is prime editing, which is reported to repair 89% of all 75,000 pathogenic human genetic variations  see in . Prime eCRISPR off is a reversible and inheritable epigenetic memory editor based on the CRISPR system  see in . With guin vivo gene delivery , and lentiviral vectors represent the majority of viral vectors used for gene therapy. AAV is a group of replication-defective, non-pathogenic virus containing a single-stranded DNA genome comprised of 4.7 kilo nucleotides (4.7knt) . Due to delivery . The avadelivery . HoweverCompared to AAVs, adenoviral vectors have larger genome size (∼30–40 kb pairs) so as to deliver much larger transgenes . AdenoviLentivirus is also a promising system for delivery of transgenes. Lentiviral vector gene–carrying capacity (8–10 kb) is between that of adenoviruses and AAVs, allowing for the delivery of most transgenes . LentiviRecently, the cell-specific targeting of these gene vectors has greatly advanced to pave the way for successful clinical trials in future. The current strategies of cell-specific targeting include modifying tropism of delivery vectors, designing to target the specific molecular markers and carrying cell-specific promoter in the viruses . A previIt is well known that glaucoma is markedly affected by genetic factors and is a complex genetic disease . There hElevated IOP, which is commonly identified in glaucoma, is caused by an imbalance between the production of aqueous humor by ciliary epithelial cells and its drainage mainly through the TM or to a lesser extent through the uveoscleral outflow pathway. In patients with POAG, increased resistance to aqueous humor outflow through the TM is responsible for the elevation of IOP. The TM is a series of fenestrated beams and sheets of extracellular matrix (ECM) covered with endothelial-like trabeculocytes. There is a growing consensus that the TM plays a central role in the pathogenesis of glaucoma. Many changes have been elucidated in the TM structure and function regarding glaucoma.Disturbances in extracellular matrix (ECM) homeostasis are known to occur in glaucomatous TM, but the mechanism remains unclear. Studies of transforming growth factor-beta 2 (TGFβ2) have revealed its effects on increasing cross-linking enzymes and ECM deposition and a potential glaucoma-TGFβ2 relationship . Other eIn addition to ECM abnormalities, studies and gene analysis of human TM cells have identified changes in cellular metabolism and expression levels of some genes. For instance, oxidative stress detected in TM epithelium cells is involved in early stage of glaucoma. The free radicals cause damage to the TM epithelium cells, which consequently leads to impaired outflow capabilities . FurtherCommon to all kinds of glaucoma is the degeneration of RGCs and optic neuropathy. Increased IOP is the main risk factor for glaucoma progression and the acceleration of optic neuropathy. Increased IOP leads to the eventual compression, deformation, and remodeling of the lamina cribrosa with mechanical axonal damage and disrupted bidirectional axonal transport within the optic nerve leading to neurotrophin deprivation. For instance, the retrograde transport of the neurotrophin brain-derived neurotrophic factor (BDNF) is blocked in RGCs . Even wiRGCs do not have the capacity for self-renewal and self-repair following their degeneration and death. It has been suggested that a combination of intrinsic cellular properties and environmental factors limits the repair and regeneration of the optic nerve. Phosphatase and tensin homolog (PTEN) is a negative regulator of the mammalian target of rapamycin (mTOR) pathway and may account for the intrinsic inability of central nervous system axons to regenerate . As for Considerable evidence indicates that deformation, remodeling, and mechanical failure of the fibrous layer, consisting of the cornea, sclera, and lamina cribrosa, is associated with glaucoma susceptibility and progression . Animal Progress based on studies of the pathogenic mechanisms of glaucoma makes the possibility of gene therapy more viable. Gene therapy in treating glaucoma would be a great improvement over that of daily eye drops and surgery and would allow for more effective, targeted, and fundamental therapeutic outcomes following a one-time injection of the vector. Among gene therapy approaches, genome editing stands out for its characteristic of allowing the precise manipulation of target genes. Here, we discuss the recent advancements in genome editing for treating glaucoma see in .Y437H)  . Ad5-crMY437H) . In addise model .Expect for TM, the aqueous fluid outflow through the Schlemm’s canal and distal vessels. The angiopoietin (ANGPT)-TEK  system is an endothelial growth factor pathway and both of ANGPT and TEK are highly expressed by SC endothelial cells. Studies have found that delivery of a recombinant ANGPT1-mimetic promoted developmental SC expansion in healthy and Angpt1 deficient eyes, suppressed intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG .Based on the mechanism of IOP elevation, other strategies have been used to lower IOP, including the targeting of ciliary epithelium cells to decrease aqueous humor production and the use of trabecular bypass to increase the aqueous humor outflow capacity. In general, most glaucoma treatments focus on two main ways to lower IOP in effort to control the progression of glaucoma, increasing aqueous humor drainage and decreasing aqueous humor production by the ciliary body epithelium. Aquaporins are a family of water-transporting trans-membrane proteins and play a significant role in the formation of aqueous humor. Efficient aquaporin 1 (Aqp1) disruption by CRISPR/Cas9 in the mouse ciliary body epithelium following intravitreal injection is able to lower IOP and prevent RGC loss in a micro-bead glaucoma mouse model .Glaucoma filtration surgery (GFS) is a common choice for controlling IOP. Aqueous humor drainage is increased through GFS, typically by diversion of the drainage under the conjunctiva and the formation of a filtration bleb. However, surgery failures commonly occur due to excessive sub-conjunctival fibrosis at the filtration bleb. Connective tissue growth factor (CTGF) is responsible for the fibrogenic reaction induced by fibroblasts; therefore, targeting CTGF to suppress fibrosis would potentially be an effective treatment to facilitate GFS success . Permane® is an encapsulated cell therapy-based NT-501intravitreal implant in which the NT-501 contains a genetically modified retinal pigment epithelium cell line that permanently secretes CNTF , nicotinamide riboside (NR), or nicotinamide mononucleotide (NMN). Among them, oral administration of the NAM vitamin B3 in mice has very strong axonal protective effects . FurtherA recent small randomised trial of 57 glaucoma patients, demonstrated that oral NAM (1.five to three g/d) for 3 months significantly improved retinal function in glaucoma determined by photopic negative response (PhNR) parameters . AnotherTo overcome the irreversible loss of RGCs and optic nerve due to their inability of regeneration requires neuro-regenerative therapy. Gene therapies have been developed that modify axonogenesis-related genes, such as PTEN, SOCS3 , c-myc  and NogoAs a result of the lack of regenerative ability of the human retina, the transplantation of living cells is the only way to recover vision loss after RGC death. The development of stem cell therapies allow for the replacement of degenerated and dead cells in glaucomatous retina using RGCs derived from stem cells, including human embryonic stem cells, iPSCs, and Müller glia cells. The discovery of Müller glia cell has generated great excitement in the field of cell replacement therapy as Müller glia cell can dedifferentiate to allow for their proliferation and differentiation into cell types that were damaged and thereby serve as retina progenitors.Obstacles to neuro-regeneration that need to be overcome before successful application include RGCs being present at low proportions and hard-to-purify in stem cell-derived cultures and regenerated optic nerves have difficulty in exiting eyes and connecting with brain nuclei. Several proteins, non-coding RNAs , and sigin vivo delivery of the CRISPR system CasRx promotes expression of neuron-specific transcription factors, thereby increasing the efficiency of conversion of Müller glia cells to RGCs (d-aspartate (NMDA)-induced retina injury mouse model. Another study revealed that trans-activation of the transcription factors Brn2, Ascl1, and Myt1l (BAM factors) by CRISPR/Cas9-based transcriptional activators can promotes epigenetic remodeling and gene over-expression, which thereby directly reprograms mouse embryonic fibroblasts to induced neuronal cells , by the  to RGCs . Notablyal cells . Furtheral cells . Similaral cells  and tranal cells .As discussed above, genome editing therapy can assist cell replacement therapy. Recent studies have suggested that applying the proper chemicals can convert fibroblasts to photoreceptors without the need of stem cells, thus opening a timesaving and clinically easy avenue for cell replacement therapy . It was Recently, investigators performed single-cell RNA sequencing (scRNA-seq) to construct the gene regulatory networks controlling Müller glia reprogramming . They fiResearch on the regeneration of RGCs and optic nerve is an essential component of curing glaucoma, but a long way remains before it can be truly applied to the clinical setting. Currently, scRNA-seq technology can be used to identify molecular changes after damage at the cellular level and then combined with the CRISPR/Cas9 gene editing system, which can achieve remarkable intervention effects by precisely targeting the relative key molecules. It is believed that with the continuing development of sequencing technology and gene editing technology, the application of RGCs and optic nerve regeneration therapy will become possible in the clinic setting and will facilitate the complete cure of glaucoma.As noted above, ocular biomechanical properties influence glaucoma susceptibility and progression. Therefore, targeting the fibrous layer consisting of the cornea, sclera, and lamina cribrosa in patients with glaucoma is an alternative avenue for treatment. While genome editing therapy targeting the sclera and lamina cribrosa has not yet been performed, corneal gene modification using the CRISPR/Cas9 system has recently been successfully executed in several disease models, including for Meesmann’s epithelial corneal dystrophy  and Fuchin vivo is able to abolish angiogenesis in an age-related macular degeneration model, supporting the possibility of applying this approach for treating secondary glaucoma after cataract surgery.Finally, anti-neovascular gene therapies may be useful for the prevention of neovascularization and uveitis and the treatment of secondary glaucoma after cataract surgery. A few such gene therapies have already been developed. For example, genome editing of vascular endothelial growth factor A (Vegfa) and hypoxia-inducible factor 1-alpha (Hif1a) by CRISPR/CjCas9 As we described, different genome editing therapies targeting different ocular components in glaucoma currently exist, but many limitations remain resulting in their limited application. First, the most important limitation is the safety concern regarding off-target effects. Gene modification beyond the pathogenic site would result in the disruption of normal genes and off-target mutations, which may result in oncogenesis. Several studies have raised concerns regarding the potential for AAV vectors to cause pro-oncogenic events in treating hematological system diseases . HoweverIn summary, genome editing therapy has advanced greatly in recent years and has enormous potential in the treatment of glaucoma. With technological advancements and the obstacles addressed, genome editing will surely become a promising therapy for treating patients with glaucoma and will be widely applied in clinical practice.


Although it is biologically plausible, findings relating radon exposure to the risk of cerebrovascular disease (CeVD) are inconsistent and inconclusive. To investigate whether radon exposure was associated with the risk of CeVD, we qualitatively and quantitatively summarized the literature on radon and CeVD in both occupational and general populations. A search of PubMed, Embase, Scopus, and Web of Science was performed for peer-reviewed articles published through March 2022. Studies were excluded if radon exposure was not assessed separately from other ionizing radiation. In the meta-analysis, excess relative risks (ERRs) were converted to relative risks (RRs), and the pooled RRs and 95% confidence intervals (CIs) were determined using the random-effects model (DerSimonian and Laird). In the systematic review, nine eligible studies were summarized. Six occupational studies indicated inconsistent associations between cumulative radon exposure and CeVD mortality among mine workers. With available data from four updated occupational studies , the pooled RR of radon exposure with CeVD mortality showed a non-significant association . Three studies  conducted in general populations consistently demonstrated a significant inverse relationship between residential radon exposure and risk of CeVD. The existing literature suggested a potential link between radon exposure and CeVD risk in general population. The inconsistent association in occupationally exposed populations may be explained by different methods of radon assessment and other methodological issues. Since radon exposure is a common public health issue, more rigorously designed epidemiologic studies, especially in the general population are warranted.The online version contains supplementary material available at 10.1007/s11356-022-20241-x. Cerebrovascular disease (CeVD), with stroke being its most common manifestation, is a health disorder of the blood vessels supplying the brain  is a colorless, odorless, and radioactive gas that occurs naturally in the environment. It is produced from the radioactive decay of uranium-238, and subsequently radium-226, and generally enters a house through cracks and fissures WHO . The radRadon exposure is considered to be similar to tobacco smoking regarding its health impact on lung cancer Alavanja . PreviouAlthough it is biologically plausible, the research has not focused on non-cancer outcomes until recent years. In particular, the studies on the association between radon and CeVD are sparse, and the findings are inconsistent and inconclusive. Therefore, we performed a systematic review and meta-analysis to qualitatively and quantitatively sum up the available epidemiologic evidence of CeVD outcomes associated with radon exposure.The study implementation was guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist . Because radon and its decay products both deliver alpha emissions, exposure in this study consisted of both radon and RDPs. Also, CeVD includes stroke, transient ischemic attack, aneurysms, vascular malformations, vascular dementia, and subarachnoid hemorrhage  screened all titles and abstracts. The second reviewer (YZ) participated in further full text inspection. Discrepancies that arose following full-text screening were resolved through discussion between the two reviewers. None of the reviewers had conflicts of interest with the relevant publications that would be included in this study.., region, study design, population, and sample size), participants’ average age at study entry, follow-up years, exposure measurement, outcomes confirmation, exposure doses, risk estimate and the corresponding 95% confidence intervals (CIs), and adjusted covariates in the final model. LL collected the data from the primary studies, and YZ provided an independent review for data accuracy.For each primary study identified, we extracted the following information: lead author, publication year, study characteristics (e.gBased on the risk of bias (ROB) rating tool for human and animal studies developed by the National Toxicology Program Office of Health Assessment and Translation (NTP/OHAT)  is the cumulative radon exposure at time t. ERR was estimated using an internal Poisson regression model with non-exposed individuals as the internal control. For example, ERR per 100 working level months (WLM) represented the increased risk of CeVD mortality with 100 WLM radon exposure relative to the baseline CeVD mortality. Because statistical methods of combining weighted ERR have not been well established, we converted ERR back to RR for the meta-analysis using the formula Some primary studies reported ERR, which was calculated using the linear model +1 Mould .Q test and I2 statistics (in forest plots)  using the DerSimonian and Laird random-effects model  to conduct all of the analyses. A We screened 245 studies from PubMed during the first round of literature search, of which 24 publications were selected for full text review. We further excluded 11 studies for the reasons indicated in Fig. Among the 17 studies, 14 studies (7 distinctive cohorts) were conducted in occupational populations and 3 studies were conducted in the general population. Of the 14 occupational studies, we further excluded 8 studies because they were published previously with a shorter follow-up on the same cohort  .Among occupational studies, a recent study from French cohort with a follow-up from 1946 to 2007 of 5400 male uranium miners revealed that radon exposure was related to an increased risk of CeVD mortality  , found no significant association , comparing the highest (800–1600 WLM) to the lowest radon exposure level (0 WLM)  , radon exposure was not shown to be associated with CeVD mortality during the follow-up from 1946 to 2008   , including 2070 workers  with a follow-up duration ranging from 49 . In the leave-one-out sensitivity analysis, no single study had a substantial influence on the pooled estimate  in New Jersey, an increased death rate for CeVD was observed as compared to the mortality of New Jersey’s general population  conducted by the American Cancer Society (ACS), the association between residential radon exposure at the county-level and CeVD mortality (per 100 Bq/m3) was either borderline significant  or significant , depending on the data sources of county-level radon exposure  South Koreans, a significant increase in the prevalence of stroke was observed among residents living in houses with elevated indoor radon levels at the major city/province level (Bq/m3) from 2012 to winter 2016  , especially in the elderly aged above 75   Table .Among the occupational population, although the existing literature included in the systematic review does not provide consistent evidence establishing a link between cumulative radon exposure and increased CeVD mortality, the pooled results of the meta-analysis from four occupational studies indicate a non-significant association of radon exposure with CeVD mortality. For the general population, published investigations consistently suggest that residential radon exposure is related to an increased CeVD risk.. no) or any dose–response relationship. Third, analyses were restricted to male individuals due to the limit number of female workers in these occupational cohorts, which may pose an issue of limited generalizability. Fourth, some established risk factors or predictors for CeVD  were not adjusted in most of the studies. For example, the covariate of smoking status was adjusted in only one occupational study ,” resulting from healthy individuals at better chance for employment was controlled to some extent in the included studies by using the internal controls; other subtypes of HWE remained. For instance, “healthy worker survivor effect” arises when the employment duration of workers is dependent on their health status Shah . TherefoNotably, cause-specific mortality was not available from several studies that reported SMR because the radon exposure could not be completely isolated from other radiation exposures such as gamma radiation, diesel exhaust, and silica dust. Also, the mortality rates of certain occupational cohorts were compared with the overall death rates of the general public; studies using external controls are in general suffering from “healthy hire bias.”Moreover, measurement error or bias may arise when personal radon exposure was not directly measured. In most occupational cohort studies, radon measurements were retrospectively estimated based on the mean radon concentration of the mine or processing facility and individuals’ working history. Of note, the radon exposure assessment in the French cohort was more precise    especially if geographic areas are included that exhibit wide variations in radon exposure within the geographic areas Puskin . While tThe study using ACS cohort reported two HRs resulting from different methods assessing the county-level ecological radon exposure  risk estimates from 1995, nearly one out of every 15 homes in the USA has radon concentration above the EPA’s action level (> 4 pCi/L) Below is the link to the electronic supplementary material.


SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been approved as a novel treatment method for osteoporosis. Oral health is one of the essential aspects of general human health. Hereditary bone dysplasia syndrome caused by sclerostin deficiency is often accompanied by some dental malformations, inspiring the therapeutic exploration of sclerostin in the oral and dental fields. Recent studies have found that sclerostin is expressed in several functional cell types in oral tissues, and the expression level of sclerostin is altered in pathological conditions. Sclerostin not only exerts similar negative outcomes on the formation of alveolar bone and bone-like tissues, including dentin and cementum, but also participates in the development of oral inflammatory diseases such as periodontitis, pulpitis, and peri-implantitis. This review aims to highlight related research progress of sclerostin in oral cavity, propose necessary further research in this field, and discuss its potential as a therapeutic target for dental indications and regenerative dentistry.Sclerostin is the protein product of the  SOST gene was initially identified in the late 1990s during the studies on sclerosteosis and Van Buchem disease, which are two rare hereditary diseases characterized by high bone mass [SOST gene, is a well-known osteogenesis inhibitor that plays a vital role in bone remodeling [The one mass . Sclerosmodeling –6. A hummodeling . In receSOST”, and terms of dental tissues, periodontal structures, oral cell types and dental diseases. Articles were screened by title and abstract. Evidence was acquired from in vivo and in vitro experimental studies and clinical trials.A PubMed and Google Scholar online database search for relevant studies was performed in October 2021 and updated in April 2022. Search terms included “sclerostin”, “SOST gene is located in the human chromosomal region 17q12-q21, with only two exons and one intron [SOST gene have been reported: three premature termination codons, two splice site mutations, and one missense mutation [SOST gene [SOST transcription start site [The e intron , 9. Six mutation , 11. Sclart site . These tSclerostin is a secretory glycoprotein containing 213 amino acids with a relative molecular weight of 40 kDa. The amino acid sequence of sclerostin in humans has 88% and 89% homology with mice and rats, respectively. Sclerostin expression can be modulated by multiple factors such as mechanical stress, oxygen, hormones, and transcription factors –17. ScleAdvanced knowledge about sclerostin's negative role in bone mass was adapted from the laboratory experimentation to the clinic. Romosozumab, a humanized monoclonal Scl-Ab, has been approved as an alternative therapy for postmenopausal women with a high risk of osteoporotic fractures, and is expected to become a novel method for accelerating fracture healing and treating sclerosteosis and myeloma bone disease , 26–29.It has been recognized that sclerostin has been exclusively expressed in the bone tissue for a long time. Sclerostin is mainly secreted by osteocytes and, to a lesser degree, by chondrocytes and osteoclasts , 20, 22.There are many cell types in dental and periodontal tissues, with different morphology and biological functions. Recent studies have confirmed that sclerostin expression in oral tissue is not only in osteocytes of alveolar bone, but also in odontoblasts and dental pulp stem cells (DPSCs) in dental pulp, cementocytes in cementum, and periodontal ligament cells (PDLCs) Fig. ; Table 1SOST knock-out mice were insensitive to unloading and did not have bone loss [Mechanical stress stimulation is a crucial factor that regulates bone growth and bone remodeling , 62. Ostone loss , 15. TheSOST knock-out mice had higher density and volume of mandibular alveolar bone than wild-type mice, and systemic Scl-Ab administration for rats with alveolar bone defects could improve bone regeneration, suggesting the essential role of sclerostin in the metabolism of alveolar bone [SOST mRNA was remarkably upregulated in the osteocytes of the opposing mandible alveolar bone, and Scl-Ab treatment could significantly increase the bone mass of opposing alveolar ridge [Alveolar bone, a highly plastic tissue surrounding the root, is the crucial supporting structure of tooth. lar bone , 66. Alvlar bone , 68. Disar ridge , therebySOST knock-out mice, the expression of RANKL and the number of osteoclasts in alveolar bone were lower than those in wild-type mice during OTM (force: 5.1 g) [Orthodontic tooth movement (OTM) is the process in which exogenous mechanical force acting on teeth is transmitted to the periodontal tissues leading to alveolar bone remodeling. During OTM, the anabolism of alveolar bone is highly active on the tension side, whereas catabolism is dominant on the compression side . Related: 5.1 g) . These rSOST knock-out or inhibition in mice would eliminate the response of PDLCs to mechanical force [2, 14 rounds/min) could improve sclerostin expression in PDLCs [2) was applied to PDLCs, the expressions of sclerostin and RANKL decreased, whereas they increased when severe compressive force (2.4 g/cm2) was applied [PDLCs in periodontal ligament are pluripotent stem cells with osteogenic potential, which are the main source of osteoblasts responsible for forming alveolar bone . Hence, al force , 75. Sclin PDLCs . Another applied . AccordiAbove all, mechanical stress can regulate sclerostin expression in osteocytes of alveolar bone and PDLCs, and sclerostin may participate in alveolar bone remodeling by directly or indirectly regulating the balance of bone formation and bone resorption.Dentin is the core tissue of tooth, which supports the enamel on the outside and protects the pulp on the inside. It resembles bone in the mesenchymal origin, composition, and especially biomineralization mechanisms that mainly involve collagen formation and matrix mineralization. Odontoblasts act as the most crucial part of dentinogenesis by synthesizing dentin matrix and regulating its mineralization. After finishing the terminal differentiation, odontoblasts can secrete type I collagen matrix, non-collagen, and proteoglycans, and then promote the transport of calcium and inorganic phosphate to the mineralization front , 77. OdoSOST knock-out mice than that in wild-type mice [The tertiary dentin, subclassified as either reparative or reactive, is newly formed after tooth eruption caused by external stimuli such as abrasion, trauma, and caries . Followiype mice .Fig. 3ScTertiary dentin holds great significance for tooth development and pulp repair. For severely damaged pulp, applying tissue engineering technology to achieve pulp/dentin regeneration has become a research hotspot and clinical trend, which is also based on the odontogenic ability of transplanted DPSCs. Up till the present studies, sclerostin has shown similar inhibitory effects on dentinogenesis as osteogenesis. In the view of the breakthrough that anti-sclerostin becomes a new target for osteoporosis treatment, future studies on the regulatory function of sclerostin on dentin biomineralization may promote the development of dentin repair and pulp regeneration. Eventually, novel strategies for preventing and treating dentin diseases such as dentin hypersensitiveness and dentin defects will evolve.Cementum, another bone-like tissue of tooth, is the bridge connecting tooth and periodontal tissues to maintain the tooth stability and periodontal health. Cementum can be divided into cellular cementum and acellular cementum, with cellular cementum having a regenerative capacity. The cellular cementum layer covering the root surface plays a protective role in root maintenance and cementum regeneration is crucial to the repairment of external root resorption under physiological or pathological condition.SOST gene deficiency in mice also induces buccal and lingual cementum thickening [Sclerostin is expressed in human and mouse cementocytes , 58, 59.ickening , which rickening .Orthodontic treatment aims to correct the teeth arrangement, but induces a severe side effect of root resorption on the compressive side during OTM . CementoCementogenesis is crucial for root development and repairment. Further identification of sclerostin’s negative effects on cementum formation and regeneration will benefit the treatment of cementum-related diseases, especially OTM-induced root resorption.Dental pulp inflammation is often a sequel to caries or trauma that facilitates the penetration of pathogens and their bacterial products. Odontoblasts occupy a particular location in the dentin-pulp interface, and their cytoplasmic processes extend along the dentinal tubules to sense the external stimulation. Consequently, odontoblasts serve as the first cellular line of host defense exposed to pathogens and initiate the pupal inflammatory immune responses by secreting various cytokines and chemokines –94. HoweSclerostin has been proposed as an inflammatory regulator based on the experimental findings that sclerostin inhibition can prevent bone loss in patients with rheumatoid arthritis and colitis –99. In DInflammation and aging often interact in dental pulp: inflammation can induce oxidative stress and DNA damage to cause the premature senescence of dental pulp cells (DPCs); aging is also accompanied by chronic inflammation because of the upregulated production of inflammatory molecules –103. RecIf pulp infection evolves into pulpitis or apical periodontitis, the patients will suffer severe pain and even tooth loss. The precise procedure and regulation of dental pulp inflammation are yet to be well elucidated. Existing experimental evidence suggests that sclerostin inhibition seems to be promising for anti-inflammation and pro-regeneration during dental pulp inflammation. More convincing evidence and extensive exploration of applications are still needed.Periodontal disease, one of the essential reasons causing tooth loss, refers to the chronic inflammation of periodontal supporting tissues caused by local factors, and includes gingivitis and periodontitis. Once gingivitis deteriorates to periodontitis, it will manifest as attachment loss, alveolar bone resorption and pathological periodontal pocket formation. Sclerostin has been shown to play a pro-inflammatory role in arthritis and colitis , 98, 106Alveolar bone loss is the critical pathological manifestation of periodontitis. Periodontitis often leads to tooth loosening and even tooth loss due to the destruction of periodontal supporting tissues. The influence of periodontitis on alveolar bone remodeling is not only reflected in occlusal stress change (described in preceding section), but more importantly, in local inflammation-caused bone resorption . EstabliSOST knock-out mice and periostin null mice did not have alveolar bone loss, and an early treatment of Scl-Ab to periostin null mice could prevent the changes of osteocytes morphology and the appearance of periodontitis symptoms, and a late treatment could increase the density and height of alveolar bone and reduce the formation of bone resorption lacunae [Periostin is an essential matrix protein for periodontal ligament formation. Periostin is highly expressed in the periodontal ligament, but the periostin level of gingival crevicular fluid in periodontitis patients was lower than in healthy people , 111. Pe lacunae . These rIn summary, current studies demonstrate that sclerostin may contribute to the development of periodontitis by regulating the anabolism and catabolism of alveolar bone, and sclerostin inhibition during periodontitis could improve alveolar bone mass and repair the morphology of periodontal ligament Fig. . The detDental implantation is a reliable treatment for repairing missing tooth in oral clinical treatment. Osseointegration is defined as the formation of a direct interface between living bone and a load-carrying implant without intervening soft tissue, which is the basic theory and pursue goal of dental implantation. Adequate bone mass at the edentulous ridge is fundamental for osseointegration after dental implant placement. The challenge of stable osseointegration lies in how to accelerate alveolar bone regeneration to shorten implant healing time and maintain long-term stability.Because sclerostin serves as a principal regulator of bone metabolism, its potential role on bone-implant osseointegration has generated extensive interest in the oral field. The application of Scl-Ab on rats with femoral implants could enhance implants retention by promoting the osteogenesis of cortical bone and bone trabecula , 115. ToSOST knock-out or Scl-Ab treatment could significantly promote the osseointegration of femoral implants and tibial implants in ovariectomized osteoporotic rodents [Osteoporosis is a potential risk factor for the failure of dental implantation because of the difficulties on bone healing and osseointegration forming. Recent research found that sclerostin deficiency increased bone regeneration within rodent calvarial defect , and scl rodents –121. TheImplant dentures provide similar esthetics and chewing functionality to natural teeth. However, the broad application of implants makes peri-implant diseases become a serious clinical challenge. The inflammatory change of soft tissue around implants is called peri-implant mucositis, and the alveolar bone defect caused by peri-implant mucositis is called peri-implantitis. The prevention and treatment of peri-implant diseases are increasingly important for oral clinicians.In a broad sense, both peri-implant mucositis and peri-implantitis belong to periodontal disease group. Two clinical studies collecting gingival crevicular fluid of patients with implants showed that the sclerostin level is significantly higher around inflamed implants than around healthy implants, suggesting that sclerostin might serve as a valuable biomarker of peri-implantitis , 35. FurSOST gene in the late 1990s, the role and mechanisms of sclerostin on bone metabolism have been extensively investigated. The monoclonal antibody romosozumab has been approved as an option for patients with osteoporosis, and is promising for treating other bone diseases such as fracture, sclerosteosis and myeloma bone disease. These clinical applications inspired the therapeutic exploration of sclerostin in clinical fields other than bone. In recent years, with the positive sclerostin expression detected in oral tissues and cells, its function in dentistry has gradually been explored and recognized.Since the discovery of In conclusion, sclerostin regulates hard tissue formation and inflammatory diseases in the oral cavity. As a bone-modifying regulator, sclerostin is an inhibitor of alveolar bone mass by regulating the balance of anabolism and catabolism, proceeding to affect the progress of periodontitis and bone-implant osseointegration. For bone-like tissue, sclerostin plays a similar negative role in dentin formation and cementum regeneration, regulating pulp/dentin regeneration after pulp extirpation and root resorption during orthodontic treatment. As an inflammatory regulator, sclerostin may exert pro-inflammatory effects in oral inflammatory diseases, and its expression level has the potential to become a diagnostic biomarker of gingivitis, periodontitis, pulpitis and peri-implantitis. However, some of existing research progress only provides preliminary proof via in vitro experiments or human source sample detection. More convincing in vivo evidence and related mechanistic investigation are required.Future research works on sclerostin in the oral and dental fields may focus on the following aspects: (1) enamel is another bone-like tissue of tooth and is crucial for tooth defense, therefore, the research gap of the effects of sclerostin on enamel formation should be filled; (2) tissue engineering and regenerative medicine based on stem cell transplantation have become frontier research topics in recent years; the effects of sclerostin on a variety of stem cell types in oral tissues  should be further improved and supplied for promoting the development of regenerative dentistry; (3) most rodent experiments about Scl-Ab and alveolar bone used systemic administration by subcutaneous injection, but the effects of Scl-Ab on whole-body bone were barely mentioned; among these previous studies, one study compared systemic and local administration of Scl-Ab and found local delivery had no healing role on alveolar bone defect ; hence, Teeth play vital roles in life. Although the underlying mechanisms of sclerostin in the oral cavity have not been fully elucidated, its functions on the metabolism of alveolar bone, dentin and cementum along with its oral inflammation regulation have become increasingly apparent. Sclerostin inhibition in particular effector cells through Scl-Ab administration has the potential to become a therapeutic target for dental indications such as periodontitis, pulpitis, orthodontic complications, and dental implantation, among others. Further research for complete understanding of sclerostin’s biology and pathophysiology has broad prospection and essential clinical significance.


Predominant affective temperament may affect adherence to prescribed pharmacotherapeutic interventions, warranting systematic review and meta-analysis.The Scopus, Web of Science, PubMed, and OVID MedLine databases were inquired since inception up to 31st of March 2022 for records of any study design documenting quantitative evidence about affective temperaments as measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-A) questionnaire and treatment adherence measured by the means of major rating scales on the matter. People with low vs. high levels of treatment adherence, matched for otherwise clinically relevant variables, were deemed as cases and controls, respectively, using standardized mean differences (SMDs) in pertinent scores under random-effects meta-analysis.p = 0.007), irritable  and depressive  TEMPS-A scores both for psychiatric and nonpsychiatric samples with poorer adherence.Nine studies encompassing 1138 subjects pointed towards significantly higher cyclothymic (SMD = −0.872; CI: [−1.51 to −0.24]; Intrinsic limitations of the present report include the heterogeneity of the operational definitions documented across different primary studies, which nonetheless reported on the sole medication-treatment adherence, thus limiting the generalizability of the present findings based on a handful of comparisons.Though further primary studies need to systematically account for different clinical and psychosocial moderators across different clinical populations and operational definitions, cyclothymic, depressive, and irritable temperament scores may nonetheless predict treatment adherence and, thus, overall treatment outcomes. Affective temperaments  represent relatively stable  —though Though void of any pathological value per se, affective temperaments may nonetheless represent vulnerability factors towards the development of various configurations of mood  as well The role of affective temperaments in prognosis and illness course in somatic illnesses in part may be related to their impact on complying with treatment recommendations. Adherence is the degree to which a patient follows therapeutic advice, including recommended lifestyle changes such as diet or exercise beyond the prescribed drugs . AccordiAffective temperaments can be readily assessed by broadly validated tools such as the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) , 22, witDespite the associated clinical and public health burden, most of the available studies documenting treatment adherence in relationship with affective temperaments is hampered by low statistical power, essentially due to the small representativeness of the samples, or they rely on inhomogeneous ratings for the same outcomes.Both of the latter issues could nonetheless be effectively addressed using a meta-analytic approach, providing a meaningful overall effect estimation from pooling low statistical original studies applying different versions of the TEMPS using SMD (standardized mean difference). The aim of the present study was to investigate the effect of affective temperaments on medication adherence in psychiatric as well as in nonpsychiatric patients using a systematic review and meta-analysis approach.The present systematic review and meta-analysis follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), 2020 edition . The revWe searched the Scopus, Web of Science, PubMed, and OVID MedLine databases from inception up to 31st of March 2022. The following search terms were used: “TEMPS-A” AND (“adherence” OR “compliance”) followed by manual search and cross-references validation.After pooling all the publications identified by the literature search across different databases, duplicate records were removed using a reference management software   before fNo study design, age group, treatment modality, or publication language was applied. Contact with the authors was planned as necessary.As our search terms included “TEMPS-A”, no qualitative studies were identified. We included studies that provided quantitative data both for the specific affective temperament types (measured with the TEMPS-A questionnaire) and for treatment adherence or compliance . For analysis of the effect size, associations of TEMPS-A scores and treatment adherence  were also required.From all included articles, we systematically extracted the following data: country of origin, characteristics of the patient populations , affective temperaments measurement scale, adherence measurement method and scale, and the reported mean affective temperament subscale ratings of the adherent and non-adherent patient groups with the corresponding indicator of standard deviation (SD), or the correlation coefficient of the different affective temperament subscale ratings and the adherence score. In those studies, where both mean and correlation was presented, we chose correlation to minimize inconsistency caused by the arbitrarily defined cut-points used to dichotomize adherence scales into adherent and non-adherent groups. In those studies, where more than two adherence subgroups were compared, or the means were reported separately by sex, we merged subgroups by calculating the weighted mean and pooled SD for the given related groups. For the meta-analysis, the extracted values were converted to standardized mean differences (SMDs) and standard deviations (SDs) for all included studies. Since we assumed significant methodological heterogeneity due to the lack of a uniform adherence measurement method, we used the random-effects method for meta-analytic pooling, based on SMDs in scores between adherent and non-adherent subjects. Meta-analytic findings are reported as pooled-SMDs with 95% confidence intervals (CIs).2, Q, and Tau2 statistics were likewise computed  [Between-study heterogeneity was determined by calculating the prediction interval of the distribution of true effects. The Is sizes) . PossiblQuality and risk of bias within studies was assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies . PublicaAll statistical analyses were implemented using the R package metaphor v.3.0 .The adopted search strategy returned a total of 219 hits, resulting in 169 records after duplicate removal, which were screened on the title and abstract for inclusion criteria, out of which 147 were excluded for not providing required information. Twenty-two records were ultimately selected for detailed review and potential inclusion. In one of the identified studies, necessary data were only partially reported, but successful contact with the authors allowed for the inclusion of that record .–Ten publications were found eligible for meta-analytic synthesis 23––32, 38, –Core characteristics of the nine analyzed reports 23–, 28–32 a–The risk of bias within studies was assessed by using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies  Supplem. Accordi23Quantitative analysis was performed for each affective temperament type to test for differences in TEMPS-A subscale scores between adherent and non-adherent subjects. A negative effect represents that subjects with higher TEMPS-A scores favoring lower adherence. All results are reported in detail in Table n = 1138 subjects), patients with lower adherence had significantly higher cyclothymic , irritable  and depressive  TEMPS-A scores compared to adherent subjects. Anxious (p = 0.072) and hyperthymic (p = 0.817) TEMPS scores were not different between the two groups.Based on nine studies meeting inclusion criteria , with wide prediction intervals for the true effect size estimation, including zero, suggesting that true effects vary from around −2.9 SMD in some populations to 1.2 SMD in others.Heterogeneity was high for all temperaments subscales  for the relevant temperament subscales  are presented in Fig. The inspection of the forest plots Fig.  revealedn = 918), insignificant heterogeneity , and a somewhat reduced but still significant negative meta-analytic association for cyclothymic, irritable and depressive temperaments. Estimated PIs do not include zero anymore, suggesting that in 95% of all comparable populations, a negative true effect exists.Exclusion of the outlying study from the meta-analysis resulted in a still large sample , there was no evidence of publication bias , but not in nonpsychiatric population . In case of hyperthymic temperament, female sex moderated the effect on medication adherence , R2 = 49.03%). All the meta-regression results are reported in Supplementary Table In case of cyclothymic, irritable, and depressive temperaments, meta-regression results didn’t show any moderating effect of age, sex, patient population, or country of origin. In case of anxious temperament subgroup analysis revealed that among psychiatric patients anxious temperament scores were significantly higher with medication non-adherence vs adherence  the biological effect modifiers  and, therefore, might also explain the dispersion of real effects and as such, the initially detected heterogeneity and the observed effect size of the outlier study. A number of patient-related risk and protective factors for adherence have been identified so far—we already mentioned some of them earlier—that can possibly be also influenced by affective temperaments to some extent. These include, but are not limited to lower socioeconomic status, ethnicity, the impact of local cultural norms, social pressure or stigmatization, adolescence and old age, loneliness in old age, psychiatric disorders associated with the disease, personality disorders, comorbid somatic diseases, drug use, cognitive impairment, pregnancy, disease severity, poor insight and negative drug-related beliefs . Also, wIn the present study, moderator analysis hasn’t identified any moderators in case of cyclothymic, irritable, and depressive temperaments, while anxious predominant temperament was found to be a possible risk factor for treatment non-adherence in psychiatric populations and hyperthymic predominant temperament as a possible protective factor against non-adherence among male subjects. It is important to note that the number of eligible studies may not have provided enough statistical power to examine moderating factors by meta-regression, furthermore, in some of the original studies, adherence and affective temperaments were not the measures of interest, but they themselves were the confounding or moderator variables, therefore no data was available on additional factors possibly moderating the affective temperament-adherence relationship.As we discussed above, adherence is a complex construct with several possible moderating and mediating factors, so research in the next step should focus on identifying these external factors indirectly affecting temperament expressions or factors moderating their effect on treatment adherence, also delineating the different causal processes behind the non-adherence—temperament relationship in case of different diseases. Especially because affective temperaments are strongly genetically- and biologically based, exhibit a stable course throughout the lifespan, and are relatively unmodifiable directly using psychological and psychotherapeutic technics, so even though they are somewhat sensitive to external stimuli and stressors, changing them cannot be a realistic goal even in case of a patient-tailored and personalized therapy. However, we also see that although temperaments may affect adherence directly to some extent through behavior consistent with those traits , temperament most often not directly, but indirectly affects adherence by shaping behavior through different perceptions and processing of environmental stimuli , 55, whiThus, rather than affective temperaments being the focus of psychotherapy themselves, we should first identify these mediating and moderating factors followed by targeting those with educational, supportive, and psychotherapeutic techniques in order to improve treatment adherence and overall treatment outcomes as a consequence. We should also understand how the genetic background and socioeconomic contributors to the development of temperaments may be related to later medication adherence.Intrinsic limitations of the present study essentially rely on the paucity of evidence eligible for inclusion as well as the various thresholds set by the authors to operationally defined adherence outcomes.To the best of our knowledge, this is the first meta-analysis to show that affective temperament scores measured by the TEMPS-A scale can contribute to identifying the risk of medication non-adherence. Though further primary studies need to systematically account for different clinical and psychosocial moderators across different clinical populations and operational definitions, cyclothymic, depressive, and irritable temperament scores may nonetheless predict treatment adherence and, thus, overall treatment outcomes. In clinical practice, the TEMPS-A scale might be useful for screening patients before treatment in order to identify non-adherent high-risk groups and support them to increase their adherence. The real goal for forthcoming ecological studies is to explain the variance of effect modifier, i.e. affective temperament beyond other confounding factors across different settings. While affective temperaments should hold relatively stable during the lifespan, they may nonetheless be sensitive to intense environmental stressors, thus understanding the residual variance of modifiable factors is crucial from a public health perspective.SUPPLEMENTARY INFORMATION