The risks of systemic anti-coagulation or its reversal are well known but accepted as necessary under certain circumstances. However, particularly in the plastic surgical patient, systemic alteration to hemostasis is often unnecessary when local therapy could provide the needed adjustments. The aim of this review was to provide a summarized overview of the clinical applications of topical anti- and pro-coagulant therapy in plastic and reconstructive surgery. While not a robust field as of yet, local tranexamic acid (TXA) has shown promise in achieving hemostasis under various circumstances, hemostats are widely used to halt bleeding, and local anticoagulants such as heparin can improve flap survival. The main challenge to the advancement of local therapy is drug delivery. However, with increasingly promising innovations underway, the field will hopefully expand to the betterment of patient care. When the homeostasis of hemostasis is disrupted, potentially devastating thrombosis or hemorrhage can result. Various therapies exist to manipulate the components of the coagulation system to achieve the desired result, but these are often administered on a systemic scale. For the surgical patient in need of pro- or anti-coagulation, local agents that could accomplish the needed alterations in coagulation without the risks of a systemic therapy would be ideal. Here, we discuss situations in which local alteration of hemostasis would be useful in the plastic surgery patient, as well as the available pharmacologic therapies.A wide range of local pro- and anti-coagulation options exist in the literature, with the earliest documented medical records of ancient Egypt, Greece, and Native America citing the use of agents common in nature such as wax, grease, barley, and animal hide to achieve hemostasis . In the Minimizing blood loss during and after surgery is critical, and many modalities exist to decrease intraoperative and postoperative bleeding. However, under certain circumstances, a systemic therapy may be undesirable, such as in the patient with a superficial injury who is anticoagulated due to a high risk for thrombotic events. Given the substantial risk of intraoperative and postoperative bleeding in such patients, management often involves the temporary pre- and post-operative interruption of the anticoagulant and (particularly in the case of vitamin K antagonists) the use of short-acting agents, such as unfractionated heparin or low-molecular-weight heparin (LMWH). Known as bridging anticoagulation, this strategy is meant to aid in achieving a normal or near-normal hemostasis at the time of surgery, while still maintaining a low risk of thromboembolism. However, this is still a departure from the patient’s standard therapy, and for particularly high-risk patients, any interruption in their anticoagulation treatment could precipitate a thrombotic event. Conversely, too short a time between the last dose of anticoagulation and surgery or between surgery and resumption of anticoagulation, could result in hemorrhage and hematoma formation, potentially compromising the results of the surgery or causing new complications. The use of LMWH is associated with an increased risk of postoperative wound hematoma following pacemaker and implantable defibrillator placement . The useTopical TXA may be used to control bleeding following oral surgery, as well as epistaxis secondary to coagulation disorders and anticoagulation ,8. An anTopical thrombin and fibrin formulations are also available to achieve hemostasis, particularly in the setting of dermatologic surgery . Fibrin A wide variety of hemostats are also available to achieve hemostasis, with the composition determined by the surgical need as well as their own advantages and disadvantages . HemostaPlease refer to Hirudo medicinalis has proven efficacy in reducing venous congestion of skin flaps in plastic surgery, thereby preventing loss of the flap [Aeromonas hydrophilia, a gram-negative bacillus native to the leech’s digestive tract [H. medicinalis in plastic and reconstructive surgery [Local anticoagulants also have their place, as systemic anticoagulation increases the risk of hemorrhage. Even twice-daily enoxaparin prophylaxis for venous thromboembolism may increase clinically relevant bleeding after plastic and reconstructive surgery . Intraopthe flap ,26. The ve tract . See Tab surgery ,29,30,31Likely the most well-known anticoagulant, heparin binds to antithrombin, potentiating and accelerating the inactivation of thrombin and factor Xa. Though often an enemy of the surgeon due to its pro-hemorrhage nature, heparin does have some surgical applications. In microsurgery, local unfractionated heparin was as effective as systemic heparin in reducing arterial thrombus size in a rat model, with less alteration to hemostatic parameters . When inOne of the most efficacious local anticoagulant agents is tissue factor pathway inhibitor, a naturally occurring protein inhibitor of factor X and the tissue factor-factor VII complex of the extrinsic pathway of coagulation. When compared in a rabbit model of near-total ear avulsion injury, topical tissue factor pathway inhibitor therapy led to significantly higher patency rates than heparin, hirudin, or control solutions . Its appLess local than targeted, catheter-directed thrombolysis is an increasingly utilized treatment option for pulmonary emboli and deep-vein thromboses, both common and feared complications of many surgeries. By focusing the anticoagulant at the clot, catheter-directed thrombolysis allows the use of lower doses of anticoagulants, theoretically reducing the risk of bleeding . In inteThe greatest challenge of any local therapy, including manipulation of coagulation, is adequate drug delivery and targeting, and its overcoming could allow for expanded utility. Catheter-directed thrombolysis is leading the way in this field by directing potent thrombolytics to the desired site. Some novel targeting methods include collagen sponges containing biodegradable thrombin-loaded microspheres and gelatin sponges layered with active coagulation proteins, though elongating shelf life and manufacturing remain difficulties . BalloonA large challenge with topical therapy in particular is the delivery of the drug through the skin, which acts as a barrier to both large and charged molecules. The outermost layer of the skin, the stratum corneum, acts as the primary barrier to molecule entry . In ordeThe main benefit of local therapy is that the systemic effects of altered coagulation are avoided. In the anticoagulated patient, local reversal of anticoagulation during and following a minor procedure could decrease the risk of stroke, deep-vein thrombosis, or other thrombotic complications that could occur if the patient were taken off their anticoagulation regimen. Likewise, systemic anticoagulation carries the risk of potentially fatal hemorrhage, which could be avoided if the patient only needs local anticoagulation for a skin graft or anastomosis.Besides drug delivery and targeting, difficulties of local therapy include the little evidence that supports their use, with hemostats being a notable exception, except for a few well-defined circumstances. The situations in which such therapy would be beneficial are also currently mostly limited to superficial injuries, though the potential exists for their application to a wide variety of surgeries. Local pro-coagulants, injected like a local anesthetic, could allow for even large surgeries, while maintaining systemic anticoagulation. While local anti-coagulants have their place in improving venous congestion and healing in superficial surgeries, they could also have a role in improving the gastrointestinal anastomosis blood flow or in enhancing the survival of vascular grafts. With alterations to hemostasis, the rewards have always come with heavy risks, but those risks could lessen substantially with the use of local therapy.Local pro- or anti-coagulation therapy shows great promise for delivering the needed alterations to hemostasis in the plastic surgical patient without the risks of systemic therapy. Unfortunately, local therapy is still limited in scope and utility, but there are great opportunities for continued research and development in the field. Advancements in topical drug delivery in particular will hopefully allow for the expansion of this field, with subsequent improvement in patient care and outcomes.


In the context of increasing applications of various nanomaterials in construction, this work reviews the renewed knowledge of nanotechnology in cement-based materials, focusing on the relevant papers published over the last decade. The addition of nanomaterials in cement-based materials, associated with their dispersion in cement composites, is explored to evaluate their effects on the resistance of cement-based materials to physical deteriorations, chemical deteriorations, and rebar corrosion. This review also examines the proposed nanoscale modeling of interactions between admixed nanomaterials and cement hydration products. At last, the recent progress of advanced characterization that employs techniques to characterize the properties of cement-based materials at the nanoscale is summarized. In the construction industry, cement paste, mortar, and concrete are the most commonly used materials, due to their easiness to fabricate, low expenditure, good performance, and versatile applications. However, the drawbacks of these cement-based materials (CBMS), such as low tensile strength, susceptibility to cracking (if tensile stress induced by deterioration exceeds tensile strength), and likelihood of sudden failure (due to their brittle nature), have led to multiple pathways of degradation in the technical properties of CBMS and high costs of repairing them . As the 2, TiO2, Al2O3, Fe2O3 etc.), nanotubes and fibers (carbon nanotubes and carbon nanofibers), and nanoplatelets  . R. R2 nano2, nano-SiO2, CNT, and GO to the cement paste yielded a C–S–H with more crystalline nanostructure , as illustrated by the TEM images in Another technique that offers high-resolution images of the material’s nanostructure is the transmission electron microscopy (TEM). Unlike AFM, TEM operates by transmitting a beam of electrons to penetrate through the material and construct an image ,134. It The helium ion microscopy (HIM) is another advanced imaging tool that can be used to examine hydration products at the nanoscale. HIM operates similar to TEM, except that electrons are replaced by Helium ions which induce less scattering when they infiltrate the solid bodies. Consequently, the imaging resolution is highly improved ,137. HIM2 and nano-SiO2 [The pore structure of hydration products at the nanoscale contributes significantly to the durability and service life of CBMS such as concrete ,141. Oneano-SiO2 . In compano-SiO2 .Another valuable nondestructive tool that can be used to characterize the pore network of hydration products at the nanoscale is the nano x-ray computed tomography (nano-CT), which uses a stack of x-ray images to build the three-dimensional (3D) image of the tested sample . Using nWenzel et al.  modifiedDispersion of nanomaterials in CBMS plays an important role in ensuring the effectiveness of nanomaterials to mitigate the deteriorations of cement composites. Common applied approaches to disperse nanomaterials include the use of surfactant, application of ultrasonication, and functionalization of nanomaterials.Physical deteriorations of CBMS including shrinkage, freeze–thaw damage, and abrasion can be reduced by the admixed nanomaterials, resulting from a denser and less permeable mixture.Adding the optimal type and dosage of nanomaterials is an effective approach to improve the resistance of CBMS to chemical deteriorations, such as sulfate attack, acid attack, alkali-aggregate reactions, and thermal degradation.Admixing nanomaterials in fresh concrete, electrically injecting nanomaterials into aged concrete, and coating the rebar with nanomodified epoxy coating are among practical and effective approaches to improve the resistance of reinforced concrete against rebar corrosion.Modeling of the interactions between C–S–H gel and the admixed nanomaterials can facilitate a mechanistic understanding of the relationship between the nanostructure and the properties of CBMS.Nanoindentation is a powerful technique used to characterize the nanoscale mechanical properties of cement composite, while MIP is usually suitable for characterization of the pore structure. The most adopted techniques for the nanoscale imaging and C–S–H structure characterizations of CBMS are AFM, TEM, and HIM, and NMR, SANS, and QENS, respectively.Nanotechnology is an effective approach to improve the durability performances of cement-based materials. This work provides a comprehensive overview with regard to the current knowledge on multiple dimensions of the effect of nanomaterials on CBMS, based mainly on the papers published over the last decade. Some key findings from the review are concluded as follows.A gap exists between the academic research at the laboratory scale and the realistic engineering applications. It is important to adapt the nanotechnology to meet the requirements and constraints of the traditional practices generally adopted by the construction industry .The cost-effectiveness of nanomaterials must be evaluated before their use in CBMS, and this should be done from a life-cycle perspective. Despite the seemingly high initial cost of most nanomaterials, nanomaterials can greatly improve the durability and service life of CBMS, resulting in much lower costs during the use phase of CBMS . Nanotechnology will likely result in a competitive life-cycle cost for many constructions using CBMS.Although nanotechnology exhibits the potential for great innovations in the construction industry, potential health risks should be assessed and addressed for practitioners to ensure appropriate use of nanomaterials by the industry.There are some knowledge gaps or remaining challenges that need to be addressed before widespread adoption of nanomaterials in the construction practices.Looking to the future, nanotechnology will continually play a powerful role in advancing cement and concrete technology and unlocking the potential of conventional and unconventional cementitious materials. It will help to establish the aforementioned fundamental understanding of the effect of nanomaterials in CBMS from the bottom up, through the use of multiscale modeling of the hydration process, rheological behavior and deterioration processes, and through the use of advanced characterization methods . Furthermore, the addition of nanomaterials  will enable the regulation and manipulation of hydration products and their microstructure in cement-based materials, to achieve their desirable properties and life-cycle performances.


Microsatellite instability (MSI) is a genomic alteration in which microsatellites, usually of one to four nucleotide repeats, accumulate mutations corresponding to deletions/insertions of a few nucleotides. The MSI phenotype has been extensively characterized in colorectal cancer and is due to a deficiency of the DNA mismatch repair system. MSI has recently been shown to be present in most types of cancer with variable frequencies (from <1 to 30%). It correlates positively to survival outcome and predicts the response to immune checkpoint blockade therapy. The different methods developed for MSI detection in cancer require taking into consideration two critical parameters which influence method performance. First, the microsatellite markers used should be chosen carefully to ensure they are highly sensitive and specific for MSI detection. Second, the analytical method used should be highly resolute to allow clear identification of MSI and of the mutant allele genotype, and should present the lowest limit of detection possible for application in samples with low mutant allele frequency. In this review, we describe all the different molecular and computational methods developed to date for the detection of MSI in cancer, how they have evolved and improved over the years, and their advantages and drawbacks. MLH1) genes in cancer (Microsatellite instability (MSI/MSI-H) is characterized by the accumulation of mutations (insertions or deletions of a few nucleotides) in microsatellites , which are continuous repetitions of 1–9 nucleotides. It has been shown that MSI is caused by loss of function of a member of the DNA mismatch repair system (MMR), which normally allows the repair and correction of DNA following DNA mismatches introduced by DNA polymerase , and is characterized by the appearance of multiple neoplasia including colorectal cancer in childhood  the amplification of one or several microsatellite markers with PCR-based methods, and (ii) the detection of MSI by methods which allow fragment length analysis Figure .MSI detection was initially performed in colorectal cancer either by using PCR on specific markers followed by polyacrylamide gel electrophoresis and autoradiography , 30, or These methods, which proved laborious and time-consuming and presented a low sizing accuracy, were supplanted by a newer approach which remains today the gold standard for MSI detection. This approach combines a PCR with fluorescent primers and capillary electrophoresis using a DNA sequencer which allows fragment analysis at single base resolution Figure  33). Th. Th33). Other read-out methods have also been used for MSI detection following PCR amplification of microsatellite markers, including denaturing high-performance liquid chromatography (DHPLC) –43 and hRecently, massive parallel next-generation sequencing (NGS) has also been used to detect MSI in cancer , 17, witMSI was initially described in 1993 in colorectal cancers in which deletions in several amplicons of mono-, di-, and tri-nucleotide repeats were shown to be present in 12% of the tumors, using an AP-PCR approach  or 6 dinIn order to standardize the panel of microsatellites used for MSI detection in cancer across the different laboratories in the world, a National Cancer Institute (NCI) workshop held in Bethesda,  proposed a panel of two mononucleotide (BAT-25 and BAT-26) and three dinucleotide  repeat microsatellites called the Bethesda/NCI panel for the detection of MSI in colorectal cancer, and according to which tumors presenting two or more unstable markers (or ≥30–40% if more markers are tested) should be defined as MSI/MSI-H . The othAlthough the Bethesda/NCI panel is recommended again in the revised Bethesda guidelines for Lynch syndrome and MSI , and remTherefore, some researchers have claimed that mononucleotide repeat microsatellites are the most appropriate markers for MSI detection, as they are more sensitive and almost monomorphic, thus requiring less use of matched normal samples , 62, 63.Several other mononucleotide repeat microsatellites have been proposed as sensitive and specific markers for MSI detection in cancer. Among these are CAT-25, a quasi-monomorphic mononucleotide repeat microsatellite in all populations, which has been put forward as a single marker for MSI detection in CRC, offering improved performance compared to the Bethesda panel, BAT-25 or BAT-26 , 69. CATSince the development of NGS, a greater number of microsatellites, and potentially all microsatellites in the genome, can now be analyzed for MSI detection, an advance which could further improve the detection of MSI in cancer. However, two studies based on WGS and WES NGS data have shown that most microsatellites in the genome are stable and therefore would not be informative in the case of MMR deficiency , 17. TheTo date, most studies on MSI detection in cancer that are based on NGS experiments have either evaluated MSI in several types of microsatellites (mono- to penta-nucleotide repeat) or refined their analysis to mononucleotide repeat microsatellites using microsatellite sequencing data available on WGS, WES or TGS of panels of genes implicated in cancer which were not initially designed for MSI detection , 28, 56.Capillary electrophoresis fragment analysis is the standard molecular method for MSI detection in cancer, however this method presents a LOD which might not be sufficient for some clinical applications such as the detection of MSI in blood, plasma, precancerous lesions, and tumors with high levels of normal cell contamination, or in tumor heterogeneity where only a small subset of the tumor cells present MSI. The particularity of the LOD of MSI is that it can vary (from 1 to 10%) according to the length of the mutant alleles and the WT genotype, so that large deletions present a lower LOD than small deletions due to the presence of stutter peaks which mask mutant alleles .ex vivo MSI phenotype during in vitro culture .–81.78–81ice-COLD-PCR, a method previously developed for enrichment of point mutations located in mutational hotspots in oncogenes such as BRAF, NRAS, and KRAS . E-. E-ice-CFinally, a post-PCR method called gMSI has been developed to improve the sensitivity of MSI detection in blood from CMMRD patients. This method relies on the analysis of the height of n+1 and n+2 stutter peaks compared to the n peak  and uses freely available software . AlthougBefore the advent of NGS, to our knowledge only two mathematical prediction models had been developed for MSI detection in colorectal and gastric cancers. These models used six and seven microsatellites (mono- and di-nucleotide repeat), respectively, and were based on a two-population (MSI vs. MSS) model in which the binomial distributions mixture was estimated by maximum likelihood using an expectation-maximization algorithm , 89.Several computational approaches based on WGS, WES, and TGS data have been used to detect MSI, taking into account the difficulties of microsatellite sequences including management of stutter peak formation induced by PCR amplification during NGS library preparation, sequencing errors induced by homopolymers, and the shortcomings of sequencing read length which limits the length of the microsatellites analyzed Figure .The first study on colorectal and endometrial cancer described an MSI detection approach using WES and WGS data from The Cancer Genome Atlas (TCGA) . This stSubsequently, different methods were developed for MSI detection in cancer, based on the comparison of the length distribution of a selection of microsatellites obtained by read count of all alleles Figure . For exaOther methods developed for MSI assessment in cancer use a different approach based on the mutation burden in all sequences and/or the burden of indels in microsatellites Figure . To dateIf the main advantage of these NGS based computational methods is that they allow a large number of microsatellite loci to be screened simultaneously, it should be remembered that NGS experiments are much more expensive to perform and require more time to generate results due to the more complex bioinformatics analysis required, and that they give similar or only slightly better sensitivity compared to standard capillary electrophoresis procedures , 46, 48.https://github.com/ding-lab/msisensor, v0.5, last updated on September 18, 2018)     , mSINGs 0, 2018) , MANTIS 9, 2018) , and MSI5, 2015)  are avaiAlthough the discovery of MSI in cancer is a quarter of a century old, it is relatively recent compared to the discovery of point mutations, epimutations, and copy number variations in cancer. The different methods developed so far for the detection and identification of MSI in cancer are mostly derived from methods created initially for the study of natural variations/polymorphisms present in the human genome or for point mutations present in cancer. These methods still appear to be in their infancy since to date only a small number have been developed for MSI detection, and of these very few are applicable to potential clinical applications of interest such as the detection of MSI in plasma, circulating tumor cells, blood, heterogeneous tumors, or tumors with a high level of normal cell contamination. In contrast, these methods have already been implemented for other types of alterations in cancer.Numerous difficulties could explain these delays in technological development, notably the high polymorphism levels of microsatellite sequences in the different human populations and the errors induced by PCR slippage during amplification of microsatellite sequences, which increases the complexity not only of the analysis of microsatellite profiles but of the MSI detection and the identification of mutant alleles. More recently, several factors such as the errors induced during the sequencing-by-synthesis of homopolymers by next-generation sequencing, the difficulties of alignment of repetitive DNA sequences due to the short read length, and the low accuracy of indel calling, have also created a computational challenge for MSI detection by NGS-based computational methods, due to the high risk of interperation errors, a problem which requires a longer duration for the development of algorithms.Given the recent discovery of MSI in dozens of types of cancer, which correlates in a positive dose-effect manner to survival outcome, and the demonstration that MSI is a major predictive biomarker for the efficacy of immune checkpoint blockade therapy in solid tumors, there is undoubtedly a need for the development of new sensitive tools for MSI detection, including clinical applications for MSI diagnosis. Future perspectives should include (i) the development of pan-cancer panels of highly sensitive and specific microsatellite markers for the detection of MSI in cancer, and (ii) the development of combined methods to improve the limit of detection of MSI, as required for certain types of clinical samples ; the latter could include the enrichment of mutant alleles prior to massively parallel NGS. These methods could then be rapidly implemented in routine clinical applications for the diagnosis of MSI in cancer.LB, J-FD, and AH-K conceived, wrote and approved the final version of the submitted manuscript. AH-K supervised the whole writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Minipuberty consists of activation of the hypothalamic-pituitary-gonadal (HPG) axis during the neonatal period, resulting in high gonadotropin and sex steroid levels, and occurs mainly in the first 3–6 months of life in both sexes. The rise in the levels of these hormones allows for the maturation of the sexual organs. In boys, the peak testosterone level is associated with penile and testicular growth and the proliferation of gonadic cells. In girls, the oestradiol levels stimulate breast tissue, but exhibit considerable fluctuations that probably reflect the cycles of maturation and atrophy of the ovarian follicles. Minipuberty allows for the development of the genital organs and creates the basis for future fertility, but further studies are necessary to understand its exact role, especially in girls. Nevertheless, no scientific study has yet elucidated how the HPG axis turns itself off and remains dormant until puberty. Additional future studies may identify clinical implications of minipuberty in selected cohorts of patients, such as premature and small for gestational age infants. Finally, minipuberty provides a fundamental 6-month window of the possibility of making early diagnoses in patients with suspected sexual reproductive disorders to enable the prompt initiation of treatment rather than delaying treatment until pubertal failure. Puberty is the period of life in which a child develops secondary sexual characteristics and reproductive function. Puberty requires activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in secretion of hypothalamic gonadotropin-releasing hormone (GnRH), which in turn stimulates secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary gland and the consequent maturation of gametogenesis as well as secretion of gonadal hormones. Before the onset of puberty, the HPG axis is temporary activated in two other periods of life, i.e., in the midgestational fetus and in the newborn. In recent years, many studies in the literature have referred to this latter period as minipuberty.Minipuberty was first described in the 1970s , but itsDuring embryogenesis, neurons that produce GnRH develop from the epithelium of the medial olfactory pit and move to the fetal hypothalamus by migrating along nerve fibers . This prThe gonadotropin levels peak at midgestation in both the pituitary gland and the serum and subsequently decrease toward birth and are suppressed at term , 9. ThisAdditionally, female fetuses produce higher LH and FSH levels than male fetuses , 11. IndDuring fetal life, the masculinization of genitalia depends on the production of testosterone (T) by the Leydig cells of the fetal testicles and on its action on target organs. During the first trimester of gestation, placental human chorio-gonadotropin (hCG) induces the differentiation of testicular mesenchymal cells into Leydig cells and stimulates T production through the activation of the LH/CG receptors expressed on their surfaces . Indeed,In female fetuses, the lack of AMH allows the mullerian ducts to develop into the fallopian tubes, uterus and upper part of the vagina . The devAt delivery, in healthy infants the LH and FSH levels are low in the cord blood in both sexes  due to tIn the first few days after birth, the fall in circulating placentally produced steroids causes a progressive lack of negative feedback on the neonatal GnRH pulse generator. In this manner, the activity of the HPG axis is reinitiated, and gonadotropin levels begin rising between days 6 and 10 after birth , 28. In Table 3, and the volume subsequently decreases to 0.31 cm3 at ~9 months  are at risk of developing metabolic and endocrinological disorders . It is wIn females, being SGA has been associated with reduced uterine and ovary size , whereasGrowth is influenced by different hormones depending on the period of life. In fact, in the first years, thyroid hormones play the main role, together with insulin and glucocorticoids. By contrast, GH becomes predominant during infancy until the period of puberty, when the rise of levels of sexual hormones results in the growth spurt, which is essential for final growth and bone maturation.Recently, new studies have described an association between minipuberty and growth, particularly in males. Indeed, sex steroids and gonadotropic hormones in the first 5 months of life seem to influence somatic development in boys during the following 6 years. Becker et al.  conducteIn the last 20 years, studies have been conducted to establish an association between minipuberty and hypogonadotropic hypogonadism (HH), especially in males, and have found that the disease is characterized by the absence of the postnatal FSH, LH, and T surge. For this reason, minipuberty provides a short-time window of opportunity to make an early diagnosis . At birtHadziselimovic et al. identified impaired minipuberty as the main reason for cryptorchidism-induced infertility . Indeed,Furthermore, the importance of minipuberty has been highlighted by evidence that orchiopexy alone does not necessary improve fertility in cryptorchid males, whereas in 6-month-olds, long targeted therapy with LH-Rh analogs following successful surgery results in the normalization of the sperm parameters in adult life . Table 2Contrasting data can be found in the literature about males with Klinefelter syndrome (KS). Lahlou et al.  found thFinally, androgen receptors also play an important role in HPG axis activity. Indeed, infants with complete androgen insensitivity who present with a mutation in the androgen receptor do not exhibit the physiological peaks in LH and consequently T during minipuberty, whereas neonates with partial androgen insensitivity exhibit high-normal levels of postnatal T and LH .The HPG axis is physiologically activated in the fetus during midgestation and gradually turns off toward term due to the negative feedback of placental hormones on the fetal hypothalamus. At birth, when the restriction is removed, the HPG axis reactivates, which results in a T peak in males between months 1 and 3; by contrast, the oestradiol levels in females fluctuate until 6 months of age. Minipuberty allows for the development of the genital organs and creates the basis for future fertility, but further studies are necessary to understand its exact role, especially in girls. Nevertheless, no scientific study has yet elucidated how the HPG axis turns itself off and remains dormant until puberty. Additional future studies may identify clinical implications of minipuberty in selected cohorts of patients, such as premature and small for gestational age infants. Finally, minipuberty provides a fundamental 6-month window of the possibility of making early diagnoses in patients with suspected sexual reproductive disorders to enable the prompt initiation of treatment rather than delaying treatment until pubertal failure.LL drafted the manuscript. MC and AL performed the literature review. LP supervised the project. SE revised the manuscript and made substantial scientific contributions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Studies of alcohol consumption among Hispanics in the United States show different patterns based on gender, country of origin, and economic status. The literature shows a lower frequency but higher volume of consumption among Mexican-American and Puerto Rican males than among non-Hispanic white males. Cuban-American males have a pattern of relatively moderate consumption that resembles that of non-Hispanic whites. Women from Mexican-American, Cuban-American, and Puerto Rican populations have low alcohol consumption rates, which appear to increase with the level of acculturation. Existing data are old, however, and new studies are needed to update information on alcohol consumption patterns of the largest Hispanic subgroups in the United States as well as the drinking habits of the growing numbers of Hispanics from places other than Mexico, Puerto Rico, and Cuba. Hispanic-Americans are one of the fastest growing minority groups in the United States, numbering more than 28 million and making up about 11 percent of the U.S. population . ApproxiEarly research reviewed by A number of studies within specific Hispanic populations have found that differences in alcohol consumption among males exist based on Hispanic origin see , p. 267.One analysis of data from the HHANES found that Mexican-American and Puerto Rican men were much more likely than Cuban-American men to report that they had experienced a period in their lives when they considered themselves to be heavy drinkers. The survey also found that those who considered themselves to have been heavy drinkers in the past were more likely to be current heavy drinkers .In addition to differences across national origin groups, Hispanic males also appear to have drinking patterns that differ by age. Using the HHANES, Among researchers, a lively interest has grown in examining the influence of various measures of acculturation on the alcohol consumption of Hispanic populations. Typically, those measures include items capturing language use and preference, ethnic identification, and nativity of both the respondent and his or her parents. Thus, the more acculturated a person is, the more likely he or she is to speak or prefer to speak English over Spanish, to identify as American rather than of Hispanic origin, and to have been born in the United States to U.S.-born parents.The effects of acculturation on alcohol consumption among Hispanic males have been studied in many different Hispanic groups, but because it is a complex issue, results have varied. One study suggested that less acculturated middle-aged Mexican-American males drink more heavily than Mexican-American males who are more acculturated, suggesting a possible acculturative stress effectResearch on Hispanic drinking has shown that despite variation in alcohol consumption among different groups, heavy drinking and drunkenness is primarily a male activity, whereas abstention and infrequent light drinking is the common pattern for women . Women iDifferences in Hispanic women’s drinking patterns do exist based on age, level of acculturation, and country of origin. Data from the HHANES, for example, showed that Mexican-American and Puerto Rican women consumed a higher volume of alcohol and more often reported heavy drinkingData from the HHANES also suggested other factors that may influence the drinking patterns of Hispanic women. For instance, employed women tended to drink more frequently but less heavily than unemployed women. Women in poverty drank less frequently than women not in poverty but drank more per drinking episode. Mexican-American women who were married also drank less frequently and consumed smaller volumes of alcohol than did unmarried women, and women with higher levels of education were also more likely to drink . The relacculturation model, which predicts that alcohol consumption of Hispanic women reflects the extent to which they have adopted the drinking norms and practices of the larger society (A number of studies have shown that a higher level of acculturation is related to greater alcohol consumption, especially in relatively young Hispanic women . Those f society . Higher  society .For women of all ages in all three major subgroups in the HHANES, acculturation was consistently correlated with both increased frequency of consumption and increased probability of being a drinker at all . AccultuChronic heavy drinking can result in alcohol-related morbidity and mortality. Both U.S. and native Mexican populations have a higher rate of alcohol-related mortality from cirrhosis of the liver than does the general U.S. population, and Mexican-Americans may be disproportionately represented in alcohol-related violence . A recenNational data have shown that Hispanics of both genders have higher rates of death from cirrhosis and liver disease than do non-Hispanics . AlthougAlthough alcohol consumption varies greatly on an individual level in all cultural groups, certain macro-level trends can be observed in the drinking patterns of Hispanic-Americans. Consumption appears to vary by gender, age, level of acculturation, and national origin. The Cuban-Americans who came to the United States in the 1960s tended to have a fairly high socioeconomic status compared with other Hispanic groups and typically display more moderate drinking patterns than do Mexican-Americans and Puerto Ricans. Specifically, studies of Mexican-American men reveal that many of those who do drink engage in low-frequency, high-volume binge drinking. Young Hispanic men have been found to have the highest level of alcohol consumption, whereas the oldest cohorts of men have very low levels of consumption. Among Hispanic-Americans, Cuban-American women appear to drink the least amount of alcohol. In addition, younger and more acculturated women drink more in quantity and frequency than do less acculturated or older women in all three Hispanic groups. Greater assimilation into American society by Hispanics may ultimately change the taboos against alcohol consumption by women and may encourage Hispanic men to become more frequent but lower quantity drinkers.Data about individual subgroups may now be dated, because data from large samples, such as the HHANES, are approximately 15 years old and may be geographically skewed. More current regional studies, however, tap only into specific geographic areas of Hispanics that are not representative of all U.S. geographic areas. Large representative studies of the various Hispanic subgroups are needed to update information on the alcohol consumption patterns of those populations. Especially needed are studies of the growing numbers of Hispanics from places other than Mexico, Puerto Rico, and Cuba.


Juvenile dermatomyositis (JDM) is a rare autoimmune disease mainly characterized by muscle and skin involvement. Vasculopathy is considered central to the pathogenesis of the disease. The exact nature of vasculopathy is not yet understood but it is a complex process with both an inflammatory and a non-inflammatory, occlusive component. Impaired function of JDM vasculature includes immune complex deposition, altered expression of cell adhesion molecules predominantly inducing Th17 cell infiltration, and endothelial cell dysfunction. Development of vasculopathy is associated with the severe extra-muscular manifestations of JDM, such as gastrointestinal and cardiac manifestations, interstitial lung disease, ulcerative skin disease or development of calcinosis, and portends a poor prognosis. Correlation of histopathological findings, autoantibodies, and extensive diagnostic workup represent key elements to the early detection of vasculopathic features and early aggressive treatment. Monitoring of vasculopathy remains challenging due to the lack of non-invasive biomarkers. Current treatment approaches provide variable benefit, but better understanding of the essential pathogenic mechanisms should help lead to improved outcomes. Whilst acknowledging that evidence is limited, this review aims to describe the vasculopathy of JDM in the context of pathophysiology, clinical features, and treatment of disease. Idiopathic Inflammatory Myopathies (IIM) consist of a group of highly heterogenous diseases characterized by a systemic inflammatory process. Muscle weakness and skin involvement are common characteristics but other organs can also be affected . JuvenilThe exact etiology of JDM is not fully understood and is thought to be multifactorial. The prevailing hypothesis is that JDM is the result of genetic susceptibility and environmental triggers, which subsequently cause dysregulation and dysfunction of the immune system resulting in tissue inflammation . VasculoThe identification of vascular involvement in JDM is challenging, and depends on extensive immune, histopathologic and imaging diagnostic approaches together with clinical experience and expertise. It may influence choice of therapeutic strategy and prediction of individual patient prognosis. Therefore, to better understand the pathophysiology, histopathological findings, clinical manifestations, and associated complications is of great clinical significance.The exact nature of vasculopathy remains unclear and is likely to change at different stages of the disease. Early on there is evidence of a true inflammatory small vessel vasculitis driven by interferons and other cytokines , 7; but Activated dendritic cells present within lesional muscle release interferons which have a range of biological effects on the endothelium, such as increased expression of major histocompatibility complex (MHC) class I and class II and adhesion molecules promoting T-cell migration , 14, 15,Later in the course of JDM, the vasculopathy is characterized by endothelial cell swelling, necrosis, and luminal occlusion of capillaries and arterioles , 8. AnotThe vasculopathy of JDM may present with different clinical phenotypes. The extent of symptoms includes mild forms limited to cutaneous vessels, and severe, life-threatening manifestations with organ involvement. The following section addresses the pathophysiology and clinical manifestations of disease relating them where possible to vasculopathy.JDM is associated with a wide range of skin rashes, illustrated and described in detail by Dugan et al. , but mosDystrophic calcification of tissues occurs in 20–40% of patients with JDM, although seen much less frequently in adults with DM . CalcinoRecent case-control echocardiographic studies in children with JDM have suggested that up to 25% of patients have evidence of subclinical left ventricular diastolic dysfunction, and a high prevalence of pathological electrocardiographic (ECG) abnormalities . ChildreAccelerated atherosclerosis has been demonstrated as an important factor of mortality and morbidity in patients with autoimmune diseases . A recenGastrointestinal tract involvement occurs in 5–37% of JDM cases . This inPulmonary involvement is much less common in children with JDM than adult-onset IIM, but interstitial lung disease (ILD) may still complicate childhood cases . ConnectAlthough rare, vasculopathy of the central nervous system has been reported in children with JDM , 55. It Myositis specific antibodies (MSA) and myositis associated antibodies (MAA) are present in at least 60% of JDM cases . Differeper se, but they represent arms for proposed comparative effectiveness studies, developed via consensus methodologies. Moreover, evidence-driven consensus-based recommendations for diagnosis and treatment of JDM have also been published as part of a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE)  .Delayed or inadequate treatment has been associated with poorer prognosis and early aggressive treatment has been demonstrated to improve the long-term outcome . PharmacNCT number: NCT02594735) is currently underway.Several therapeutic agents have been proposed for the treatment of severe/refractory JDM cases. A randomized trial that included 152 adults with myositis and 48 children with JDM demonstrated that 83% of patients met the definition of improvement on rituximab , even thCyclophosphamide (CyC) is another third line therapeutic agent mainly reserved for JDM cases refractory to most other therapies and for cases with significant organ involvement such as cardiopulmonary involvement, skin ulceration or gastrointestinal vasculopathy. Several case studies demonstrate the efficacy of treatment with CyC in both pediatric and adult patients with IIMs , 85. A rAs JDM is now increasingly recognized as a condition that falls into the category of diseases driven by interferons , JAK inhJDM represents the commonest idiopathic inflammatory myopathy of childhood. When looking at affected tissues, vascular and perivascular inflammation is a predominant feature of the disease, thus early descriptions recognize JDM as a systemic angiopathy of the childhood. The presence and persistence of vascular involvement is associated with more severe and refractory disease and the development of life-threatening complications. With recent therapeutic strategies, survival, and outcomes of JDM have improved significantly with a reported mortality of <2% , but theCP and LM have contributed to the draft and made significant intellectual contribution to the generation of the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drosophila, and the ability to easily manipulate them genetically, has made the fruit fly a useful model organism to study cancer biology. In this review we outline the basic mechanisms and signaling pathways conserved between humans and flies responsible of inducing uncontrolled growth and cancer development. Second, we describe classic and novel Drosophila models used to study different cancers, with the objective to discuss their strengths and limitations on their use to identify signals driving growth cell autonomously and within organs, drug discovery and for therapeutic approaches.Cancer is a multistep disease driven by the activation of specific oncogenic pathways concomitantly with the loss of function of tumor suppressor genes that act as sentinels to control physiological growth. The conservation of most of these signaling pathways in  Drosophila melanogaster, is used as a model organism to study disciplines ranging from fundamental genetics to the development of tissues and organs. Drosophila genome is 60% homologous to that of humans, less redundant, and about 75% of the genes responsible for human diseases have homologs in flies , to novel approaches for studying tumor-induced angiogenesis, prostate, thyroid and lung cancers, with the goal to discuss their strengths and limitations. In the second part, we analyze few physiological mechanisms that uncover potential non-autonomous mechanisms controlling growth, including the relation between the immune cells (macrophages) and the growth of epithelial cells, or the function of lipid metabolism in cancer growth. Finally, we discuss how RB (retinoblastoma-associated) and TP53 genes  and of pro-survival factors  or by downregulating the action of pro-apoptotic genes  , which function downstream of receptor signaling cascades, and are deregulated in 25% of human tumors . In epithelial tumors, this condition triggers the so-called angiogenic “switch” where the quiescent vascular network is induced to proliferate by the secretion of pro-angiogenic factors, such as VEGF  and FGF (Fibroblast Growth Factor) , lytic enzymes that degrade the extracellular matrix (ECM) allowing tumor cells to escape and colonize an environment that suites them and to acquire new oncogenic properties  to the tumor mass  and, basally to the notum, by a layer of myoblasts embedded in Extracellular Matrix, and constitute a perfect system in which to model the onset of epithelial cancer progression. These larval organs are indeed morphologically and biochemically comparable to mammalian epithelia  and the Scrib/Dlg/Lgl  complexes, which are respectively placed at the apical, subapical and baso-lateral membrane domains. Alterations in these proteins provoke continued cell proliferation, loss of differentiation and complete loss of tissue architecture, resulting in neoplastic overgrowth   tumor suppressor pathway was discovered first in Drosophila as a regulator of organ size , an upstream regulator of the cascade that binds to and inhibits Wts kinase activity , and by Eiger, the Drosophila homolog of TNF-α. Its function is variable and depends also on the cellular environment: it can indeed induce cell proliferation and migration, but its major role is to induce apoptosis  and is the final effector of the cascade  gives cells invasive and metastatic abilities, highlighting how these pathways converge to induce transformation in epithelia.The s Igaki, . The sigs Igaki, , Basket/s Igaki,  and the s Igaki, . The AP-PI3K/Target of rapamycin (TOR) signaling pathway is a highly conserved key regulator of growth. The binding of insulin-like peptides (ILPs) (fly's insulin) to the receptor (InR) results in the phosphorylation of chico/IRS1-4, and the production of phosphatidylinositol-3, 4,5-triphosphate (PIP3) by PI3K, a reaction that is counteracted by the lipid phosphatase PTEN , where cells carrying tsc1 or tsc2 mutations display an abnormal increase in size and exhibit constitutive phosphorylation of S6K    and by endocytic genes (such as Rab5). Cells mutant for these genes behave as losers and were eliminated by wild-type cells  that differentiate to either enteroblasts (EB) or pre-enteroendocrine cells (pre-EE), that then differentiate into absorptive enterocytes (EC) or secretory enteroendocrine cells (EE). Thanks to significant similarities in the physiology between the Drosophila gut and the intestine of vertebrates  to Intestinal Stem Cells (ISCs) renewal  cancer syndrome are associated with activation of Wnt signaling  also results in JAK-STAT and EGFR pathway hyper-activation, and their removal suppresses the intestinal hyperplasia resulting from Apc1 loss, revealing an underlying conserved signaling between flies and mammals that controls ISCs proliferation and gut homeostasis  induces proliferation of the ISCs cells in wild-type animals, and reduction of their expression is sufficient to inhibit ISCs' hyper-proliferation of Apc mutant cells , or in the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene. Complex interactions were found between members of the PI3K/AKT/mTOR pathway and MAPK-, JAK/STAT, and Notch-1-mediated pathways that contribute to meningioma progression  was associated with hereditary meningiomas  signaling  pathway  is the most aggressive form of gliomas, accounting for approximately 50% of all glial tumors , where mutation of a single gene, brain tumor (brat), was shown to alter asymmetric stem cell division in larval development, and to generate massive neoplastic growth and enlarged adult brain formed entirely of neoplastic NBs , was shown to be necessary to suppress NOTCH1 signaling and to control stem cell activity during development to reduce tumor growth  the Drosophila ortholog of Hugl-1, in the type II NBs of the central brain  gene , the Drosophila homolog of Fibroblast Growth Factors , and suffered from oxygen shortage (hypoxia). In addition, it was observed a trans-differentiation of tumor cells into pseudo-tracheal cells with and the formation of new vessels, mimicking human FGF-mediated vascularization in cancer  that fuse with sperm to modulate its activity and protect its homeostasis , a widespread form of leukemia, and to identify the genes responsible for the disease. AML1 is a transcription factor, responsible for activating myeloid differentiation, which has a counterpart in the fly  in cancer cells requires the activation of the JAK-STAT, JNK, TNF-α, and Toll/Imd/TLR signaling pathways , binds two receptors called Wengen , it was shown that cancer cells induce hemocyte's recruitment and proliferation in vivo by activating JNK signaling to cause the expression of JAK/STAT cytokines , AcetylCo-A Carboxylase (ACC) and Stearoyl-CoA desaturase-1 (SCD), are targets of pharmacological inhibitors to decrease cancer proliferation , however numerous cohort studies reported that overweight people are more likely to develop certain types of cancer including endometrial, breast, liver, and ovarian cancer Cancer, . Obese pDrosophila is convenient to use as it provides many tools for genetic and molecular investigations. Adult stem cells are required for tissue homeostasis and repair after injury and in adult flies, populations of stem cells are present in the posterior midgut, testis, and ovarian follicle rendering it again a good system to dissect these stem cell programs  in the division of stem cells  have more features than tissue stem cells because they are able to initiate the tumor growth and fuel its maintenance and metastasis  the leading contributor to early-stage drug discovery. HTS consists of random screening of chemicals to find an affinity for a specific protein or biological activity characteristic of a disorder. Once identified Drosophila for several disorders affecting the central nervous system, kidney and metabolism , the importance of tumor microenvironment, cancer cachexia, drug resistance and tumor-associated vasculogenesis, which was recently found to be functionally conserved in fly's cancer. Additional cancer hallmarks such as genomic instability, resistance to cell death, cell metabolism reprogramming, tumor-promoting inflammation and evasion from the immune system, have been studied and extensively characterized in Drosophila. Finally, although the evolutionary difference between Drosophila and humans certainly represents a restriction to the use of the fruit fly in drug discovery and development, phenotypic screenings have proven relevant to identify potential drugs that would elude the classic screens in the absence of targets. Drosophila is also offering a significant contribution to the investigation of organotypic cancers, since despite the evident differences at the macroscopic level, organ cells and functional units are usually well conserved at the biochemical and structural levels respectively. This conservation allowed to develop thyroid, lung, prostate, gut, brain and blood cancer models starting from the most characteristic genetic lesions found in the same human cancers. These models, as described in the review, are greatly helping in dissecting the contribution of specific molecular pathways to the final cancer phenotype. Given the heterogeneous nature of mammalian solid cancers, new strategies are being developed to decipher cancers at single-cell resolution. The international Drosophila community has always been engaged in the development of novel, sophisticated genetic tools, which allowed in the last 30 years to revolutionate functional gene analysis. For this reason, we anticipate that the use of the fruit fly will move fast into the field of precision medicine, contributing to seminal findings in this new era of cancer research.The communication between tumor cells and their microenvironment is largely implicated in neoplastic growth, hence the substantial difficulty to recapitulate the features of malignant transformation in cellular systems. Cancer research needs All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The authors report a case of progressive ossifying myositis (POM) in a 13-year-old boy, revealed by dry cough and dyspnea. Conventional chest x-rays and whole-body CT showed extraskeletal ossification that seems to affect the left bronchial strain and trachea. This lesional topography, if established, not yet described to our knowledge, contrasts with the observations of all the authors, including Munchmeyer, for whom smooth muscles and muscles attached to the skeleton by a single end are spared by the heterotopic ossifications characteristic of the disease. Therefore, this observation raises the question of the ubiquity of muscle ossifications during POM. Progressive ossifying myositis or fibrodysplasia (POM or POF), also known as Munchmeyer's disease, is an extremely rare genetic disease –3. The hIt is about a boy of 13 years old, cachectic, received for management of a dyspnea occurring on chronic dry cough. Physical examination showed a condensation syndrome of the base of the left pulmonary field. He presented with a fever, physical deformities made of bilateral nonpainful back swelling, dorsolumbar scoliosis , and bilIn total, we noted active atelectasis of the left lung by tracheobronchial stenosis related to ossification of the muscles of the wall of these airways, all occurring in a context of extraskeletal heterotopic ossification of muscular origin, accompanied by characteristic deformities including bilateral hallux valgus. We retained the diagnosis of progressive ossifying myositis. Due to the risk of iatrogenic ossification, no biopsy or other diagnostic or therapeutic surgical procedures were performed. He received nonsteroidal anti-inflammatory drugs, antibiotics associated with respiratory physiotherapy sessions.Our observation thus reports a case of progressive ossifying myositis with heterotopic ossification that seems to affect the smooth and connective muscle wall of the trachea and the left bronchus strain. This topography of lesions contrasts with Munchmeyer, Hasan, and Kaplan's remarks, according to which progressive ossifying myositis spares smooth muscles and muscles that do not fit on the skeleton by their two extremities such as ocular muscles, diaphragm, tongue, pharynx, and larynx muscles –7. IndeeThis case of progressive ossifying fibrodysplasia with a potential ossification of the tracheobronchial airway wall muscles leads us to question the ubiquitous nature of heterotopic ossifications during POM.


The global increase in the frequency and severity of natural hazards and extreme climatic events necessitates more efficient global and national strategies to reduce the likelihood and impact of traumatic consequences for disaster-affected populations. The recent inclusion of mental health in the Sendai Framework for Disaster Risk Reduction marks a pivotal point in the recognition of the significant burden of disasters on mental health, and a global commitment to reducing its impacts. Nevertheless, effective agreement implementation and efforts to reduce disaster mental health risks are facing significant challenges. These include a lack of clarity about the conceptual interlinkages and place of disaster risk reduction principles within the field of disaster mental health, which is traditionally marked by a prevailing recovery orientation, and the need for effective translation into disaster mental health policy and practice. Therefore, this study drew on data from interviews with European disaster mental health and risk reduction experts in order to appraise the merit and implications of a global disaster risk reduction policy for advancing population mental health in the context of disaster. Study findings outline existing opportunities, challenges, and key strategies for the integration of disaster risk reduction within disaster mental health policy and practice. At the global level, human mental health and wellbeing is being increasingly jeopardised through rising trends in population exposure to severe natural hazards and extreme climatic events ,2. DespiInternational recognition of the need to better manage the varied risks associated with disaster exposure has resulted in seminal intergovernmental agreements and policy frameworks to guide global and societal disaster risk reduction ,7. The SThe Sendai Framework is structured around the key elements of a global goal and expected outcome, operationalised through seven global targets primarily aimed at reducing: disaster mortality, the number of people affected, economic losses, damage to infrastructure, and disruption of basic  services. In addition, four cross-cutting priority areas for global action highlight the critical importance of: (1) understanding disaster risk, (2) strengthening disaster risk governance, (3) investing in disaster risk reduction, and (4) enhancing disaster preparedness for effective response and to ‘build back better’. As part of a concerted implementation effort, the Sendai Framework also outlines local, national, and regional level stakeholder roles and responsibilities.One of the cornerstones of the Sendai Framework is its strong emphasis on human health. This is particularly evident in 35 direct references to health, the explicit inclusion of health in the expected Sendai outcome , and direct links to health in four of the framework’s seven global targets ,9. WithiHowever, despite the formal inclusion and recognition of the importance of population mental health, significant challenges remain to the effective Sendai agreement implementation and associated efforts to reduce disaster mental health risks and consequences. These include a lack of clarity about the conceptual interlinkages and place of disaster risk reduction principles within the field of disaster mental health, which is traditionally marked by a prevailing recovery orientation, and the need for translation into disaster mental health policy and practice.Conversely, key aspects relevant to disaster mental health have thus far received relatively little systematic attention in the context of disaster risk reduction frameworks. This, however, is in stark contrast to more general and public health domains, which are increasingly being considered in disaster risk reduction contexts ,9,11,12.For brevity, this article adopts an inclusive definition of disaster mental health (DMH) as a scientific discipline and field of practice that is concerned with understanding, preventing, and addressing mental health problems and promoting psychosocial wellbeing and resilience in disaster and emergency contexts. Thus understood, DMH is not merely limited to efforts that seek to better understand or address psychiatric phenomena via therapeutic interventions, but rather includes recognition of the vital importance of a broader range of psycho-social factors, outcomes, and support strategies in disaster and emergency contexts. Emerging from traditions, such as trauma and stress studies, and incorporating related humanitarian practice fields, such as Mental Health and Psychosocial Support, DMH has amassed a considerable body of knowledge about the potential spectrum of disaster mental health outcomes and relevant intervention and support strategies over time ,15. Yet,This study therefore drew on data from interviews with European disaster mental health and risk reduction experts in order to appraise the merit and implications of global disaster risk reduction policy for advancing population mental health in the context of disaster. More specifically, this study examined the conceptual nature of disaster mental health risks, as well as concrete opportunities, current challenges, and key strategies for the integration of disaster risk reduction within disaster mental health policy and practice.This study drew on data from interviews with 17 European key informants (including 14 DMH and 3 DRR experts), which were conducted between May and September 2016, as part of a larger research project that examined the early implementation of the Sendai Framework in Europe. In view of the relatively small pool of key informants in this area, this exploratory study adopted a purposive sampling frame informed by prior stakeholder mapping to recruit eminent DMH and DRR experts at the European regional and national levels  for participation in semi-structured interviews. Participating DRR experts represented three of the 17 DRR experts recruited for the larger study who were both directly involved in the Sendai implementation and in a position to complete an interview schedule focused on disaster mental health. Key informants  were typically affiliated with scientific institutions and national DMH or DRR advisory bodies across the UK, the Netherlands, and Germany, or European-based advisory bodies with a broader international mandate.Semi-structured interviews were conducted on the basis of an interview schedule. The schedule included 15 questions that explored the intersection of DRR and DMH by eliciting information on: principal mental health risks in disaster contexts, DMH strategies to address these risks, and existing opportunities, current challenges, and key strategies for the integration of disaster risk reduction and disaster mental health. A copy of the full interview schedule is available from the author upon request. The interviews, which lasted between 40 and 95 minutes, were conducted either in person or remotely (via telephone or Skype), audio-recorded, and analysed thematically using NVivo11 . All key informants provided consent for study participation. The study protocol was approved by the Human Research Ethics Committee at the University of Melbourne (ID: 1646655.1).Key themes resulting from the expert interviews are summarised in the following, with the study’s thematic coding framework and illustrative participant quotes outlined in Key informants were asked about what they would regard as the principal mental health risks in disaster contexts. The principal mental health risks identified by the experts fell into five broad thematic categories. The first two of these highlighted commonly established risk factors for adverse mental health outcomes, as well as newly emerging risks that were contextually bound to the unfolding European refugee/migration crisis. The three remaining categories were focused on risks associated with the conduct of appropriate disaster mental health responses and intervention strategies, e.g., in relation to the adequate recognition and detection of complex mental health impacts, the provision of appropriate mental health support, and overarching disaster response communication and coordination.Key informants frequently identified established risk factors for adverse mental health outcomes. These factors included, amongst others, the nature of the hazard, exposure level, peri-traumatic and post-event reactions, various forms of loss , lack of (received or perceived) social support, distress impacting on normal functioning, the decay of the recovery environment, and secondary stressors in the disaster aftermath . Vulnerable population groups identified to be at particular risk and warranting special attention included those with pre-existing difficulties or severe mental illness, children, the elderly, socially isolated individuals, and people with disabilities.A second set of emerging mental health risks revolved around the unfolding refugee and migration crisis in Europe, with many experts indicating involvement in this crisis either inside or outside of Europe. Principal mental health risks identified in this context were often reflective of underpinning social and physical determinants of health. These highlighted the role of displacement as a major mental health risk factor given the loss of continuity of care, the impact of family separation , as well as frequent occurrences of unresolved missing person situations (which provided no opportunity for closure or appropriate mourning). Mental health risks specific to younger generations were posed by: disrupted education and development paths for youth ; the impact of disrupted schooling and language barriers on cognitive development; as well as lacking access to normal peers, play, and structure for children; and the impacts of malnutrition on the mother-child bond, routine lactation, and cognitive/physical development of infants.Failure to recognise the complexity and diversity of mental health impacts in disaster-affected populations was identified as a pivotal risk in the design and conduct of appropriate disaster mental health responses. Importantly, this included the risk of failing to detect those individuals who proceed to develop more persistent or severe mental health problems, distinct from those who initially experience common transitory distress responses. The shortcomings of a reductionist view were highlighted in terms of the failure to differentiate varying mental health risks of specific population groups , and in terms of a sole focus on specific signature disorders (such as post-traumatic stress disorder), rather than the relevant broader spectrum of disaster mental health outcomes and psychosocial consequences. Over-pathologisation on the part of disaster response planners further entails the risk of mismanaging normal human distress reactions to abnormal or disastrous circumstances. However, under-pathologisation may run the risk of failing to identify or reach those with significant mental health problems who may not otherwise readily access or seek support. Varied mental health risks posed by different disaster types and contexts, and interactions with pre-existing problems in disaster-affected communities, further compound the challenge of recognising complex disaster impacts in the design of appropriate mental health responses.Specific risks associated with the provision of appropriate mental health support to disaster-affected populations include the potential use of ineffective early interventions (such as debriefing), the lack of timely psychosocial care, the absence of clear and timely community information, and the lack of recognition of longer-term mental health provisions that needed to be put in place. In view of diverse emerging mental health problems and known barriers in the access to mental healthcare, the need was highlighted for a delicate balance between an emphasis on proactive support intervention and a stance of watchful waiting. This balance would help optimally align support efforts with the stage of recovery and nature of presenting problems, and not alienate affected individuals and communities in the process.Broader mental health risks were also identified in the context of disaster response communication and coordination. Non-consultative and top-down approaches of disaster response authorities can create mental health risks for affected communities further down the track. Politician behavior in disaster contexts can also be informed by and affecting public sentiment, whereas public perception of the way in which presenting health problems are handled or addressed by responsible authorities may pose a political risk for decision makers. Inherent risks of public disaster response communication included a general lack of communication, the uncertainty of (intended) outcomes, and possibility of unintended consequences. Moreover, disaster-poor countries can face challenges in communicating disaster risks to the wider public with a view to motivate self-protective action, which may lead to a stronger reliance on public authorities and experts in disaster contexts. Hierarchically organised civil protection systems, which are not traditionally citizen-centric, have therefore often failed to recognise existing community agency, resources, and self-help potential, or have struggled to translate a prevailing rhetoric of citizen engagement into effective practice. Conversely, the lack of public risk awareness, proper citizen engagement, and overarching stakeholder coordination and cooperation also increases the risk of adverse disaster outcomes and consequences.When asked about key strategies through which the DMH field was addressing these principal disaster mental health risks, experts identified strategies within four main areas.The development of overarching psychosocial disaster guidelines and response plans was seen as pivotal to the design and conduct of effective disaster responses and to addressing mental health risks in disaster contexts. Specifically, organisations with routine involvement in disaster responses will need to have psychosocial disaster plans in place. Although generic plans may never be specific enough to capture unique disaster circumstances, these nevertheless provide an important planning framework that can be adapted to concrete scenarios.Key mechanisms to detect and direct disaster-affected individuals to appropriate mental health support included the establishment of on-scene information and advice centres, the implementation of psychological screen and treat programs, and the establishment of disaster health registers. The role of public mental health awareness and wellbeing campaigns was raised in this context, as was the newly-developed concept of health passports for refugees and migrants, which may assist in providing greater continuity of care and access to vital medications across national boundaries.Designated mental health support strategies emphasised the need to provide screening, effective early intervention, and psychosocial support within the broader context of practical assistance. The need for basic psychosocial support strategies that could be provided by lay people and volunteer-based disaster relief agencies was highlighted. Specific psychosocial support strategies identified included the creation of safe spaces for vulnerable groups , as well as the provision of parental support, livelihood skill building, general information, or legal advice. Awareness raising for the specific situation and issues affecting (and advocating the protection of) vulnerable groups was considered particularly critical in the context of violence against women and for residents of psychiatric institutions. The integration of mental health support within primary care and ceasing of opportunities to strengthen existing mental health systems and ‘build back better’ after disaster were equally highlighted as key avenues to address systemic mental health risks in disaster contexts.Other strategies and avenues to reduce disaster mental health risks were identified in the context of disaster preparedness planning. These included the provision of dedicated first responder training, the establishment of organisational support systems, mechanisms to facilitate multiagency networking, cooperation and joint planning, and the mapping of existing services. The importance of prior vulnerability and needs assessments  was highlighted, as was the need to involve these groups and the broader public in disaster preparedness planning. The resulting need to adapt existing alert systems, evacuation plans, and risk/crisis communication to the needs of vulnerable groups was emphasised, as was the potential to adopt a stronger focus on resilience-building activities throughout the whole cycle of disaster prevention, preparedness, response, and recovery planning.Several questions explored the intersection of DMH and DRR in more depth, including existing challenges and opportunities for the integration of the two fields. Key integration challenges highlighted DMH and DRR as rather separate fields of practice, marked by practitioners from different professional backgrounds and a mutual lack of awareness. The use of technical jargon on either side was seen as an impediment to effective integration, as was the lack of DMH stakeholder involvement in the Sendai implementation process. The relative vagueness of the Sendai Framework, which does not specify key mental health risks to be addressed, along with its broad aims were seen to harbor the potential to lead to mental health initiatives that are not necessarily the most beneficial. Key challenges to greater recognition and use of existing DMH strategies within DRR included the lack of an empirical evidence base for specific psychosocial support strategies (which science requires to inform policy), and challenges in effective targeting of more preventative resilience-building initiatives before disaster strikes. Conversely, it was recognised that the Sendai implementation process did not necessarily follow a uniform international pattern but rather required unique integration within national systems and structures. Potential professional role and resource implications of the integration of the two fields were raised in terms of the necessary willingness of professionals to step outside of their brief, the perception that extra work or resources may be required, or that a stronger focus on community empowerment within DMH could result in less funding for traditional clinical or other core work. Other integration challenges included the limited sustainability of project-based initiatives, and lacking recognition of the vital role of DMH stakeholders in joint pre-disaster planning (beyond common ad-hoc involvement in response and recovery).Notwithstanding these challenges, experts identified wide ranging opportunities for the stronger integration of the two fields. Key integration avenues involved the use of inter-sectoral platforms, joint stakeholder meetings, and preparedness summits, as well as disaster-related information and referral websites, and mobile phone applications. Joint DRR-DMH fact sheets and DRR primers for DMH staff may facilitate mutual practitioner understanding. Building on existing European projects and networks, the development of a shared European position was regarded as useful. In this context, major disaster events were also seen as progress catalysts that can provide opportunities to explore new solutions and trial different ways of operating.DMH experts and practitioners can facilitate DMH/DRR integration by advocating the recognition of mental health issues in disaster prevention and response planning, integrating mental health knowledge at higher strategy and local planning levels, providing guidance on where mental health funding and efforts are best spent, and by continuing to build the underpinning DMH evidence base. Simultaneously, it was recognised that DMH must become better at providing clear and understandable messages and at marketing DMH knowledge, so that it can be more readily used by local authorities and stakeholders. Other DMH contributions to foster integration included psychosocial capacity analysis at the municipal level, prior vulnerability mapping, and knowledge and skill building in vulnerable groups to enhance self-help capacity and psychosocial stress management.Integration can also be facilitated by expanding the prevailing DRR mandate to include mental health, such as by addressing psychological stressors in public crisis communication, including mental health messaging in non-formal education, as well as through professional selection and equipment of first responders with the vital skills to handle common stress reactions.Promising conceptual interlinkages that facilitate future DMH/DRR integration efforts revolved around a shared focus on resilience building, the use of health promotion strategies, community-based and self-help approaches, and community mobilisation concepts that are already embedded in international guidelines for psychosocial emergency response. Other interlinkages exist between health and disaster literacy approaches, and between healthy cities and urban resilience frameworks.Formal integration steps highlighted the benefits of incorporating DMH guidelines as an appendix to the Sendai Framework, the need to operationalise DMH/DRR linkages and interventions to support broader application and effectiveness testing, devote project funding to integration efforts, and mandate stronger interdisciplinary and interagency work, such as in joint disaster planning.The findings of this exploratory study provide a first look at the DMH field through a DRR lens, and a vital perspective on the intersection of these two fields that can facilitate future integration efforts. Study findings indicate that it is clearly early days in terms of the formal integration of the fields, and that Sendai disaster policy awareness within the mental health field may be limited. Yet, the impending application of DRR concepts and approaches across varied societal sectors and health domains in the context of the Sendai implementation provides a pertinent and timely opportunity to examine its conceptual and practical implications for DMH and other established fields of practice.Application of the Sendai objective of understanding disaster risk within the context of a specific health domain and field of practice (such as DMH) inevitably involves the task of fleshing out an otherwise generic  notion of disaster risk, with domain-specifically relevant content that is consistent with the broader Sendai notion. A better understanding of pre-existing notions of disaster risk held among practitioners within a given health domain therefore constitutes an important preliminary step in developing a shared conceptual understanding and joint future integration and work agenda.In appraising the nature of principal DMH risks identified by the experts, and the place of risk within the DMH field more broadly, it is evident that DMH has developed an existing risk vocabulary (and associated evidence base) that is primarily centered on established risk factors for adverse disaster mental health outcomes. Such risk factors include a wide range of predisposing factors , as well as factors related to disaster exposure and secondary stressors, all of which have been well established in the literature .Nevertheless, beyond the primacy of this risk factor-driven understanding, the broad scope of identified principal DMH risks also spanned newly emerging mental health risks  and risks associated with the design and delivery of adequate support interventions . As a whole, these principal DMH risks are reflective of the developmental stage, existing sophistication, and key challenges of the field. Moreover, all these DMH risk notions (either directly or indirectly) have a shared concern with the potential for adverse disaster mental health outcomes.Specific DMH risk factors identified in this study are structurally different from the broader (probabilistic) notion of disaster risk, elaborated and defined in the Sendai Framework as “The potential loss of life, injury, or destroyed or damaged assets which could occur to a system, society, or a community in a specific period of time, determined probabilistically as a function of hazard, exposure, vulnerability, and capacity” . DMH ris(1)Newly emerging or exacerbated mental health issues among disaster-affected populations (Type A)(2)Adverse impacts on existing mental health support systems (Type B), for example, in terms of client/staff safety and wellbeing, infrastructure damage, service disruption, surge capacity, evacuation, and business continuity(3)Secondary effects of A and B on individual, community, business, and societal functioning (Type C)When DMH risks are classified in terms of the specific nature of adverse disaster outcomes considered, it becomes possible to distinguish at least three different types of DMH risk, and to conceive of DMH risk more generally, as the likelihood and severity of:(4)Lack of DMH preparedness or capacity (Type D)(5)Poor quality, lacking efficiency, efficacy, and coordination of DMH responses (Type E)Beyond these principal DMH risk types, it is also possible to identify more intermediate DMH risks, such as:Nevertheless, although these latter intermediate risks may constitute ongoing key challenges of the field, these can also generally be regarded subordinate to principal DMH risks of Types A and B. In considering the nature of domain-specific DMH risks of Types A–C, it is again helpful to draw upon the broader Sendai notion of disaster risk. This notion calls us to move beyond the mere consideration of adverse outcomes, and to adopt a comprehensive understanding of disaster risk as determined by the key aspects of hazard, exposure, and existing vulnerabilities and capacities .In view of the nature of identified mental health risks in disaster contexts, much of the existing arsenal of DMH strategies has traditionally been focused on addressing these risks during disaster response and recovery phases. As such, these strategies could be seen to require the prior occurrence of disaster event exposure in order to become relevant or applicable. Yet, interview data also suggested an increasing trend toward the exploration of more proactive, preventative, and resilience building initiatives within DMH, which, while still fledging in terms of an empirical evidence base , would aIn this context, it is interesting to note that the principal reference to mental health in the Sendai Framework  encapsulates an implicit understanding of DMH that firmly locates the role of the field within disaster recovery and building back better phases. As such, this conceptual understanding also reinforces the traditional DMH focus and self-understanding. It is also in this narrow sense that the genuine conceptual challenge posed by the Sendai Framework for DMH policy may be considered comparatively negligible, notwithstanding substantial variability in the existing capacity of countries to effectively apply DMH policy and know-how in practice . Put difYet, while undoubtedly more work must be done in terms of strengthening the existing capacity, effectiveness, integration, and sustainability of DMH systems , Sendai’Global Sendai Framework implementation between 2015 and 2030 will be monitored on the basis of national progress reporting across UN member states against agreed targets and indicators . The abiWhen these health-related Sendai implementation requirements are viewed through the lens of the above DMH risk typology, these would primarily call for a better understanding and the reduction of principal DMH risks of Type A  and Type B , whereas wider societal benefits of monitoring, enumerating, and reducing secondary, or more intermediate DMH risks of Types C–E, are also evident.In this context, the Bangkok Principles, in support of the implementation of the health aspects of the Sendai Framework  and relaAs the first study explicitly focussing on the nexus of DMH and DRR, this study adopted an open-exploratory and not theoretically-driven approach to examining DMH risks, strategies, and conceptual interlinkages of these fields from the perspective of European DMH and DRR experts. In view of the social construction of disaster risk , it is cDMH is in a favorable position to tackle the Sendai challenge to both inform DRR, and in turn, be informed by DRR. Expert identification of mental health risks and strategies does not necessarily imply that these risks are generally well understood or that such strategies are already widely in place across countries. The inclusion of mental health in the Sendai Framework is laudable, yet its general formulation does not reflect the existing key challenges and sophistication of the DMH field. DMH therefore needs to guide DRR on the relevant mental health risks and aspects of disasters and on the choice of effective strategies to address these. In turn, a shift in DMH orientation and further steps will be required to effectively translate DRR principles and concepts into DMH policy and practice.This study outlined several strategies and conceptual interlinkages that can facilitate future DMH/DRR integration efforts and provided valuable insights and lessons for the integration of global disaster policy in other health domains and established fields of practice.Future efforts to integrate global DRR policy within a given health domain need to address several interrelated levels. At a conceptual level, key DRR concepts and principles, such as disaster risk and risk reduction, need to be examined in terms of their compatibility with and implications for prevailing doctrines and practice approaches . The appAt a policy level, integration can be facilitated through systematic mapping of the Sendai Framework against existing policies and practice guidelines to identify key areas of overlap, existing gaps, inform strategic future planning, and focus areas for further development. Insightful examples of comprehensive Sendai mapping exercises already exist in regard to EU policies , and theAt a translational level, results of these foundational exercises can inform the shape and focus of key activities to operationalize existing linkages between these fields. These include the identification of promising bridging approaches or innovative case studies—at policy, service, or practical intervention levels—that can be applied more broadly and tested for effectiveness. Capitalizing upon and further developing existing avenues for joint cooperation between DMH and DRR sectors will become increasingly important, as is ensuring adequate DMH and health sector representation at all levels of the Sendai implementation process. In this respect, it is critical that mental health specific indicators be developed that align with broader Sendai indicators to facilitate ongoing monitoring and reporting of Sendai progress in terms of reduced mental health impacts at population and service system levels over time. One of the key strengths of the Sendai Framework is that it combines an ambitious and timely global policy program with broad multinational buy-in and clear guidance to facilitate its implementation at global, regional, national, and local levels.Health domain-specific DRR integration efforts can complement broad-based, whole-society DRR approaches by highlighting the relevance of DRR policy and implications of key DRR concepts, addressing existing translation barriers, and helping to unlock the unique DRR potential within established fields of practice. Notably, designated DMH interventions constitute one key element in the broader arsenal of DRR strategies that can reduce future risk of disaster exposure, associated traumatic impacts, and adverse mental health consequences. Therefore, effective disaster mental health risk reduction requires the application and integration of effective DMH strategies in the context of broad-based DRR strategies . To furtSuccessful Sendai Framework implementation and efforts to reduce disaster mental health risks critically hinge upon the application of both concerted broad-based DRR and effective DMH strategies, and on the effective integration of DRR principles within existing health domains and established fields of practice.