Endometriosis represents a frequently diagnosed gynecological affliction in the reproductive timespan of women, defined by symptoms ranging from pelvic pain to infertility. A complex interplay between the genetic profile, hormonal activity, menstrual cyclicity, inflammation status, and immunological factors define the phenotypic presentation of endometriosis. To date, imaging techniques represent the gold standard in diagnosing endometriosis, of which transvaginal ultrasonography and magnetic resonance imaging bring the most value to the diagnostic step. Current medical treatment options for endometriosis-associated infertility focus on either stimulating the follicular development and ovulation or on inhibiting the growth and development of endometriotic lesions. Techniques of assisted reproduction consisting of superovulation with in vitro fertilization or intrauterine insemination represent effective treatment alternatives that improve fertility in patients suffering from endometriosis. Emerging therapies such as the usage of antioxidant molecules and stem cells still need future research to prove the therapeutic efficacy in this pathology. Endometriosis is a challenging condition of reproductive-aged women, causing problems ranging from chronic pain to infertility. It is characterized by an estrogen-dependent stroma and endometrial glands found predominantly, but not exclusively, in the pelvic compartment . Due to Although the relation between endometriosis and infertility as a matter of a definitive cause-effect connection is still debatable, it is clinically recognized and well supported throughout the literature . CurrentThis manuscript constitutes a critical review and analysis of the literature and focuses on the epidemiological and clinical aspects of endometriosis as a disease and the current tools used for diagnosing this ailment, as well as several proposed mechanisms for infertility development and its current treatment options.Even though significant insight was gained on the disease through research initiatives in the last decades, the exact cause of endometriosis remains unclear. It has been accepted that the genetic profile, hormonal activity, inflammation status, and immunological environment, play an important role in the manifestation and progression of endometriosis . From anConcerning the environmental factors, it has been suggested that exposure to elevated levels of polychlorinated biphenyls , dioxin As for behavioral traits, the relationship between dietary preferences, alcohol and caffeine intake, smoking, and physical activity in regards to involvement in developing endometriosis has been studied . Some diIn terms of reproductive and gynecological factors, most of the risk factors associated with endometriosis focus on age at menarche, menstrual cycle length, duration of flow, and parity . MenarchGlobal efforts combining genetic and genomic technologies have been made to provide insight into the pathophysiology of this disease, resulting in the discovery of several regions linked to an increased risk of endometriosis . To dateFurthermore, recent insights have been gained through the study of this disease from a genetic/epigenetic perspective, suggesting that the endometriotic lesions might develop by implantation of floating endometrial cells possessing inherited and non-expressed DNA defects, a process aided by other factors such as immunologic imbalances, inflammation, and oxidative stress disturbances .The clinical presentation of reproductive-aged women suffering from endometriosis is highly variable, with symptoms ranging from pelvic pain, dysmenorrhea, to infertility , thus haStrenuous efforts have been made in order to present a clear classification of the disease, nevertheless, the World Endometriosis Consensus decided in 2014 that the best classification model should be a toolbox consisting of several other classification systems including the American Society for Reproductive Medicine (rASRM) and the Enzian classifications along with the endometriosis fertility index (EFI) . rASRM iThe constellation of symptoms relays mostly on the anatomic sites of involvement, represented in decreasing order of frequency by the ovaries, anterior and posterior cul-de-sac, posterior broad ligaments, uterosacral ligaments, uterus, fallopian tubes, sigmoid colon and appendix, and round ligaments . EndometAs for the clinical presentation of endometriosis located outside the gynecological sphere, bladder involvement can cause recurrent dysuria and suprapubic pain, and cyclic microscopic hematuria when localized in the ureters ,46. GastDiagnosing endometriosis requires a vast array of tools related not only to clinical assessment but also to biological clues as well as imaging techniques, whether non-invasive such as ultrasonography or surgical methods for direct visualization. Evaluating the presence of symptoms and performing a physical examination represent the first steps in diagnosing endometriosis ,52. As mPhysical examination, while executing the bimanual pelvic maneuver, points toward diagnosing endometriosis when several criteria are met such as palpable nodularity and abnormal pelvic anatomy, especially when located in the vagina and the rectovaginal space, the pouch of Douglas, the rectosigmoid, as well as the posterior wall of the urinary bladder ,51,52. OIn regards to laboratory findings, strenuous research has been made to identify the serum markers which can be used as screening tests for endometriosis, yet currently, none of the discoveries can be accounted as an effective tool due to inadequate sensitivity and specificity indexes . To dateA special interest has been shown towards CA-125, a high-molecular-weight glycoprotein antigen expressed in some derivatives of the celomic epithelium , used asImaging techniques have an important role in aiding the endometriosis diagnostic, whether non-invasive or invasive in nature, due to their power of pointing the exact location of lesions and assessing the disease extent. In this regard, numerous non-invasive imaging tools can be used, including ultrasonography and magnetic resonance imaging.Ultrasonography represents one of the cheapest, highly available, and non-invasive imaging tools for assessing endometriosis, either by transabdominal, transvaginal, or transrectal approach, being frequently used as an incipient screening test for endometriosis, as well as a preoperative tool for estimating the length of the surgical maneuvers . This imTo date, transvaginal ultrasonography represents the standard imaging technique for identifying ovarian endometriomas due to its high values in sensitivity (93%) and specificity (97%) when performed by an expert operator ,71,72. NNumerous attempts have been made to standardize the ultrasonographic method in order assure a complete evaluation of the lesions and in 2016, an international consensus group implemented a four-step systematic approach which includes four steps, respectively: in the first step a routine evaluation of uterus and adnexa is conducted, focusing on ultrasonographic features of adenomyosis and endometrioma; in the second step tenderness and ovarian mobility is evaluated; the third step involves assessment of the pouch of Douglas using the ‘sliding sign’; the fourth step focuses on exploring the anterior and posterior compartment, assessing deep infiltrative endometriosis nodules . DespiteMagnetic resonance imaging (MRI) is increasingly being used in the evaluation of patients with endometriosis, as a complementary method to transvaginal ultrasonography , particuExtensive efforts have been conducted to standardize the systems scores used to grade the disease’s extension by a consensus group focused on reproductive medicine that have materialized in the form of a classification system. This system assigns corresponding values to endometriotic lesions regarding the size of the lesions and the presence of adhesions material found on the gynecological structures. It is compartmentalized into four stages pertaining to the severity . DespiteSurgical exploration represents an invasive visualization technique used specially to acquire qualitative assessment data about the true extent of the endometriotic lesions. Despite all available imaging techniques, the laparoscopic inspection along with histologic confirmation , remainsDuring the last decades, enhanced laparoscopic imaging techniques have emerged, showing improvement in the detection and differentiation of specific tissues with the aid of either of narrow-band imaging (NBI), autofluorescence (AFI), or 5-aminolevulinic acid-induced fluorescence (5-ALA) . Even thUnderstanding the intricate mechanisms concerning the etiopathogenesis of endometriosis and infertility as a complication, was an enigmatic task in the era of limited diagnostic techniques, when the genetic, cytogenetic, and molecular tools were not yet fully developed. Although several studies have been focusing on the topic, there still little agreement regarding all the aspects that link these two medical entities. To date, in the case of not objectifying anatomical distortions such as adhesions and fibrotic tissue, few mechanisms shed light on the exact steps that lead to infertility .Over the years, the most acknowledged theory concerning the etiopathogenesis of endometriosis was that of the retrograde menstruation, described by the endometrial cell implantation in different peritoneal locations, cells that sidestep the fallopian tubes and implant in the peritoneum, where the newly created immune microenvironment aids in the survival of these cells  90]..90].While endometriosis is a chronic inflammatory disease that involves the presence of extrauterine endometrial-like tissue, adenomyosis is a benign condition that occurs at the level of uterus, within the myometrium, being characterized by the presence of ectopic endometrial tissue glands and stroma in this area ,92. ThisAlthough adenomyosis has many features in common with endometriosis and often coexists ,96,97, tRegarding female fertility, it has been suggested that 30–50% of those diagnosed with endometriosis are infertile , with anFunctional and structural changes in the eutopic endometrium and inner myometrium are characteristic of endometriosis and adenomyosis, these changes having negative consequences for female fertility. Altered endometrial receptivity in patients with endometriosis and adenomyosis is also linked to some molecular events that are associated with the process of implantation and embryo development .Disorder of these processes is associated with an increased likelihood of abnormal endometrial molecular expressions of genes that are part of the homeobox (Hox) gene family, as well as other autocrine and paracrine factors, growth and transcription factors, steroid hormones, molecules cell adhesion, immune and inflammatory mediators, and other factors, including myometrial contractility and uterine peristalsis ,102.Along with the technological advancements, several new mechanisms that could explain this link have been proposed such as endocrine and immunological abnormalities. From an endocrine perspective, most of the theories take into consideration defects in folliculogenesis and ovulation, as well as abnormal hormonal serum levels such as hyperprolactinemia. Mechanisms concerning the immunological alterations focus on events like sperm phagocytosis, embryotoxicity along with implantation defects that happen due to alteration on a molecular level . NeverthEven though the theory of retrograde menstruation  is stillThe first studies regarding the genetic predisposition of this ailment were conducted in 1981 when Simpson and colleagues  observedRecent findings of Rekker et al. (2018), suggested that changing the miRNA expression patterns of the endometrial stromal cells could to be involved in the pathogenesis of endometriosis . In theiMany studies have been performed to identify the polymorphism of genes involved in various molecular pathways specific to the pathogenesis of several diseases, especially those with an inappropriate immunological response, such as endometriosis.Among the pathways involved in the immune response that are disrupted in autoimmune diseases, inflammatory processes, allergies, and endometriosis, the family of genes that regulate Toll-like receptors (TLRs) ,134, typTLR receptors regulate the activity of immune and inflammatory factors that modulate the innate immune response, and the activation of the persistent inflammation phase by triggering oxidative stress. Due to activation of TLR4 signaling pathway, some specific process for endometrial proliferation are initiated by secretion of cytokine and other specific immune cells responsible for the regulation of inflammatory microenvironment . Some stThe link between infertility and endometriosis is complex, and understanding it implies unraveling multiple intricate pathways. From a biochemical perspective, oxidative stress represents one of the most researched factors linked to endometrial induced infertility. Aberrant increased levels of reactive oxygen species (ROS) resulted from oxygen metabolism impact the endometrial cells by damaging not only proteins and lipids but also DNA structure, thus altering the cellular cycle and function. One study focused on assessing the biochemical imbalances for women undergoing surgery for gynecological problems, found increased serum levels of such markers including advanced oxidation protein products as well as nitrates/nitrites, especially in patients suffering from advanced stages of endometrial disease .As with any other chronic inflammatory affliction, endometriosis has been proved by several studies to be characterized by a complex landscape of increased levels of inflammatory molecules such as cytokines, prostaglandins, and metalloproteinases, aiding thus in the development and progress of the disease ,142,143.Regarding the theory of immunological dysfunction, several research studies focused on the role of humoral and cellular immunity in the generation and progression of the disease ,151, fouThere are three therapeutic options available as a therapy for endometriosis-associated infertility: medical treatment , surgeryMedical therapy for patients with endometriosis-associated infertility involves two strategies, with the main purpose of improving fertility: either stimulation of ovulation and of the follicular development process or suppression of follicular development to generate amenorrhea and inhibit the enlargement of endometriotic lesions. A Cochrane review showed that suppressing ovulation using gonadotropin-releasing hormone (GnRH) agonists, oral contraceptives, progestins, and danazol is not considered a suitable therapeutic option for women suffering from infertility associated with endometriosis due to similar outcome regarding pregnancy when compared with women on placebo or no treatment .Medical treatment with these therapeutic agents tends to ameliorate pain symptoms, but they usually cause subfertility and therefore are not useful for patients with endometriosis-associated infertility with the purpose of increasing pregnancy rates and live births ,167.For ovulation induction, clomiphene citrate has been the most widely prescribed treatment, either alone or combined with gonadotropins ,167. AnoStudies have shown that prolonged treatment with GnRH agonists before IVF or ICSI may improve pregnancy outcomes in women suffering from advanced forms of endometriosis. Pre-treatment with GnRH agonists can improve the oocyte quality and the ovarian microenvironment ,170,171.Choosing the best suited therapeutic option for endometriosis-associated infertility represents a challenging task since various parameters such as the woman’s age, ovarian reserve, duration of infertility, the presence of pelvic pain, family history, ability to undergo IVF have not been properly evaluated in randomized clinical trials ,172.For younger infertile women (under 35 years) with minimal-mild endometriosis, a good first-line treatment is represented by expectant management or the use of supraovulation (SO) with intrauterine insemination (IUI). Older women with stage I–II endometriosis-associated infertility can greatly benefit from be a more aggressive treatment with SO/IUI or IVF. For infertile patients suffering from stage III–IV endometriosis, conservative surgery with laparoscopy or possible laparotomy could be the best available therapeutic option. IVF may be an efficient treatment for women with moderate to severe endometriosis, if all the aforementioned treatments do not meet the desirable fertility outcome .It was proven that prolonged treatment with GnRH agonists before IVF or ICSI may improve pregnancy outcomes in women suffering from advanced forms of endometriosis. Pre-treatment with GnRH agonists can improve the oocyte quality and the ovarian microenvironment ,170,171.Surgical treatment options in endometriosis-associated infertility are laparotomy, laparoscopy, or robotic surgery. Laparoscopic intervention is most frequently used due to its advantages, including a lower cost and a shorter recovery and hospitalization . SurgicaStudies have shown that surgical treatments have a series of potential disadvantages, such as surgical complications, a decline in ovarian reserve, postoperative adhesions, a possible postponement in infertility treatment ,177. ForNewer studies suggest that laparoscopic surgery as an investigative and corrective tool of the underlying pathologies prior to initiating numerous and various therapeutic attempts, should be taken into consideration for women suffering from unidentified infertility etiology, as it can greatly impact the outcome, as well as improving the overall costs of the lengthy treatment plan and ultimately the quality of life of the women going through this journey towards child conceiving . The samART includes a number of treatment methods that combine follicle stimulation with the handling and preparation of gametes in order to overcome infertility-related problems. This technology is comprised of in vivo or in vitro methods. In vitro fertilization implies that the oocytes are extracted, that they are fecundated and grown in the laboratory before being transferred back into the uterus. The most common in vivo technique is intrauterine insemination (IUI) that includes follicle stimulation or not, followed by the transfer of the semen into the uterine cavity. The most frequently in vitro method used in couples with a standard sperm count is in vitro fertilization (IVF). In situations of severely decreased sperm quality, an intracytoplasmic sperm injection can be used as a therapeutic option to increase rates of a good fertility outcome (ICSI) .IUI is a relatively simple method and has been subject to a number of studies regarding couples characterized by milder stages of endometriosis and normal semen quality. Since tubal pathology is one of the most frequent causes of infertility, it is essential to assess the tubal patency prior to IUI procedure. Hysterosalpingograpy (HSG) is commonly used as the first-line of action to evaluate the patency of the fallopian tubes and the uterine anatomy ,185.Patients with minimal to mild endometriosis that have been surgically diagnosed and have not shown any anatomic distortion, were directed to ovarian stimulation (with gonadotropins or clomiphene citrate) followed by IUI, which can be a suitable alternative to IUI alone or IVF ,186,187.Women suffering from moderate to severe forms of endometriosis do not benefit from IUI, on account of a probable impact on the uterine tubes. Consequently, it can be more relevant to compare minimally to mild endometriosis-associated infertility with unexplained infertility. Infertile patients suffering from mild forms of endometriosis achieve lower pregnancy rates following controlled stimulation and IUI than patients with unexplained infertility . NeverthStudies have showed that for every 12 women with minimal to mild endometriosis-associated infertility that underwent laparoscopic interventions for ablation of the endometrial implants, an additional pregnancy might develop when compared with the situation of no administered treatment. The number of laparoscopic interventions required to obtain an additional pregnancy in asymptomatic women with unexplained infertility is estimated around 40 ,190.Currently, IVF is the most successful treatment for infertile women with endometriosis and includes a few steps. The first step is ovarian stimulation initiated by drugs and the suppression of the menstrual cycle using other medications. After follicle stimulation, monitoring is performed at certain intervals to evaluate the follicle’s growth. Once the follicles have reached a proper dimension, medication is administered to induce the final stage of maturation of the oocyte. The next step implies collecting the egg, followed by the fertilization process. In cases of male infertility, the fertilization is completed by ICSI. The fertilized egg is cultured in a specific media for a few days and then the embryos are transferred into the uterus .A meta-analysis has shown that patients suffering from endometrioma that underwent IVF had comparable live birth rates as well as clinical pregnancy and miscarriage rates when compared to women that were not affected by this disease, even though the mean number of oocytes and the antral follicle count were lower and the risk of cycle cancellation was increased in women with endometrioma . StudiesA 2020 meta-analysis investigated the efficiency of the GnRH-a short protocol, GnRH-a long protocol, and GnRH-a ultra-long protocol used in IVF-embryo transfer in women suffering from endometriosis-associated infertility. The analysis of the randomized controlled trials has revealed that the clinical pregnancy outcome, especially in women with moderate to severe forms of endometriosis was significantly higher in GnRH-a ultra-long protocol group when compared with the GnRH-a long protocol group. On the other hand, in the observational studies no significant difference was observed between the two groups regarding the pregnancy rate .Systematic reviews reported that second-line conservative surgery for recurrent endometriosis has a negative effect on the IVF outcomes. The number of mature oocytes retrieved following IVF procedure and high-quality embryos was considerably reduced after second-line conservative surgery than after the initial conservative surgical intervention. Second-line surgery seems to significantly diminish the ovarian reserve and therefore this procedure should be attentively considered as an alternative therapeutic method of women who desire a future pregnancy ,195.The majority of medical treatment options available for endometriosis are suppressive rather than curative and symptoms reappear when medication is interrupted, therefore there is a need for novel developments in this domain. Elagolix, an oral anti-gonadotrophic agent is a novel and promising therapeutic method for endometriosis, that seems to stop the evolution of the disease and significantly reduce pain . ResveraTherapy based on mesenchymal stem cells has been applied in infertility treatment for women with premature ovarian failure and Asherman’s syndrome . Due to Multiple studies have indicated that circulating miRNAs are promising candidates as non-invasive biomarkers in the diagnosis of endometriosis .Endometriosis is a disorder that affects women of reproductive age, causing pain and infertility problems. Even though the association between infertility and endometriosis is still controversial, it is clinically recognized and well supported by many studies.The treatment of endometriosis-associated infertility consists of reducing or removing the ectopic endometrial implant and restoring normal pelvic anatomy through medical and/or surgical treatment and assisted reproduction technology. Medical treatments of endometriosis-associated infertility tend to ameliorate pain symptoms, but they are not effective in infertility treatment. These treatments should be utilized as an adjuvant to ART. ART includes IUI and IVF and comes into play when neither medical nor surgical therapy meets the desired outcome. IUI is efficient in patients with minimal to mild endometriosis, that have been surgically diagnosed and have not shown any anatomic distortion. IVF has shown to be the most successful treatment for infertile women with severe endometriosis.


In December 2019, a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that caused severe disease clusters was first reported in Wuhan, the capital of China's Hubei province. This viral disease, which is reported to originate from a seafood market where wild animals are illegally sold, has been transmitted among humans worldwide through close contact. Given the growing number of infected people worldwide and the disastrous consequences in all aspects of life, COVID-19 is a serious public health issue that requires special attention. In some countries, the epidemic curve of infection which was in the plateau phase or decreasing phase during the lockdown period increases day by day since the reopening, indicating the second phase of contamination. Therefore, the preventive measures recommended by the World Health Organization (WHO) must be respected to stop the spread of the disease. The international crisis due to the COVID-19 pandemic negatively affects many sectors, including animal production and its related industries. Indeed, with the cessation of imports and exports between countries, it is not possible to provide feeds that are considered as basic raw materials in livestock raising. This situation impairs animal movements, decreases production inputs availability, and negatively affects the economy. The sustainability of animal production is also affected by a shortage of workers due to the lockdown/curfew, the strong decrease in the purchasing power of the consumer, and the intensification of health care tasks. To prevent contamination of animal products and the spread of the disease with food, the U.S. Centers for Disease Control and Prevention (CDC) recommends frequent disinfection of food and human contact surfaces at production sites using an appropriate antiseptic. The purpose of this review article is to describe the current status of COVID-19 and investigate its effects on animal production. We propose potential approaches to keep animal products processing units and staff safe from SARS-CoV-2 infection and some strategies to improve animal production quantity and economy. Virology is the science that studies viruses that can be transmitted by food, soil, air, and contact , 2. ViraIn December 2019, an unknown epidemic of lung infections occurred in Wuhan, China, and spread to the whole country in a short period of 2–3 weeks. It was determined that the pathogen causing this epidemic was a coronavirus and the International Virus Taxonomy Committee named the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), based on taxonomy , 8. ThisThe COVID-19 pandemic has direct impacts on food systems, especially through changing the food supply-demand system, and indirect impacts through decreasing purchasing power and the capacity of food distribution and marketing, and increasing healthcare tasks . For insThe epidemic curve of infection is generally divided into 3 parts: increasing, plateau, and declining phases . The 3 pIn general, the peak of infection and deaths in the world is not yet observed. The total confirmed COVID-19 cases and deaths are 14.89 million and 610097, respectively as of July 22, 2020 [, HIV, Ebola, Hendra, and Nipah  and azithromycin (an antibiotic agent) has been approved to be effective in many countries, based on the works conducted in China , 41 and in vitro . A cliniin vitro . Indeed,in vitro  demonstrnd Nipah –46.in vitro study demonstrated the inhibitory potential of lopinavir and ritonavir against SARSCoV , remdesivir (an anti-ebola drug), lopinavir and ritonavi (commonly used against HIV) and pegylated interferon with ribavirin (used in the treatment of HBV and HCV) were urgently administered to patients with COVID-19 , 47, 48. SARSCoV , no clin SARSCoV . ClinicaThe use of serum or convalescent plasma from patients recovered from COVID-19 represents an effective treatment strategy because the treated patients from the viral infection produced a specific antibody in response to SARS-CoV-2 . AlthougQingfei paidu decoction, a clinical improvement was observed in 449 patients while 212 cases were stable  of some Indian plants including reported . These IAloe vera, Angelica gigas, Panax ginseng, Scutellaria baicalensis, Trichilia dregeana, Detarium microcarpum, Phragmanthera capitate, and Phyllanthus muellerianus have been reported to exhibit antiviral and immunomodulatory properties through stimulation of cytokines, activation of lymphocytes and improvement of macrophage actions . However, experimental and clinical studies are underway by international researchers to confirm the effectiveness of CVO for the treatment of COVID-19. Researchers at Germany's Max Planck Institute of Colloids and Interfaces in Potsdam are among a group of scientists from Germany and Denmark in collaboration with the US company ArtemiLife to conduct a project on the effects of Artemisia annua on COVID-19  composed of COVID-19 . On the COVID-19 , 64.Lawsonia alba (hina), Echinacea purpurea (eastern purple coneflower), Plumbago zeylanica (Ceylon leadwort), and Cissampelos pareira Linn (velvetleaf) also exhibit immunomodulatory properties by stimulating phagocytosis  has been used for decades in the treatment of influenza (a coronavirus) , it may ocytosis , 64. UsiAlthough there is sufficient information about the direct transmission of the new type of beta coronavirus agent, the information about the indirect transmission is not clear. Although there is no evidence that the disease agent is contaminated with food in the studies conducted up to this time, it is known that there is a possibility of contamination from the virus-contaminated surfaces. Based on this information, an idea can be made about how the disease can be transmitted from food contaminated by the disease. In the statement published by the FDA (US Food and Drug Administration) in February 2020, there was no evidence that COVID-19 could be contaminated with consumed food and nutrient packaging, but it has been stated that it is always important for general hygiene and sanitation to be thoroughly disinfected the hands and surfaces when handling food, cooking, and serving. Raw meat products should not be kept together with other foods, and food should be cooked at the right temperatureAccording to the report published by the WHO, there is no information that the SARS-CoV-2 virus has been transmitted by foods, but according to the previous coronavirus outbreaks (SARS-CoV and MERS-CoV), it has been reported that there are some suspicions about the coronavirus can be found in animal foods that have not been heated treatment . This shIt has been reported that coronaviruses remain stable in cold environments . It is aThe COVID-19 outbreak has raised concerns about potential medical supply issues, including both pharmaceuticals and medical products such as personal protective equipment  and surgical drapes . When woA small number of animals worldwide have been reported to be infected with SARS-CoV-2, mostly after close contact with people infected with COVID-19. In March 2020, two dogs (in Hong Kong) and two domestic cats  belonging to SARS-CoV-2 infected persons and exhibiting COVD-19 symptoms were tested positive for SARS-CoV-2 –80.On March 27, 2020, a four-year-old tiger at the Bronx Zoo in New York City developed a dry cough and some wheezing. On April 2, 2020, the samples were collected from the tiger and she was tested positive for SARS-CoV-2 . By ApriPresently , the United States Department of Agriculture (USDA) has reported numerous cases of SARS-CoV-2 in cats, dogs, lions, tigers, and minksAlthough routine testing of animals for SARS-CoV-2 is not recommended, adequate measures  must be implemented immediately in the case of suspected cases , using a One Health approach between local, state, and/or federal public health and animal health officials, as recommended by the Centers for Disease Control and Prevention, US Department of AgricultureAdequate surveillance is needed to detect infected animals and workers at an early stage for efficient response to prevent the spread of disease. The WHO in cooperation with the Food and Agriculture Organization of the United Nations and OIE-World Organization for Animal Health encouraged collaboration, networking, and technical consultation for jointly analyzing epidemiological and human-animal interfaces and promptly sharing and distributing public health information .The severity of the effects of the COVID-19 pandemic on agriculture, food, and therefore feed sector varies by country . Many faFor instance, in Turkey, the price of maize, barley, cracked wheat, and wheat decreased from January to June 2020 . During In the UK, the COVID-19 crisis increased the price of feedstuff. Indeed, the price of wheat, barley, oats, soybean, soybean meal, rape meal, sunflower meal, corn gluten feed, and molasses increased from January to May 2020, with a peak generally observed in March-April  . The peaRations cannot be prepared as desired due to the inability to import feed. The basic principle taken into account when preparing the ration is to give animals the carbohydrates, protein, fat, vitamins, and minerals they need to obtain maximum efficiency with minimum cost. Productivity per animal is likely to decrease due to the lack of basic nutrients in animal feed. According to a study with 1,008 participants in Wuhan Province of China during the beginning of the disease, it has been reported that people's interest in game meat has decreased and the demand for organically produced animal products in farms has increased .During the COVID-19 pandemic, the transportation of animal feeds and food, including animal production products, encountered many obstacles. For instance, in China, milk transport was disrupted by tight road traffic controls, leading to milk dumping . MoreoveThe impact of the COVID-19 pandemic on animal disease prevention and control is observed around the world. Some examples are summarized in The closure of markets during the COVID-19 crisis created an imbalance between production and consumption, leading to lower demand, lower sales, and falling prices. For instance, American pig prices dropped by about 27 percent in just over a weekAs reported by Hafez et al. , the strThe impact of the COVID-19 crisis on animal production is serious. The maintenance of animal production activities should be seen among the priority sectors and the decisions of the governments should be in this direction. Some recommendations and precautionary measures are given below:- To maintain animal production and prevent possible adversities, it is necessary to ensure the sustainability of ordinary processes such as feed shipment and supply of feed raw materials by applying the necessary disinfection processes . It is a- The animal health professionals should be informed (from trusted sources) of the evolution of the COVID-19 pandemic in particular in their locality and of the clinical and therapeutic progress of the disease to implement new preventive methods and biosafety measures if necessary.- Anyone with COVID-19 symptoms (confirmed or suspected cases) including asymptomatic or recovering patients should avoid close contact with animals until cleared by medical providers.- Prevent animal diseases by maintaining good animal husbandry and production practices.- Workers, especially veterinarians, should have a contingency plan, such as keeping an inventory of chemicals and equipment and implementing the latest laws and regulations regarding online veterinary consultation during the COVID-19 crisis.- Animal health professionals should collaborate with pharmaceutical industries, communication channels , and staff in charge of the prevention and treatment of COVID-19 to organize meetings and seminars, preferably webinars, to raise awareness in animal production with important recommendations that can stabilize the activity.- The countries should maintain open borders for imports and exports to allow trade while respecting all COVID-19 preventives measures.- The government should provide financial means or loans to animal production centers to increase the supply of animal feed and pay the wages of workers.- The government should promote alternative sales channels of animal products such as e-commerce instead of public markets to avoid physical contact between people to prevent disease transmission and boost the economy.- Develop an alternative and effective strategy to increase production with fewer workers, for example by adjusting working arrangements if an employee is absent due to COVID19 or in quarantine and by adjusting the sick leave policy of workers.- To ensure the optimal functioning of the animal products supply chain, governments can promote collective marketing to maintain demand, and coordinate with suppliers to buy products and redistribute them through adequate channels .The increasing prevalence of COVID-19 infection worldwide is a serious international public health issue as it affects all aspects of life. Although some countries are reopening, the number of confirmed COVID-19 cases is still increasing day by day and the second phase of contamination is observed in many countries. Some researchers have proposed the use of some vitamins  and foods to boost the immune system and prevent COVID-19 infection, but a specific effective treatment or vaccine against COVID-19 is not yet available. It is imperative to follow the preventive methods recommended by the WHO to limit the spread of this disease. Recent data reported the possibility of transmission from infected patients to animals, so adequate surveillance is also needed to detect infected animals and workers at an early stage for efficient response. Although there is no evidence of disease transmission through the foodstuff or its packaging, it is important to reinforce the current hygiene rules and to make them more attentive to eliminate concerns in consumers' approach to the consumption of foodstuffs. To meet the demand for animal products and boost the economy, it is essential to resolve access to animal feed and other raw materials on a state basis.PBDD, VK, CO, and KS participated in the study conception, implementation and data analysis, and drafted the manuscript. KS supervised this study from the conception to manuscript review and validation. All co-authors read and approved 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. The handling editor declared a past co-authorship with one of the authors KS.


Hypopharyngeal glands (HGs) are the most important organ of hymenopterans which play critical roles for the insect physiology. In honey bees, HGs are paired structures located bilaterally in the head, in front of the brain between compound eyes. Each gland is composed of thousands of secretory units connecting to secretory duct in worker bees. To better understand the recent progress made in understanding the structure and function of these glands, we here review the ontogeny of HGs, and the factors affecting the morphology, physiology, and molecular basis of the functionality of the glands. We also review the morphogenesis of HGs in the pupal and adult stages, and the secretory role of the glands across the ages for the first time. Furthermore, recent transcriptome, proteome, and phosphoproteome analyses have elucidated the potential mechanisms driving the HGs development and functionality. This adds a comprehensive novel knowledge of the development and physiology of HGs in honey bees over time, which may be helpful for future research investigations. Exocrine glands have the potential to release their secretions to the external of the insect through a duct and can be categorized into pheromone producing (mandibular glands) and non-pheromone producing  structures. The hypopharyngeal glands (HGs) were first reported in 1846 by Nickel , the development process of HGs could be divided into several key events  Groh an. At pupaFurthermore, the basal portion has nuclei that contain condensed and fragmented chromatin , the HGs are in the phase of rapid development, small sized and well-structured cell cytoplasm with the acinus only being a cavity. Nuclei are larger and round with an obvious chromatin granulation and small vesicles around the nucleus , secretory vesicles have developed on 3rd day; the acini size and number of secretory vesicles peak during 6–10 days , these glands are composed of several acini smaller than those of NBs. Moreover, the HGs gradually shrink and their secretory activity decreases , a strain of honey bees selected from Italian bees (ITBs), possess larger acini size as compared to ITBs  during winter and summer seasons. The foragers in all bee races presented higher lipofuscin accumulation than nurse bees during both seasons. Thus, irrespective of seasons, the acini size and lipofuscin accumulation are inversely correlated with each other in the nurses and foragers of all bee races  and ribosomal proteins are expressed higher in NBs, whereas they rapidly decrease their expression in foragers , the mammalian target of rapamycin (mTOR), and transforming growth factor-beta (TGF-β) signaling involve nutrient availability, intrinsic developmental program, metabolism (Barchuk et al., Understanding the morphogenesis of honey bee HGs and the factors which regulate HG development is essential for further investigations of the functionality of the glands. HGs are age-dependent structures in honey bees that change with the acinus size and correlate with different social behavior. Various factors including honey bee races, food, colony size, season, pesticides, and Varroa infestation affect the ontogeny and physiology of HGs. In the pupal stage, the HGs are comprised of incomplete structures and irregular shape of secretory units. In worker honey bees, each gland consists of thousands of two cell units, secretory cell, and duct cell. HGs of NBs are well-developed and synthesize RJ; while in FBs, the glands shrink and synthesize α-glucosidase, glucose oxidase, and invertase that convert nectar into honey. In addition, a subset of genes, proteins, and phosphoproteins underpin the morphogenesis and physiology of HGs. Further studies using gene-editing tools are required to investigate the specific function of genes or protein that regulate the ontology and physiology of HGs in the worker bees.SA prepared the original draft. SK and KK review the manuscript. JL conceived the manuscript and supervision. All authors have read and agreed to the published version 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.


Anatomically, the brain is a symmetric structure. However, growing evidence suggests that certain higher brain functions are regulated by only one of the otherwise duplicated (and symmetric) brain halves. Hemispheric specialization correlates with phylogeny supporting intellectual evolution by providing an ergonomic way of brain processing. The more complex the task, the higher are the benefits of the functional lateralization . Functional asymmetry has been broadly studied in several brain areas with mirrored halves, such as the telencephalon, hippocampus, etc. Despite its paired structure, the hypothalamus has been generally considered as a functionally unpaired unit, nonetheless the regulation of a vast number of strongly interrelated homeostatic processes are attributed to this relatively small brain region. In this review, we collected all available knowledge supporting the hypothesis that a functional lateralization of the hypothalamus exists. We collected and discussed findings from previous studies that have demonstrated lateralized hypothalamic control of the reproductive functions and energy expenditure. Also, sporadic data claims the existence of a partial functional asymmetry in the regulation of the circadian rhythm, body temperature and circulatory functions. This hitherto neglected data highlights the likely high-level ergonomics provided by such functional asymmetry. The mammalian brain is an organ with symmetrical organization. Anatomically, the mid-sagittal plane cuts the brain into two identical halves with a mirror-symmetric organization in the halves’ histology. However, careful comparison of the two sides shows a number of macro- and microanatomical differences between the sides, which include asymmetrical densities and distribution of distinct types of neurons, the size of specialized circuits or regions, etc.Morphological differences imply accompanied functional asymmetries. Paul Broca, a French physician was the first to report lateralized functioning in the brain . Broca dThe lateralized task-management of the hemispheres provides an elegant solution for “ergonomic use” of brain resources. As an evolutionary tendency to optimize energy utilization, it was reasonable to assume that other brain areas also display functional asymmetry. Indeed, after the initial findings of cortical lateralization, studies have described functional asymmetries in other brain parts such as the hippocampus, habenulae and thalamus, not to mention the characteristic localization of spinal tracts and associated gray matter regions ,3,4.Similar to other brain areas, functional asymmetry of the hypothalamus has also been demonstrated as early as the late 1970s ,6. InterFunctional aspects of the hypothalamic asymmetry could be at least in part coupled with micro-morphologic lateralization. Such morphological basis of the functional asymmetry might manifest in the synaptic plasticity (synaptic remodeling) of the hypothalamic neuronal circuitries previously described as a crucial event in the hypothalamic regulation of the ovarian cycle ,8,9. UnfAsymmetry of the neuroendocrine system has been last reviewed in 1997 ; howeverThe hypothalamus is part of the basal forebrain, belongs to the diencephalon and is connected to the pituitary gland by the pituitary stalk. The two hypothalamic sides contain like-named nuclei showing a (mirror) symmetric tissue architecture. The corresponding nuclei of the two sides are thought to (collectively) integrate the same peripheral and central signals that strengthen the idea that the hypothalamus  works in unity as a diencephalic functional module.The hypothalamus is involved in the mediation of endocrine, autonomic and behavioral functions, such as reproduction ,13,14, tBased on the above-mentioned phenomenon, hypothalamic processes are strongly interrelated and interdependent; however, for didactic reasons, we are going to discuss them separately.One of the most important, at the same time most investigated roles of the hypothalamus is the regulation of reproductive functions. Intrahypothalamic pathways controlling the ovarian cycle (through the regulation of gonadotrophin-releasing hormone (GnRH) and consequential pituitary LH release) converge on GnRH containing neurons in the left and right hypothalamic sides to maintain the normal—also cyclic in females —reproductive activity. However, hypothalamic functions, being physiologically strongly linked, are regulated by neuronal populations whose partial morphological overlap (neurons participating in more than one regulatory function). This attribute of the hypothalamic machinery should be considered during the below discussion of the previously reported functional aspects of hypothalamic asymmetry.Among the pioneers, Gerendai et al. examined the asymmetry in female reproductive functions by hemi-gonadectomy and found vastly higher GnRH concentrations in the right side of the hypothalamus compared to the left side  . Based oAmong these early morpho-functional experiments, impact of hypothalamic asymmetry on gender-specific differentiation and behavior was also studied. For example, it turned out that left- and right-sided estradiol implants have different effects in neonatal female pups , and uniAs experimental methods have improved, more reports show that the direction and degree of hypothalamic lateralization may be reflected by the consecutive phases of the estrous cycle and that the timing of ovulation might also be determined by lateralized actions of the neuroendocrine hypothalamus. In 1994, Moran et al. showed decreased (or even ceased) ovulation rate in female animals whose right anterior hypothalamic area (responsible for GnRH-release) was surgically lesioned . In the Recently, a new aspect of hypothalamic asymmetry research emerged, when our research group measured mitochondrial metabolism separately in the left and right hypothalamic sides ,9,45. AnSynapses connecting distinct hypothalamic areas rearrange during a remarkably rapid remodeling driven by endocrine and paracrine effects of both local neurohormones and peripheral signals such as the gonadal estrogen feedback. Due the high energy needs of these micro-morphologic changes, synaptic events are reflected in the fluctuation of the intensity of cellular metabolism and dynamic changes in mitochondrial activity. Indeed, our results describing the estrogen-related hypothalamic asymmetry can be nicely appended to the previously described estrogen-dependent mechanisms  and events that lead to the short-term neuronal plasticity-related to GnRH peak ,49.The regulation of male reproductive processes are based on the very same morphological basis (HPG axis and GnRH neurons), but the main difference is that in males, due to the early masculinization of the brain, the hypothalamus is not able to respond to rapidly growing estrogen levels with a surge in GnRH and consequently, luteinizing hormone (LH) levels; thus, gonadal steroids have only negative feedback effects. Due to this developmental difference, the main difference compared to females is the lack of reproductive cyclicity.Early experiments in the 1970s already indicated an asymmetry in the neuroendocrine regulation of reproductive functions in male rats. An asymmetric distribution of GnRH-immunoreactive cells was detected in male mice with a right-sided dominance . InteresAs in the case of females, hemigonadectomy  helped in understanding of the hypothalamic asymmetry in male animals, and unilateral connection has also been found between the gonads and the hypothalamic sides ,53. ThesIt was a further addition to our knowledge on hypothalamic asymmetry that exposure to a mild cold stress (two hours before sacrifice) elicits asymmetric response in the GnRH release  . This fiFinally, on the contrary to female rats, mitochondrial activity measurements failed to demonstrate any reproduction-related metabolic asymmetry in male hypothalami .The main neuronal populations regulating food intake and energy homeostasis are also located in the hypothalamus. Based on their mechanism of action, these neurons can be divided into two groups—orexigenic (increasing hunger and food intake) and anorexigenic (decreasing hunger and food intake). The orexigenic and anorexigenic neurons in both hypothalamic sides form complex circuitries, known as the melanocortin system .There are reports to suggest that unilateral neural pathways connect feeding centers to hypothalamic structures with asymmetric functions ,57,58. IThe first evidence for hypothalamic asymmetry with regard to control of food intake appeared in 1996 . This stIn consonance with the above data, our study on fed and fasted (24 h food-deprivation) female rats showed asymmetric metabolic changes between the two hypothalamic sides . In femaAs mentioned earlier, related to the reproductive function, hypothalamic circuits involved in regulation of energy expenditure and food intake remain plastic through the adulthood (reviewed in ). CriticThe suprachiasmatic nucleus (SCN), the master clock of the body, is a paired hypothalamic nucleus located bilaterally on the dorsal side of the optic chiasm. Neurons projecting from the nucleus control the endogenous fluctuations that occur in the body with a rhythmic pattern which begins a cycle in about every 24 h following the environmental light–dark (day–night) periods .Per gene was unilaterally expressed on either the left or the right side, while Bmal1 was only found on the contralateral side to Per [arginine vasopressin and c-Fos genes, as well. Later, Mahoney et al. evaluated the contribution of neural pathways to the determination of the circadian oscillation peripherally through assessing expression of the above clock genes [As expected, the regulation of the circadian rhythm also shows some degree of left-right asymmetry. Most research on the regulation of the circadian rhythm was carried out on golden hamsters kept in constant illumination resulting in a phenomenon termed as “splitting”. Several species of mammals and birds, if exposed to constant lighting, can exhibit a disrupted activity of the circadian pacemakers leading to a behavioral arrhythmicity. This arrhythmicity is characterized by a dissociated (or “split”) locomotor or physiological activity in which a single daily period of activity is divided (or “split”) into two periods of equivalent activities (around 12 h apart) with a resting period between them ,63. Datae to Per . The samck genes . ResultsLocomotor activity and GnRH release share a common circadian pacemaker in the suprachiasmatic nucleus (SCN), thus de la Iglesia et al. speculated that in split hamsters, the activity of the left and right GnRH neurons may reflect the sequential activity of neurons in the ipsilateral SCN . Indeed,At the same time, there is evidence to suggest that both hypothalamic sides maintain separate circadian oscillators and the SCN functions independently on the left and right sides . FurtherWhen examining the hypothalamic regulation of food intake, our research group also revealed some insights to the asymmetric nature of circadian events. In ad libitum-fed animals, the left hypothalamic side showed a higher metabolic activity around the day-to-night and night-to-day transitions see C. While Besides the above functions, the hypothalamus also governs autonomic responses to temperature changes ,76,77. DThere is a well-established connection to the regulation of food intake and energy balance, thus one could easily presuppose that the TRH and thermoregulation is just as lateralized as the other physiological processes detailed above. Despite of this, only one study has been published that directly examined the hypothalamus from this aspect . In thisFurther research on the thyroid gland demonstrated obvious side-linked differences regarding the size, vascularization and innervation of the gland ,83. FurtThe hypothalamus can also influence heart rate, vasoconstriction, and stress reactions through neural pathways projecting to the lateral medulla . CardiovBased on anatomic lateralization in the pathways from DMH, functional lateralization in the control of cardiac functions was studied by Xavier et al. . They foThe hypothalamus plays a central role in the induction of immune responses via neural and humoral pathways to either enhance or depress the immune response ,91,92.First, Betancur noted an asymmetry in the control of the immune system when investigated how a lesion to the cortical area of the brain affects natural killer cell activity . The natAvailable data suggests that the side-specific responsiveness depends on the actual state of the immune response. While the left side may be involved in early-state inflammation, mature immunity may trigger the right side. The lateralization observed in serotonergic metabolism supports the above hypothesis on the left-sided dominance in hyperthermia and related somnolence.Despite of its relatively small size, the hypothalamus regulates a multitude of physiological processes in order to maintain the physiological parameters of homeostasis and reproduction. The hypothalamic regulation of most of these relevant neuroendocrine processes have been well studied and understood. However, the question of how the multitude of regulatory afferents are entrained into and assigned to the hypothalamic nuclei to precisely orchestrate the simultaneous regulatory functions in their known complexity has received little, if any, attention. Until recently, the hypothalamus was believed to be an unpaired brain structure, in which the two symmetrical sides equally control the same functions. Therefore, this scientific “dogma” meant that the several roles (functions) to regulate homeostatic processes are  crammed into each half of the hypothalamus to work simultaneously, in tandem.At this point, it seems that the hypothalamic sides are able to regulate the same functions but with different intensity . This gives us a handy solution for the evolutionary question: should the hypothalamus work in a duplex manner or could it spare at least some of its resources. In physiological circumstances, if the two sides are intact and fully functioning, the hypothalamus, by a yet unclear mechanism, is able to outsource functions to only one side. On the other hand, in case of a unilateral lesion, the uninjured side can further regulate the given homeostatic process. The clear understanding of this phenomenon, in other words, the better understanding of hypothalamic functions together with an established future in vivo diagnostic imaging method of the hypothalamus  carries the potential to help in improving therapies used in hypothalamus-linked health conditions.As described above, the topic of hypothalamic asymmetry has not been studied as intensely as it would have been necessary, however, by now it has become a rapidly developing research area and represents a very interesting field of neuroscience. Based on the limited number of papers, it appears that many researchers, after obtaining valuable and interesting data indicating asymmetric functioning, cease to carry on with their research in this field. This may be due to the enormous complexity of the hypothalamic functions, by which this extremely small brain area is able to orchestrate the normal vegetative and reproductive processes of the organism. Broad and systematic morpho-functional analyses could clarify the nature and significance of the functional lateralization of this brain area. Recent technologies of simultaneous positron emission tomography and magnetic resonance imaging or computer tomography enable a spatial resolution as low as 1–1.5 mm, which also allows a real time function-based mapping of diencephalic areas on rodent model using relevant radiotracers . This maWe hope that this review will attract more focus on the topic of the hypothalamic asymmetry. As this special field of research grows, accumulating data indicates that the correct understanding of the hypothalamic regulation of homeostasis requires the full exploration of the nature of task-sharing between the hypothalamic nuclei and the clarification of the involved neural pathways. Studies reporting that disturbances of lateralized functions may take part in the pathogenesis of hypothalamus-linked health conditions  suggest


Like other sensory systems, olfactory function deteriorates with age. Epidemiological studies have revealed that the incidence of olfactory dysfunction increases at the age of 60 and older and males are more affected than females. Moreover, smoking, heavy alcohol use, sinonasal diseases, and Down’s syndrome are associated with an increased incidence of olfactory dysfunction. Although the pathophysiology of olfactory dysfunction in humans remains largely unknown, studies in laboratory animals have demonstrated that both the peripheral and central olfactory nervous systems are affected by aging. Aged olfactory neuroepithelium in the nasal cavity shows the loss of mature olfactory neurons, replacement of olfactory neuroepithelium by respiratory epithelium, and a decrease in basal cell proliferation both in the normal state and after injury. In the central olfactory pathway, a decrease in the turnover of interneurons in the olfactory bulb (OB) and reduced activity in the olfactory cortex under olfactory stimulation is observed. Recently, the association between olfactory impairment and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), has gained attention. Evidence-based pharmacotherapy to suppress or improve age-related olfactory dysfunction has not yet been established, but preliminary results suggest that olfactory training using odorants may be useful to improve some aspects of age-related olfactory impairment. Olfaction is a sense that allows the detection of odors in the surrounding environment. Olfaction is necessary to identify food, predators, and sexual partners for most of the wildlife, being indispensable for species survival. Moreover, in humans, olfaction not only guarantees greater safety by allowing the detection of fire, gas leakage, and spoiled foods but also a greater quality of life through the appreciation of food, wine, and pleasant smells. Nonetheless, olfactory impairment has traditionally received less attention compared to visual and auditory impairment. Thus, it may even be difficult for healthy individuals to understand the inconvenience of olfactory impairment. However, patients with olfactory impairment face a series of daily-life problems . The generated neuroblasts migrate to the OB, where they differentiate into interneurons  using a smell identification test, the prevalence of olfactory dysfunction was estimated as 21.6%  and tumor necrosis factor-alpha (TNF-α). This phenomenon is designated as the senescence-associated secretory phenotype  has demonstrated that changes in the expression of genes associated with chemosensory detection, immune barrier function, xenobiotic metabolism, cell cycle progression, and cell death were particularly prominent in old SAM strains  changes with age. Khan et al.  have repHuman studies have reported that the volume of the OB, the glomerular layer thickness, the number of glomeruli, and the concentration of mitral cells per unit area all decrease with increasing age  have yielded mixed results. One study suggests that among the olfactory-related brain structures, the volume of the piriform cortex and that of the amygdala cortex do not reduce with age, while the volume of the orbitofrontal cortex significantly decreases  when neurologists can make a diagnosis according to the accepted clinical diagnostic criteria (Becker et al., The prevention of olfaction dysfunction may lead to happier and more successful aging. In the case of olfactory impairment, clinical management may help patients to overcome the difficulties associated with their impairment. Although, several drugs have been tested for the treatment of age-related sensorineural olfactory dysfunction including zinc, vitamins, and herbal medicines, no evidence-based medicine has been established to improve age-related olfactory dysfunction (Miwa et al., Recently, olfactory training has been reported to be useful for the treatment of sensorineural olfactory disorders (Hummel et al., The mechanism underlying odor stimulation-dependent improvement is unclear, but as described above, the number of interneurons in the OB is regulated depending on odor stimulation (Yokoyama et al., Although still at the experimental stage, the intranasal application of growth factors, gene therapy, and stem cell transplantation have been tested as a treatment of sensorineural olfactory degeneration (Choi and Goldstein, Intranasal administration of drugs has also been extensively studied as a treatment of central nervous system diseases, because the olfactory mucosa may be used as a route to deliver drugs to the intracranial space bypassing the blood-brain barrier (Chapman et al., Another problem to be addressed is malnutrition due to olfactory impairment. It is reported that the addition of flavor to the food may increase appetite and improve the nutritional condition (Schiffman and Warwick, All authors wrote the manuscript. SK and KK designed the figures. All authors reviewed and approved the final version 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.


Migrants and ethnic minorities who lack access to health services and information are particularly vulnerable to the impact of COVID-19. In this opinion, we aimed to explain how these challenges can affect the spread of COVID-19 in the European Union and the United Kingdom, and to stress the importance of universal and equitable access to healthcare services during and after the COVID-19 crisis.On March 13, 2020, the World Health Organization declared Europe as the new epicenter of the COVID-19 pandemic –6. SimilThese findings may be worrying for the European Union (EU) countries and the UK, given that ~30 million migrants currently live in these countries , 13. UnlLessons from previous epidemics and pandemics show that pre-existing health inequalities and underlying health conditions could disproportionally affect morbidity and mortality among disadvantaged populations . There iMoreover, pre-existing social and socioeconomic inequalities among migrants in Europe, such as housing, income, poverty, employment, and access to social security, can also contribute to the high rates of COVID-19 infections among migrants. Historically, social determinants of health and socioeconomic factors play an important role among socially disadvantaged populations during epidemics as it predisposes high risk populations to unfavorable health outcomes , 34. ExaHousing, which is another key factor for living conditions and well-being, represents another aspect of disparity among migrants in Europe. For example, non-EU citizens are more likely to live in overcrowded places when compared to nationals, 35 and 17%, respectively . MoreoveAnother aspect that requires great precaution is how any economic downturn can affect the migrant labor forces in Europe. The expectations of an inevitable global recession due to COVID-19 require a careful understanding of how any potential financial crisis may affect the health of international labor workers in the EU and the UK. It is estimated that almost 40 million people are migrant workers in an area mainly formed by the EU-27 countries and the UK, which accounts for 23.9% of the world's international workforce . We mighMoreover, lack of access to healthcare and economic instability during the COVID-19 epidemic shows how mental health among migrants could be affected due to concerns of contracting the disease, income loss, or mental stress imposed by the lockdown. In particular, migrants and refugees may exhibit symptoms of mental disorders due to exposure to unpleasant events before, during or after migration . AccordiWe should bear in mind that if we aim to achieve the control of SARS-CoV-2 infection, no population at high risk of infection can be excluded. Although no single solution can address these deeply rooted health and socioeconomic inequalities among migrants in Europe, urgent initiatives should be adopted to mitigate the effect of COVID-19 among these vulnerable populations. These initiatives should emphasize the importance of interventions that guarantee the full integration of migrants and ethnic minorities in the health system regardless of their migration status. Policies should also be developed to ensure access to information and prevention services without bearing any financial or legal consequences, especially among undocumented migrants. The assessment of migrants' health needs and barriers to access health services is critical for mitigating any future public health crisis such as COVID-19. Protective plans should be introduced to prevent the pandemic's long-term side effects on different vital aspects of life among migrants, such as unemployment, poor housing, and mental health issues. Moreover, governments are required to provide more comprehensive strategies and solutions to the apparent pre-existing health socioeconomic inequalities among migrants in Europe. The development of any strategies or policies against COVID-19 that do not consider an equitable health coverage of the whole population, including migrants, will be doomed to failure and will halt any efforts in controlling the spread of the infection.AS conceived the work, reviewed the literature and wrote the manuscript. BP and MM supervised the work and wrote the manuscript. All authors have agreed on the final version 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.


When older adult patients with hip fracture (HFx) have unplanned hospital readmissions within 30 days of discharge, it doubles their 1-year mortality, resulting in substantial personal and financial burdens. Although such unplanned readmissions are predominantly caused by reasons not related to HFx surgery, few studies have focused on how pre-existing high-risk comorbidities co-occur within and across subgroups of patients with HFx.This study aims to use a combination of supervised and unsupervised visual analytical methods to (1) obtain an integrated understanding of comorbidity risk, comorbidity co-occurrence, and patient subgroups, and (2) enable a team of clinical and methodological stakeholders to infer the processes that precipitate unplanned hospital readmission, with the goal of designing targeted interventions.We extracted a training data set consisting of 16,886 patients (8443 readmitted patients with HFx and 8443 matched controls) and a replication data set consisting of 16,222 patients (8111 readmitted patients with HFx and 8111 matched controls) from the 2010 and 2009 Medicare database, respectively. The analyses consisted of a supervised combinatorial analysis to identify and replicate combinations of comorbidities that conferred significant risk for readmission, an unsupervised bipartite network analysis to identify and replicate how high-risk comorbidity combinations co-occur across readmitted patients with HFx, and an integrated visualization and analysis of comorbidity risk, comorbidity co-occurrence, and patient subgroups to enable clinician stakeholders to infer the processes that precipitate readmission in patient subgroups and to propose targeted interventions.P<.001 to P=.01) for a 30-day readmission, (2) 7 biclusters of patients and comorbidities with a significant bicluster modularity , indicating strong heterogeneity in the comorbidity profiles of readmitted patients, and (3) inter- and intracluster risk associations, which enabled clinician stakeholders to infer the processes involved in the exacerbation of specific combinations of comorbidities leading to readmission in patient subgroups.The analyses helped to identify (1) 11 comorbidity combinations that conferred significantly higher risk  the management of comorbidities targeted at high-risk subgroups of patients with the goal of pre-emptively reducing their risk of readmission and (2) the development of more accurate risk prediction models that incorporate information about patient subgroups. Although it is well known that hip fractures (HFx) in older adults are a leading cause of morbidity, long-term functional impairment, and mortality , these oWhile many readmissions are unavoidable, unplanned hospital readmissions can easily negate the functional gains painstakingly achieved through weeks of post–acute rehabilitation and can increase the risk of infections acquired during hospital stays . This loAlthough such incentives initially appeared to improve the readmission rates in US hospitals , recent co-occur within and across subgroups of patients, a critical step in the design of targeted interventions to reduce readmissions.As hospital readmissions in the older adult HFx population are predominantly for reasons not related to the HFx surgery , severalco-occurrence of pre-existing comorbidities has not yet been analyzed in readmitted patients with HFx, it has been analyzed in other index conditions ) compared to 1000 random permutations of the network while preserving the network size (number of nodes) and network density (number of edges). The corresponding network generated from the replication data set also had 7 biclusters, a modularity of 0.444, which was also highly significant  compared to 1000 random permutations of the data while preserving network size and density.The network had a modularity of 0.440, which was significant , indicating a strong similar and significant co-occurrence pattern of comorbidities in the 2 networks. The training and test bipartite networks were therefore strongly biclustered (as measured by the similarly high biclustered modularity), highly significant (as measured by the permutation test), had a similar pattern of co-occurrence (as measured by the RI and its significance), and had the same number (7) of biclusters.The co-occurrence of comorbidities within and across clusters (as measured by the RI) between the training and replication data sets was significant .As shown in The bipartite network analysis therefore not only revealed how the comorbidities co-occurred across patient subgroups but also the patient heterogeneity at the network-wide level and at the bicluster-specific level, revealing the real-world variations in the comorbidity profiles of patients with HFx.As shown in asymmetrical hub (more edges pointing in than those pointing out). This meant that the implicated pairs connecting the nodes had significantly higher risk compared with RF and diabetes alone, but not significantly higher risk compared with the other members of the pair. For example, the directed edge starting from COPD and pointing to diabetes indicated that patients with COPD and diabetes have a significantly higher risk compared with diabetes alone, but not a significantly higher risk compared with COPD alone.As the clinician stakeholders were most interested in the interrelationship of risk between multi-organ and organ-specific comorbidities, we bolded all the edges that started from an organ-specific comorbidity  and ended at a multi-organ comorbidity (RF or diabetes). As shown in The asymmetrical risk hubs of RF and diabetes suggested that because they have multi-organ consequences, their outcomes are largely chronic and therefore require considerable severity on their own before they become the sole risk factors for readmission . However, when they co-occur with an organ-specific disease such as CHF, arrhythmia, stroke, MCMCT, or COPD, it can exacerbate those pre-existing conditions leading to a significantly higher risk of readmission. This pattern of asymmetrical risks resulted in the following hypothesis for a 2-tiered comorbidity exacerbation risk model with significantly higher risk at each subsequent tier:Tier 1 risk (only multi-organ comorbidities): RF, diabetes. This tier consists of patients in the RF-diabetes cluster.Tier 2 risk (multi-organ plus organ-specific comorbidities): RF plus CHF or arrhythmia or stroke or MCMCT or COPD (patients in the inner part of the biclusters) in addition to patients with CHF, arrhythmia, stroke, MCMCT, or COPD (patients in the outer part of the respective biclusters).Combining the above risk model with their own domain experience, the physician and the occupational therapist on the stakeholder team inferred hypotheses for the processes precipitating readmission in patients with HFx and provided corroborative evidence from the literature to support their inferences. They noted that when a patient is discharged from a hospital after an HFx surgery, the standard-of-care in generating discharge notes and order sets is focused on wound healing, postoperative delirium, mobilization, rehabilitation, and nutritional needs ,32. Howebefore discharge and the level of multidisciplinary care after discharge could be prime targets for reducing the risk of hospital readmission in specific subgroups of patients with HFx.The nurse practitioner on the stakeholder team further stated that a contributing factor to the above cascade of events could be the lack of multidisciplinary care when patients with HFx are discharged after surgery. As stated in a recent review , HFx manOur approach to integrate the results from supervised and unsupervised approaches into the CoRisk network helped to reveal (1) the overlap among the high-risk pairs, resulting in the stakeholders identifying the asymmetrical hub, and (2) the relationship of high-risk pairs to the network-wide and bicluster-specific patient heterogeneity. These results enabled the clinician stakeholders to infer hypotheses about the processes that precipitate readmission through a comorbidity exacerbation risk model. These results have the following implications for the design of interventions and predictive modeling.both RF and CHF should have their volume status more closely monitored, as they are more likely to develop an acute CHF exacerbation than patients with CHF alone. This is because patients with RF have a reduced ability to regulate the volume status and small fluctuations can precipitate acute CHF exacerbation, resulting in cardiorenal syndrome [When a patient with HFx is discharged, the discharge notes and order sets could state which of the seven high-risk pre-existing comorbidities exist in the patient, with the respective recommendations for recognizing the early signs of the worsening of those comorbidities. For example, patients with RF should be monitored by rehabilitation or home health providers for urine output or weight gain, and those with diabetes should have more than usual monitoring of blood glucose during the convalescent period. However, patients with syndrome .Furthermore, rehabilitation providers  should be specifically trained to recognize and report changes in physical status, such as reduced oral intake, which might be an early warning of impending exacerbation of the specific comorbidities identified in the analysis. Finally, given the scarcity of rehab resources, clinicians could use the 2-tiered significant risk profile discussed above in triaging care, such as conducting more frequent evaluations of patients with HFx with COPD and RF compared with those with only RF. Future clinical trials could test whether improved discharge notes and order sets, in addition to early identification and treatment of worsening comorbidities through multidisciplinary team monitoring, can help to reduce the risk of readmission in patients with HFx.unmodifiable readmission risks that outweigh the benefits of surgery and therefore could be better served with more conservative approaches.The results also suggest that combinations of high-risk comorbidities could be used to fine-tune the current criteria to select patients who should undergo HFx surgery. For example, certain comorbidity combinations could simply reflect the overall poor performance status of a patient, for whom postoperative interventions, no matter how robust, might end up being largely ineffective in preventing readmission. Future models could identify which subsets of patients have such The bipartite network analysis of patients and comorbidities showed significant and replicated heterogeneity among the readmitted patients based on their comorbidity profiles. However, current logistic regression models designed to predict readmission do not consider such heterogeneity in readmitted patients. For example, the regression model developed for CMS to predict readmission in arthroplasty or hip replacement patients  uses a sa priori understanding of the domain, which might miss important patterns in the data.As stated by the biostatistician on the stakeholder team, a common approach to address such heterogeneity is to develop stratified regression models ,48, one In contrast to the above approach of selecting patient subgroups, we believe our approach can enable the automatic identification of patient stratification that is data-driven and furthermore tested for significance and replicability, as we have demonstrated. Such information could then be used to develop stratified regression models to test whether they reveal heterogeneity in prediction accuracy for one or more patient subgroups. For example, stratified regression models could be developed and tested for each of the 7 clusters shown in Improvements achieved through stratified regression models are dependent on a host of factors, including the degree of homogeneity in patient subgroups, the adequacy of sample size within those subgroups, and the tradeoff between prediction accuracy and model complexity. Future research should, therefore, determine whether stratified regression models based on automatically identified patient subgroups can produce more robust predictive models for hospital readmission.The strength of this study is that we integrated the results from well-known methods with novel approaches, which together enabled a deeper understanding of the associations between risk, co-occurrence, and subgroups. This in turn led to insights related to targeted interventions , in addition to the design of predictive models. Furthermore, the analytical results were replicated in another year, demonstrating its generalizability. Critical to this process was the team-centered informatics approach  we pursuA limitation of this study is that we tested the method on just one index condition, and our ongoing research  is testiFully cognizant that few data sets are without limitations, we consciously chose to analyze Medicare data because of its scale , availability of data over multiple years , and generalizability . However, given that Medicare data are collected mainly for administrative purposes, it has well-known limitations, including the lack of test results, which could enable a finer understanding of the severity of comorbidities. Furthermore, comorbidities associated with mental health are known to be undercoded in the Medicare database, which could bias our results. Therefore, when clinical data across hospitals become available in future (eg, through the PCORnet  funded bMethodologically, our approach of integrating supervised and unsupervised visual analytical approaches is just one of the many possible ways such integration can be achieved . In our


Maedi-visna is a chronic viral disease of sheep with worldwide prevalence. It is caused by a small ruminant lentivirus. Its clinical manifestation includes primarily pneumonia and mastitis, and secondarily, arthritis and encephalitis. It causes substantial economic losses associated with involuntary culling or death of infected animals and reduced productivity, challenging the sustainability of dairy sheep farms. The extensive spread of the disease and the lack of treatment or vaccines render surveillance and prevention strategies indispensable. Currently, the major obstacles in controlling the disease are (i) the absence of an effective protocol for the early and definitive diagnosis of infected animals, utilizing appropriate, universally accepted serological and molecular techniques, (ii) the long interval between infection and seroconversion, and (iii) lack of understanding whether horizontal or vertical transmission are the most important route of infection. Therefore, the most appropriate measures for the control of the disease should include more frequent serological testing with available diagnostics and isolation or culling of seropositive animals, incorporation of artificial suckling, and strengthening of hygiene and biosecurity protocols.Maedi-visna (MV) in sheep is caused by maedi-visna virus (MVV), a small ruminant lentivirus (SRLV) that causes chronic infection and inflammatory lesions in infected animals. Pneumonia and mastitis are its predominant clinical manifestations, and the tissues infected by MVV are mainly the lungs, the mammary gland, the nervous system and the joints. MV has a worldwide distribution with distinct MVV transmission patterns depending on circulating strains and regionally applied control/eradication schemes. Nevertheless, the prevalence rate of MV universally increases. Currently, gaps in understanding the epizootiology of MV, the continuous mutation of existing and the emergence of new small ruminant lentiviruses (SRLVs) strains, lack of an effective detection protocol and the inefficiency of currently applied preventive measures render elimination of MV an unrealistic target. Therefore, modifications on the existing MV surveillance and control schemes on an evidentiary basis are necessary. Updated control schemes require the development of diagnostic protocols for the early and definitive diagnosis of MVV infections. The objectives of this review are to summarize the current knowledge in the epizootiology and control of MV in dairy sheep, to describe the research framework and to cover existing gaps in understanding future challenges regarding MV. Maedi-visna (MV)  is an incurable viral disease of sheep with very long incubation period that leads to life-long infection . It is cRecognizing the socio-economic impact of MV, the World Organization for Animal Health (OIE) has included it in the list of notifiable terrestrial and aquatic animal diseases, with significant impact on international trade of animals and their products . In dairAs there is no treatment against MV and all efforts for the development of vaccines did not produce any satisfactory results , the conMV was initially described in Iceland in 1939, possibly originating from the importation of live animals from Germany. Although clinical signs were apparent, the situation was likely underestimated or misdiagnosed for many years ,15. EvenNowadays, MV has a worldwide spread, with the exception of Iceland, New Zealand, and Australia which are considered MVV-free regions, but not CAEV-free . DespiteThe majority of SRLVs epizootiological studies worldwide  is limitThere is a continuous effort for the identification and classification of SRLVs strains due to large genetic diversity of the isolated viruses ,29. To dRecently, phylogenetic analysis revealed a new strain (CRF01_ABSRLV) which was isolated from Canadian goats and possibly originating from the combination of A2 and B1 subtypes . The mecIn the majority of cases, virus replication is slow and the number of infected blood cells in the circulation is very low . TherefoClinical manifestation of SRLVs infection depends on the virus strain, the host immune response and the host genetic profile regarding resistance or susceptibility to the virus ,55. LesiRespiratory clinical signs include dyspnea and increased respiratory rate, caused by the characteristic lymphocytic interstitial pneumonia; at necropsy, the lungs appear discolored, enlarged, and diffusely firm with grey spots on the pleural surface and the mediastinal lymph nodes are often enlarged ,23.Symptoms from the nervous system include ataxia, paresis, weakness in hind limbs, incoordination or, in heavier cases, total paralysis, due to meningoencephalitis, astrocytosis, microgliosis, and focal secondary demyelination in the brain and the spinal cord ,19.In mammary gland, MVV can cause an indurative non-suppurative interstitial mastitis ,19. The Arthritis can also be the outcome of MVV infection, although it is less common in sheep ,16,18,19The mechanisms and the significance of horizontal and vertical transmission of the MVV have not been fully clarified yet . The majThe vertical transmission of MVV refers to the transmission of the virus from the ewe to the lamb during pregnancy , at lambing or during suckling . OpinionThe most significant route of vertical transmission is considered to be the lactogenic, through the ingestion of colostrum and milk from infected dams . MVV shoHorizontal transmission of MVV includes the environmental, mechanical and iatrogenic routes and mainly refers to the transmission through respiratory secretions . Lungs aBrucella ovis [Sexual transmission of the MVV is theoretically possible but not yet confirmed. However, there is evidence of virus proliferation in the genitals of infected rams and the virus has been found in the semen of rams with leucocytospermia and rams positive for lla ovis ,66. In alla ovis . There are several risk factors that influence transmission of MVV between and within flocks. These factors determine the likelihood of infection, the prevalence, the incidence rate and other epizootiological characteristics of the disease. Identification and mitigation of risk factors at the farm level is therefore crucial when establishing a MVV control/eradication program. Flock size/stocking density, intensity of the farming system ,12,26,27Inappropriate cleaning and disinfection of milking equipment ,19, reusImportation of breeding stocks from flocks of unknown MVV-status is associated with increased seroprevalence of MV ,27. The TMEM154 (Transmembrane protein 154) gene have been found to be associated with the occurrence of MV. Haplotypes carrying nucleotide sequences that code for the amino acid glutamate at position 35 are associated with increased susceptibility to MV, whereas haplotypes carrying nucleotide sequences that code for lysine at the same position are associated with resistance to MV [TMEM154 mutations and control of MVV infection, there is no proven association for all the haplotypes [DPPA2 /DPPA4 , SYTL3 (Synaptotagmin-Like 3), CCR5 (Chemokine receptor 5), MHC (Major Histocompatability Complex), TLR7, TLR8, TLR9 (Toll-like receptors) genes, and APOBEC3 (Apolipoprotein B mRNA-editing enzyme) proteins [C19orf42 (Chromosome 19 Open Reading Frame 19)/TMEM38A (Transmembrane Protein 38A) and DLGAP1 (Discs Large (Drosophila) Homolog-Associated Protein 1) genes may be used in genetic selection programs to facilitate the control of the disease [There is evidence of genetic resistance/susceptibility against SRLVs . Differece to MV ,73,74. Aproteins ,76,77, w disease . Τhe tri disease .Early and efficient diagnosis of MV is a critical parameter for the control and eradication of the disease. The diagnosis of SRLVs infections is based on the detection of antibodies against the virus proteins or the viral genome. Current control and eradication programs are based on serological tests (mainly enzyme-linked immunosorbent assays (ELISAs)) to detect antibodies against the virus . TherefoAGID test is commonly used as a diagnostic tool in MV control programs due to its simplicity. It is a highly specific diagnostic method but less sensitive than ELISA ,19,20,21RIPA is as old as WB and both of them are considered as the reference standards. They have similar sensitivity and are mainly used as confirmatory assays ,22. RIPAWB is a confirmatory laboratory test which has been used to detect antibodies in serum that recognize viral proteins. In general, WB is more sensitive than the ELISAs but more cumbersome and with lower throughput ,21. CrosELISA is the most commonly used test in population screening and for the surveillance of SRLVs. It detects antiviral antibodies with satisfactory sensitivity and specificity, indicating the occurrence of infection and seroconversion at some point ,20. SeroPCR can directly detect proviral DNA in fluids and tissues across the animal body . The most reliable cells for the detection of virus are the peripheral blood mononuclear cells ,21. The There is neither a treatment nor an effective vaccine against MV. In the past, there have been attempts for the development of attenuated and subunit vaccines but none of them proved to be effective in preventing viral infections ,87,88,89The preventive measures and management interventions that could aid in controlling or eradicating MV should be decided on case by case and include the following:1. Annual, biannual, or more frequent blood sampling from the breeding stocks and serological and molecular testing for the diagnosis of the infected animals.2. Post-lambing management primarily based on the application of artificial suckling and the use of colostrum and milk substitutes or pasteurized colostrum/milk. The management of colostrum involves the administration of bovine colostrum, commercial sheep colostrum or colostrum only from uninfected ewes or heat-treated colostrum (56 °C for 60 min) ,90. Arti3. Immediate removal of animals with apparent clinical signs and positive laboratory diagnosis. The selective culling of these animals and their replacements with seronegative animals, or the grouping of animals according to their seroconversion status can be applied in areas with moderate seroprevalence ,20,91. T4. Keeping the replacement animals, post-weaning, in separate housing facilities to avoid horizontal transmission of MVV through the contact with adult animals of the remaining flock.5. Purchased animals should be from certified MVV-free farms. Imported animals need to remain on quarantine until the MV-status is determined using the most appropriate assays.6. Regular cleaning and disinfection of facilities and equipment with appropriate disinfectants. The cleaning and disinfection schedule must include the barn , the milking machine, the feeders and the waterers. 7. Reduction of stocking density (sufficient area and volume) and adequate ventilation. 8. Implementation of general good hygiene practices. Use of disposable needles or sterilization of metal needles before their reuse is necessary. Similarly, the medical equipment should be sterilized after its use. 9. MV seronegative milking ewes should be grouped separately and machine-milked before the seropositive ones. 10. Grazing in communal pastures and sharing of infrastructures and equipment should be avoided when the MVV-status of the flocks is unknown.11. Rams used either for mating or for semen collection need to be MVV-free . Current12. Breeding for resistance could also be considered, but universally accepted resistant genotypes are yet to be developed . The characterization of a flock as MVV-free demands two to five successive negative tests every 6 months, yearly or every 2 years (depending on the country). The trade of live animals is allowed when the animals have no clinical signs of MV, the adult animals are seronegative and MV has neither been clinically nor serologically diagnosed in the sheep flocks of origin during the last three years. Also, artificial insemination is allowed only using semen from seronegative rams. According to OIE, a country is considered MVV-free when <1.0% of herds are infected with 99.0% probability.After the first implemented eradication program in Iceland, a lot of countries applied their own eradication programs  with variable results. The major obstacles for the successful implementation of eradication programs are (i) the possible refusal of farmers’ participation ,9, (ii) The eradication measures when considered in a country-wide scale should include both species of small ruminants due to the fact that the cross transmission has been proven and is a significant risk factor in the spread of the virus . MoreoveTotal replacement of seropositive flocks with breeding stocks from MVV-free flocks could be a sustainable option only in areas where the seroprevalence is very low and MVV-free flocks are available. Otherwise, there is a serious threat for significant monetary losses and restriction of genetic resources which may undermine the sustainability of the farms, particularly in areas with developed dairy sheep farming industry .Epizootiological investigations regarding SRLVs infections are essential for the territorial mapping of virus distribution. The scarcity of detailed epizootiological data, in combination with the continuous mutations of SRLVs strains, render the creation of a universal, reliable and valid diagnostic protocol, and consequently the control of SRLVs, a rather complicated task. For the early and definitive diagnosis of SRLVs infections, development of appropriate combinations of serological and molecular tests (ELISAs and PCR) on an evidential basis is suggested and forms a challenging research field in the future. Determining the epizootiological traits of SRLVs infections and particularly the significance of the different routes of viral transmission will facilitate the decision-making process towards the determination of the most effective measures for the creation of MVV-free flocks. The global spread of SRLVs highlights the underestimation of the problem by the farmers and the insufficient implementation of the suggested preventive measures, which mainly focus on the lactogenic and airborne transmission of the disease, but may also be indicative of the failure in controlling the disease using these measures. Therefore, the significance of every other possible route of transmission  needs to be carefully assessed and revised, and relevant preventive measures need to be integrated in the MV control protocols. Exploitation of active surveillance programs and quantification of the consequences of SRLVs’ infection on production , health Breeding for resistance against SRLVs is an emerging research field. Specific genes have already been found to be associated with resistance or susceptibility to the disease and the discovery of additional genomic regions may increase the options for its control through marker-assisted selection (MAS) .Despite the significant advances accomplished in SRLVs immunization studies, there are still important challenges to address, as vaccination against SRLVs may contribute to either controlling or enhancing MV . Therefo