Pulmonary Metastasis of Ewing’s Sarcoma in Pediatric Age Literature Review and Case Report

Introduction

Ewing’s Sarcoma (ES) is a malignant neoplasm of mesenchymal origin that affects children and adolescents, with a peak incidence in the second decade of life. The average age being between 13 and 16 years [1,2] It was described by the American histopathologist, oncologist, and hematologist James Stephen Ewing in 1921. [1,2] The annual incidence is [1-3] cases per million children under 15 years of age. Ewing’s sarcoma accounts for about 1.5% of all childhood cancers and is the second most common type of bone sarcoma. [1,2] It appears in patients in the stage of life of greater exercise and changes in the body typical of adolescence, so it can be confused at first with bone growth pains, with banal local traumas of exercise in daily activities. [1.3-5] Clinically, it presents as a picture characterized by intermittent bone pain at the site of the injury, which increases at night and increases in intensity, may be accompanied by increased local volume, in the form of a mass that may be painful on palpation, sometimes It is accompanied by fever and constitutional syndrome due to weight loss, asthenia and anorexia. [1,3,4] The most affected bone sites are: metaphysis of the long bones (around 56%, costal arches approximately 15 to 17%, flat bones 16% and skull between 3 to 4%) [1,2,6,7]. Ewing’s sarcoma produces metastases via the hematogenous route to the lung in more than half of the cases, to the bone, brain and bone marrow, less frequently via the lymphatic route to distant nodes.

It is good to point out that in most cases these metastases are present from the beginning of the disease. [2,7,8] Diagnosis is based on imaging studies: X-rays of the affected limb or site, Computerized Axial Tomography (CAT) and Nuclear Magnetic Resonance Imaging (MRI). [1,6,9] Primary tumor biopsy is mandatory. Definite diagnosis requires histological evaluation and confirmation with cytogenetic or molecular biology techniques. The defining characteristic of these tumors is the presence of a series of chromosomal translocations that culminate in the fusion of the EWSR1 gene, on chromosome 22, with one of several members of the ETS family of transcription factors. The most common of these translocations, t (11; 22) (q24; q12), which fuses the EWSR1 gene with the FLI1 gene on chromosome 11, is present in approximately 90% of cases immunohistochemistry demonstrates CD 99 positive [9]. Treatment is based on extensive surgery of the lesion with free section margins whenever the site or location of the tumor allows it, chemotherapy with high-dose drug association, and radiotherapy. [2,3,8,10] The prognosis of this variant of tumor depends on age, clinical stage at diagnosis, since the presence of metastases at the time of diagnosis overshadows the prognosis, especially in the lung, causing a low survival rate of around 21%, [2,11] while patients diagnosed early in the initial stages of the disease have a better survival of around 50%.[1,2] Mortality is high, especially in the first year after diagnosis in cases with lung metastases. Fiveyear disease-free survival is very low, around 10% to 31% of cases [2,6,12].

Case Presentation

We present the case of a mestizo female patient from the province of Camaguey, who at 2 years of age begins with an increase in volume in the anterolateral face of the left lower limb, of two months of evolution accompanied by intermittent fever, in her area of health interpret the symptoms as if it were acute osteomyelitis of the tibia, so they sent her to the Pediatric Hospital of her native province they admitted her with a diagnosis of possible osteomyelitis and started antibiotic treatment with phosphocin first intravenously and then orally, also with non-steroidal antiinflammatory drugs, evolutionarily they did not see clinical improvement and radiographic studies of the lower left extremity were performed, detecting osteolytic lesion and bone destruction. A CT scan is performed, verifying a destructive bone tumor lesion of the proximal third of the anterior face of the left tibia. Clinically, the visible and palpable tumor lesion in the anteromadial aspect of the upper third of the left lower extremity continued to increase in size, so the relatives decided to travel to the capital of the country where they were admitted to our hospital in December 2019, studies were completed and a CT scan of the lung is performed, a single metastatic lesion is confirmed in the lower lobe projection of the left lung, without associated respiratory symptoms. The diagnosis was made by surgical biopsy of the tibial bone lesion, yielding the histopathological study: Ewing’s sarcoma. The general physical examination maintained good coloration of the skin and mucous membranes.

Chest

symmetrical with adequate ventilatory movements, without alterations of the vesicular murmur in the lung fields, no rales. Rf: 28xmin

Cardiovascular

Rhythmic heart tones, not murmurs. HR: 88xmin AT: 90/50. Examination of the lower left extremity below the patella detected a painful tumor lesion of approximately 8 to 12 centimeters in diameter, somewhat painful on palpation, firm consistency, welldefined borders, non-movable. No peripheral lymph nodes. Free sensory. No meningeal signs. Sensory and motor reflexes preserved. It is discussed in a multidisciplinary team and it is decided to start treatment with high-dose chemotherapy and evaluate at the end of the first 4 cycles VAC/IE (vincristine, cyclophosphamide, doxorubicin alternating with ifosfamide/etoposide, it was evaluated and the response was very poor with only a clinical and imaging reduction of the tumor lesion from 1.5 to 2 cm, it is agreed in Within the tumor committee with the authorization of the parents to perform the surgery in the month of May 2020, the supracondylar amputation of the affected limb was performed, with very good postoperative evolution and healing of the stump.

Pathological Anatomy Result

Ewing’s sarcoma of the upper third of the tibia, with extensive necrosis, bone section edges and soft tissue free of tumor. Immunohistochemical studies showed CD 99 positive. The postoperative chemotherapy scheme with cytostatic drugs is continued for 6 complete cycles in order to reduce or disappear the metastatic lesion of the left lung, which from the beginning measured 19 mm x 22 mm, thus maintaining that diameter throughout the systemic treatment. which ends in September 2021. She is studied again at the end of the chemotherapy treatment and the patient maintains a pulmonary metastatic lesion in projection of the lower lobe of the left lung, but with slight growth to 20x28mm in the chest X-ray, but in the CT the lesion was 28x34mm. (Figure 1) The multidisciplinary team discussed it again and it was agreed to perform the metastasis through the left anteroposterior thoracotomy. On November 4, 2021, she was operated on, and a wide resection of the lesion was performed at the level of the lower segment of the lingula of the left lung (Figures 2A & 2B).

Figure 1: Contrast-enhanced CT scan of the chest sagittal view, where a metastatic lesion of the lower lobe of the left lung is displayed.

Figure 2: A. Wide resection surgery of the left lung metastasis together with adjacent tissue of the lingula where it was inserted. Figure 2B.

Pathological Anatomy Result

Small blue cell tumor metastasis with mitotic index greater than 10 per field, tumor necrosis index 5%, presence of vascular permeation, histological picture compatible with Ewing Sarcoma metastasis. The postoperative evolution was good, the wound healed without complications. He presented fever 11 days after surgery and a mild inflammatory process was found at the base of the left lung without pleural effusion by ultrasound or chest X-rays. He completed antibiotic treatment first with Piperacillin with Tazobactan and Amikacin, but the fever persisted and on the fifth day the antibiotic treatment was changed due to Staphylococcus epidermitidis growth in blood culture performed to Vancomycin and Meronem, the fever disappearing, and he always maintained a very good general condition. Locoregional radiotherapy of the left lung was then performed for six sessions during the month of December 2021. The postoperative chemotherapy treatment was completed in the months of January and February 2022. To date, the patient is stable. Two months after finishing treatment, a positron emission tomography (PEC/CT) scan was performed from the apex of the skull to the middle third of the femurs, which did not reveal abnormal areas of glycolytic hypermetabolism. Conclusions of the study no tumor metabolic lesion was observed at the bone, lung or ganglionic chain level. This case is brought to collation due to the rarity of this tumor variant in early ages of life, and due to its presentation in an advanced stage of the disease from the beginning (Stage IV). Highlighting the value of surgery in disease control combined with other therapeutic weapons: chemotherapy and ionizing radiation.

Discussion

Ewing’s sarcoma is a primary malignant bone tumor that is common in children, preceded in frequency by osteosarcoma. [2,9] It is a very aggressive tumor, its etiology is unknown, it is more common in males, it is located more common in the lower half of the skeleton. [1,3,4] It tends to metastasize early, mainly to the lung. It should be noted that primary lung neoplasms are infrequent in children, they are usually secondary lesions or metastases of malignant solid tumors typical of childhood, and their clinical manifestations are initially confused with an infectious process. [2,5] There are few case reports of this tumor variant in early life. (Izaguirre, et al. [3]) reported a 13-year-old patient with Ewing’s sarcoma of the left fibula, but at such a young age as in our case it is extremely rare. The symptoms are common to other bone tumors: intermittent pain and inflammation located in the affected area. [2,4,9] Generally, these symptoms are confused with inflammatory processes. In order to establish an early diagnosis of the bone lesion, in addition to the symptoms, imaging studies of the chest X-ray, CT and MRI are required. It is also important to evaluate early for disease recurrence [3,9,10-14].

The main treatment weapon for this variant of malignant tumor is surgery with en bloc resection of the tumor and nearby soft tissues or amputation of the limb, in very specific cases limb salvage surgery is proposed [2,3, 9,15]. Sánchez Saba, et al. [9] in their study of 88 patients diagnosed with Ewing’s sarcoma of bone treated with preoperative chemotherapy and limb-sparing surgery, the overall survival rates were 79.5% at 2 years, 69% at 5 years and 64% at 10 years considered that limb-sparing surgery associated with pre- and postoperative chemotherapy should be the treatment for Ewing’s sarcoma of bone that meets certain requirements that allow its performance. In our case, it did not meet the necessary requirements and demands for its performance since the disease was metastatic since its diagnosis. [9,10] Most authors agree that chemotherapy is mandatory for disease control before (neoadjuvant) and after surgery (adjuvant), the most widely used regimens worldwide are VACA (vincristine, actinomycin, cyclophosphamide doxorubicin) and VAC/IE (vincristine, cyclophosphamide, doxorubicin alternating with ifosfamide/ etoposide) [3,9].

Other protocols are VAI (vincristine – actinomycin – ifosfamide) and VIDE between 6 and 8 cycles. For a definitive diagnosis, histopathological studies with immunohistochemical technique are required, the realization of the CD99 immunomarker is necessary to confirm this entity since it gives us a sensitivity of more than 90%. [2,3,7,9,11] Definite diagnosis requires histological evaluation and confirmation with cytogenetic or molecular biology techniques. Under the light microscope, Ewing’s sarcoma appears as a tumor of small, round, blue cells, with different architectural patterns and variable protein expression, detectable by immunohistochemical techniques [3,9,10]. Stéphanie Foulon et al. [16] in a study conducted stated that although the role of radiotherapy has been discussed, it demonstrated that the use of radiotherapy helps in local control of the disease and reduction of tumor volume [15-17].

For more Articles on: https://biomedres01.blogspot.com/

 

Dilemma in Management of Endometriotic Ovarian Cyst

Introduction

Ovarian endometrioma or chocolate cyst is ectopic endometrial tissue lining ovarian cyst [1]. Presence of endometrial glands and stroma outside the uterine cavity is known as endometriosis [2]. Endometriosis may present as peritoneal lesions, deep endometriosis and ovarian endometriomas. Due to relative ease of diagnosis endometriomas are the most diagnosed form of endometriosis. Endometriosis have been reported in 17-44% [3]. With 10-20% in women in reproductive age most commonly between 40 and 44 years and approximately 17% of women suffering from infertility [4]. This condition is prevalent among the East Asian race [5]. Endometriosis and endometriomas have the multifactorial ethology [6]. Endometriomas are mostly unilateral, commonly left-sided, they are either asymptomatic or may present with symptoms. It is not infrequent to have under diagnosis or misdiagnosis and this is quite common in adolescent women [7]. Treatment of endometrioma is a clinical dilemma that if found in imaging then whether to treat or not and if yes then how to treat. Symptoms of a patient will guide for available options either conservative, medical, surgical or combination of both or sclerotherapy [8].

Discussion

The presence of ovarian endometrioses has been found to be associated with deep endometriosis and multifocal deep lesions [9]. Endometriomas are mostly unilateral, commonly left-sided [10]. Left sided predisposition is explained by anatomic barriers like sigmoid colon that may delay in eliminations of endometriotic tissue from left side of pelvis and promotes left sided cysts, in support this is explained by theory of retrograde menstruation [11]. The pathogenesis of endometrioma is explained as implantation of endometrial cells on ovarian surface via tubular lumen that causes persistent inflammation, bleeding, cyst formation at implantation site resulting invagination of ovarian cortex, adhesions secondary to metaplasia which may result in progressive damage of healthy ovarian tissue [12]. Endometrioma pseudo capsule is ovarian epithelium containing oocytes and follicular structures. The reason of endometrioma-related infertility remains unclear. Possible theories may be damage to affected ovary or tubo-ovarian distortion anatomy and cellular damage resulting in follicular loss [13]. Other factors may be involved including immune factors, inflammatory factors, environmental toxins, and genetic factors [14]. Endometrioma may present with dyspareunia, dysmenorrhea, pelvic pain, bleeding, infertility, and dysuria. It is not infrequent to have under diagnosis or misdiagnosis and this is quite common in adolescent women. Ovarian endometriomas may predispose to ovarian malignancies, especially clear cell carcinoma and endometrioid adenocarcinoma.

For Endometrioma diagnosis, transvaginal ultrasonography is a very sensitive and specific. Unilocular cyst with a “ground glass” homogeneity, low levels of echogenicity, and poor vascularization, one to four compartments and no papillary structures with detectable blood flow [15], which had been adopted in the ESHRE guidelines [16] are typical ultrasound characteristics of endometriomas [17]. One useful diagnostic indicator is immobility as adherent to pelvic side wall. Diagnosis and treatment of endometrioma another useful tool is laparoscopy. A new promising biomarker is Human epidydimal secretory protein E4 used in the differential diagnosis of endometriosis cyst. The combination of HE4 and CA 125 assay could discriminate ovarian endometriosis cysts from malignant ovarian tumours effectively [18]. The advantage of HE4 over CA125 is mainly in the detection of borderline ovarian tumours and early-stage epithelial ovarian and tubal cancers. After diagnosis, possible options are either expectant management or treatment depending on symptoms, age, fertility concerns, ovarian reserve and previous history of treatment with specific reference to past surgical interventions; nature of the cyst; and the fertility wishes of the woman [19]. Treatment of incidental disease in otherwise asymptomatic women is currently not recommended, as still the natural progression and development history of endometriomas is not well understood.

Treatment of endometrioma is a clinical dilemma that if found in imaging then whether to treat or not and if yes then how to treat. Symptoms of a patient will guide for available options either medical treatment progestins , oestrogen suppression or surgical or combination of both. An incidental finding of an ovarian endometrioma in young women with regular menstrual cycles and without suspicion of malignancy who wish to conceive should be encouraged for natural conception before seeking fertility treatment. While the evidence of the impact of an endometrioma on spontaneous conception is limited. Aim of surgical treatment is removal of endometriotic tissue, to have sufficient sample for histopathology and to preserve maximum ovarian tissue in cases where fertility is desired and to avoid risk of menopause. With surgical treatment risk is unintentional removal of ovarian follicles which is later shown by reduced levels or antral follicle count on ultrasound or reduction in serum anti- Müllerian hormone (AMH) [20]. To reduce recurrence after surgery medical therapy may be used. Recurrence rate of endometriomas after surgical treatment are 30-40 % [21]. So to delay recurrence of ovarian endometrioma in 2014, European Society of Human Reproduction and Embryology (ESHRE) recommended for ovarian cystectomy instead of drainage and coagulation of endometriosis in cases of surgical treatment, since ovarian cystectomy can reduce endometriosis-associated pain and recurrence rate effectively [22]. Fertility is affected by presence of endometrioma [23], while after IVF overall pregnancy rates are unaffected [24]. Any surgical intervention to remove endometrioma may be associated with decrease ovarian reserve and possible recurrence [25]. At present, no consensus has been reached on the timing of surgery in young women; whether surgery should be delayed in infertile women planning IVF is still debated [26].

Possible complications with non-surgical approach are:

1) Difficulties during oocyte retrieval

2) Progression of endometriosis

3) Missing an occult early-stage malignancy

4) Risk of development of a pelvic abscess or rupture of the endometrioma

5) Follicular fluid contamination with endometrioma content

Most common mode of treatment is surgical which is laparoscopic cystectomy, benefit is reduced pain symptoms and recurrence. Excision of endometrioma in comparison with drainage of endometrioma with or without ablation of pseudo capsule is associated with better outcome and higher pregnancy rates [27]. However, ovarian cystectomy can lead to decreased ovarian reserve or due to excessive coagulation can be reason [28]. So to attain follicular development, increased amounts of gonadotropins are needed [29]. Laparoscopic cyst fenestration and ablation of the cyst capsule is another alternative method which improve pelvic pain and result in high patient satisfaction but high recurrence. That’s why opinion shifted towards more conservative approach. In 2013, The European Society of Human Reproduction and Embryology guideline suggested that surgery should be considered only if size of endometrioma is >3 cm, to improve access to follicles or pain [30]. Size play an important role in decrease ovarian reserve before surgery and difficulty for complete removal in case of superficial destruction as well as damage to ovary in case of surgical excision. Post-operative medical treatment markedly reduces the recurrence rate of endometrioma [31]. Therefore, long-term medical treatment to prevent recurrence is routinely recommended [32]. Post-operative medical treatments including oral contraceptives GnRH agonists, and progesterone commonly used to suppress possible residual lesions due to the oestrogen-reducing effects [33]. However, each of these treatments has reported adverse effects. Post operative medication needs, or efficacy was not studied in women aged 40 year or more.

Medical treatment used for treatment of endometrioma include Oral contraceptive pills, progestins, gonadotropin-releasing hormone agonists [34] as well as aromatase inhibitors are helpful to reduce size, symptoms, and post-surgery recurrence [35]. However, problem is reappearance of symptoms after stopping medical treatment [36]. To reduce recurrence after aspiration another promising method is sclerotherapy [37]. It involves injecting into cyst cavity a sclerosing agent which can be either removed by washing or left within cyst. It is thought that it will work by causing inflammation and fibrosis causing destruction of epithelial lining of cyst and at the end will cause obliteration of cyst [38]. It has been shown that sclerotherapy is cost effective method for endometrioma but not widely used [39]. Pain improved in 68- 96% independent from duration of ethanol inside endometriotic cyst. Compared to laparoscopic cystectomy, with sclerotherapy number of oocytes retrieved during IVF treatments was higher but no difference in pregnancy rates after sclerotherapy and untreated cases. Sclerotherapy was found to be safe with possible complication of transient abdominal pain. After sclerotherapy difference in the recurrence rate in studies can be due to variation in selection criteria (cyst size and number of cysts), technique used (sclerosing agent, concentration, installed volume, and retention time), duration of ethanol inside the endometrioma and the followup time. Risk of unexpected malignancy with typical features of endometrioma has been found in 1% in patients [40]. Other factors will influence the decision in an asymptomatic patient like the rate of growth, the age of patients, personal and family history of breast and ovarian malignancies [41].

Other alternative is phytotherapeutic options obtained from plants or herbal preparations some of them work by influencing apoptosis, epigenetic factors, angiogenetic processes, cell survival, oxidative stress and oestrogen modulation [42]. During course of fertility treatment, endometrioma often present a clinical dilemma due to uncertainty regarding decision of either to operate or manage conservatively while balancing possible risk of surgery on ovarian reserve. So far guidance available from either small and/ or retrospective controlled studies. Surgery does not improve the results of IVF treatment [43], but a sequential use of surgery and IVF in those that do not conceive spontaneously probably results in slightly higher cumulative pregnancy rates [44]. There may be spilling of chocolate fluid of endometrioma in peritoneal cavity in women undergoing IVF. This fluid may not induce endometriosis but is adhesiogenic [45]. Considering the risk of ovarian damage during surgery and the excellent results of IVF, actual guidelines [46] therefore have concluded that if IVF indicated then should not undergo surgery if size of endometrioma is ˂ than 3-4cm. Surgical treatment of endometriomas prior to IVF is widely practiced, [47] although debatable on its effect and need. To date, there has been no evidence that surgical treatment improves reproductive outcome of women treated with the use of ART, no difference in the clinical pregnancy rate and the number of oocytes retrieved from women who had surgical treatment compared with those with intact endometrioma. Cancellation rate and number of retrieved oocytes were comparable. After surgical treatment of endometrioma there is lower antral follicle count and higher doses of gonadotrophins required for ovarian stimulation.

Women of advanced reproductive age, asymptomatic, those with reduced ovarian reserve, bilateral endometriomas or a history of prior ovarian surgery may benefit from proceeding directly with IVF, as Ovarian reserve may be compromised further after surgery. In case of symptomatic women, large endometrioma, intact ovarian reserve, suspicious features of cyst on radiological investigations or with clinical features surgery may be considered. There is risk of Infertility and Premature Ovarian failure after treatment of endometrioma in very young women. Pathophysiology and manifestation of endometriomas in adolescents may be different than adult women [48]. The diagnosis of endometriosis in adolescents is often delayed due to several factors. Regarding early diagnosis followed by surgical removal of endometriomas in the adolescent population, currently no original studies are present as fertility is a major concern as well as future recurrence. New concept is early treatment instead of postponing surgery to prevent adhesions, ovarian damage and recurrence. Considering that the endometriosis in cystic ovarian endometriosis is only superficial, a superficial destruction by electro surgery, CO2 laser or alcohol should be sufficient before the development of more lesions and size of endometrioma is getting more or symptoms becoming more severe or concern of fertility arises. With these concepts, the use of THL in women with infertility should be reconsidered. Transvaginal hydro-laparoscopy (THL) [49,50] offers a minimal invasive procedure for early diagnosis and treatment of small endometrioma up to a diameter of 20 mm not seldom these small endometriotic cyst are missed at routine vaginal ultrasound examination in approximately 50% of the cases.

It is always surprising after opening of such small cysts to see the pronounced presence of inflammation and neo-angiogenesis, a signature for the aggressiveness of the disease in these early stages. Due to concern of ovarian reserve early stages treatment using ablative technique with a bipolar 5Fr probe causes a minimal trauma and a lower risk for recurrences [51]. In absence of suspicious radiological, clinical features chances of missing an occult malignancy in an endometrioma is extremely low and surgery is not advised. But in later life risk of developing ovarian cancer can be a concern with the lifetime probability increasing from 1% to 2% in the presence of an endometrioma [52].

Conclusion

Need clear guidelines for when to treat, when to stay conservative and if need treatment then what mode of treatment out of available options should be used keeping in view risk of recurrence, reduced ovarian reserve and fertility concerns. All available options have their own benefits and risks. So in current circumstances we need to decide either to stay conservative or treatment depending on symptoms or need for intervention.

For more Articles on: https://biomedres01.blogspot.com/

 

Chemistry of Gliotoxins and their Derivatives

Introduction

Research on gliotoxins at CSIR started in the 1960s when the gliotoxins were produced as standards and making it available to the agricultural and pharmaceutical sectors. Research has also been done on the behaviour and chemistry of gliotoxins, and on methods of how to deactivate them and combine them with fertilizer to enhance crop production. Gliotoxin is effective in the inhibition of several phytopathogenic fungi such as Rhizoctonia solani, Botrytis cinerea, Colletotrichum spp., Pythium ultimum, Fusarium spp. and other fungal species. Some of the other benefits of deactivated gliotoxins are that they can be used as antibiotics. Gliotoxin research is ongoing and could contribute to improved food security by enhancing food crop production by preventing plant diseases.

Experimental Methods

Growth conditions were optimised for growing the gliotoxin using isolates of Aspergillus Fumigatus culture from ATCC stored at -70°C using a bead cryopreservation system. The three A. fumigatus isolates were grown on Sabouraud glucose agar (SAB) plates for 2 days at 37 °C and the conidia were then extracted with sterile 0·5% Tween 20 and adjusted to a concentration of 107 conidia ml−1 in distilled water based on haemocytometer counts. One millilitre volume of this conidial suspension was used to inoculate 100 ml of liquid medium, Czapek-Dox broth (CDB; 30 g carbohydrate (glucose, lactose, maltose or sucrose), 3 g Na2NO3, 0·5 g MgSO4·7H2O, 0·5 g KCl, 0·01 g FSO4 in 1 l distilled water), in 250 ml flasks. The cultures were incubated at 37 °C in a shaking incubator at 1400 rpm for 2, 4, 6 or 10 days the broth was filtered and separately the broth and supernatant were extracted using chloroform and chloroform/ methanol 1:1 v;v respectively. Various experimental derivatives were obtained from gliotoxin. Reactions were monitored on Merck F254 silica gel plates and chromatography for both gliotoxin and derivatives purified using Merck 230-400 mesh silica gel. Solvents used in reactions were anhydrous solvents obtained from Merck chemical company as starting which were later screened for various therapeutic areas [1-3].

Results

Toxicity Data

All derivatives and their by-products are given orally to rats and did not show any evident sign of toxicity at the test concentrations of 3000-2000mg/kg except for gliotoxin which was toxic. 1H NMR spectrum (DMSO-d6, 400 MHz): 3.44 (1H, dd, J = 4.8, H-3a), 4.28 (1H, dd, J = 9.9, H-3a), 4.39 (1H, dd, J = 6.8, H-5), 4.842 (1H, m, H-6), 5.78 (1H, d, J = 9.9, H-7), 5.95 (1H, m, H-8), 6.00 (1H, m, H-9), 2.96, 3,73 (1H, d, J = 18.1, H-10), 3.20 (3H, s, H-11). 13C NMR spectrum (DMSO-d 6, 100 MHz): 166.0 (C-1), 77.2 (C-3), 60.5 (C-3), 165.2 (C-4), 69.8 (C-5), 75.6 (C-6), 129.9 (C-7), 123.4 (C-8), 120.2 (C-9), 130.7 (C-19a), 36.6 (C-10), 73.1 (C-10a), 27.5 (C-11). LREI-MS m/z: 349 [M]+ (C21H23N3O2). LREI-MS m/z: 326.38 [M]+ (C13H14N2O4 S2).

Figure 1.

Figure 2.

Figure 3: Control land without treatment

Figure 4: Farmland treated with Activated Gliotoxin

Conclusion

Biological assays were conducted on the gliotoxin derivatives and the by-products in vitro and in vivo potent for anti-viral, antifungal, and antibacterial activities and growth stimulants.

For more Articles on: https://biomedres01.blogspot.com/

 

Machine Learning Application to Combat Superbugs in Hospitals: A Primer to Infection Prevention Practitioners

Introduction

Healthcare-Associated Infections (HAIs) which defined as infections arising and developing during hospital stay or during the process of medical care in healthcare facilities. It is also defined as infections which are not present or incubating when the patient is hospitalized and are acquired after 48 hours of hospital stay [1]. HAIs represent the most serious threat to patient safety, and it also represent global public health concern [2]. HAIs have a significant clinical as well as financial impact due to prolonged hospitalization, increased mortality, and morbidity, increased antimicrobial resistance and increased direct costs for medical services [2]. Antimicrobial resistance is on the rise, raising worries about the impact on individuals with multidrug resistance bacteria [3]. As a result, significant efforts have been made to investigate the clinical outcomes of patients infected with such pathogens, which have shown higher mortality and treatment failure rates than those infected with susceptible isolates [3]. The rise of resistant hospital pathogens has posed a difficulty to providing high-quality inpatient treatment. The overuse of antibiotics in hospitals is largely to blame for this problem [4].

Resistant bacterial infections have a negative impact on the treatment outcomes, cost, disease spread, and sickness duration, offering a severe challenge to future chemotherapies [4]. The systematic collection of data on the occurrence of HAIs, analysis and transformation of the data into valuable information, and dissemination of this knowledge with those who may take action to avoid HAIs are all part of HAIs surviellance systems [5]. The first criteria in an infection preventionist’s minimum standard of practice are surviellance and epidemiology [5]. Already 40 years ago, many studies proved that there is 32% reduction in HAIs rates in hospitals with active surveillance programs compared with those without such programs [6]. The first goal of any surveillance system is to determine infection rates, infection sites, common pathogens, and antibiotic use, as appropriate empiric therapy is recognized to be the most crucial component in patient’s outcome. As a result, it is crucial to identify the microorganisms that cause infections as well as their antimicrobial resistance pattern to find the optimal antimicrobial treatment [6]. Surviellance in its conventional way, in which every patient’s file is reviewed for the presence of HAIs, is time consuming and labor intensive [5]. To improve the efficiency and strength of infection prevention and surveillance systems, information technology, data science and artificial intelligence have been recently applied. We need tools that help prediction, early diagnosis, surveillance, and treatment of HAIs to prevent human efforts of disease containment from being overwhelmed.

Definition of Artificial Intelligence and Machine Learning

Artificial intelligence (AI), which is defined as computer algorithms with cognitive-like characteristics such as learning capabilities, is already having an impact on our lives in a variety of ways [7]. In radiology, dermatology and pathology, AI- assisted image analysis has already established a significant position. In genomics, another data-intensive science, AI aids in the prediction of phenotypes from genotypes [7]. Also, AI has been applied in infectious disease management specially to aid the detection and prevention of diseases [7]. The application of AI in healthcare began with the creation of expert systems based on rules extracted from interviews with medical specialists and experts, which were then translated and programmed [8]. The first expert system in medicine was developed in 1976 aiming at suggesting antimicrobial treatment for severe bacterial infections [8]. Machine learning (ML) considered a subset of AI, demonstrates the experiential “learning” associated with human intelligence, while also having the ability to learn and improve its analysis via the use of computing algorithms [9].

These algorithms recognize patterns and effectively “learn” in order to teach the computer to make autonomous suggestions or decisions using vast volumes of data inputs and outputs. The machine can take and input and anticipate a result with enough repetitions and modifications to the algorithm [9]. The algorithm’s accuracy is then judged by comparing the output to a collection of known outcomes, which is then iteratively changed to perfect the capacity to anticipate future results [9]. The predictive capabilities of machine learning are rapidly being employed in the realm of healthcare. ML models have been presented and evaluated as potential answers to a range of challenges involving diagnostic errors, treatment errors, workflow inefficiencies and obstacles to value-based care as a convergence between health and data science [9].

Machine Learning Methods

ML is divided into three main categories: supervised learning, unsupervised learning, and reinforcement learning. The term “supervised learning” refers to algorithms that use labeled data as a training dataset. Labeled data are datasets in which the outcome of interest has already been determined; for example, to train an algorithm for sepsis prediction, we utilize a dataset in which patients are already classified as having sepsis or not. The algorithm will then select the best model to predict the desired outcome [8]. Unsupervised learning is the utilization of data without a specified or predefined outcome of interest. Algorithm are left to detect patterns and extract hidden structure from data on their own, with no expert labeling. Unsupervised learning is mostly used in medicine for clustering with the goal of discovering groups in data, such as related groups of patients based on clinical data [8]. Through trial and error, reinforcement learning algorithms uncover activities that provide the greatest rewards. In this category, the algorithm is set up to consider survival or a shorter hospital stay as a reward. The approach employs a training dataset to run several tests in order to generate the model with the highest reward [8].

ML in Infection Prevention and Control

AI and ML offer huge potential in Infection Prevention and Control (IPC) [10]. Its applications in IPC have enormous promise for implementing WHO core components. [10]. AI and ML have potential benefits in the three main areas highlighted by the WHO: 1- HAIs surviellance, 2- Improved laboratory diagnosis to facilitate IPC interventions, 3- Hand hygiene practice [10]. In HAIs surviellance, ML application have been used to monitor trends, identify clusters and outbreaks in a timely manner. It is also used in outbreak simulation to mitigate interventions. Also, ML is a very helpful tool in predicting the risk of nosocomial infections as nosocomial Clostridium difficile infection [10]. While more research is needed to validate these findings, this method has the potential to change HAIs surveillance and IPC [10].

ML data mining tools as well could use the clinical microbiology laboratory results to detect and predict clusters or outbreaks of multidrug resistant pathogens in healthcare settings [10]. AI and ML enhanced laboratory microscopy could speed up infection diagnosis and aid AMR prevention initiatives by facilitating targeted antibiotic management and IPC intervention [10]. Studies showed that gram stain interpretation with AI-assisted tools could lower cost and time with good accuracy [10]. Wearable technology using ML applications provide benefits for healthcare environment in general and IPC in specific in the form of supporting healthcare staff IPC education, audit and behavior change.

ML in Prediction and Early Detection of HAIs

AI and ML are being used by researchers in public health surveillance to predict disease outbreaks and evaluate surveillance tools [11]. Identifying patients at increased risk of HAIs in ICUs is a serious public health concern. ML could improve patient risk classification and lead to more specific infection prevention and control study.

ML models could be made for surveillance of Blood Stream Infections (BSI), CD Infections (CDI), Urinary Tract Infections (UTI), pneumonia and Surgical Site Infections (SSI). Vab der Werff, et al. [12] developed a fully automated Surviellance algorithm for hospital acquired UTI using electronic health record (EHR) data. This study concluded that a fully automated surveillance algorithm based on artificial intelligence and machine learning to detect UTI symptoms from EHR had acceptable performance HAUTI compared to manual record review. Taylor, et al. [13] showed that machine learning algorithms accurately diagnosed positive urine culture results and accurately predict UTIs in emergency department.

Mancini, et al. [14] built a predictive model using a cloud platform (DSaaS), online and user-friendly platform, to predict Multi-Drug Resistant (MDR) UTI in hospitals. DSaas can help physicians to build easy prediction models that could help them to treat hospitalized patients. Their model is based on supervised ML regression and classification algorithms. They developed this model to assist in the antimicrobial stewardship program implemented in their hospital [14]. Nemati, et al. [15] developed an Artificial Intelligence Sepsis Expert (AISE) algorithm for early prediction of sepsis. Using data available in the ICU in real time, AISE can accurately predict the onset of sepsis in an ICU patient 4 to 12 hours prior to clinical recognition [15]. Many studies showed that ML based clinical decision support (CDS) tools embedded within electronic medical record improve early detection and therapy in patients with early blood stream infections and can predict septic shock [16].

Conclusion

Many studies suggest that machine learning algorithms outperforms conventional statistical approaches in term of predictive performance, implying that the machine learning approaches could be used to identify and predict patients at higher risk of HAIs at hospital admission, giving clinicians enough time to potentially prevent HAIs and mitigate their severity by targeting specific infection prevention and control interventions at high-risk groups in order to improve quality of care.

For more Articles on: https://biomedres01.blogspot.com/

 

Review on Evaluation of the Efficiency of Epidemiological Surveillance for Echinococcosis in the Kyrgyz Republic

Introduction

The work assessed the effectiveness of epidemiological surveillance of echinococcosis in the Kyrgyz Republic (KR), set out in the Order of the Ministry of Health of the KR № 666 “On strengthening measures to control and prevent echinococcosis and alveococcosis in the KR “ dated December 18, 2008, based on the following criteria: effectiveness anti-epidemic and preventive measures: epidemiological, social, economic, diagnostic and clinical, the degree of simplicity, the degree of acceptability and efficiency. The research materials were statistical reports of the Department of Disease Prevention and State Sanitary and Epidemiological Surveillance of the Ministry of Health of the KR. Were analyzed and systematized the legal norms governing the prevention and control of echinococcosis in dogs, and human protection, studied the laws and by-laws of the KR in the field of veterinary medicine, sanitary rules and norms, as well as epidemiological and epizootic reporting. Research methods: retrospective epidemiological, descriptive, analytical, statistical. Based on the favorable trend of many criteria characterizing the effectiveness of anti-epidemic and anti-epizootic measures, a preliminary conclusion can be drawn about the correct choice of organizational and methodological approaches in conducting epidemiological surveillance of echinococcosis in the KR and the following criteria are assessed: the effectiveness of antiepidemic and preventive measures is satisfactory, epidemiological effectiveness - low, social efficiency - high, economic efficiency - satisfactory, diagnostic and clinical efficiency - high, degree of simplicity - high, degree of acceptability - low, efficiency - high.

The years of potentially lost life in echinococcosis in the KR have been calculated. Echinococcosis is a zoonotic natural anthropurgic helminthiasis caused by tapeworms Echinococcus granulosus (Echinococcus) and Echinococcus multilocularis (Alveococcus). Human echinococcosis is a serious parasitic disease that affects both different segments of the population and different age groups [1,2]. Echinococcosis is widespread throughout the world, the prevalence of the population is higher in areas with developed pasture animal husbandry. The source of the pathogen for farm animals, pigs - dogs affected by larvae (hydatids) of echinococcus, for wild ruminants - wolves, foxes, jackals and arctic foxes, infested by the imaginal stage and excreting mature segments of this parasite with feces, and for carnivores - ruminants and pigs. The transmission factors of the pathogen are grass, various types of feed and water contaminated with segments and eggs of echinococci, excreted by dogs, wolves and other carnivores with feces and swallowed by ruminants and omnivores. The factor of transmission of echinococcus to definitive hosts is the organ affected by parasites. Shepherds, shepherds, fur breeders, hunters and other persons who have constant contact with the final hosts of echinococcus or alveococcus get sick more often [3,4]. Echinococcosis is an urgent socio-economic problem in the Central Asian region and the Kyrgyz Republic in particular. Echinococcosis subsequently leads to severe complications, both in the postoperative period and in the long-term.

Despite the long-standing struggle against these parasitic diseases, the Kyrgyz Republic still remains an unfavorable hyperendemic region in terms of the prevalence of echinococcosis, which has the status of a nationwide problem due to its wide distribution and huge economic damage to public health and animal husbandry [5]. Measures to combat hydatidosis are carried out in a complex way (by medical, veterinary, communal and hunting organizations). Mutual information about cases of hydatidosis in humans, farm and wild animals should be provided between medical and veterinary workers [6]. Recently, the epidemic situation of echinococcosis in the Kyrgyz Republic is quite tense. At the end of the 20th and the beginning of the 21st century, a sharp increase in the incidence of echinococcosis began throughout the territory of the Kyrgyz Republic, including among the child population [7,8]. This was the reason for the development of a new program of epidemiological surveillance, set out in the Order of the Ministry of Health of the Kyrgyz Republic No. 666 “On strengthening measures to combat and prevent echinococcosis and alveococcosis in the Kyrgyz Republic” dated 12/18/2008.The purpose of this work is to evaluate the effectiveness of epidemiological surveillance of echinococcosis in the Kyrgyz Republic.

Tasks

- To determine the criteria for evaluating the effectiveness of epidemiological surveillance of echinococcosis;

- To conduct a comparative epidemiological analysis of these criteria for evaluating the effectiveness of epidemiological surveillance of echinococcosis;

- On the basis of the analysis carried out, to assess the effectiveness of epidemiological surveillance of echinococcosis in the Kyrgyz Republic.

Materials and Methods

Statistical reports of the Ministry of Health of the Kyrgyz Republic DPZiSSES served as the research materials. The legal norms regulating the implementation of the prevention and control of canine echinococcosis, and human protection were analyzed and systematized, the laws and by-laws of the Kyrgyz Republic in the field of veterinary medicine, sanitary rules and regulations, as well as epidemiological and epizootological reporting were studied. Research methods: retrospective epidemiological, descriptive, analytical, statistical.

Results and Its Discussion

As our studies show, the epidemiological situation of echinococcosis in the Kyrgyz Republic is rather ambiguous. Despite the introduction of a new epidemic surveillance program, the incidence of echinococcosis and alveococcosis continued to grow until 2014 and 2015, respectively, and it was under the new program that the peak incidence of both diseases was recorded. On the one hand, this is due to the increase in the quantity and quality of preventive examinations and examinations according to epidemic indications, as well as the introduction of new methods for diagnosing echinococcosis, which increased the detection of these parasitic diseases, which, in turn, affected the growth of infestation. This also explains the serious decline in incidence following the peak, also due to an increase in the quantity and quality of preventive and anti-epidemic measures, as well as the diagnosis and treatment of echinococcosis. On the other hand, it is impossible not to note the cyclicity characteristic of echinococcosis in 7-8 years. It is this cycle that can explain the observed decline in the incidence of this disease in the population. 2019 is the borderline, the lowest point of the cycle, after which there may be another growth characteristic of the beginning of the next cycle.

The trend towards an increase in the incidence of echinococcosis during the introduction of a new epidemiological surveillance program also does not inspire confidence in the effectiveness of the new epidemiological surveillance program for echinococcosis, but does not give a clear answer due to the increased detection rate. Despite this, the impact of the child population in the Kyrgyz Republic gives less controversial results. The increase in the proportion of childhood susceptibility to echinococcosis and alveococcosis in the Kyrgyz Republic, as well as the increase in the proportion of child susceptibility, indicate the low epidemic effectiveness of the new program for epidemiological surveillance of echinococcosis. It should be noted that this could also be affected by an increase in the detection of echinococcosis among the child population due to new diagnostic methods and an increase in preventive examinations, but in this case this is unlikely. Considering all of the above, we can conclude that this period is not enough for a full assessment of the effectiveness of anti-epidemic and preventive measures. For an accurate assessment, it is necessary to continue monitoring the incidence of echinococcosis in subsequent years in order to dismiss, or vice versa, confirm the role of cyclicity in the decline in incidence in the period after the introduction of a new program for epidemiological surveillance of echinococcosis.

However, during the implementation of the program, modern complex diagnostic methods and screening studies of the population were used, which helped to establish not only natural, but also anthropurgic foci of alveococcosis, as well as the proportion of children under 14 years of age with these invasions. Therefore, the effectiveness of preventive and anti-epidemic measures, as well as the epidemiological effectiveness of the current program for epidemiological surveillance of echinococcosis is not at a high, but at a satisfactory level.It is also impossible to discount the features of the clinical picture of echinococcosis, when the manifest stage of the disease is remote from the time of infection and manifests itself after many years of invasion with severe complications leading to disability and, often, death of the patient. A complete epidemiological characterization of the incidence of echinococcosis is possible only on the basis of the results of mass sero-epidemiological surveys of the population from risk groups (living in endemic areas or at occupational risk of infection with echinococcosis) [9]. Evaluation of social efficiency is also difficult for objective reasons.First, especially in remote regions, there is a serious problem with the registration of deaths from echinococcosis.

Patients after surgery with a diagnosis of echinococcosis and alveococcosis, after death, other diagnoses are made, such as: cirrhosis of the liver, hepatitis, liver failure, and therefore these cases are not included in the reporting form No. 1 of the State statistical reporting “Report on infectious and parasitic diseases” as dead from echinococoses. In this regard, the mortality rate from echinococcosis is slightly underestimated compared to the real situation. Secondly, due to the lack of criteria regulating indications for disability for echinococcosis, there is no way to evaluate it. But, even taking into account these two factors, the current program for the epidemiological surveillance of echinococcosis provides for more rational accounting, registration of morbidity and mortality from echinococcosis in medical institutions and centers of state sanitary and epidemiological surveillance with monitoring of reporting data horizontally and vertically, which, with relatively equivalent mortality rates, indicates a higher social efficiency of the new program for epidemiological surveillance of echinococcosis. Since during the operation of the new epidemic surveillance program the number of sanitary and educational activities carried out with the use of radio, TV, newspapers, seminars, conferences increased, many rural gatherings began to be held, etc., the number and quality of preventive and anti-epidemic measures increased, as well as however, more expensive diagnostic methods have been introduced, naturally, and the costs of implementing epidemiological surveillance have increased compared to the period before the introduction of the new program.

However, given that at the moment the program of epidemiological surveillance of echinococcosis has shown satisfactory effectiveness of preventive and anti-epidemic measures, the economic efficiency is also at a satisfactory level. The introduction into wide practice of serological testing of patients suspected of being affected by echinococcosis, provided for by new methodological guidelines for the clinical and laboratory diagnosis and treatment of echinococcosis and alveococcosis, has made it possible to increase the detection rate and thus start the treatment of these parasitic diseases in a timely manner. This indicates a high diagnostic efficiency of the new program for epidemiological surveillance of echinococcosis. The text of the Order of the Ministry of Health of the Kyrgyz Republic No. 666 “On Strengthening Measures for the Control and Prevention of Echinococcosis and Alveococcosis in the Kyrgyz Republic” dated December 18, 2008 was executed in accordance with all the rules for compiling regulatory documentation, all terms and formulations used are of an exclusively legal and medical nature, do not have fuzzy wording or phrases with two meanings. Therefore, the degree of simplicity of the echinococcosis epidemiological surveillance program is assessed as understandable by specialists whose work duties are regulated by this regulatory document. In general, the surveillance system for echinococcosis is simple to implement. However, the omission of the implementation of anti-epidemic and antiepizootic measures depends on the qualifications of specialists, the degree of acceptability of administration employees, medical organizations and ordinary citizens. In medical institutions, the collection, processing, transmission and analysis of information, as well as keeping journals, compiling forms and reports according to the schemes provided for by the Order of the Ministry of Health of the Kyrgyz Republic No. 666, is carried out in a timely manner and on time. The system of registration, registration of new cases of infection and deaths from echinococcosis, as well as epidemiological investigations of each case of echinococcosis and identification of foci has been worked out, which ensures completeness, reliability, timeliness and high efficiency of epidemiological surveillance of echinococcosis.

Conclusion

1. After analyzing the data collected for the period before and after the introduction of epidemiological surveillance of echinococcosis, set out in the Order of the Ministry of Health of the Kyrgyz Republic No. 666 “On strengthening measures for the control and prevention of echinococcosis and alveococcosis in the Kyrgyz Republic” dated December 18, 2008, the following criteria were assessed

A. The effectiveness of anti-epidemic and preventive measures is satisfactory.

B. Epidemiological effectiveness is low.

C. Social efficiency is high.

D. Economic efficiency is satisfactory

E. The degree of simplicity is high

F. Efficiency is high

G. Diagnostic and clinical efficiency is high

H. The degree of acceptability is low

Therefore, based on the evaluation of the criteria characterizing the effectiveness of anti-epidemic and anti-epizootic measures for echinococcosis, we can conclude that the correct choice of organizational and methodological approaches in conducting epidemiological surveillance of echinococcosis, set out in the Order of the Ministry of Health of the Kyrgyz Republic No. 666 “On strengthening measures to combat and prevent echinococcosis and alveococcosis in the Kyrgyz Republic” from 12/18/2008.

2. Years of potentially lost life due to echinococcosis for the period from 2013 to 2019 in the Kyrgyz Republic amounted to 4331.9 years.

For more Articles on: https://biomedres01.blogspot.com/