Cutaneous Lesions in the Gular Region Caused by Feather Follicle Infestation with Harpirhynchidae sp. Mites in Great Crested Flycatchers (Myiarchus crinitus) in New York, USA 2016-23.

Great Crested Flycatchers (Myiarchus crinitus), migratory passerines with a breeding range throughout the northeastern, midwestern, and southern US, are banded annually at the Braddock Bay Bird Observatory located on the southern shore of Lake Ontario, New York, USA. In 2016, a Great Crested Flycatcher was observed with distinct lesions in the gular and ventral neck region, which prompted evaluation for similar lesions in subsequently trapped flycatchers and other passerine species. From 2016 to 2023, 62/102 banded Great Crested Flycatchers had their gular region examined, and seven were found to have lesions (11.3% incidence). Similar lesions were not found in any other species. Lesions were localized to the gular region and included extensive feather loss with thickened, corrugated, pale-yellow skin. Grossly visible 1- to 2-mm-diameter, raised, white-to-yellow foci throughout the affected region corresponded microscopically to feather follicles that were massively dilated with mites. Morphologic analysis of mites obtained from skin scrapes revealed that this mite species belongs to the family Harpirhynchidae. Mites in this family have restricted avian host ranges and cause varying clinical presentations in passerines, though many species remain unidentified. PCR efforts were unsuccessful in yielding a species-level identification. Further monitoring of Great Crested Flycatchers and other avian species is warranted, as the fitness implications of this ectoparasitism at the individual and population levels are not known.

A clinical dimple on facial skin related to dental origin: A case report.

INTRODUCTION AND IMPORTANCE: Facial skin may experience many clinical manifestations which are numerous and need accurate diagnosis to reach the best treatment immediately and effectively. Dimpling of the skin may be diagnosed improperly due to lack of information related to diseases of dental origin. The objective of this study is to provide clarity on dental diagnosis and treatment options for extraoral dimpling caused by odontogenic infections. CASE PRESENTATION: A 19-year-old girl presented with a dimple on her facial skin developed during the last month before her consultation. The dimple was located where a vertical line from the distal canthus crosses a horizontal line from the nasal alar. No systemic disease was discovered, and the dental history revealed recurrent failure of root canal treatment in the upper first molar. CLINICAL DISCUSSION: Cutaneous sinuses originating from dental issues are characterized by a connection between the skin surface and a periapical dental abscess, which is caused by a long-dated tooth infection. Due to the patient's previous dental abscess in close proximity to the skin defect, a clinical diagnosis of an odontogenic cutaneous sinus was established. CONCLUSION: It is crucial to recognize that skin lesions in the face and neck area can be a result of odontogenic infections. Careful clinical and radiographic examinations should be conducted to accurately diagnose and differentiate these conditions. By identifying the tooth associated with the lesion, unnecessary medications and incorrect interventions can be avoided, ensuring the implementation of appropriate treatment.

Clinicopathologic features of ecthyma gangrenosum: a single integrated health system cohort.

Ecthyma gangrenosum is an uncommon cutaneous eruption that can initially present with painless macules, which rapidly evolve into necrotic ulcers. This study sought to characterize clinicopathologic features of ecthyma gangrenosum from a single integrated health system. Our cohort consisted of 82 individuals diagnosed with ecthyma gangrenosum. Lesions were most commonly found in the lower extremities (55%) and the truncal region (20%). A wide variety of fungal and bacterial etiologies were found among our cohort. The majority of patients with EG were immunocompromised (79%) and 38% of patients also experienced sepsis. The mortality rate seen in our cohort was approximately 34%. No statistical differences in mortality outcome due to EG related complications were seen between pathogen etiology, and distribution or location of lesions. Patients who were septic or immunocompromised died more frequently than non-septic or immunocompetent patients, suggesting poorer prognosis.

Clinical analysis of 20 cases of cutaneous extranodal NK/T-Cell lymphoma.

Background To investigate the clinical features, pathological features and prognostic factors of cutaneous extranodal natural killer/T-cell lymphoma (CENKTL). Methods A total of 20 cases with CENKTL from February 2013 to November 2021 were analysed retrospectively. Results The patients included 15 men and five women, and their ages ranged from 19 to 92 (median age of 61) years. The most common lesions were on the extremities, followed by the trunk. Histopathological examination showed atypical lymphocyte infiltrate in dermis and subcutaneous fat. The tumour tissue showed vascular proliferation, vascular occlusion, and coagulation necrosis. In situ hybridisation revealed that 20 patients were positive for Epstein-Barr virus-coding ribonucleic acid. Immunohistochemistry showed that the tumour cells were positive for CD3 (18/20 and 90%), CD56 (19/20 and 95%), T-cell intracellular antigen (TIA-1) (13/14 and 92.9%) and CD20 (5/20, 25%). About 20 patients were positive for Ki-67 with values of 30-90%. A total of 11 of the 20 patients died, and two patients were lost to follow-up. The 2-year overall survival was 24%, and the median overall survival was 17 months. Univariate analysis revealed that involvement of lymph nodes (P = 0.042) correlated with worse survival. Limitation This is a retrospective study design and has a limited number of patients. Conclusion CENKTL is rare and has a poor prognosis. Diagnosis is challenging due to non-specific clinical symptoms and histopathology results. A comprehensive judgement should be made based on related clinical manifestations and histopathological and molecular examination. Lymph node involvement is an independent prognostic factor for CENKTL.

Unraveling the distinctive venomous features of the saturniid Hylesia sp.: An integrative approach of a public health concern in Argentina.

The saturniid genus Hylesia is well known for the cutaneous lepidopterism induced by airborne setae on contact with the skin. Although several cases of such dermatitis have been reported in Argentina, no information about their venoms and toxicological implications on human health is available yet. Thus, we conducted a morphological analysis of the setae/spines and a toxinological characterization (through biological assays and proteomic techniques) of the bristle extract from caterpillars and moths of Hylesia sp. from Misiones, Argentina. By scanning electron microscopy, we revealed the various and distinctive types of urticating structures: harpoon-shaped or spiny setae in caterpillars, and setae with barb-like structures in female moths. Their venom electrophoretic profiles were substantially different, presenting proteins related to toxicity, such as serpins and serine peptidases. The female moth venom exhibited higher caseinolytic activity than the caterpillar venom, and coincidentally only the former noticeably hydrolyzed fibrinogen and gelatin. In addition, the female venom displayed a dose-dependent procoagulant effect. The injection of this venom into mouse skin led to the rapid detection of an increased number of intact and degranulated mast cells in the dermis; a few areas of focal subcutaneous hemorrhage were also observed after 5 h of injection. Altogether, this study provides relevant information about the pathophysiological mechanisms whereby Hylesia sp. from northeastern Argentina can induce toxicity on human beings, and paves the way for treatment strategies of accidents caused by this saturniid lepidopteran.

Cutaneous Management after Extravasation of High-Concentrated Amino Acid Solution Administered for Renal Protection in PRRT.

High-concentrated amino acid solution is used to protect the kidneys during peptide receptor radionuclide therapy (PPRT) in patients with neuroendocrine tumors (NETs). Extravasation of the solution can cause cutaneous complications. In this study, we described a 66-year-old man with metastatic medullary thyroid cancer and a 32-year-old woman with metastatic pancreatic NET who developed cutaneous lesions caused by the extravasation of an amino acid solution (25 g of lysine and 25 g of arginine in 1 L of normal saline) during PRRT with [177Lu]Lu-DOTA-TATE. Both were treated conservatively, and these cutaneous lesions gradually improved. The patient with metastatic pancreatic NET rejected the amino acid infusion in subsequent cycles of PRRT and therefore received [177Lu]Lu-DOTA-TATE alone, and her serum creatinine level and estimated glomerular filtration rate (eGFR) remained normal for 2 months after the last treatment. These two cases revealed cutaneous complications resulting from high-concentrated amino acid solution during PRRT because of hyperosmolarity. Health care providers should be aware of this complication to ensure its prevention and appropriate management. Preserved renal function was demonstrated after [177Lu]Lu-DOTA-TATE treatment in the absence of the infusion of a high-concentrated amino acid solution. However, long-term follow-up of renal function is suggested.

A Challenging Cutaneous Lesion in a Patient With Chronic Idiopathic Neutropenia.

Ecthyma gangrenosum (EG) is an uncommon necrotizing vasculitis that affects mainly immunocompromised and burn patients, and it is frequently associated with Pseudomonas aeruginosa bacteremia. However, cases of EG with other related pathogens and cases of EG affecting immunocompetent hosts have also been described in the literature. Besides, less common cases of EG without bacteremia have been reported. Herein, we describe a rare case of EG due to Pseudomonas aeruginosa without bacteremia in a patient with chronic idiopathic neutropenia (CIN). Considering the high mortality rate associated with EG, early diagnosis and appropriate effective treatment are crucial.

Cutaneous Lesion of the Nose as Initial Presentation of Esophageal Adenocarcinoma.

BACKGROUND/AIM: Cutaneous manifestations of disease are exceedingly rare and commonly overlooked in clinical practice. Allergies or contact dermatitis, autoimmune disease or skin cancer are the most common conditions typically associated with skin lesions. Rarely, cutaneous lesions may be the first sign of internal malignancy, or even resemble recurrent disease in those with history of cancer. CASE REPORT: Herein, we report a case of an otherwise healthy male who presented to his primary care provider (PCP) with a skin lesion misdiagnosed as a furuncle, which eventually led to diagnosis of metastatic esophageal cancer. The patient was a 64-year-old male, presenting with a fungating lesion on the tip of his nose which was biopsied, confirming adenocarcinoma likely from a gastrointestinal source. Staging imaging showed extensive lung, liver, and boney metastatic disease. He was initially treated with chemotherapy and trastuzumab. CONCLUSION: Cutaneous lesions are a rare presenting sign of malignancy, but rapidly growing lesions should be evaluated for possible metastatic disease.

Hypertriglyceridemia and massive rhabdomyolysis in a patient with disseminated legionella.

Legionella most commonly presents as pneumonia but can have disseminated involvement, presenting as extra-pulmonary disease involving gastrointestinal, neurological, cardiac, renal, and musculoskeletal systems, and skin and soft tissues. We present a case of a patient with pneumonia, rhabdomyolysis, renal failure, hypertriglyceridemia, pancreatitis, and cutaneous involvement. This case highlights the breath of involvement legionella can have, including the never previously documented manifestation of hypertriglyceridemia and severe rhabdomyolysis with the highest creatinine kinase recorded.

Clinical features and prognosis of nocardiosis in patients with connective tissue diseases.

OBJECTIVES: To investigate the clinical features and prognosis of nocardiosis complicated by connective tissue diseases (CTDs). METHODS: We examined patients with CTDs who were diagnosed with nocardiosis from October 2004 to 2019. We retrospectively investigated patient characteristics and therapeutic outcomes. We then performed a comparison between survivors and non-survivors. RESULTS: Fourteen patients were examined. Underlying CTDs were systemic lupus erythematosus (28.6%), vasculitis syndrome (28.6%), rheumatoid arthritis (21.4%), adult Still disease (14.3%) and dermatomyositis (7.1%). Infected organs were lung (85.7%), brain (42.9%), skin/cutaneous lesions (28.6%) and muscle (7.1%). Disseminated infections were seen in nine patients (64.3%). At the onset of nocardiosis, all patients were given prednisolone (23.2 ± 11.9 mg/day). Only two patients (14.3%) were given TMP-SMX for prophylaxis of pneumocystis pneumonia. Relapse occurred in one patient (7.1%) and four patients (28.6%) died from nocardiosis for a cumulative survival rate at 52 weeks of 76.9%. In a comparison of survivors (71.4%) and non-survivors (28.6%), cutaneous lesions were significantly more frequent in the latter (10 vs 75%, p = .04) with an odds ratio of 27.0 (95% CI: 1.7-453.4). CONCLUSION: Cutaneous lesions as a result of dissemination might be a risk factor for nocardiosis mortality in patients with CTDs.

Atlantoaxial limited dorsal myeloschisis: A report of two cases and review of literature.

Introduction: Limited dorsal myeloschisis (LDM) is a rare form of spinal dysraphism that is characterised by a distinctive fibroneural stalk connecting the spinal cord to the overlying skin lesion. The skin lesions associated with LDM can appear benign clinically and careful evaluation with an MRI scan is essential for diagnosing LDM and to differentiate this entity from other forms of spinal dysraphism and benign causes of skin lesions. Research question: There is a lack of reported atlantoaxial LDM in the literature. We sought to report the clinical presentation, radiological features and surgical management of the first two reported atlantoaxial LDM. Material and methods: Clinical findings and radiological images of the two cases of atlantoaxial LDM that underwent surgical intervention at our institution were retrieved from the medical notes, operative records and imaging system. Results: Both cases of atlantoaxial LDM (C0-1 and C1-2 respectively) underwent successful resection of the overlying cutaneous lesions and stalks to release the tethered spinal cords. Discussion: The surgical management of LDM have been associated with good outcomes and consists of resecting the fibroneural stalk close to the underlying cord, releasing the tethered spinal cord and removing the overlying cutaneous lesion. Conclusion: These are the first two reported cases of atlantoaxial LDM in the literature. We aim to raise awareness of this pathological entity and highlight the importance of establishing the correct diagnosis to guide definitive management, and report the favourable neurological outcome in these cases despite the rostral location.

Historical analysis of leishmaniasis cases in the transamazonian region: from 2009 to 2019 / Análise histórica dos casos de leishmaniose na região transamazônica: de 2009 a 2019 / Análisis histórico de casos de leishmaniasis en la región transamazónica: de 2009 a 2019

Objective: To determine the total number of notified cases, new cases and recurrence of American Tegumentary Leishmaniasis (ATL), to investigate the association between HIV coinfection and the presence of cutaneous lesion, as well to assess the concordance of two different laboratorial procedures: parasitological and histopathological in this region. Methods:This is a cross-sectional study. The research used data from the Information System for Notifiable Diseases, hence forth designated as SINAN (Sistema de Informação de Agravos de Notificação) that contained 6,183 cases of leishmaniasis in 9 municipalities. Results:As results, 5795 were of new cases and 351 recurrence cases. Among the cases 1,146 patients were tested for HIV, 16 presented coinfection from these 15 developed cutaneous lesion. In the overall studied population 5,690 subjects manifested cutaneous lesion. There was no agreement of the results regarding the quality of the parasitological and histopathological exams, demonstrating that they are poorly replicable (p <0.005). Conclusion:The ATL is endemic in the transamazonian region posing as a major public health problem. All patients with leishmaniasis must be tested for HIV and health professionals must register on the notification form. The tests to diagnose leishmaniasis need to be more specific and sensitive.

Objetivo: Determinar o número total de casos notificados, casos novos e recorrência da Leishmaniose Tegumentar Americana (LTA), investigar a associação entre a coinfecção pelo HIV e a presença de lesão cutânea, bem como avaliar a concordância de dois procedimentos laboratoriais distintos: parasitológico e histopatológico nessa região. Métodos: Este é um estudo transversal. A pesquisa utilizou dados do Sistema de Informação de Agravos de Notificação, doravante denominado SINAN, que continha 6.183 casos de leishmaniose em 9 municípios. Resultados: Como resultados, 5795 eram de casos novos e 351 casos de recorrência. Dos casos 1.146 pacientes testados para HIV, 16 apresentaram coinfecção, destes 15 desenvolveram lesão cutânea. Na população geral estudada 5.690 indivíduos manifestaram lesão cutânea. Não houve concordância dos resultados quanto à qualidade dos exames parasitológicos e histopatológicos, demonstrando que são pouco replicáveis ​​(p <0,005). Conclusão: A ATL é endêmica na região transamazônica e constitui um importante problema de saúde pública. Todos os pacientes com leishmaniose devem ser testados para HIV e os profissionais de saúde devem se cadastrar na ficha de notificação. Os testes para diagnosticar a leishmaniose precisam ser mais específicos e sensíveis.

Vasculopathy-related cutaneous lesions and intrahepatic cholestasis as synchronous manifestations in a COVID-19 patient; a case report.

Today, COVID-19 pneumonia causes global concern. The World Health Organization (WHO) has reported many mortalities from this disease all around the world. Therefore, recognizing new cases of COVID-19 is crucial during this pandemic. Many studies have shown that COVID-19 has a broad spectrum of signs and symptoms, including GI and cutaneous manifestations. Previous studies have reported liver enzyme changes as well as diarrhea as a common GI manifestation of COVID-19. However, there are few reports about COVID-19 synchronous cutaneous and liver involvement. Additionally, there are few reports about intrahepatic cholestasis in COVID-19 patients. In this article, a confirmed case of COVID-19 with vasculopathy-related cutaneous manifestation and liver cholestasis is reported. A 67-year-old Iranian woman was admitted to Taleghani Hospital with epigastric pain, vomiting, anosmia, rising liver enzyme levels, fever, itching, and skin rashes. Skin and liver biopsies were performed during the patient's admission; the results suggested vasculopathy-related cutaneous lesion and liver cholestasis. Plasmapheresis was initiated and all manifestations disappeared after treatment. All atypical presentations, including cutaneous lesions and liver manifestations, should be considered as COVID-19 and evaluated.

User satisfaction with a smartphone-compatible, artificial intelligence-based cutaneous pigmented lesion evaluator.

INTRODUCTION: Melanoma is the most aggressive type of skin cancer, and it may arise from a cutaneous pigmented lesion. As artificial intelligence (AI)-based teledermatology services hold promise in redefining the melanoma screening paradigm, a study that evaluates user satisfaction with a smartphone-compatible, AI-based cutaneous pigmented lesion evaluator is lacking. METHODS: Data was collected between April and May 2019 in Taiwan. To assess user satisfaction with MoleMe, an AI-based cutaneous pigmented lesion evaluator on a smartphone, users were asked to complete a questionnaire designed to evaluate four aspects, including interaction, impact on daily life, usability, and overall performance, after completing a MoleMe evaluation session. For each question, users could rank their satisfaction level from 1 to 5, with five showing strongly satisfied and one showing strongly unsatisfied. The Kruskal-Wallis and Wilcoxon rank-sum tests were used to compare user satisfaction among different age groups, genders, and risk predictions received. RESULT: A total of 1231 questionnaires were collected for analysis. Over 90% of the participants were satisfied (score = 4 or 5) and over 75% of the participants were strongly satisfied (score 5) with MoleMe, in terms of usability, interaction, and impact on daily life. The user satisfaction did not show a significant difference between genders, age groups, and risk predictions received. (all P > 0.05) CONCLUSION: With high user satisfaction regardless of age group, gender, and risk prediction received, AI-based teledermatology services on a smartphone such as MoleMe may potentially achieve widespread usage and be beneficial to both patients and physicians.

Melanocortin-1 receptor (MC1R) genotypes do not correlate with size in two cohorts of medium-to-giant congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are cutaneous malformations whose prevalence is inversely correlated with projected adult size. CMN are caused by somatic mutations, but epidemiological studies suggest that germline genetic factors may influence CMN development. In CMN patients from the U.K., genetic variants in MC1R, such as p.V92M and loss-of-function variants, have been previously associated with larger CMN. We analyzed the association of MC1R variants with CMN characteristics in two distinct cohorts of medium-to-giant CMN patients from Spain (N = 113) and from France, Norway, Canada, and the United States (N = 53), similar at the clinical and phenotypical level except for the number of nevi per patient. We found that the p.V92M or loss-of-function MC1R variants either alone or in combination did not correlate with CMN size, in contrast to the U.K. CMN patients. An additional case-control analysis with 259 unaffected Spanish individuals showed a higher frequency of MC1R compound heterozygous or homozygous variant genotypes in Spanish CMN patients compared to the control population (15.9% vs. 9.3%; p = .075). Altogether, this study suggests that MC1R variants are not associated with CMN size in these non-UK cohorts. Additional studies are required to define the potential role of MC1R as a risk factor in CMN development.

Successful treatment of late-onset nevus comedonicus with Er:YAG laser.

Nevus comedonicus, a rare congenital hamartoma of the pilosebaceous unit, is characterized by keratotic plugging. It usually occurs after birth and during early childhood. It rarely appears in adulthood. Despite the benign nature of the condition, it usually requires treatment due to aesthetic reasons. Several treatments have been reported in nevus comedonicus, most of them resulting with recurrences. Here, we report a case of nevus comedonicus with adult onset, successfully treated with erbium-doped yttrium aluminum garnet (Er:YAG) laser therapy.

Understanding toxicological implications of accidents with caterpillars Megalopyge lanata and Podalia orsilochus (Lepidoptera: Megalopygidae).

Megalopygids Megalopyge lanata and Podalia orsilochus are common causative agents of accidents in agricultural workers. These accidents are provoked by dermal contact at their larval stage and are characterized by cutaneous reactions, such as burning pain, edema and erythema, typically mild and self-limited. There is very little information about their venoms and their toxicological implications on human health. Thus, we employed proteomic techniques and biological assays to characterize venoms (bristle extracts) from caterpillars of both species collected from Misiones, Argentina. The electrophoretic profiles of both venoms were substantially different, and they presented proteins related to toxicity, such as serinepeptidases, serpins and lectins. P. orsilochus venom exhibited higher caseinolytic activity than M. lanata venom, agreeing with the fact that only P. orsilochus venom hydrolyzed human fibrin(ogen). In addition, the latter shortened the clotting time triggered by calcium. While the venom of M. lanata induced a mild inflammatory lesion in mouse skin, P. orsilochus venom caused prominent necrosis, inflammatory infiltration and hemorrhage at the site of venom injection. On the other hand, P. orsilochus venom was better recognized by Lonomia obliqua antivenom, although many of its proteins could not be cross-reacted, what may explain the difference in the clinical manifestations between accidents by Podalia and those by Lonomia. Altogether, this study provides relevant information about the pathophysiological mechanisms whereby both caterpillars can induce toxicity on human beings, and paves the way for novel discovery of naturally occurring bioactive compounds.

Cutaneous Metastasis via Surgical Planes After Lumbar Spinal Reconstruction for Spinal Metastatic Disease.

BACKGROUND: Cervical squamous cell carcinoma is the second most common cancer in women worldwide and the third most common cause of female cancer mortality. It frequently metastasizes to the osseous spine and has been rarely reported to cause cutaneous metastases at gynecologic surgical scars. CASE DESCRIPTION: A 63-year-old woman with known metastatic cervical squamous cell carcinoma presented with a pathologic fracture of the L2 vertebra, unrelenting back pain, bilateral lower extremity weakness, and inability to ambulate. The patient elected to undergo an L2 corpectomy with intervertebral cage placement via the right-sided retroperitoneal approach followed by percutaneous L1-L4 pedicle screw instrumentation in the same operative setting. Her immediate postoperative course was uneventful. Eight weeks after surgery, both her flank and posterior incisions became painful and swollen. She underwent irrigation and debridement of the right flank incision due to elevated inflammatory markers and concern for surgical site infection. Multiple intraoperative cultures were obtained and were ultimately negative for bacterial or fungal growth. Several weeks later, the patient presented with worsening painful growths of her incisions. Excisional biopsy and debulking of the masses in the operating room revealed squamous cell carcinoma with areas of cystic change and tumor necrosis consistent with progression of the patient's metastatic cervical cancer. CONCLUSIONS: Cervical squamous cell carcinoma can metastasize regionally via surgical planes and manifest as cutaneous lesions. Local metastasis should be included in the differential in cases of postoperative wound complications.

Understanding toxicological implications of accidents with caterpillars Megalopyge lanata and Podalia orsilochus (Lepidoptera: Megalopygidae)

Megalopygids Megalopyge lanata and Podalia orsilochus are common causative agents of accidents in agricultural workers. These accidents are provoked by dermal contact at their larval stage and are characterized by cutaneous reactions, such as burning pain, edema and erythema, typically mild and self-limited. There is very little information about their venoms and their toxicological implications on human health. Thus, we employed proteomic techniques and biological assays to characterize venoms (bristle extracts) from caterpillars of both species collected from Misiones, Argentina. The electrophoretic profiles of both venoms were substantially different, and they presented proteins related to toxicity, such as serinepeptidases, serpins and lectins. P. orsilochus venom exhibited higher caseinolytic activity than M. lanata venom, agreeing with the fact that only P. orsilochus venom hydrolyzed human fibrin(ogen). In addition, the latter shortened the clotting time triggered by calcium. While the venom of M. lanata induced a mild inflammatory lesion in mouse skin, P. orsilochus venom caused prominent necrosis, inflammatory infiltration and hemorrhage at the site of venom injection. On the other hand, P. orsilochus venom was better recognized by Lonomia obliqua antivenom, although many of its proteins could not be cross-reacted, what may explain the difference in the clinical manifestations between accidents by Podalia and those by Lonomia. Altogether, this study provides relevant information about the pathophysiological mechanisms whereby both caterpillars can induce toxicity on human beings, and paves the way for novel discovery of naturally occurring bioactive compounds.