A case-based review on the neuroendoscopic management of intraventricular and subarachnoid basal neurocysticercosis.

OBJECTIVE: Extraparenchymal localization of neurocysticercosis (NCC) is rare in non-endemic areas. A case of mixed (intraventricular, IV, and subarachnoid basal, SAB) NCC was surgically treated using the neuroendoscope and a systematic review of the literature was performed with the aim to analyze the use of this instrument in the management of the extraparenchymal forms of the parasitic disease. MATERIALS AND METHODS: Medline and Embase databases were searched for studies where the neuroendoscope was used for the management of IV/SAB NCC cysts, either for the cerebrospinal fluid diversion or cyst removal. Cyst location, complete removal, cyst breakage during removal, intraoperative and postoperative complications, administration of antihelmintic therapy, outcome and follow-up period were extracted from the articles. RESULTS: 281 patients were treated by means of the neuroendoscope. 254 patients who were described in retrospective cohort studies, came all from endemic areas, with no significant difference between sexes. Mean age at surgery was 30.7 years. Of all cysts reported in retrospective studies, 37.9% were located in the fourth ventricle. An attempt of cyst removal was described in the 84.6% of cases and an endoscopic third ventriculostomy was performed in another 76.4%. A small number of complications were reported intraoperatively (9.1%) obtaining, but a good recovery was achieved at follow-up. Only 17 ventriculoperitoneal shunts were placed after the first procedure, defining a low risk of postoperative hydrocephalus even in case of partial cyst removal. CONCLUSION: Neuroendoscopic removal of an extraparenchymal NCC cyst is a safe procedure that should be preferred for lateral and third ventricle localization and, in a specialized centre, even for a localization in the fourth ventricle if feasible. It is also efficient because of the possibility of performing an internal CSF diversion concomitantly to cyst removal, avoiding the complication registered with VPS. The need for cysticidal treatment after surgery should be addressed in a prospective study.

Neurocysticercosis Presenting as Migraine in the United States.

BACKGROUND Cysticercosis is a condition caused by infection with the larval form of Taenia solium, a pork tapeworm that uses pigs as an intermediate host. Humans become infected when they ingest water or food contaminated with tapeworm cysts. Cysticercosis is increasing in frequency in developed countries due to increased access to travel. Neurocysticercosis occurs when Taenia solium cysts embed within the nervous system. The clinical presentation of neurocysticercosis ranges from asymptomatic to life-threatening, largely depending on the brain parenchymal involvement. The diagnosis is typically made with a combination of clinical evaluation, serology, and neuroimaging. Treatment for parenchymal neurocysticercosis may involve anthelmintic agents, symptomatic agents, surgery, or a combination of methods. CASE REPORT A 52-year-old man with a medical history of migraine headaches, complicated type 2 diabetes mellitus, and obesity presented with a 4-month change in his migraines becoming severe, worse over his occiput bilaterally, and unresponsive to abortive therapy. His exposure history was unremarkable except for a habit of eating undercooked bacon, by which he would have developed neurocysticercosis via autoinfection. Neuroimaging and serology confirmed a diagnosis of neurocysticercosis and he was treated accordingly with antiparasitic and anti-inflammatory medications. CONCLUSIONS This presentation is nonspecific and can easily be overlooked, especially if there is an underlying known neurological condition such as migraine. This case illustrates that neurocysticercosis should be considered when an existing neuropathological condition displays a change in presentation or requires a change in therapeutic management, even without obvious risk factors.

Calcified cerebral toxoplasmosis associated with recurrent perilesional edema causing neurological manifestations in an HIV-infected individual: case report with a decade-long follow-up.

Four cases of people living with HIV/AIDS (PLWHA) with calcified cerebral toxoplasmosis associated with perilesional edema causing a single episode of neurological manifestations have recently been reported. Here, we describe the first detailed description of perilesional edema associated with calcified cerebral toxoplasmosis causing three episodes of neurological manifestations in a PLWHA, including seizures in two of them. These recurrences occurred over approximately a decade. Throughout this period, the patient showed immunological and virological control of the HIV infection, while using antiretroviral therapy regularly. This case broadens the spectrum of an emerging presentation of calcified cerebral toxoplasmosis, mimicking a well-described finding of neurocysticercosis in immunocompetent hosts.

Silent Intruder: Unusual Presentation of Neurocysticercosis in an HIV-Infected Patient from the Far Northern Brazilian Amazon.

Neurocysticercosis, a parasitic infection of the central nervous system (CNS), is a significant public health issue globally, including in Brazil. This article presents a case report of a 44-year-old male patient residing in the rural area of Roraima, the northernmost region of Brazil within the Amazon Forest. The patient, with chronic HIV infection, acquired the Taenia solium helminth, resulting in neurocysticercosis development. Remarkably, the diagnosis of neurocysticercosis was not initially apparent but emerged through meticulous analysis following a motorcycle accident. The absence of seizures, a common clinical manifestation, complicated the diagnostic process, making it an uncommon case of NCC, which may be related to co-infection. As the patient's condition progressed, multiple complications arose, requiring additional medical attention and interventions. This case underscores the immense challenges faced by healthcare teams in managing neurocysticercosis effectively. It emphasizes the critical need for a comprehensive, multidisciplinary approach to provide optimal care for such complex cases. The study's findings underscore the importance of raising awareness and implementing improved strategies for tackling neurocysticercosis, particularly in regions where it remains a prevalent concern.

Top-50 cited articles on cysticercosis and neurocysticercosis.

BACKGROUND: Identifying the most highly cited papers in a given field can help researchers and professionals understand the milestones and research areas that are generating the most impact. This study aimed to identify and describe the 50 most frequently cited manuscripts on cysticercosis and neurocysticercosis. METHODS: We identified the 50 most cited papers (articles and reviews) on cysticercosis and neurocysticercosis from the MEDLINE database and indexed in Web of Science-Core Collection, analyzing their bibliographic and content characteristics. RESULTS: The most cited documents comprised 29 (58%) original articles and 21 (42%) reviews, the bulk of which were narrative reviews (n = 17), with a negligible presence of other types of reviews with high-level scientific evidence. Six journals published 42% of the articles. In addition to the USA, Mexico and Peru were prominent countries of origin among leading researchers. The main research topics were the central nervous system and epilepsy on the one hand, and diagnostic and therapeutic approaches on the other. CONCLUSION: Our findings shed light on the dissemination of knowledge about cysticercosis and neurocysticercosis in recent decades, identifying the most highly cited contributions that have driven research in the field.

Postsurgical Outcomes of Mesial Temporal Lobe Epilepsy due to Hippocampal Sclerosis Associated with Calcified Neurocysticercosis.

The aim of this study was to analyze postsurgical outcomes for individuals with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who underwent anterior temporal lobectomy, based on the presence of calcified neurocysticercosis (cNCC). A retrospective cross-sectional study was conducted on 89 patients with MTLE-HS who underwent anterior temporal lobectomy between January 2012 and December 2020 at a basic epilepsy surgery center located in Lima, Peru. We collected sociodemographic, clinical, and diagnostic information. The postsurgical results were analyzed using bivariate analysis according to the Engel classification. We included 89 individuals with a median age of 28 years (interquartile range [IQR]: 24-37), and more than half (55.1%) were male. Seventeen (19.1%) were diagnosed with cNCC. A greater number of patients with cNCC had lived in rural areas of Peru during their early life compared with those without cNCC (12 [70.6%] versus 26 [36.1%]; P = 0.010). Patients with cNCC exhibited a greater median frequency of focal to bilateral tonic-clonic seizures per month (1 [IQR: 0-2] versus 0 [0-0.5]; P = 0.009). Conversely, a lower proportion of patients with cNCC reported a history of an initial precipitating injury in comparison to the group without cNCC (4 [23.5%] versus 42 [58.3%]; P = 0.014). At the 1-year follow-up, most patients (82.4%) with cNCC were categorized as Engel IA. Similarly, at the 2-year follow-up, nine (75.0%) were classified as Engel IA. Our findings suggest that most patients diagnosed with cNCC exhibit favorable postsurgical outcomes, comparable to those without cNCC. Additionally, it can be postulated that cNCC may play a role as an initial precipitating injury.

Taenia martis Neurocysticercosis-Like Lesion in Child, Associated with Local Source, the Netherlands.

A neurocysticercosis-like lesion in an 11-year-old boy in the Netherlands was determined to be caused by the zoonotic Taenia martis tapeworm. Subsequent testing revealed that 15% of wild martens tested in that region were infected with T. martis tapeworms with 100% genetic similarity; thus, the infection source was most likely local.

[Diagnosis of neurocysticercosis in patients with epilepsy living in the south-western Dominican Republic]. / Diagnóstico de neurocisticercosis en pacientes con epilepsia residentes en el suroeste de la República Dominicana.

INTRODUCTION: Neurocysticercosis (NCC), a possible cause of epilepsy with limited epidemiological data in the Dominican Republic, is endemic in four provinces in the country's south-western region. This study aimed to determine the association between NCC and epilepsy among people living in these endemic regions, and to obtain preliminary data on the prevalence of NCC in these provinces. PATIENTS AND METHODS: A case-control design was used, consisting of 111 patients with epilepsy with unknown causes, and 60 controls without epilepsy or NCC. The diagnosis of NCC was based on computed tomography and magnetic resonance imaging of the skull, as well as Western immunoblotting for serum antibodies using Taenia solium, following the criteria of Del Brutto et al. RESULTS. NCC was found in 27% of the epileptic patients (n = 30/111) and in 5% of the controls (n = 3/60); the probability of the epileptic patients having NCC was seven times higher than the controls (odds ratio = 7.04, 95% confidence interval: 2.04-24.18; p < 0.001). The participants' sociodemographic characteristics, including their age, sex, level of education, occupation, and province of residence presented no statistical significance in terms of their association with NCC. CONCLUSIONS: This study suggests that NCC is strongly associated with epilepsy in the south-western region of the Dominican Republic, and highlights the need for public health measures to improve the prevention, diagnosis and treatment of both diseases.

TITLE: Diagnóstico de neurocisticercosis en pacientes con epilepsia residentes en el suroeste de la República Dominicana.Introducción. La neurocisticercosis (NCC), una posible causa de epilepsia con datos epidemiológicos limitados en la República Dominicana, es endémica en cuatro provincias de la región suroeste. El objetivo de este estudio fue determinar la asociación entre la NCC y la epilepsia en personas que viven en estas regiones endémicas, así como obtener datos preliminares sobre la prevalencia de NCC en estas provincias. Sujetos y métodos. Se utilizó un diseño de casos y controles compuesto por 111 pacientes con epilepsia de causa desconocida y 60 controles sin epilepsia ni NCC. El diagnóstico de NCC se basó en la tomografía computarizada y la resonancia magnética del cráneo, así como en el inmunotransferencia de Western para anticuerpos séricos contra Taenia solium, siguiendo los criterios de Del Brutto et al. Resultados. Se encontró NCC en el 27% de los pacientes con epilepsia (n = 30/111) y en el 5% de los controles (n = 3/60); los casos de epilepsia tenían siete veces más probabilidades de tener NCC que los controles (odds ratio = 7,04, intervalo de confianza al 95%: 2,04-24,18; p < 0,001). Las características sociodemográficas de los participantes, como la edad, el sexo, el nivel de escolaridad, la ocupación y la provincia de residencia no mostraron significación estadística en cuanto a la asociación con NCC. Conclusiones. Este estudio sugiere que la NCC está fuertemente asociada con la epilepsia en la región suroeste de la República Dominicana, y destaca la necesidad de medidas de salud pública para mejorar la prevención, el diagnóstico y el tratamiento de ambas enfermedades.

Neurocysticercosis: The duration of its preclinical phase relies on the parasite location.

OBJECTIVES: Neurocysticercosis (NC) is a heterogeneous disease particularly in terms of response to treatment and prognosis. Parasite localization is one of the main factors involved in this heterogeneity. In this study we aim to determine whether differences in the duration of the preclinical phase associated with parasite location, could contribute to said heterogeneity. METHODS: Ninety-nine patients were included, 24 with parasites in the parenchyma (PAR), 56 in the subarachnoid (SA) space and 19 in the ventricular system (IV). A questionnaire designed to assess exposure to classic NC risk factors 5, 10, 15, 20 and more than 20 years prior to diagnosis was applied. The results were compared between the three groups. Also, asymptomatic relatives of patients who had shared their living conditions in childhood or more recently were included and underwent brain scan and blood testing for specific antibodies. RESULTS: Over the course of their lives, exposure to risk factors decreased significantly for all patients, although the decrease was more evident in patients with parasites in the SA space (p < 0.001) compared to patients with PAR (p = 0.011) or IV cysts (p = 0.020). Five years prior to diagnosis, exposure to risk factors was significantly higher in patients with PAR or IV NC than in patients with SA NC (p = 0.04). Furthermore, individuals in close contact with PAR or IV patients in the years preceding diagnosis were more likely to have asymptomatic NC, specific antibodies in sera, particularly IgM, compared to individuals in close contact with SA patients during the same period. CONCLUSIONS: All these findings are highly suggestive of the possibility of a more recent infection of patients affected by parenchymal and ventricular NC than of patients with subarachnoid NC. Consequently, subarachnoid disease could be considered a chronic disease, which, probably contributes to the severity of the disease as well as the minimal response to medical treatment.

Massive neurocysticercosis in a ten-year-old girl: a case report.

BACKGROUND: Massive neurocysticercosis is a rare form of neurocysticercosis, and can lead to serious conditions and even death. CASE PRESENTATION: Here we present a case of ten-year-old Tibetan girl who developed headache and vomiting. Her brain magnetic resonance imaging (MRI) illustrated lots of intracranial cystic lesions, and no obvious extracranial lesions were found. Serum immunoglobulin G antibodies against cysticerci were positive by the use of an enzyme-linked immunosorbent assay (ELISA). These results in combination with her medical history were in line with massive neurocysticercosis. The patients recovered well after supportive management and antiparasitic treatment. CONCLUSIONS: This case provides insights on the diagnosis and treatment of massive neurocysticercosis. The treatment of patients with massive neurocysticercosis should be in an individualized fashion, and the use of antiparasitic drugs in these patients must be decided after carefully weighing the risks and benefits.

Evaluation of a point-of-care test for the diagnosis of Taenia solium neurocysticercosis in rural southern Tanzania: a diagnostic accuracy study.

BACKGROUND: Neurocysticercosis is a common cause of epilepsy in Taenia solium-endemic areas in sub-Saharan Africa but is often undiagnosed because of an absence of affordable diagnostic tools. This study evaluated the diagnostic accuracy of a T solium cysticercosis antibody-detecting lateral-flow point-of-care assay (TS POC test) for the neuroimaging-based diagnosis of neurocysticercosis. METHODS: Patients with epileptic seizures or severe progressive headache were recruited consecutively from three hospitals in southern Tanzania. All patients were tested with the TS POC test. All patients positive for cysticercosis on the TS POC test and every tenth patient who was negative for cysticercosis received a brain CT examination and underwent reference testing for T solium cysticercosis (ie, rT24H-EITB, LLGP-EITB, and antigen ELISA). The primary outcome of the study was the sensitivity of the TS POC test for the diagnosis of neurocysticercosis. FINDINGS: Of the 601 recruited participants, 102 (17%) tested positive for cysticercosis with the TS POC test. Overall, 48 (62%) of the 77 patients positive for cysticercosis and five (17%) of the 29 patients negative for cysticercosis on the TS POC test had CT-confirmed neurocysticercosis. The TS POC test yielded a sensitivity of 49% (uncertainty interval [UI] 41-58) for neurocysticercosis. Sensitivity was similar to that of the rT24H-EITB (44%, UI 37-51) and the antigen ELISA (50%, 43-56). For the subset of neurocysticercosis cases with at least one active (ie, vesicular) lesion, sensitivity was above 98% for the TS POC test, the rT24H-ETIB, and the antigen ELISA. INTERPRETATION: The TS POC test showed promising results for the diagnosis of neurocysticercosis in patients with vesicular lesions, which need to be confirmed in a larger study. This test could be considered to support policies on screening patients with suspected neurocysticercosis in clinical settings, which would allow appropriate referral for neuroimaging and early treatment. FUNDING: German Federal Ministry of Education and Research and the European & Developing Countries Clinical Trials Partnership. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Epilepsy and neurocysticercosis in rural areas of the Bolivian Chaco: What has changed during the last 30 years?

OBJECTIVE: Neurocysticercosis (NCC) is considered the major cause of epilepsy in endemic regions. In the rural areas of the Bolivian Chaco prevalence of NCC among people with epilepsy (PWE) was 27.4%, according to a population-based survey carried out in 1994. The aim of the study was to estimate the prevalence of Epilepsy Associated with Tonic-Clonic Seizures (EATCS) and to evaluate the prevalence of NCC among PWE in the rural communities of the Bolivian Chaco after 30 years. METHODS: Twenty-two rural communities (total population 12 852) were involved in the study. PWE in the study area were ascertained by multiple sources and the diagnosis was confirmed by a neurologist. All PWE identified were invited to undergo brain CT scan examination and diagnosis of NCC was sought according to the revised Del Brutto criteria. RESULTS: Seventy-eight PWE (30 men, 38.4%; mean age at onset was 12.7 ± 13.2 years) with EATCS were identified giving a crude prevalence of 6.1/1000 (95% CI: 4.7-7.3). Due to the COVID-19 lockdown, the study was interrupted in 2020 and only 36 PWE (46%) of the whole sample underwent CT scan examination. Of these, 8 (22.2%) fulfilled the criteria for NCC of whom 6 (75%) presented only single or multiple calcifications. SIGNIFICANCE: This is the first study reassessing the prevalence of NCC among PWE after 30 years, in the same rural area and using a population-based design. T. solium is still endemic in the Bolivian Chaco where more than 20% of EATCS may be attributable to NCC. Our findings show a substantially unchanged prevalence of NCC over the past 30 years despite improved knowledge, underlining the need for active intervention programs to control T. solium transmission in this area. PLAIN LANGUAGE SUMMARY: Neurocysticercosis is still endemic in the Bolivian Chaco. The proportion of epilepsy attributable to neurocysticercosis is about 22%. Systematic efforts towards elimination of neurocysticercosis in these areas should be implemented.

Is Antihelminthics Necessary in Postoperative Treatment of Intraventricular Neurocysticercosis? A Systematic Review.

OBJECTIVE: Patients with intraventricular neurocysticercosis (IVNCC) may require cerebrospinal fluid diversion surgery for late-onset hydrocephalus in the postsurgical period. Controversy exists regarding cysticidal treatment. Our main objective was to compare surgically treated cases of IVNCC that received postoperative anthelmintics with those that did not regard the incidence and treatment of late-onset hydrocephalus. METHODS: We searched the Medline database and extracted the following data: age, gender, stage of development of cysticercosis, type of operation, frequency of delayed hydrocephalus, cerebrospinal fluid diversion surgery, outcome, and follow-up. RESULTS: We analyzed 130 articles on intraventricular cysticercosis and identified 117 cases of isolated IVNCC and 314 patients in the case-control series who met inclusion criteria. There was no significant difference in postoperative delayed hydrocephalus between isolated IVNCC and case-control study groups. Children under the age of 16 received anthelmintic drugs more frequently during the postoperative period. Statistical relevance was observed in all patient groups regarding the application of steroids in favor of cysticidal therapy Endoscopy was a better option than craniotomy for cases of isolated IVNCC and case-control studies. Other variables were not relevant. CONCLUSIONS: Patients who received antihelminths did not show a statistically significant reduction in delayed hydrocephalus compared to individuals who did not receive after surgical resection of the parasite. Corticosteroid therapy prevailed in people who have been treated with anthelmintics. Children under the age of 16 were administered anthelmintic drugs more frequently during the postoperative period. Endoscopy was the preferred method for all groups, but some patients with cysts in the fourth ventricle required a craniotomy.

Incident Breakthrough Seizures, Serum Matrix Metalloproteinase-9 and Perfusion Magnetic Resonance Imaging Parameters in a Cohort of Children and Adolescents With Neurocysticercosis: A Longitudinal Observational Study.

BACKGROUND: The current study estimated incident breakthrough seizures, serum matrix metalloproteinase-9 (MMP-9), and perfusion magnetic resonance imaging (MRI) parameters in five- to 18-year-olds with neurocysticercosis (NCC) from colloidal or vesicular through calcified stages over at least 24 months' follow-up. METHODS: Single, colloidal, or vesicular parenchymal NCC cases were treated with albendazole and steroids and followed at a tertiary care north Indian hospital. Serum MMP-9 was estimated in colloidal or vesicular treatment-naive state and in a subset of calcified cases at six-month follow-up. The same subset of calcified cases also underwent perfusion MRI of the brain at six-month follow-up. RESULTS: Among 70 cases, 70% calcified at six-month follow-up. Over a median follow-up of 30 months, the incidence of breakthrough seizures was 48.6% (61.2% in calcified and 19.2% in resolved, P = 0.001; 32.9% early [within six months] and 15.7% late [beyond six months], P = 0.02). Serum MMP-9 levels were higher in colloidal and vesicular compared with calcified stage (242.5 vs 159.8 ng/mL, P = 0.007); however, there was no significant association with breakthrough seizures and/or calcification in follow-up. In a subgroup of calcified cases (n = 31), the median relative cerebral blood volume on perfusion MRI in and around the lesion was lower in those with seizures (n = 12) than in those without (n = 19) (10.7 vs 25.2 mL/100 g, P = 0.05). CONCLUSIONS: In post-treatment colloidal or vesicular NCC, incident breakthrough seizures decrease beyond six months. In calcified NCC with remote breakthrough seizures, significant perilesional hypoperfusion is seen compared with those without seizures.

Taenia solium excretory secretory proteins (ESPs) suppresses TLR4/AKT mediated ROS formation in human macrophages via hsa-miR-125.

BACKGROUND: Helminth infections are a global health menace affecting 24% of the world population. They continue to increase global disease burden as their unclear pathology imposes serious challenges to patient management. Neurocysticercosis is classified as neglected tropical disease and is caused by larvae of helminthic cestode Taenia solium. The larvae infect humans and localize in central nervous system and cause NCC; a leading etiological agent of acquired epilepsy in the developing world. The parasite has an intricate antigenic make-up and causes active immune suppression in the residing host. It communicates with the host via its secretome which is complex mixture of proteins also called excretory secretory products (ESPs). Understanding the ESPs interaction with host can identify therapeutic intervention hot spots. In our research, we studied the effect of T. solium ESPs on human macrophages and investigated the post-translation switch involved in its immunopathogenesis. METHODOLOGY: T. solium cysts were cultured in vitro to get ESPs and used for treating human macrophages. These macrophages were studied for cellular signaling and miR expression and quantification at transcript and protein level. CONCLUSION: We found that T. solium cyst ESPs treatment to human macrophages leads to activation of Th2 immune response. A complex cytokine expression by macrophages was also observed with both Th1 and Th2 cytokines in milieu. But, at the same time ESPs modulated the macrophage function by altering the host miR expression as seen with altered ROS activity, apoptosis and phagocytosis. This leads to activated yet compromised functional macrophages, which provides a niche to support parasite survival. Thus T. solium secretome induces Th2 phenomenon in macrophages which may promote parasite's survival and delay their recognition by host immune system.

Multiantigen print immunoassay (MAPIA) for the diagnosis of neurocysticercosis: a single-center diagnostic optimization and accuracy study in Lima, Peru.

Neurocysticercosis (NCC) is the most common helminthic infection of the human central nervous system. The antibody detection assay of choice is the enzyme-linked immunoelectrotransfer blot assay using lentil-lectin purified parasite antigens (LLGP-EITB, Western blot), an immunoassay with exceptional performance in clinical samples. However, its use is mainly restricted to a few research laboratories because the assay is labor-intensive and requires sophisticated equipment, expertise, and large amounts of parasite material for preparation of reagents. We report a new immunoprint assay (MAPIA) that overcomes most of these barriers. We initially compared the performance of five different antigen combinations in a subset of defined samples in the MAPIA format. After selecting the best-performing assay format (a combination of rGP50 + rT24H + sTs14 antigens), 148 archived serum samples were tested, including 40 from individuals with parenchymal NCC, 40 with subarachnoid NCC, and 68 healthy controls with no evidence of neurologic disease. MAPIA using three antigens (rGP50 + rT24H + sTs14) was highly sensitive and specific for detecting antibodies in NCC. It detected 39 out of 40 (97.5%) parenchymal NCC cases and 40/40 (100%) subarachnoid cases and was negative in 67 out of 68 (98.53%) negative samples. MAPIA using three recombinant and synthetic antigens is a simple and economical tool with a performance equivalent to the LLGP-EITB assay for the detection of specific antibodies to NCC. The MAPIA overcomes existing barriers to adoption of the EITG LLGP and is a candidate for worldwide use.