68 Ga-Pentixafor PET/CT for In Vivo Imaging of CXCR4 Receptors in Glioma Demonstrating a Potential for Response Assessment to Radiochemotherapy: Preliminary Results.

PURPOSE: The aim of this study was to evaluate the diagnostic potential of 68 Ga-pentixafor PET/CT for in vivo CXCR4 receptors imaging in glioma and its possible role in response assessment to radiochemotherapy (R-CT). METHODS: Nineteen (12 men, 7 women) patients with glioblastoma multiforme (GBM) underwent 68 Ga-pentixafor PET/CT, contrast-enhanced MR, and MR spectroscopy. Patients were divided in to 2 groups, that is, group I was the presurgical (n = 9) group in which the scanning was done before surgery, and PET findings were correlated with CXCR4 receptors' density. The group II was the postsurgical (n = 10) group in which the scanning was done before and after R-CT and used for treatment response evaluation. The quantitative analysis of 68 Ga-pentixafor PET/CT evaluated the mean SUV max , SUV mean , SUV peak , and T/B values. MR spectroscopy data evaluated the ratios of tumor metabolites (choline, NAA, creatine). RESULTS: 68 Ga-Pentixafor uptake was noted in all (n = 19) the patients. In the group I, the mean SUV max , SUV mean , SUV peak , and T/B values were found to be 4.5 ± 1.6, 0.60 ± 0.26, 1.95 ± 0.8, and 6.9 ± 4.6, respectively. A significant correlation ( P < 0.005) was found between SUV mean and choline/NAA ratio. Immunohistochemistry performed in 7/9 showed CXCR4 receptors' positivity (intensity 3 + ; stained cells >50.0%). In the group II, the mean SUV max at baseline was 4.6 ± 2.1 and did not differ (4.4 ± 1.6) significantly from the value noted at post-R-CT follow-up PET/CT imaging. At 6 months' clinical follow-up, 4 patients showed stable disease. SUV max and T/B ratios at follow-up imaging were lower (3.70 ± 0.90, 2.64 ± 1.35) than the corresponding values (4.40 ± 2.8; 2.91 ± 0.93) noted at baseline. Six (6/10) patients showed disease progression, and the mean SUV max , and T/B ratio in these patients were significantly ( P < 0.05) higher than the corresponding values at baseline and also higher than that noted in the stable patients. CONCLUSIONS: 68 Ga-Pentixafor PET/CT can be used for in vivo mapping of CXCR4 receptors in GBM. The technique after validation in a large cohort of patients may have added diagnostic value for the early detection of GBM recurrence and for treatment response evaluation.

Neurocognitive Functions After 6-Month Buprenorphine (Naloxone)-Based Opioid Agonist Maintenance Treatment: A Controlled Prospective Study.

BACKGROUND: Medications for opioid use disorder (OUD) may influence neurocognitive functions. Inadequate power, confounders, and practice effects limit the validity of the existing research. We examined the change in cognitive functions in patients with OUD at 6-month buprenorphine (naloxone) posttreatment and compared the cognitive performance of the buprenorphine-treated group with control subjects. METHODS: We recruited 498 patients with OUD within a week of initiating buprenorphine. Assessments were done twice-at baseline and 6 months. Those abstinent from illicit opioids and adherent to treatment (n = 199) underwent follow-up assessments. Ninety-eight non-substance-using control subjects were recruited from the community. The neurocognitive assessments comprised the Wisconsin Card Sorting Test, Iowa Gambling Task, Trail-Making Tests A and B (TMT-A and TMT-B), and verbal and visual N-Back Test. We controlled for potential effect modifiers. RESULTS: Twenty-five of the 32 test parameters significantly improved with 6 months of buprenorphine treatment; 20 parameters withstood corrections for multiple comparisons (P < 0.001). The improved test domains spread across cognitive tests: Wisconsin Card Sorting Test (perseverative errors and response, categories completed, conceptual responses), TMTs (time to complete), verbal and visual N-Back Tests (hits, omission, and total errors). After treatment, OUD (vs control subjects) had less perseverative response and error (P < 0.001) and higher conceptual response (P = 0.004) and took lesser time to complete TMT-A (P < 0.001) and TMT-B (P = 0.005). The baseline neurocognitive functions did not differ between those who retained and those who discontinued the treatment. CONCLUSION: Cognitive functions improve in patients with OUD on buprenorphine. This improvement is unlikely to be accounted for by the practice effect, selective attrition, and potential confounders.

Electroclinical Landscape of Infantile Epileptic Spasms Syndrome.

OBJECTIVES: To elucidate the electroclinical characteristics of infantile epileptic spasms syndrome (IESS) and to determine any potential association among these with underlying etiologies and response to therapy. METHODS: Sixty-eight, treatment-naive children with IESS underwent long-term video electroencephalogram (EEG) recording, which was used to characterize the semiology, ictal, and inter-ictal EEG patterns. Children were further followed up to assess electroclinical predictors of etiologies and short-term therapeutic response. RESULTS: Of 68 children enrolled (69% boys), the median age at enrollment was 10.5 mo (IQR-8). Eighty-eight percent of children had flexor spasms, followed by mixed (7%) and extensor (4.4%). Asymmetrical spasms were noted in 17.6% children, and all of them had underlying structural etiology. Two children had the status of epileptic spasms. In the present cohort, authors recognized five distinct ictal EEG correlates of epileptic spasms; the frontocentral dominant slow wave was the most prevalent (32%), followed by the generalized slow-wave complex with superimposed fast rhythm in 29.4%. The occipital dominant slow wave complex was a peculiar pattern in 16%. The major underlying etiologies were hypoxic-ischemic brain injuries (36.7%) and neonatal hypoglycemic brain injuries (22%). Besides asymmetric spasms, authors could not identify any significant association among electroclinical characteristics, underlying etiologies and response to therapy in this study. CONCLUSIONS: The electroclinical landscape of IESS is peculiar and diverse in developing countries. The presence of asymmetrical spasms indicated underlying structural etiology.

Neurocognitive Dysfunctions in People with Concurrent Cannabis Use and Opioid Dependence: A Cross-Sectional, Controlled Study.

Cannabis and opioid co-dependence is independently associated with cognitive impairments. We examined neurocognitive dysfunctions in people with concurrent opioid dependence with cannabis dependence (OD+CD) or cannabis use (OD+CU) compared to those with only opioid dependence (OD) and healthy controls (HC). We selected adult participants, any sex, who met the diagnosis of OD (N = 268), OD+CU (N = 58), and OD + CD (N = 115). We recruited 68 education-matched HC. We administeredStandard progressive matrices (SPM), Wisconsin card sorting test (WCST), Iowa gambling task (IGT), Trail making tests A and B (TMT), and verbal and visual working memory 1-, 2-backtests. 496 (97.5%) were men, and 13 (2.5%) were women. In WCST, OD and OD+CD had significantly higher non-perseverative errors than HC. OD+CD group completed significantly lesser categories than HC. In verbal working memory 2-back, HC scored significantly fewer errors than OD and OD +CD. All patient groups, OD, OD+CU, and OD+CD, scored higher commission errors than HC in visual working memory 1-back. OD and OD+CD scored higher commission and total errors than the controls. OD+CU showed lesser error score than HC in TMT B. Cannabis and opioid co-dependence contribute to cognitive impairments, especially in working memory and executive functions.

Suprasellar masquerader: Chordoid glioma.

BACKGROUND: Chordoid glioma is a rare well-circumscribed glial neoplasm arising in adults and predominantly affects females. Tanycytes of the third ventricle have been proposed as the cell of origin owing to its location. It is characterized by chordoid features with myxoid and inflammatory stroma and recurrent PRKCA p.D463H missense mutation. CASE REPORT: We present two cases (30-year-old female and 45-year-old male) with similar complaints of behavioral change and headache. Midline suprasellar homogeneously enhancing mass was seen on contrast-enhanced magnetic resonance imaging. Histopathology and immunohistochemistry was characteristic of chordoid glioma with cords and clusters of epithelioid cells arranged in a solid pattern. There were variable amounts of myxoid stroma and lymphoplasmacytic infiltrate. No mitosis, necrosis, or brain invasion was noted. The cells expressed strong diffuse positivity for glial fibrillary acid protein (GFAP) and weak nuclear thyroid transcription factor (TTF-1). Epithelial membrane antigen (EMA)and brachyury were negative. Subsequently, the lady underwent gross total excision and died soon after the operation. The male patient received radiotherapy and is currently doing well after 6 months of follow-up. CONCLUSION: The rare occurrence as well as the radiological and morphological overlaps in chordoid gliomas make them a true masquerader. Combination of GFAP and TTF-1 in the immunohistochemical panel can be useful in differential diagnosis. Mainstay of treatment is complete surgical excision, with adjuvant radiotherapy becoming increasingly important.

Multi-Level Residual Dual Attention Network for Major Cerebral Arteries Segmentation in MRA Toward Diagnosis of Cerebrovascular Disorders.

Segmentation of major brain vessels is very important for the diagnosis of cerebrovascular disorders and subsequent surgical planning. Vessel segmentation is an important preprocessing step for a wide range of algorithms for the automatic diagnosis or treatment of several vascular pathologies and as such, it is valuable to have a well-performing vascular segmentation pipeline. In this article, we propose an end-to-end multiscale residual dual attention deep neural network for resilient major brain vessel segmentation. In the proposed network, the encoder and decoder blocks of the U-Net are replaced with the multi-level atrous residual blocks to enhance the learning capability by increasing the receptive field to extract the various semantic coarse- and fine-grained features. Dual attention block is incorporated in the bottleneck to perform effective multiscale information fusion to obtain detailed structure of blood vessels. The methods were evaluated on the publicly available TubeTK data set. The proposed method outperforms the state-of-the-art techniques with dice of 0.79 on the whole-brain prediction. The statistical and visual assessments indicate that proposed network is robust to outliers and maintains higher consistency in vessel continuity than the traditional U-Net and its variations.

Pediatric primary intracranial angiosarcoma with epithelioid differentiation: a surgeon's dilemma.

Angiosarcoma is a rare form of soft tissue sarcoma originating from endothelial tissue, accounting for < 1% of all sarcomas. Primary epithelioid angiosarcomas of the central nervous system (CNS) are even more elusive, with only four reports described in the literature. In this article, we describe the first case in pediatric population, with a brief literature review regarding this entity. A 13-year-old girl presented to emergency services with raised intracranial pressure. MRI demonstrated a heterogenous lesion in the temporal lobe. She underwent emergency craniotomy and subtotal excision of the tumor. Eventually the patient developed multiple infarcts and succumbed post operatively. Pre-operative diagnosis on radiology is difficult considering the rarity of this entity and heterogeneity in radiological appearance. One needs to have a high degree of suspicion to consider angiosarcoma as a radiological differential. Overall prognosis remains poor. Early adjuvant treatment may improve overall survival.

Prevalence of asymptomatic brain metastases in metastatic nonsquamous nonsmall cell lung cancer: Treatment implications for resource-constrained settings.

BACKGROUND: Brain metastases (BM) are common in metastatic nonsmall cell lung cancer (NSCLC). However, routine neuroimaging in asymptomatic patients with metastatic NSCLC is controversial as there is no conclusive evidence of benefit from the detection and treatment of asymptomatic BM. Herein, we evaluated the prevalence of asymptomatic BM and its treatment implications in a resource-limited setting. METHODS: Consecutive patients with newly diagnosed, treatment-naïve, metastatic, nonsquamous NSCLC (NS-NSCLC) were included. Subjects who already had clinical or radiological features suggestive of BM were excluded from the study. All eligible subjects underwent contrast-enhanced magnetic resonance imaging (MRI) of the brain. Management of the detected BM was at the discretion of the treating clinicians. RESULTS: Among 809 subjects who were screened, 100 (12.4%) were included in the study and underwent MRI. BM was present in 30 (30%) of the subjects and absent in the remaining 70 subjects. A majority of BM were multiple (70%), involved the frontal lobe commonly (73.3%), and had a mean (standard deviation) size of 13.2 (7.3) mm. Detection of BM resulted in a treatment alteration in 17 (17%) of the study subjects (brain irradiation, n = 17, change in targeted therapy, n = 3) with BM. There was no difference in survival of patients who underwent treatment alteration for management of BM compared to those who did not (P = 0.132). CONCLUSIONS: About one-third of patients with metastatic NS-NSCLC had BM in MRI despite the absence of symptoms. Despite treatment of the majority of the patients with BM with brain irradiation, there was no demonstrable survival benefit. Hence, we conclude that although routine neuroimaging of asymptomatic patients with newly diagnosed metastatic NSCLC may result in treatment alteration (primarily brain irradiation) in a small proportion of patients, it may not influence outcomes in resource-constrained settings.

A Case Series of Scrub Meningoencephalitis from a Tertiary Care Center in North India.

Scrub typhus infection is reemerging leading cause of acute febrile illnesses in post-rainy or monsoon season in Southeast Asia. It is caused by Orientia tsutsugamushi and spread by the bite of chiggers, larval forms of trombiculid mites. The clinical picture can range from simple acute febrile illness to multiorgan dysfunction. Neurological manifestations also vary from aseptic meningitis, meningoencephalitis, cerebral infarction, acute disseminated encephalomyelitis, transverse myelitis, and psychiatric manifestations. Here, we present a case series of eight cases of scrub meningoencephalitis diagnosed based on clinical, laboratory, and radiological criteria.

Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial.

Background: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24 h, day 3, and day 7. The primary outcome was an improvement in encephalopathy by ≥ 1 grade at 72 h. Patients and methods: European association for study of liver (EASL) defined ACLF patients with overt HE were assessed and randomized into the experimental arm (IV-BCAA - 500 mL/day for 3 days + Lactulose; n = 39) and the comparator arm (Lactulose alone; n = 37). Six patients developed COVID-19 after randomization and were excluded (4-experimental arm and 2-comparator arm). Results: Of 222 screened patients, 70 (35 in each arm) were included in the analysis. Baseline characteristics, including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7; P = 0.86) and (chronic liver failure) CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7; P = 0.65), were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%; P = 0.14). Improvement in hepatic encephalopathy scoring algorithm (HESA) by ≥ 1 grade at 24 h occurred in 14 patients (40%) in the BCAA arm and 6 patients (17.1%) in the control group (P = 0.03) which translated to a shorter intensive care unit (ICU) stay. The median change in HESA at 24 h was greater in the BCAA arm than the control arm (P = 0.006), which was not sustained at days 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient (ρ) = - 0.0843; P = 0.29). Conclusion: Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF. Trial registration no: NCT04238416 (clinicaltrials.gov).

Primary Dural Acute Lymphoblastic Leukaemia/Lymphoma Masquerading Meningioma: Report of a Case and Review of Literature.

Acute lymphoblastic leukaemia/lymphoma (ALL) is a systemic disease which primarily involves bone marrow or lymphoid organs. Extranodal presentation of ALL is uncommon, and ALL presenting as a dural mass is exceedingly rare. Here we present a case of primary dural B-cell ALL which was preoperatively diagnosed as meningioma on clinico-radiological grounds. A 27-year-old female patient presented with left hemicranial headache for one month's duration along with progressive vision loss of in both eye and altered behaviour. Contrast enhanced magnetic resonance imaging (CE-MRI) suggest dural based mass with dural tail sign. Histopathological examination of the resected specimen revealed B-cell ALL. Further systemic investigations didn't suggest any peripheral blood, bone marrow or lymph node involvement. To the best of our knowledge, only two cases of primary dural ALL have been reported in the literature so far. This report highlights the diagnostic difficulty in extramedullary precursor lymphoid neoplasm.

Changing Clinical Profile and Predictors of Mortality in Patients of Acute Febrile Encephalopathy from North India.

Introduction: Acute encephalitis syndrome (AES) or acute febrile encephalopathy is a clinical condition characterized by altered mental status occurring after or along with a short febrile illness. In developing countries, infections are the predominant cause of AES. Prominent infections known to cause AES include viruses (such as herpes simplex virus [HSV], Japanese Encephalitis [JE] virus, dengue, enteroviruses [EVs]), bacteria, fungus, and parasites. In the present study, we aim to analyze the etiology, clinical features, and predictors of mortality in patients presenting with acute febrile encephalopathy or acute encephalitic syndrome. The present study was a prospective observational study conducted at Post Graduate Institute of Medical Education and Research a tertiary care center in Chandigarh, India. Methods: A total of 105 patients with ≥18 years of age with fever (body temperature >101° F for duration ≤14 days) and altered sensorium (Glasgow coma scale [GCS] score ≤10) lasting for more than 24 h, either accompanying the fever or following it were enrolled. Demographic and clinical details were recorded on pro forma. Cerebrospinal fluid (CSF) analysis was performed for all the enrolled patients at admission for cytology, CSF glucose to blood glucose ratio, protein levels, gram stain and culture sensitivity, adenosine deaminase levels, polymerase chain reaction for HSV/EV/mycobacterium tuberculosis (TB) and immunoglobulin M Enzyme-linked immune assay for JE. Computed tomography of the brain was done in all patients while magnetic resonance imaging (MRI) of the brain was carried out in 75 patients. Results: Among the 105 patients, tubercular meningitis was seen in 27 (25.7%) patients followed by acute pyogenic meningitis in 18 (17.1%) patients. Probable viral encephalitis was present in 12 (11.4%) cases. Septic encephalopathy (n = 10) and scrub typhus encephalitis (n = 8), HSV encephalitis (n = 6), dengue encephalitis (n = 4), leptospirosis (n = 3) were the other infections causing acute febrile encephalitis in our study. In addition to fever and altered sensorium common symptoms observed were headache (52.4%), vomiting (35.2%), and seizures (29.5%). The factors predicting increased mortality were female gender, fever of more than 38°C at admission, GCS <7, MRI showing disease-related findings like altered signal intensity bilateral medial temporal and insular area in herpes simplex encephalitis, etc., changes, and the group of patients where a definite diagnosis could not be established during the hospital stay. Conclusions: Tubercular meningitis/central nervous system TB is the predominant cause of acute febrile encephalopathy in developing countries. Scrub and dengue encephalitis are emerging as an important cause of acute febrile encephalopathy and occur predominantly in postmonsoon seasons. Acute febrile encephalopathy remains an important cause of mortality in patients presenting to Emergency Department (ER). The strongest predictors of mortality are low GCS and undiagnosed cases of AES.

Morphology of intra tumoral cystic vestibular schwannoma and their response to gammaknife radiosurgery.

BACKGROUND: Cystic vestibular schwannoma (CVS) traditionally considered as poor responder to gammaknife radiosurgery (GKRS). Their longterm radiobiological behavior is less known. Here we discuss 38 cases with intra tumoral cyst CVS primarily treated with GKRS. Tumor morphology was assessed to understand their response to GKRS. METHODS: Total 38 patients(21 male and 17 female with median age of 41.7 years) of CVS treated with GKRS were retrospectively analysed. Tumors were divided as predominantly (greater than50% of total tumor volume) cystic or solid. They were subclassified as type 1 (predominantly cystic CVS, single cyst), type 2 (predominantly solid CVS, single cysts), type 3 (multicystic CVS). The entire cyst was incorporated for radiosurgery. The results were compared with volume matched control of 58 solid tumors(SVS). RESULT: The median tumor volume of CVS was 5.8 cc. The median tumor volume reduction was 44.5 % at a median follow-up of 68.5 months (30-110 months). Median tumor volume reduction was 68.5 %, 34.0%, 11.0.%, 30.5% at a median follow up of 52.5months, 66 months, 78.6 months, 96.5 months for type 1 CVS, type 2 CVS, type 3 CVS and SVS respectively. One patient with multicystic CVS showed increased tumor volume and expired after 9 months of surgery.The tumor volume reduction in type 1CVS was statistically significant as compared to type 3 CVS and SVS. However the tumor volume reduction among other groups did not differ significantly. CONCLUSION: Intra tumoral cystic components respond better to gammaknife radiosurgery in CVS. Tumor with single cyst respond better than multicystic vestibular schwannoma.

Clinicoradiological Profile of COVID-19-Associated Rhino-Orbital Cerebral Mucormycosis with a Focus on Computed Tomography: A Clinical Case Series and Review.

COVID-19-associated rhino-orbital cerebral mucormycosis (ROCM) has a rapidly evolving course with high morbidity and mortality. We describe imaging features of COVID-19-associated ROCM based on noncontrast computed tomography (NCCT). This retrospective single-center observational study included 50 patients with COVID-19 from January 1, 2021 to June 30, 2021 who subsequently developed ROCM confirmed by fungal culture studies. All patients underwent NCCT of the paranasal sinuses as the diagnostic workup. The involvement of the nasal cavity, paranasal sinuses, orbits, and intracranial cavity was identified and graded. The ethmoid sinuses were most commonly involved [right (n = 46 of 50) > left (n = 45 of 50)], followed by the maxillary, sphenoid, and frontal sinuses. Thinning and erosions of the hard palate were noted in 18% of patients (n = 9), whereas 34% (n = 17) showed dehiscence of the lamina papyracea. Retromaxillary fat stranding was noted in 68% of patients (n = 34). Severe ethmoid sinusitis was associated significantly with ipsilateral pterygopalatine fossa involvement. The extraocular muscles were involved in 64% of patients (n = 32), with 84% (n = 42) showing orbital fat stranding. Proptosis of the affected eye was seen in 66% of patients, optic nerve involvement in 52%, and irregularity of globe contour in 12% (n = 6). The cavernous sinuses were affected in 10% of patients (n = 5), with three of them having temporal infarcts. COVID-19-associated ROCM is an acute, invasive fungal disease characterized by multisinus involvement, often with orbital and intracranial extension. Bilateral involvement with rapid progression should alert one to underlying COVID-19 disease.

Neurocognitive Analysis of Low-level Arsenic Exposure and Executive Function Mediated by Brain Anomalies Among Children, Adolescents, and Young Adults in India.

Importance: Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic content in water. Objective: To identify cognitive impairments following commonly prevalent low-level arsenic exposure and characterize their underlying brain mechanisms. Design, Setting, and Participants: This multicenter population-based cohort study analyzed cross-sectional data of the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, recruited between November 4, 2016, and May 4, 2019. Participants aged 6 to 23 years were characterized using deep phenotyping measures of behavior, neuropsychology, psychopathology, brain neuroimaging, and exposure to developmental adversities and environmental neurotoxins. All analyses were performed between June 1, 2020, and December 31, 2021. Exposure: Arsenic levels were measured in urine as an index of exposure. Main Outcomes and Measures: Executive function measured using the cVEDA neuropsychological battery, gray matter volume (GMV) from T1-weighted magnetic resonance imaging, and functional network connectivity measures from resting state functional magnetic resonance imaging. Results: A total of 1014 participants aged 6 to 23 years (589 male [58.1%]; mean [SD] age, 14.86 [4.79] years) were included from 5 geographic locations. Sparse-partial least squares analysis was used to describe a negative association of arsenic exposure with executive function (r = -0.12 [P = 5.4 × 10-4]), brain structure (r = -0.20 [P = 1.8 × 10-8]), and functional connectivity (within network, r = -0.12 [P = 7.5 × 10-4]; between network, r = -0.23 [P = 1.8 × 10-10]). Alterations in executive function were partially mediated by GMV (b = -0.004 [95% CI, -0.007 to -0.002]) and within-network functional connectivity (b = -0.004 [95% CI, -0.008 to -0.002]). Socioeconomic status and body mass index moderated the association between arsenic and GMV, such that the association was strongest in participants with lower socioeconomic status and body mass index. Conclusions and Relevance: The findings of this cross-sectional study suggest that low-level arsenic exposure was associated with alterations in executive functioning and underlying brain correlates. These results indicate potential detrimental consequences of arsenic exposure that are below the currently recommended guidelines and may extend beyond endemic risk areas. Precision medicine approaches to study global mental health vulnerabilities highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development.