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Five decades of pneumococcal meningitis in Spain: a single-centre, clinical and genomic, retrospective, observational study.

BACKGROUND: Pneumococcal meningitis remains a major threat, with high fatality rates and long-term sequelae, despite advances in vaccination and treatment. We aimed to examine the associations between pneumococcal serotypes, Global Pneumococcal Sequence Cluster (GPSC), antimicrobial resistance, source of infection, and clinical outcomes in adults with pneumococcal meningitis. METHODS: In this single-centre, clinical and genomic, retrospective, observational study, we analysed all laboratory-confirmed cases of adult pneumococcal meningitis recorded at Hospital Universitari de Bellvitge, Spain. Clinical data were obtained from a prospectively maintained clinical database and linked to microbiological and genomic data by unique patient identifiers. Clinical sources of infection were classified as cerebrospinal fluid leakage, acute otitis media, or haematogenous origin. Disease severity was defined as shock at presentation, sequelae as any persistent neurological deficit at discharge, and mortality as death within 30 days. Serotype data were available for 265 isolates, and whole-genome sequencing was done on 200 viable isolates. For outcome analyses, patients who did not receive dexamethasone were excluded. Serotype, GPSCs, antimicrobial susceptibility, phylogenetic, and genome-wide association study (GWAS) data were analysed to assess determinants of meningitis source, disease severity, sequelae, and 30-day mortality. FINDINGS: 387 adult patients (median age 58 years [IQR 45-68]; 54% male) with pneumococcal meningitis were recorded between Jan 1, 1974, and Dec 31, 2023. Acute otitis media was the most frequent source of pneumococcal meningitis (174 [45%] of 387 cases) and was mainly caused by serotype 3 (pneumococcal conjugate vaccine [PCV]13; GPSC12). The 30-day case-fatality rate in this group was 17 (10%) of 174 (95% CI 5&#xb7;8-15&#xb7;2). Haematogenous episodes accounted for 104 (27%) of 387 cases and had a significantly higher 30-day case-fatality rate (50 [48%] of 104; 95% CI 38&#xb7;2-58&#xb7;1; p<0&#xb7;0001) with a higher frequency of serotype 4. Cerebrospinal fluid leakage accounted for 105 (27%) of 387 cases and had the lowest 30-day case-fatality rate (nine [9%] of 105; 95% CI 4&#xb7;0-15&#xb7;6) and broader serotype diversity. The introduction of PCV7 and PCV13 resulted in declines in vaccine-targeted serotypes and &#x3b2;-lactam resistance. Whole-genome sequencing identified 60 distinct GPSCs. Among prevalent lineages, GPSC16 (20 [10%] of 200; serotypes 19A and 23F) and GPSC6 (18 [9%] of 200; serotypes 9V, 11A, and 14) were associated with &#x3b2;-lactam resistance. GWAS did not identify genetic variants significantly associated with severity, sequelae, or mortality. INTERPRETATION: This longitudinal study provides a comprehensive view of adult pneumococcal meningitis over five decades, revealing changes in sources of infection, serotype distribution, pneumococcal lineages, and antimicrobial resistance patterns over time. Lineage-level findings suggested variability in clinical outcomes, underscoring the importance of continued genomic surveillance and supporting consideration of broader vaccine targets. GPSC12 predominance and its association with mortality and more severe outcomes highlight the need for preventive measures against serotype 3, although these findings require confirmation in larger multicentre cohorts. FUNDING: Instituto de Salud Carlos III, cofunded by European Social Fund, and the Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red de Enfermedades Respiratorias, and the Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red de Enfermedades Infecciosas, both at the Instituto de Salud Carlos III.

Journal Article↗

Aseptic meningitis after neurosurgery: a demonstration of bacterial involvement.

OBJECTIVE: To evaluate the presence of bacteria in samples from patients suffering from 'aseptic' meningitis following craniotomy. METHODS: Prospective study in which cerebrospinal fluid (CSF) from patients suffering from post-craniotomy meningitis and negative control patients were submitted to conventional culture and to polymerase chain reaction (PCR) using bacterial 16S rRNA universal primers, followed in some cases by DNA sequencing of the PCR product and phylogenetic analysis. RESULTS: CSF from patients with either culture-positive or culture-negative meningitis yielded positive amplifications, whereas no amplification was obtained with CSF from control patients. All positive signals were confirmed by Southern hybridization with a prokaryote 16S RNA-specific probe. Six PCR products, of which three were collected from later cases of culture-negative meningitis, were cloned and sequenced. Sequence analysis suggested affinities with Pseudomonas in three cases, with Escherichia in two cases and with Rhodococcus in one case. CONCLUSIONS: Many cases of culture-negative (aseptic) meningitis are probably bacterial meningitis and justify antibiotic treatment. The bacteria responsible for these cases of culture-negative meningitis might have peculiar growth requirements in vitro.

Journal Article↗

Meningeal enhancement on magnetic resonance imaging in 15 dogs and 3 cats.

A retrospective study of 15 dogs and three cats was done to characterize the appearance of meningeal enhancement on magnetic resonance (MR) images of the brain, and to correlate this appearance with its underlying cause. Two patterns of meningeal enhancement (pial and dural) were identified. Enhancement of the pia mater was evident in four dogs and one cat, while enhancement of the dura mater was seen in 11 dogs and 2 cats. A variety of causes of meningeal enhancement were identified, including bacterial and cryptococcal meningitis, plasmacytic meningitis with associated subdural fluid accumulation, granulomatous meningoencephalomyelitis, inflammation secondary to otitis interna, feline infectious peritonitis, and neoplasia. The present study confirms that pial or dural meningeal enhancement may be present on MR images of the brain of dogs or cats in association with a variety of central nervous system diseases. A larger prospective study is required to further establish the incidence of specific patterns of meningeal enhancement seen in association with specific diseases.

Animals↗

[Etiological profile of bacterial meningitis in children].

OBJECTIVE: To determine the etiologic profile and analyze some epidemiological aspects of children with bacterial meningitis admitted to a public teaching hospital. METHODS: A prospective study was conducted on children with clinical and laboratory diagnosis of bacterial meningitis, admitted to Hospital das Clínicas da Universidade Federal de Uberlândia, from January 1987 to January 2001. Patients with meningitis associated with trauma, intracranial devices or malformations of the neural tube, and tuberculosis, were not included in the study. RESULTS: From a total of 415 children with bacterial meningitis, the etiologic agent was detected in 315 (75.9%): Haemophilus influenzae b in 54.2%, meningococci in 20.6%, pneumococci in 18.1% and other agents, in 6.9%. Previous antibiotic treatment, observed in 47.2% of the cases, led to a significant decrease in positive blood cultures (from 50.8% to 38.7%) and in cerebrospinal fluid cultures (from 71.7% to 57.6%). Among children younger than 48 months Haemophilus influenzae b was predominant, particularly when compared to meningococci. The overall mortality was 10.1%, with a significant difference between the rates of pneumococcal (17.5%) and meningococcal meningitis (4.6%). CONCLUSIONS: Children affected by Haemophilus influenzae b and by pneumococci were younger than those with meningitis caused by meningococci. The blood and/or cerebrospinal fluid culture remains an important laboratory tool for etiologic diagnosis, despite the negative impact caused by antibiotic previous treatment. The agents most commonly detected were Haemophilus influenzae b, meningococci and pneumococci. Bacterial meningitis continues to present an important mortality among children, particularly when caused by pneumococci.

English Abstract↗

Acute severe spinal cord dysfunction in bacterial meningitis in adults: MRI findings suggest extensive myelitis.

BACKGROUND: Bacterial meningitis is rarely complicated by acute spinal cord involvement (eg, myelitis, ischemic infarction, spinal abscess, or epidural hemorrhage). In spinal cord dysfunction, magnetic resonance imaging (MRI) is the imaging modality of choice. Still, MRI findings of myelitis due to bacterial meningitis in adults have not been reported. METHODS: Spinal MRIs were obtained during the acute stage of meningitis and on follow-up in 3 adults with bacterial meningitis that was complicated by paraparesis or tetraparesis and bowel and bladder incontinence. The causative pathogens were Streptococcus pneumoniae and Neisseria meningitidis; in 1 patient, the pathogen was not identified. RESULTS: In all cases, spinal MRI ruled out a compression of the cord by an extramedullary mass but demonstrated hyperintensities on T2-weighted images that predominantly involved the gray matter and extended from the cervical to the lumbar cord. Leptomeningeal and discrete nodular intramedullary enhancement on T1-weighted images was detected only in 1 patient. Follow-up examinations revealed that hyperintensities resolved completely in 1 patient, while a central cavitation developed in the cervical spinal cord of another, and the MRI findings were progressive during the first 4 weeks in the third patient. In all cases, severe paresis and bowel and bladder incontinence persisted. CONCLUSION: We demonstrate for the first time the MRI findings of adults with acute spinal cord involvement during bacterial meningitis. Magnetic resonance imaging showed central intramedullary hyperintensities on T2-weighted images that extended from the cervical to the lumbar cord, indicating myelitis. Clinical follow-up examinations suggest that myelitis during bacterial meningitis has an unfavorable prognosis.

Adolescent↗

Carcinomatous meningitis in patients with breast cancer. An aggressive disease variant.

BACKGROUND: Carcinomatous meningitis is a rare and often devastating complication in patients with breast cancer, and the treatment is controversial. METHODS: A retrospective analysis of 35 patients with carcinomatous meningitis from breast cancer was performed to define the biology of the disease and to guide treatment. RESULTS: An aggressive variant of breast cancer was revealed: meningeal metastasis complicates less than 3.5% of cases of metastatic breast carcinoma. Sixty-seven percent of these patients had tumors that were lobular or combined lobular/ductal histology; the median intervals from primary treatment to disease recurrence and from recurrence to death were 10.9 and 15 months, respectively. The median survival after diagnosis of carcinomatous meningitis was 77 days. The most significant prognostic factor was the Karnofsky performance status (KP) at presentation of meningeal disease. Patients with a KP greater or equal to 70 survived a median of 313 days, whereas those with a KP of 60 or less survived for a median of 36 days (P = 0.0002). In addition, there was a trend suggesting that the response 2 weeks after treatment was initiated, correlated with survival. CONCLUSIONS: Carcinomatous meningitis from breast carcinoma is an aggressive metastatic complication with a poor prognosis. The authors suggest that patients with a poor KP (< 70) should be treated symptomatically and those with a good KP (> or = 70) should receive more aggressive treatment. The patients' survival in this study compared well with other reports, and yet, only one patient was treated with intraventricular chemotherapy. Therefore, these data question the superiority of intraventricular treatment versus other modalities.

Adult↗

Hearing loss as a sequela of meningitis.

A retrospective study of 547 cases of meningitis was performed. Of these, 236 were bacterial, 304 were viral, and 7 were fungal in etiology. Of 110 survivors of bacterial meningitis over the age of 2 1/2 years, 23 or 21% suffered partial or complete sensorineural hearing loss. The site of auditory injury in cases of partial loss was the cochlea by audiologic criteria. A positive correlation with hearing loss was found for the species of organism, delay before treatment, low CSF sugar, and CSF pleocytosis. Of 7 patients with fungal meningitis, 3 suffered hearing loss with signs of a retrocochlear site. Of 304 cases of aseptic meningitis, none developed a hearing loss. The pathophysiology of hearing loss as a sequela of meningitis and the possible explanations for absence of hearing loss in viral meningitis are discussed.

Adolescent↗

Identification of antibody responses to Mycobacterium tuberculosis antigens in the CSF of tuberculous meningitis patients by Western blotting.

One of the adjunctive modes of diagnosing tuberculous meningitis (TBM) is to detect immune responses in the cerebrospinal fluid (CSF) to the Mycobacterium tuberculosis antigen. Up to 70% of clinical TBM reveal the presence of antimycobacterial antibody by the enzyme-linked immunosorbant assay. Defining the specificity of this immune response by Western blotting on separated M. tuberculosis antigen has been attempted in this study. Only antimycobacterial antibody-positive TBM cases were included in the study. An analysis of 30 such TBM cases showed a major immune reactivity to the 30- to 40-kDa region (93%) while a lower degree of immune reactivity was seen to the 14-kDa region (87%) and to the 18- to 25-kDa region (60%). Grossly the antibody reactivity on Western blot correlated with the ELISA results. Assessment of antimycobacterial antibody in the neurologic control CSF samples of pyogenic meningitis [n = 10], cryptococcal meningitis [6], neurocysticercosis [28], neurosyphilis [8], viral meningoencephalitis [8], carcinomatous meningitis [8], iatrogenic meningitis [6], and nonneurological control CSF samples from patients undergoing spinal anesthesia [20] revealed the presence of antibody in the CSF of 2 of the 10 pyogenic meningitis and 5 of the 28 neurocysticercosis cases. A Western blot analysis of these 7 cases revealed immune reactivity to 30- to 40-kDa regions only in 2 cases (1 of pyogenic and 1 of neurocysticercosis). The remaining 5 CSF samples did not reveal any immune reactivity on Western blotting, although ELISA demonstrated antimycobacterial antibodies. The antibody response to M. tuberculosis lipoarabinomannan and 38-kDa antigen by ELISA revealed 70.58 and 41.17% positivity, respectively. Thus this study has demonstrated that, by Western blotting, the major immune response is to the 30- to 40-kDa region, namely, lipoarabinomannan. Further, this finding will be useful for specific immunodiagnosis of the TBM.

Antibodies, Bacterial↗

The differential diagnosis of bacterial and aseptic meningitis using cerebrospinal fluid laboratory tests.

The lactate, lysozyme, C-reactive protein and serum amyloid-A protein concentrations in cerebrospinal fluid were measured in 11 patients with bacterial meningitis, 27 patients with aseptic meningitis and in 31 control patients. The mean concentration of each parameter was significantly higher (p less than or equal to 0.0001) in patients with bacterial meningitis than in those with aseptic meningitis or those without meningitis. The reliability of these tests in the differential diagnosis of bacterial and aseptic meningitis was compared with leucocyte counts in cerebrospinal fluid. Gram staining for bacteria, and protein and glucose levels. The cerebrospinal fluid lactate level proved to be more sensitive than lysozyme. C-reactive protein or serum amyloid-A protein and had a high degree of specificity.

Adult↗

Liposomal cytarabine (DepoCyte) for the treatment of neoplastic meningitis.

Neoplastic meningitis is a feared complication in cancer patients, the median survival ranging from some weeks to a few months. Management is palliative and aims to provide symptoms relief while delaying neurological deterioration. Intrathecal methotrexate and/or cytarabine is the most widely used treatment in such clinical situations. These drugs are administered 2 or 3 times a week--a circumstance that is both bothersome for the patient and time-costly for the medical personnel. Liposomal cytarabine is a sustained-release cytarabine formulation specifically developed for the treatment of neoplastic meningitis. Its administration on a twice-weekly basis ensures sustained cytotoxic drug concentrations in cerebrospinal fluid. Controlled clinical trials have shown liposomal cytarabine to be equally or more effective than the classical treatment for neoplastic meningitis. In lymphomatous meningitis, liposomal cytarabine offers superior response rates, improved patient quality of life, and a prolongation of the time to neurological progression. When the cause of meningitis is a solid tumor, liposomal cytarabine prolongs the time to neurological progression and improves quality of life. These observations indicate that DepoCyte is a convenient treatment for patients with neoplastic meningitis, due to its efficacy and easy of administration characteristics.

Antimetabolites, Antineoplastic↗

Aseptic meningitis: diagnosis and management.

The term aseptic meningitis encompasses all types of inflammations of the brain meninges other than that caused by pus producing organisms. It is usually a benign illness. Etiology of aseptic meningitis is very wide and includes many infections - both viral and non viral, drugs, malignancy and systemic illness. The most common cause is viral infection and enteroviruses - Coxsackie and ECHO viruses account for more than half of all cases. Clinical manifestations include headache, fever, malaise, photophobia and meningeal signs. Convulsions, neurological deficits and severe obtundation are rare except with certain non viral infectious meningitis. Diagnostic work up includes blood and cerebrospinal fluid (CSF) examination and serology for infectious meningitis. The polymerase chain reaction is a rapid and accurate method for detection of microbial DNA in CSF. Treatment is mainly supportive, except for the nonviral infectious etiology.

Brucellosis↗

MRI of primary meningeal sarcomas in two children: differential diagnostic considerations.

Meningeal sarcomas are very rare, highly aggressive tumours affecting children more frequently than adults. The clinical course and MRI of meningeal sarcomas in two cases are discussed with special regard to possible misinterpretation. In one case MRI demonstrated a circumscribed mass in contact with the meninges, with central areas of haemorrhage. In the other, a case of primary leptomeningeal sarcomatosis, several MRI examinations over the course of almost a year were unhelpful, despite severe neurological complaints. Then MRI revealed meningeal contrast enhancement all over the brain and spinal canal, together with cerebral infarcts. MRI of meningeal sarcomas has not been discussed in the literature. MRI did not permit specific diagnosis, but enabled visualisation of the extent of the tumour and/or meningeal involvement. Early histological diagnosis is indispensable for adequate treatment.

Child↗

Validation of a diagnosis model for differentiating bacterial from viral meningitis in infants and children under 3.5 years of age.

The aim of this study was to validate, in a population of infants and children under 3.5 years of age, a diagnosis model that provides a figure for the probability of bacterial meningitis (pABM), based on four parameters collected at the time of the first lumbar tap: the cerebrospinal fluid (CSF) protein level, CSF polymorphonuclear cell count, blood glucose level, and leucocyte count. The best cut-off value for distinguishing between bacterial and viral meningitis was previously found to be 0.1, since 99% of meningitides associated with pABM<0.1 were viral. The charts of 103 consecutive children aged 0.1-3.5 years who had been hospitalised for acute meningitis were reviewed. Each case was sorted into the following three categories for aetiology: bacterial (positive CSF culture, n=48); viral (negative CSF culture and no other aetiology, and no antibiotic treatment after diagnosis, n=36); and undetermined (fitting neither of the first two definitions, n=19). After computation of pABM values in each case, the predictive values of the model were calculated for different pABM cut-off values. The results confirmed that the best cut-off pABM value was 0.1, for which the positive and negative predictive values in this model were 96% and 97%, respectively. Only one case of bacterial meningitis (lumbar tap performed early in an infant with meningococcal purpura fulminans with negative CSF culture) was associated with a pABM value of <0.1. This model is quite reliable for differentiating between bacterial and viral meningitis in children under 3.5 years of age, and it may enable physicians to withhold antibiotics in cases of meningitis of uncertain aetiology.

Blood Glucose↗

Experience with the use of cefotaxime in the treatment of bacterial meningitis.

Information on 62 bacteriologically confirmed cases of bacterial meningitis treated with cefotaxime in this country was obtained retrospectively from infectious disease consultants. This series of cases differed markedly from the world cumulative case data thus far presented. One of the two most common organisms treated was the pneumococcus (allergy to penicillin or misdiagnosis of the Gram stain results were the major reasons given). The other organism was Klebsiella. Unanticipated bacteriologic successes were noted in two cases of staphylococcal meningitis secondary to parameningeal foci. The bacteriologic cure rate and survival rate were about 85 percent. Failure of monotherapy was seen in one case of Pseudomonas meningitis, as well as in three of five cases of Enterobacter meningitis. In addition, two cases of Escherichia coli meningitis in which moxalactam therapy inexplicably failed were cured with cefotaxime. Close analysis of killing kinetics appeared to explain the Enterobacter and E. coli failures. Thus, overall not all gram-negative species and not all isolates of any particular species that cause meningitis can be successfully treated by cephalosporins. Data obtained during the investigative trials do not appear to be entirely predicative of what occurred during the free clinical use of an antibiotic. Post-investigatory follow-up and surveillance of all newly introduced therapeutic agents are needed.

Adult↗

Cochlear implantation and meningitis.

OBJECTIVE: Study clinical presentation, diagnosis and treatment of cochlear implant patients diagnosed with bacterial meningitis. BACKGROUND: Cochlear implantation in children is necessary for the optimal development of speech in the developing child diagnosed with profound sensorineural hearing loss. Approximately 60,000 devices have been inserted in adults and children worldwide to date. SETTING: The Department of Pediatric Otolaryngology of a tertiary care children's hospital. METHODS: All patients undergoing cochlear implantation from April 1997 were identified. Patients diagnosed with bacterial meningitis after implantation were selected for study. RESULTS: Of 30 children, two developed bacterial meningitis after cochlear implantation. One patient developed Streptococcus pneumoniae meningitis. One patient developed nontypable Haemophilus influenzae bacterial meningitis. Both patients made a complete recovery. CONCLUSIONS: Prompt diagnosis and treatment of meningitis is essential to optimize outcome.

Child, Preschool↗

Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy.

We hypothesized that plasma arginine vasopressin (AVP) concentrations in children with meningitis are appropriate for the children's degree of hypovolemia, even though the concentrations were higher than expected for the serum osmolality. A randomized study was conducted to compare the effect on plasma AVP concentrations of giving maintenance fluid requirements plus replacement of any deficit versus restricting fluids to two thirds of maintenance requirements for 24 hours. Plasma AVP concentrations and serum osmolality were measured before fluid therapy was begun and again after 24 hours. Nineteen children, 2 months to 17 years of age, were studied; 13 had bacterial meningitis (12 with Haemophilus influenzae type b). Ten children (seven with bacterial meningitis) received a mean of 1.42 times the calculated maintenance fluid requirements, and nine (six with bacterial meningitis) were restricted to a mean of 0.65 times maintenance. Children in the maintenance group also received significantly more sodium (mean = 6.3 mEq/kg/24 hr) than children in the fluid-restricted group (mean = 2.0 mEq/kg/24 hr). The two groups were comparable for plasma AVP concentration and serum osmolality before fluid therapy was begun. The plasma AVP concentration was significantly lower after 24 hours of maintenance plus replacement fluids than after fluid restriction (p = 0.005), and the change in AVP concentration correlated with the amount of sodium given (p less than 0.02). This study supports the hypothesis that serum AVP concentrations are elevated in patients with meningitis because of hypovolemia and become normal when sufficient sodium is given to facilitate reabsorption of water by the proximal tubule of the kidney. Patients with meningitis can be given maintenance plus replacement fluids but should be monitored for the development of the syndrome of inappropriate secretion of antidiuretic hormone.

Adolescent↗

Chemokines and chemotaxis of leukocytes in infectious meningitis.

Chemokines constitute a constantly growing family of small inflammatory cytokines. They have been implied in many different diseases of the CNS including trauma, stroke and inflammation, e.g., multiple sclerosis. In this review we focus on the role of chemokines in infectious meningitis of bacterial or viral origin. In experimental bacterial meningitis induced by Listeria monocytogeneses both CXC and CC chemokines namely MIP-1alpha, MIP-1beta and MIP-2 are produced intrathecally by meningeal macrophages and leukocytes which infiltrate into the CNS. In patients with bacterial meningitis, IL-8, GROalpha, MCP-1, MIP-1alpha and MIP-1beta are detectable in the CSF. These chemokines contribute to CSF mediated chemotaxis on neutrophils and PBMC in vitro. In viral meningitis IL-8, IP-10 and MCP-1 are identified in the CSF to be responsible for chemotactic activity on neutrophils, PBMC and activated T cells. Taken collectively these data indicate that the recruitment of leukocytes in infectious meningitis involves the intrathecal production of chemokines.

Chemokines↗

Audiovestibular and neuropsychological outcome of adults who had recovered from childhood bacterial meningitis.

A sample of 22 subjects was studied from a population of adults who had suffered from bacterial meningitis in childhood. Audiovestibular, oculomotor and neuropsychological investigations were performed and quality of life was assessed. An age-matched control group of 20 subjects was recruited. In the meningitis group, nine subjects had abnormal pure tone audiograms. One was previously undiagnosed and a progression was found in four. There was an overrepresentation of subclinical vestibular pathology (6 out of 9 (67%)) in this group. Audiovestibular test results showed a peripheral pattern and oculomotor tests were normal. The quality of life scores of those with hearing loss were significantly higher than those in the control group. Neuropsychological tests of brain dysfunction were abnormal in six out of 22 (27%) who had recovered from meningitis. The prevalence of such dysfunctions was not related to audiovestibular disorder. The quality of life scores of those with brain dysfunctions were similar to those of the control group. The findings of reduced auditory memory and tone level perception in four out of 22 (18%), suggest that lesions of central auditory pathways may follow from bacterial meningitis. The results support the idea that inner ear damage is the major cause of hearing loss after bacterial meningitis. Despite the absence of brainstem involvement, central nervous system lesions with disturbed auditory processing and language functions can be of significance. The high frequency of discrete brain dysfunctions indicate that a thorough neuropsychological investigation is required after bacterial meningitis.

Adult↗