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The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March-December 2019 and March-December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality., (© 2022. The Author(s).)

Objective: Psychoeducational parent training is an economic way to provide care for parents of children newly diagnosed with an autism spectrum disorder (ASD). This study explores pre-post effect sizes of the manualized autism-specific parent training FAUT-E (Frankfurter Autismus-Elterntraining). Method: Two behaviorally trained therapists worked with 6-10 parents in eight group sessions. Twenty-four parents of 24 children with ASD participated in the study. Outcomes were child- and parent-related measures obtained at T0 (first measurement), T1 (second measurement), T2 (postintervention), and T3 (3 months after intervention). Results: Children showed improved behavior in the parent-rated Aberrant Behavior Checklist (ABC) total score after therapy ( p = .001; ES T1T2 = .73) and at T3 ( p = .018; ES T1-T3 = -.51), and a lower intensity of parent-rated problem behavior at T3 ( p This study found medium pre-post effects on the child's behavior by FAUT-E between T1 and T2/T3; these were not observed between the measurements T0-T1. FAUT-E was easy to implement and did not increase parental stress. This is in line with results of studies on other training programs to teach parents to use effective behavioral strategies with ASD.Conclusions: This study found medium pre-post effects on the child's behavior by FAUT-E between T1 and T2/T3; these were not observed between the measurements T0-T1. FAUT-E was easy to implement and did not increase parental stress. This is in line with results of studies on other training programs to teach parents to use effective behavioral strategies with ASD.

In Autism Spectrum Disorders (ASD), impaired response inhibition and lack of adaptation are hypothesized to underlie core ASD symptoms, such as social communication and repetitive, stereotyped behavior. Thus, the aim of the present study was to compare neural correlates of inhibition, post-error adaptation, and reaction time variability in ASD and neuro-typical control (NTC) participants by investigating possible differences in error-related changes of oscillatory MEG activity. Twelve male NTC (mean age 20.3 ± 3.7) and fourteen male patients with ASD (mean age 17.8 ± 2.9) were included in the analysis. Subjects with ASD showed increased error-related reaction time variability. MEG analysis revealed decreased beta power in the ASD group in comparison to the NTC group over the centro-parietal channels in both, the pre-stimulus and post-response interval. In the ASD group, mean centro-parietal beta power negatively correlated with dimensional autism symptoms. In both groups, false alarms were followed by an early increase in temporo-frontal theta to alpha power; and by a later decrease in alpha to beta power at central and posterior sensors. Single trial correlations were additionally studied in the ASD group, who showed a positive correlation of pre-stimulus beta power with post-response theta, alpha, and beta power, particularly after hit trials. On a broader scale, the results deliver important insights into top-down control deficits that may relate to core symptoms observed in ASD.

Background: Texts and interpretations on the lawfulness of abortion and associated administrative requirements can be vague and confusing. It can also be difficult for a woman or provider to know exactly where to look for and how to interpret laws on abortion. To increase transparency, the Global Abortion Policies Database (GAPD), launched in 2017, facilitates the strengthening of knowledge and understanding of the complexities and nuances around lawful abortion as explicitly stated in laws and policies., Methods: We report on data available in the GAPD as of May 2018. We reviewed the content and wording of laws, policies, standards and guidelines, judgments and other official statements for all countries where data is available in the GAPD. We analyzed data for 158 countries, where abortion is lawful on the woman's request with no requirement for justification and/or for at least one legal ground, including additional indications that are nonequivalent to a single common legal ground. We classified laws on the basis of the explicit wording of the text. The GAPD treats legal categories as the circumstances under which abortion is lawful, that is, allowed or not contrary to law, or explicitly permitted or specified by law., Results: 32% of countries allow or permit abortion at the woman's request with no requirement for justification. Approximately 82% of countries allow or permit abortion to save the woman's life. 64% of countries specify health, physical health and/or mental (or psychological) health. 51% allow or permit abortion based on a fetal condition, 46% of countries allow or permit abortion where the pregnancy is the result of rape, and 10% specify an economic or social ground. Laws may also specify several additional indications that are nonequivalent to a single legal ground., Conclusions: The GAPD reflects details that exist within countries' laws and highlights the nuance within legal categories of abortion; no assumptions are made as to how laws are interpreted or applied in practice. By examining the text of the law, additional complexities related to the legal categories of abortion become more apparent.

Background: The Global Abortion Policies Database (GAPD), launched in June 2017, provides a verifiable, comprehensive, nuanced approach to information and data sources on abortion law and policy. Abortion laws, policies, and guidelines from United Nations (UN) and World Health Organization (WHO) Member States are juxtaposed to information and recommendations from WHO safe abortion guidance, national sexual and reproductive health indicators, and relevant UN human rights bodies' concluding observations to countries., Main Body: The Global Abortion Policies Database aims to increase transparency of information and accountability of states for the protection of individuals' health and human rights. The database presents current information on abortion laws and policies that goes beyond categories of lawful abortion to include information on additional access requirements, service provision, conscientious objection, and penalties. Wide-ranging variations among countries' legal requirements and criminal penalties raise questions about the evidentiary and human rights basis for abortion laws and policies. Source documents found in the database highlight that in many jurisdictions legal and policy guidance is either non-existent, not clear, or conflicting. By juxtaposing a jurisdiction's abortion laws and policies to relevant WHO guidance and by facilitating comparisons of countries' sexual and reproductive health indicators, the database can enable deep policy analysis of states' obligations to meet the health needs and human rights of individuals in the context of abortion. Policy analysis in the context of authoritative guidance on human rights standards can enable health and rights advocates to hold governments accountable for respecting, protecting, and fulfilling individuals' human rights., Conclusion: The GAPD is a comprehensive tool that can be used to strengthen knowledge, inform law and policy research to generate evidence on the impact of laws and policies in practice, and facilitate greater awareness of the many challenges to creating enabling policy environments for safe abortion.

The neurophysiological underpinnings of the nonsocial symptoms of autism spectrum disorder (ASD) which include sensory and perceptual atypicalities remain poorly understood. Well-known accounts of less dominant top-down influences and more dominant bottom-up processes compete to explain these characteristics. These accounts have been recently embedded in the popular framework of predictive coding theory. To differentiate between competing accounts, we studied altered information dynamics in ASD by quantifying predictable information in neural signals. Predictable information in neural signals measures the amount of stored information that is used for the next time step of a neural process. Thus, predictable information limits the (prior) information which might be available for other brain areas, for example, to build predictions for upcoming sensory information. We studied predictable information in neural signals based on resting-state magnetoencephalography (MEG) recordings of 19 ASD patients and 19 neurotypical controls aged between 14 and 27 years. Using whole-brain beamformer source analysis, we found reduced predictable information in ASD patients across the whole brain, but in particular in posterior regions of the default mode network. In these regions, epoch-by-epoch predictable information was positively correlated with source power in the alpha and beta frequency range as well as autocorrelation decay time. Predictable information in precuneus and cerebellum was negatively associated with nonsocial symptom severity, indicating a relevance of the analysis of predictable information for clinical research in ASD. Our findings are compatible with the assumption that use or precision of prior knowledge is reduced in ASD patients., (© 2018 Wiley Periodicals, Inc.)

Impaired facial affect recognition (FAR) is observed in schizophrenia and autism spectrum disorder (ASD) and has been linked to amygdala and fusiform gyrus dysfunction. ASD patient's impairments seem to be more pronounced during implicit rather than explicit FAR, whereas for schizophrenia data are inconsistent. However, there are no studies comparing both patient groups in an identical design. The aim of this three-group study was to identify (i) whether FAR alterations are equally present in both groups, (ii) whether they are present rather during implicit or explicit FAR, (iii) and whether they are conveyed by similar or disorder-specific neural mechanisms. Using fMRI, we investigated neural activation during explicit and implicit negative and neutral FAR in 33 young-adult individuals with ASD, 20 subjects with paranoid-schizophrenia and 25 IQ- and gender-matched controls individuals. Differences in activation patterns between each clinical group and controls, respectively were found exclusively for implicit FAR in amygdala and fusiform gyrus. In addition, the ASD group additionally showed reduced activations in medial prefrontal cortex (PFC), bilateral dorso-lateral PFC, ventro-lateral PFC, posterior-superior temporal sulcus and left temporo-parietal junction. Although subjects with ASD showed more widespread altered activation patterns, a direct comparison between both patient groups did not show disorder-specific deficits in neither patient group. In summary, our findings are consistent with a common neural deficit during implicit negative facial affect recognition in schizophrenia and autism spectrum disorders., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Background: Autism spectrum disorder (ASD) is linked to social brain activity and facial affect recognition (FAR)., Aims: To examine social brain plasticity in ASD., Method: Using FAR tests and functional magnetic resonance imaging tasks for FAR, we compared 32 individuals with ASD and 25 controls. Subsequently, the participants with ASD were assigned to FAR computer-aided cognitive training or a control group., Results: The ASD group performed more poorly than controls on explicit behavioural FAR tests. In the scanner, during implicit FAR, the amygdala, fusiform gyrus and other regions of the social brain were less activated bilaterally. The training group improved on behavioural FAR tests, and cerebral response to implicit affect processing tasks increased bilaterally post-training in the social brain., Conclusions: Individuals with ASD show FAR impairments associated with hypoactivation of the social brain. Computer-based training improves explicit FAR and neuronal responses during implicit FAR, indicating neuroplasticity in the social brain in ASD., (© The Royal College of Psychiatrists, all rights reserved.)

Both schizophrenia (SCZ) and autism spectrum disorder (ASD) are characterized by mentalizing problems and associated neural dysfunction of the social brain. However, the deficits in mental state attribution are somehow opposed: Whereas patients with SCZ tend to over-attribute intentions to agents and physical events ("hyper-intentionality"), patients with autism treat people as devoid of intentions ("hypo-intentionality"). Here we aimed to investigate whether this hypo-hyper-intentionality hypothesis can be supported by neural evidence during a mentalizing task. Using functional magnetic resonance imaging (fMRI), we investigated the neural responses and functional connectivity during reading others intention. Scanning was performed in 23 individuals with ASD, 18 with paranoid SCZ and 23 gender and IQ matched control subjects. Both clinical groups showed reduced brain activation compared to controls for the contrast intentional vs physical information processing in left posterior superior temporal sulcus (pSTS) and ventral medial prefrontal cortex (vMPFC) for SCZ, and right pSTS in ASD. As predicted, these effects were caused in a group specific way: Relative increased activation for physical information processing in SCZ that was also correlated with positive PANNS score and relative decreased activation for intentional information processing in ASD. Additionally, we could demonstrate opposed connectivity patterns between the right pSTS and vMPFC in the clinical groups, ie, increased for SCZ, decreased for ASD. These findings represent opposed neural signatures in key regions of the social brain as predicted by the hyper-hypo-intentionality hypothesis., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Schizophrenia (SZ) and autism spectrum disorder (ASD) share deficits in emotion processing. In order to identify convergent and divergent mechanisms, we investigated facial emotion recognition in SZ, high-functioning ASD (HFASD), and typically developed controls (TD). Different degrees of task difficulty and emotion complexity (face, eyes; basic emotions, complex emotions) were used. Two Benton tests were implemented in order to elicit potentially confounding visuo-perceptual functioning and facial processing. Nineteen participants with paranoid SZ, 22 with HFASD and 20 TD were included, aged between 14 and 33 years. Individuals with SZ were comparable to TD in all obtained emotion recognition measures, but showed reduced basic visuo-perceptual abilities. The HFASD group was impaired in the recognition of basic and complex emotions compared to both, SZ and TD. When facial identity recognition was adjusted for, group differences remained for the recognition of complex emotions only. Our results suggest that there is a SZ subgroup with predominantly paranoid symptoms that does not show problems in face processing and emotion recognition, but visuo-perceptual impairments. They also confirm the notion of a general facial and emotion recognition deficit in HFASD. No shared emotion recognition deficit was found for paranoid SZ and HFASD, emphasizing the differential cognitive underpinnings of both disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.

Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.

Autism spectrum disorder (ASD) is a common developmental disorder characterized by communication difficulties and impaired social interaction. Recent results suggest altered brain dynamics as a potential cause of symptoms in ASD. Here, we aim to describe potential information-processing consequences of these alterations by measuring active information storage (AIS)-a key quantity in the theory of distributed computation in biological networks. AIS is defined as the mutual information between the past state of a process and its next measurement. It measures the amount of stored information that is used for computation of the next time step of a process. AIS is high for rich but predictable dynamics. We recorded magnetoencephalography (MEG) signals in 10 ASD patients and 14 matched control subjects in a visual task. After a beamformer source analysis, 12 task-relevant sources were obtained. For these sources, stationary baseline activity was analyzed using AIS. Our results showed a decrease of AIS values in the hippocampus of ASD patients in comparison with controls, meaning that brain signals in ASD were either less predictable, reduced in their dynamic richness or both. Our study suggests the usefulness of AIS to detect an abnormal type of dynamics in ASD. The observed changes in AIS are compatible with Bayesian theories of reduced use or precision of priors in ASD.

This study broadly examines executive (EF) and visuo-motor function in 30 adolescent and adult individuals with high-functioning autism spectrum disorder (ASD) in comparison to 28 controls matched for age, gender, and IQ. ASD individuals showed impaired spatial working memory, whereas planning, cognitive flexibility, and inhibition were spared. Pure movement execution during visuo-motor information processing also was intact. In contrast, execution time of reading, naming, and of visuo-motor information processing tasks including a choice component was increased in the ASD group. Results of this study are in line with previous studies reporting only minimal EF difficulties in older individuals with ASD when assessed by computerized tasks. The finding of impaired visuo-motor information processing should be accounted for in further neuropsychological studies in ASD.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

A new approach to determining the unit-cell vectors from single-crystal diffraction data based on clustering analysis is proposed. The method uses the density-based clustering algorithm DBSCAN. Unit-cell determination through the clustering procedure is particularly useful for limited tilt sequences and noisy data, and therefore is optimal for single-crystal electron-diffraction automated diffraction tomography (ADT) data. The unit-cell determination of various materials from ADT data as well as single-crystal X-ray data is demonstrated.

Autism spectrum disorders (ASD) have been associated with sensory hypersensitivity. A recent study reported visual acuity (VA) in ASD in the region reported for birds of prey. The validity of the results was subsequently doubted. This study examined VA in 34 individuals with ASD, 16 with schizophrenia (SCH), and 26 typically developing (TYP). Participants with ASD did not show higher VA than those with SCH and TYP. There were no substantial correlations of VA with clinical severity in ASD or SCH. This study could not confirm the eagle-eyed acuity hypothesis of ASD, or find evidence for a connection of VA and clinical phenotypes. Research needs to further address the origins and circumstances associated with altered sensory or perceptual processing in ASD.

The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism., (Copyright © 2011 Wiley-Liss, Inc.)

The objective of this pilot study was to evaluate the effectiveness of a group-based intervention aiming at improving social and communication skills in individuals with autism spectrum disorder. Over a period of 11 months, N = 17 children and adolescents received treatment according to the manualised Frankfurt Social Skills Training (KONTAKT). Parent, teacher, expert and blind expert ratings were assessed to judge outcome regarding peer interaction, autistic behaviours, adaptive functioning and family burden. The participants exhibited improvements pre to follow-up treatment, particularly in the area of autistic symptomatology. Effect sizes (partial eta squared) ranged from 0.02 to 0.69. Among other things, regression models showed a positive influence of IQ and language skills on gains in social skills. Findings indicate that KONTAKT might be useful for enhancing social skills and reducing autism-related psychopathology over time in different contexts. Nevertheless, controlled trials are needed to reassure its effectiveness.

A number of reports have described different Doppler echocardiographic methods to calculate left ventricular stroke volume and cardiac output, but the clinical application of the noninvasive measurements of cardiac function remains in the early stages of development. This slow dissemination may be partly explained by the varying success of these ultrasound methods in determining accurate left ventricular stroke volume. The purpose of this study was to improve the simplicity and accuracy of Doppler stroke volume determination so that it could be more easily applied to patient management. Stroke volume was measured using the product of the integral of aortic velocity obtained by continuous wave Doppler technique and the M-mode tracing of the aortic valve, validating the data against cardiac output obtained by thermodilution technique in 41 patients (r = 0.95, SEE = 7 cc). Intra- and interobserver variability was between 9 and 11%. The results of different sampling sites and the temporal relation between Doppler and thermodilution measurements were also studied. Analysis of 21 patients who had M-mode and two-dimensional echocardiographic studies of the aortic root revealed that the method using M-mode measurement of aortic valve area was most accurate in determining left ventricular stroke volume (r = 0.94, SEE = 10 cc), stroke volume being overestimated when area measurements of the ascending aorta were used. In conclusion, maximal ascending aortic velocity determined by continuous wave Doppler echocardiography with M-mode measurement of aortic valve area can be used to calculate left ventricular stroke volume and cardiac output. The simplicity and practicality of this method should enhance the clinical application of Doppler echocardiography as a noninvasive monitoring technique.

Twenty-seven cold-sensitive mutants of Neurospora crassa were isolated by mutagenesis of wild-type conidia followed by filtration enrichment in complete medium at the nonpermissive temperature (10 C). Zone sedimentation analyses of cytoplasmic ribosomes isolated from the wild-type strain and from 14 of the mutant strains grown at 10 C indicate that one cold-sensitive mutant is defective in ribosome biosynthesis at that temperature: instead of the 2.3:1 mass ratio of 60S:37S ribosomal subunits characteristic of wild type, the mutant strain PJ30201 (called crib-1 for cytoplasmic ribosome biosynthesis) exhibits a mass ratio of approximately 7.2:1. Ribosomal subunits synthesized by strain PJ30201 at 25 C are present in wild-type proportions. The cold-sensitive and ribosomal phenotypes segregate together in tetrads isolated from crosses between strain PJ30201 and the wild type indicating that a single nuclear gene mutation is probably responsible for both mutant phenotypes. The crib-1 locus lies near the centromere in linkage group IV.

Two kynureninase activities are known in Neurospora crassa, one of which (kynureninase I) is inducible, the other (kynureninase II) being constitutive. A method is described for the isolation of low-kynureninase mutants of N. crassa. When grown on an inducer, the mutants show significantly less kynureninase I activity compared with wild type, whereas constitutive kynureninase II activity is unaffected. Since a low level of kynureninase I activity remains in the mutants examined, the mutations may be in a regulatory gene or genes. Other experiments are described concerning the molecular weights of the two enzymes and the intracellular localization and specificity of kynureninase II.