Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

BACKGROUND: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital. METHODS: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program. All patients undergoing elective colorectal surgery following ERP implementation were included. Current procedural terminology (CPT) codes were used to identify patients who underwent similar procedures prior to ERP implementation. RESULTS: Our study included 417 patients (314 pre-ERP vs. 103 ERP), 97.1% of which were male, with an average age of 62.32 (interquartile range (IQR): 25-90). ERP patients overall had a significantly shorter post-operative length of stay (pLOS) vs. pre-ERP patients (median 4 days (IQR: 3-6.5) vs. 6 days (IQR: 4-9) days (p < 0.001)). Within the pre-ERP group, median pLOS for both races was 6 days (IQR: 4-6; p < 0.976) and both groups experienced a decrease in median pLOS (4 vs. 6 days; p < 0.009 and p < 0.001) following ERP implementation. CONCLUSIONS: Racial disparities did not exist in patients undergoing elective surgery at a single VA Medical Center. Implementation of an ERP significantly reduced pLOS for black and white patients.

Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

This corrects the article DOI: 10.1038/leu.2017.177.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.

Patient-specific chondrolabral contact mechanics in patients with acetabular dysplasia following treatment with peri-acetabular osteotomy.

OBJECTIVE: Using a validated, patient-specific finite element (FE) modeling protocol, we evaluated cartilage and labrum (i.e., chondrolabral) mechanics before and after peri-acetabular osteotomy (PAO) to provide insight into the ability of this procedure to improve mechanics in dysplastic hips. DESIGN: Five patients with acetabular dysplasia were recruited in this case-controlled, prospective study. Models, which included anatomy for bone, cartilage, and labrum, were generated from computed tomography (CT) arthrography scans acquired before and after PAO. Cartilage and labrum contact stress and contact area were quantified overall and regionally. Load supported by the labrum, expressed as a percentage of the total hip force, was analyzed. RESULTS: Percent cartilage contact area increased post-operatively overall, medially, and superiorly. Peak acetabular contact stress decreased overall, laterally, anteriorly, and superiorly. Average contact stress decreased overall, laterally, anteriorly, and posteriorly. Only average contact stress on the superior labrum and peak labrum stress overall decreased. Load supported by the labrum did not change significantly. CONCLUSIONS: PAO was efficacious at medializing cartilage contact and reducing cartilage contact stresses, and therefore may minimize deleterious loading to focal cartilage lesions, subchondral cysts, and cartilage delaminations often observed in the lateral acetabulum of dysplastic hips. However, the excessively prominent, hypertrophied labrum of dysplastic hips remains in contact with the femoral head, which continues to load the labrum following PAO. The clinical ramifications of continued labral loading following PAO are not known. However, it is plausible that failure to reduce the load experienced by the labrum could result in end-stage hip OA following PAO.

A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.

Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia.

Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies.

Behaviour and metabolic control in children with Type 1 diabetes mellitus on insulin pump therapy: 2-year follow-up.

AIMS: This study investigated whether continuous subcutaneous insulin infusion is associated with sustained improvement in behaviour and metabolic control. METHODS: Children with Type 1 diabetes mellitus (n = 27, 8-18 years old) who had been assessed previously prior to commencing continuous subcutaneous insulin infusion, and 6-8 weeks later, were re-evaluated 2 years after commencing insulin pump therapy. Behaviour was reassessed using the Behavioral Assessment System for Children-2nd edition (BASC-2) and current HbA(1c) levels were recorded. RESULTS: Two years after commencing continuous subcutaneous insulin infusion, parent-reported internalizing and externalizing symptoms were significantly lower than pre-insulin pump therapy commencement levels. Self reports of internalizing and externalizing problems did not differ significantly across the three assessment points. There was no significant difference between pre-insulin pump therapy HbA(1c) and HbA(1c) after 2 years on continuous subcutaneous insulin infusion, despite an initial improvement 6-8 weeks after commencing the therapy. CONCLUSIONS: Children with Type 1 diabetes mellitus showed sustained improvements in parent-reported behaviour, but not in self reports of behaviour or in metabolic control 2 years after commencement of continuous subcutaneous insulin infusion.

Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications.

The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E-H) to the commonly deleted/duplicated region. To date, 21 index cases with 'distal' 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit 'digenic' model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome.

BACKGROUND: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. METHODS: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. RESULTS: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. CONCLUSIONS: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.

BACKGROUND: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. METHODS AND RESULTS: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). CONCLUSION: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Idiopathic learning disability and genome imbalance.

Learning disability (LD) is a very common, lifelong and disabling condition, affecting about 3% of the population. Despite this, it is only over the past 10-15 years that major progress has been made towards understanding the origins of LD. In particular, genetics driven advances in technology have led to the unequivocal demonstration of the importance of genome imbalance in the aetiology of idiopathic LD (ILD). In this review we provide an overview of these advances, discussing technologies such as multi-telomere FISH and array CGH that have already emerged as well as new approaches that show diagnostic potential for the future. The advances to date have highlighted new considerations such as copy number polymorphisms (CNPs) that can complicate the interpretation of genome imbalance and its relevance to ILD. More importantly though, they have provided a remarkable approximately 15-20% improvement in diagnostic capability as well as facilitating genotype/phenotype correlations and providing new avenues for the identification and understanding of genes involved in neurocognitive function.

Lack of caregivers limits use of outpatient hematopoietic stem cell transplant program.

Our goal was to compare direct and indirect medical costs and quality of life associated with inpatient vs outpatient autologous hematopoietic stem cell transplantation (AuHSCT). Twenty-one sequential outpatients and 26 inpatients were enrolled on this prospective trial. All candidates for AuHSCT were screened for eligibility for outpatient transplantation. Patients with either breast cancer or hematologic malignancy, insurance coverage for the outpatient procedure, one to three caregivers available to provide 24 h coverage, and no significant comorbidities were eligible to participate. Patients without caregivers or insurance coverage for outpatient transplant were accrued to the study in a consecutive manner as inpatient controls, based on willingness to participate in the quality of life portion of the study and to permit review of their hospital and billing records. Approximately half of all 139 prospective outpatient candidates were ineligible because they lacked a caregiver. Most commonly, the patient without a caregiver was single or widowed or their family and friends were needed to provide childcare. Most caregivers were college educated from families with incomes greater than US dollars 80000. Indirect costs to the caregivers totaled a median of US dollars 2520 (range US dollars 684-US dollars 4508), with the majority attributed to lost 'opportunity costs'. Overall, there were significant differences in the total costs of treatment for inpatient vs outpatient AuHSCT (US dollars 40985 vs US dollars 29210, P < 0.01)). In general, no significant differences were detected between inpatient and outpatient scores on quality of life measures. Although significant cost savings were associated with outpatient transplantation, this approach was applicable to only half of our otherwise eligible candidates because of a lack of caregivers. The financial burden associated with the caretaking role may underlie this finding.

Health literacy and shared decision making for prostate cancer patients with low socioeconomic status.

Quality of life (QOL) considerations are important in the treatment decision making process for prostate cancer patients. Although patient involvement in the treatment decision process has been encouraged, low health literacy can limit patient understanding of the complex information about treatments and their probable QOL outcomes and is a barrier to patient participation in the decision-making process. The objectives of the study were to evaluate (i) knowledge, level of satisfaction, and treatment preferences and intentions of men newly diagnosed with prostate cancer after participation in a CD-ROM shared decision making program; and (ii) the relationship between prostate cancer knowledge and health literacy. Thirty newly diagnosed prostate cancer patients from two Veteran's Administration (VA) hospitals in Chicago completed a demographic questionnaire and participated in an interactive CD-ROM shared decision making program. Subsequently, knowledge of prostate cancer, satisfaction with the information in the computer CD-ROM program, treatment preferences, and likelihood of following treatment preferences were assessed using interviewer-administered questionnaires. Health literacy was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). The Pearson correlation test was used to assess the relationship between health literacy and prostate cancer knowledge. The chi2 test and the Fischer exact test were used to evaluate relationships between patient demographics and other variables. More than three-quarters of the patients rated the information in the CD-ROM as "very satisfactory" (highest possible rating). Two-thirds of the patients (21 of 30) selected a treatment after participation in the CD-ROM program and 90.5% of these patients stated that they were very or somewhat likely to adhere to their selection. However, prostate cancer knowledge was variable, with one-third of the patients scoring 69.9% or lower. Participants' health literacy was equivalent to a 7th-8th grade reading level (mean = 57.1+/-10.9), and more than one-third of participants (36.7%) had lower than 9th grade literacy levels. Participants' prostate cancer knowledge was correlated with health literacy (Pearson correlation rhor = 0.65, rhop = 0.0001). Patients were satisfied with the interactive shared decision making CD-ROM program, and two-thirds of patients were able to select a preferred treatment based on the information presented in the program that they intended to follow. However, prostate cancer knowledge scores varied among participants after participation in the CD-ROM program, raising doubts that patients were adequately informed to make appropriate choices regarding their treatment. Lower prostate cancer knowledge scores corresponded to lower literacy scores, indicating that low literacy may have hindered patient understanding of the shared decision making program. The development of shared decision making tools should include collaborative efforts with the target population to improve the success of shared decision making programs among patients with low health literacy.

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist.

BACKGROUND: Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. METHODS: We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. RESULTS: Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. CONCLUSIONS: Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.

Submicroscopic 8pter deletion, mild mental retardation, and behavioral problems caused by a familial t(8;20)(p23;p13).

Microscopically visible distal 8p deletions have been associated with growth and mental impairment, minor facial anomalies, congenital heart defects, and behavioral problems. We report two cousins with mild retardation and behavioral problems, including inappropriate sexual behavior and pyromania. Familial learning difficulties on the grandfather's side incompatible with Mendelian inheritance prompted telomere screening, which detected a submicroscopic terminal 8p deletion of < 5.1 Mb. The cousins' mothers both carried a t(8;20)(p23;p13) balanced translocation. The frequently observed microcephaly in patients with microscopically visible deletions of 8pter is lacking in both cousins, suggesting that the gene(s) causing the microcephaly is centromeric to the deleted region. The absence of cardiac defects in the cousins confirms the more proximal location of gene(s) causing these abnormalities in other reported cases with microscopically visible 8pter deletions and supports involvement of the GATA4 gene. Moreover, the current cases predict the presence of a putative gene(s) involved in behavior in the most telomeric 5.1 Mb of the p-arm of chromosome 8. This first clinical report of a submicroscopic subtelomeric 8p deletion gives more insight into the so-called 8p- syndrome and demonstrates the difficulty in making a clinical diagnosis for a submicroscopic 8pter deletion in an individual patient with mental retardation.

Spouse ratings of quality of life in patients with metastatic prostate cancer of lower socioeconomic status: an assessment of feasibility, reliability, and validity.

OBJECTIVES: To examine the reliability and validity of spousal assessments by evaluating the collateral quality-of-life (QOL) ratings of patients of lower socioeconomic status with metastatic prostate cancer because collateral ratings provide supplemental information when advanced cancer limits patient self-report. METHODS: Patients with Stage D2 prostate cancer (n = 36) of lower socioeconomic status completed validated QOL instruments (Functional Assessment of Cancer Therapy-General [FACT-G], European Organization for Research and Treatment of Cancer-Quality of Life-30, and Quality of Life Index). Spouses completed a modified FACT-G, and physicians rated performance status using Karnofsky's scale. RESULTS: The internal consistency reliability was moderate to high for patient ratings on all FACT-G subscales and for spousal ratings on the modified FACT-G physical, functional, and emotional subscales. The spouses' ratings of the patients on the social and doctor relationship subscales were below the accepted criterion for a measure's use in group comparisons. The comparisons of the mean values of the FACT-G revealed agreement between patients and spouses, except that the spouses rated the patients as having poorer emotional function than did the patients. The intraclass correlations were moderate to high for the functional and emotional subscales and were low, but significant, for the physical and social subscales. The patient and spouse FACT-G ratings correlated with the patient ratings and physician ratings across the instruments for the functional and physical domains (r = 0.48 to 0.77, for patients; r = 0.31 to 0.70, for spouses), with less consistent relationships for the social and emotional domains. CONCLUSIONS: The collateral QOL assessments from spouses are potentially useful in assessing the functional status in patients of lower socioeconomic status with metastatic prostate cancer. For subjective domains, such as the social domain, direct patient assessments are needed.