Incidental cardiac uptake of 99mTc-diphosphonates is predictive of poor outcome: data from 9616 bone scintigraphies.

BACKGROUND: Bone scintigraphy (BS) is highly diagnostic for amyloid transthyretin (ATTR) cardiomyopathy. Prevalence and prognostic value of BS cardiac uptake is not well established. Our aim was to assess the prevalence of subclinical cardiac ATTR amyloidosis in patients undergoing [99mTc]MDP/DPD scintigraphy and to define their phenotype and prognosis. METHODS AND RESULTS: BS scans performed for any clinical indications from 2009 to 2020 were reviewed. Patients were stratified according to Perugini visual score of cardiac uptake. Follow-up data were collected. Among 9616 BS scans, 0.7% (n = 67) showed cardiac uptake. In 47 (70%) patients, Perugini score was 1 and in 20 (30%) patients uptake was ≥ 2, suggesting cardiac ATTR amyloidosis. Forty subjects (61%) died during the follow-up (mean 47 ± 30 months). Compared with patients with Perugini score 1, those Perugini score ≥ 2 showed increased death rate (P = .018). Two (2/67) subjects were investigated for TTR gene mutations resulting negative. CONCLUSIONS: In patients undergoing BS for different clinical indications, cardiac uptake suggesting cardiac ATTR amyloidosis is a rare, but still neglected finding, thus preventing possible diagnosis of ATTR cardiomyopathy. Importantly, cardiac uptake negatively affects the survival. Physicians should be aware of this rare, but crucial finding for timely diagnosis and treatment.

Comparative efficacy and acceptability of psychological interventions for the treatment of adult outpatients with anorexia nervosa: a systematic review and network meta-analysis.

BACKGROUND: No consistent first-option psychological interventions for adult outpatients with anorexia nervosa emerges from guidelines. We aimed to compare stand-alone psychological interventions for adult outpatients with anorexia nervosa with a specific focus on body-mass index, eating disorder symptoms, and all-cause dropout rate. METHODS: In this systematic review and network meta-analysis, we assessed randomised controlled trials about stand-alone pharmacological or non-pharmacological treatments of adult outpatients with anorexia nervosa, defined according to standardised criteria, with data for at least two timepoints relating to either body-mass index or global eating disorder psychopathology. We searched Cochrane CENTRAL, CINAHL, MEDLINE, and PsychINFO for published and unpublished literature from inception until March 20, 2020. The primary outcomes were the change in body mass index and clinical symptoms, and the secondary outcome was all-cause dropout rate, which were all assessed for treatment as usual, cognitive behavioural therapy (CBT), Maudsley anorexia treatment for adults, family-based treatment, psychodynamic-oriented psychotherapies, a form of CBT targeting compulsive exercise, and cognitive remediation therapy followed by CBT. Global and local inconsistencies for the network meta-analysis were measured, and CINeMA was used to assess the confidence in evidence for primary outcomes. The protocol is registered in PROSPERO (CRD42017064429). FINDINGS: Of 14 003 studies assessed for their title and abstract, 16 (0·1%) randomised controlled trials for psychological treatments were included in the systematic review, of which 13 (0·1%) contributed to the network meta-analysis, with 1047 patients in total (of whom 1020 [97·4%] were female). None of the interventions outperformed treatment as usual in our primary outcomes, but the all-cause dropout rate was lower for CBT than for psychodynamic-oriented psychotherapies (OR 0·54, 95% CI 0·31-0·93). Heterogeneity or inconsistency emerged only for a few comparisons. Confidence in the evidence was low to very low. INTERPRETATION: Compared with treatment as usual, specific psychological treatments for adult outpatients with anorexia nervosa can be associated with modest improvements in terms of clinical course and quality of life, but no reliable evidence supports clear superiority or inferiority of the specific treatments that are recommended by clinical guidelines internationally. Our analysis is based on the best data from existing clinical studies, but these findings should not be seen as definitive or universally applicable. There is an urgent need to fund new research to develop and improve therapies for adults with anorexia nervosa. Meanwhile, to better understand the effects of available treatments, participant-level data should be made freely accessible to researchers to eventually identify whether specific subgroups of patients are more likely to respond to specific treatments. FUNDING: Flinders University, National Institute for Health Research Oxford Health Biomedical Research Centre.

Maximizing the use of social and behavioural information from secondary care mental health electronic health records.

PURPOSE: The contribution of social and behavioural factors in the development of mental health conditions and treatment effectiveness is widely supported, yet there are weak population level data sources on social and behavioural determinants of mental health. Enriching these data gaps will be crucial to accelerating precision medicine. Some have suggested the broader use of electronic health records (EHR) as a source of non-clinical determinants, although social and behavioural information are not systematically collected metrics in EHRs, internationally. OBJECTIVE: In this commentary, we highlight the nature and quality of key available structured and unstructured social and behavioural data using a case example of value counts from secondary mental health data available in the UK from the UK Clinical Record Interactive Search (CRIS) database; highlight the methodological challenges in the use of such data; and possible solutions and opportunities involving the use of natural language processing (NLP) of unstructured EHR text. CONCLUSIONS: Most structured non-clinical data fields within secondary care mental health EHR data have too much missing data for adequate use. The utility of other non-clinical fields reported semi-consistently (e.g., ethnicity and marital status) is entirely dependent on treating them appropriately in analyses, quantifying the many reasons behind missingness in consideration of selection biases. Advancements in NLP offer new opportunities in the exploitation of unstructured text from secondary care EHR data particularly given that clinical notes and attachments are available in large volumes of patients and are more routinely completed by clinicians. Tackling ways to re-use, harmonize, and improve our existing and future secondary care mental health data, leveraging advanced analytics such as NLP is worth the effort in an attempt to fill the data gap on social and behavioural contributors to mental health conditions and will be necessary to fulfill all of the domains needed to inform personalized interventions.

No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.

BACKGROUND: In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side-effects permit provides additional benefits is unknown. METHODS: We did a systematic review of placebo-controlled randomized trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included drop-outs due to adverse effects and drop-outs for any reason. We conducted random-effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. RESULTS: We included 123 published and unpublished randomized controlled trials (29 420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95% CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75 and 150 mg over the fixed 75 mg (1.30, 1.02 to 1.65). CONCLUSION: There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.

IL-22Ra1 is induced during influenza infection by direct and indirect TLR3 induction of STAT1.

BACKGROUND: Influenza attacks the epithelium of the lung, causing cell death and disruption of the epithelial barrier leading to fluid buildup in the lung and impairment of gas exchange. Limited treatment options for severe influenza pneumonia prioritize the need for the discovery of effective therapies. IL-22 is a cytokine that promotes tissue integrity and has strong promise as a treatment option. While research has been focused on the cytokine itself, there is limited understanding of the regulation of the IL-22 receptor (IL-22Ra1) at the epithelial surface during infection. METHODS: IL-22Ra1 levels were measured by qRT-PCR, western blot and immunofluorescence following H1N1 influenza infection (A/PR/8/34 H1N1) or synthetic TLR3 mimetic, Poly (I:C). Regulation of the receptor was determined using STAT inhibitors (STAT1, STAT3 and PanSTAT inhibitors), TLR3 inhibition, and neutralization of interferon alpha receptor 2 (IFNAR2). Significance was determined by a p-value of greater than 0.05. Significance between two groups was measured using unpaired t-test and significance between more than two groups was measured using one-way ANOVA with Tukey Multiple Comparison Test. RESULTS: Here we show both in vivo and in vitro that IL-22Ra1 was induced as early as 24 h after influenza (H1N1 PR8) infection. This induction was triggered by toll-like receptor 3 (TLR3) as a TLR3 mimetic [Poly (I:C)] also induced IL-22Ra1 and inhibition of endosomal formation required for TLR3 function inhibited this process. This upregulation was dependent upon IFNß signaling through STAT1. Importantly, induction of IL-22Ra1 significantly increased IL-22 signaling as evidenced by pSTAT3 levels following IL-22 treatment. CONCLUSION: Collectively, these data suggest epithelial cells may optimize the beneficial effects of IL-22 through the induction of the IL-22 receptor during viral infection in the lung.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).

BACKGROUND: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review.

BACKGROUND: Epidemiological, clinical, and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence. Moreover, clinically significant manic symptoms may occur even earlier, especially in children at familial risk. Lithium is the gold standard treatment for acute mania in adults, yet to our knowledge, there is no published systematic review assessing lithium treatment of mania in children or adolescents. This is a major gap in knowledge needed to inform clinical practice. AIM: As a working group within the ISBD Task Force on Lithium Treatment ( http://www.isbd.org/active-task-forces ), our aim is to complete a systematic review of the efficacy, tolerability, and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder. METHODS: We will include double- or single-blind randomized controlled trials in patients aged less than 18 years. No restrictions will be made by study publication date or language. Several electronic databases will be searched along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies. Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome. Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts, respectively. Secondary outcomes will include rates of remission, severity of manic symptoms at different time points, and incidence of specific adverse events. DISCUSSION: Findings from this systematic review are critically needed to inform clinical practice. We should not generalize findings from adult studies, as children and adolescents are undergoing accelerated physiological and brain development. Therefore, efficacy, tolerability, and acceptability of lithium treatment of acute mania in children compared to adults may be very different. This systematic review has been registered in PROSPERO (CRD42017055675).

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Clinical and regulatory implications of active run-in phases in long-term studies for bipolar disorder.

OBJECTIVE: The integration of new treatments into the market and routine clinical practice should be dependent on robustness of evidence from randomised controlled trials (RCTs). We assessed study designs of long-term studies for bipolar disorder of all second-generation antipsychotics (SGAs) submitted to the Food and Drug Administration (FDA) and the completeness of evidence submitted to the regulatory agency. METHOD: Systematic review of double-blind RCTs comparing SGAs with placebo or active drugs in adults. FDA website and electronic databases were searched until July 2013. RESULTS: Six placebo-controlled trials comparing aripiprazole, olanzapine, quetiapine and ziprasidone were found in the FDA website. Electronic searches found four additional RCTs about aripiprazole, olanzapine or quetiapine. All RCTs (either submitted to FDA or not) selected patients who responded to acute treatment to increase the treatment effect observed in the long-term phase (enrichment design). By contrast, in the prescribing information sheets for all SGAs, the reported indication was 'maintenance treatment of bipolar disorder'. CONCLUSION: Extrapolation of results from enrichment studies to the more general population of patients should be carried out cautiously because average treatment benefits are likely to be less in unselected patients. Clear guidance for regulatory submission of RCTs is needed.

Benzodiazepines and risk of dementia: true association or reverse causation?

According to a recently published population study conducted in France, exposure to benzodiazepines may be associated with an approximately 50% increase in the risk of dementia in the elderly. However, the clinical interpretation of this finding raised some concerns. A causal link between benzodiazepine use and diagnosis of dementia may be real, but it is nevertheless possible that the increased risk might be due to other confounding factors. In this article, the main strengths and weaknesses of this study are briefly analysed, including the possibility of reverse causation. Implications for research and current practice are discussed.

What is a factorial trial?

Randomized controlled trials (RCTs), typically, randomize participants to one of two intervention groups. It has been shown, however, that about 25% of RCTs published in the scientific literature randomize participants to three or more treatment groups. These studies are called 'multi-arm' trials: there may be, for instance, two or more experimental intervention groups with a common control group, or two control intervention groups such as a placebo group and a standard treatment group. A special case of multi-arm studies are factorial trials, which address two or more intervention comparisons carried out simultaneously, using four or more intervention groups.

Planning deep inferior epigastric perforator flaps for breast reconstruction: a comparison between multidetector computed tomography and magnetic resonance angiography.

OBJECTIVES: Deep inferior epigastric perforator (DIEP) flaps have become the state of the art in breast reconstruction. We compared the diagnostic performance of multidetector computed tomography (CTA) and magnetic resonance angiography (MRA) in DIEP flap planning. METHODS: Twenty-three women (mean age 48.0 years, range 26-72 years) underwent preoperative blinded evaluation using 64-slice CTA and 1.5-T MRA. Perforator identification, measurement of their calibre, intramuscular course (IMC), assessment of direct venous connections (DVC) with main superficial veins, superficial venous communications (SVC) between the right and left hemi-abdomen and deep inferior epigastric artery (DIEA) branching type were performed. Surgery was carried out by the same team. Intraoperative findings were the standard of reference. RESULTS: Accuracy in identifying dominant perforators was 91.3 % for both techniques and mean error in calibre measurement 1.18 ± 0.35 mm for CTA and 1.63 ± 0.39 mm for MRA. Accuracy in assessing perforator IMCs was 97.1 % for CTA and 88.4 % for MRA, DVC 94.4 % for both techniques, SVC 91.3 % as well, and DIEA branching type 100 % for CTA and 91.3 % for MRA. Image acquisition and interpretation time was 21 ± 3 min for CTA (35 ± 5 min for MRA). CONCLUSIONS: In a strategy to optimise DIEP flap planning avoiding radiation exposure, MRA can be proposed alternatively to CTA. KEY POINTS: • Identification of deep inferior epigastric perforators (DIEP) is important before breast reconstruction. • Both CT and MR angiography are accurate in identifying DIEA perforator branches. • CTA and MRA are equivalent in demonstrating perforator-venous connections. • MRA can be proposed as an alternative to CTA in DIEP planning.

Use of antipsychotic drugs and mood stabilizers in women of childbearing age with schizophrenia and bipolar disorder: epidemiological survey.

Aims. To determine the prevalence of women of childbearing age with schizophrenia and bipolar disorder exposed to antipsychotic (AP) drugs and mood stabilizers (MS) in Lombardy, a European region of 10 million inhabitants and 1 752 285 women of childbearing age. Methods. The data concerning psychiatric care, drug treatments and pregnancy outcomes were retrieved from local administrative databases during a 12-month census period. Results. During a 12-month census period, 2893 women of childbearing age with schizophrenia (74.8% of all women of childbearing age with schizophrenia) and 918 with bipolar disorder (80.1% of all women of childbearing age with bipolar disorder) were exposed to AP drugs or MS, yielding a prevalence of exposure for women with schizophrenia of 1.65 (95% confidence interval (CI) 1.59-1.71) per 1000 female inhabitants, and for women with bipolar disorder of 0.52 (95% CI 0.49-0.55) per 1000 female inhabitants. Persistent exposure to potentially teratogenic medications accounted for one in every 1000 women of childbearing age. Of the 57 pregnancies in women with schizophrenia, normal delivery was recorded in 23 (40%) cases; of the 26 pregnancies in women with bipolar disorder, normal delivery was recorded in 10 (38%) cases. Conclusions. In women of childbearing age with severe mental disorders, exposure to psychotropic drugs is substantial, which suggests that the issue of reproductive health is epidemiologically relevant and a major public health concern.

Reversible myoclonus in a patient undergoing transcervical hysteroscopic surgery.

We describe a 58-year-old woman who underwent hysteroscopic myomectomy to treat a large submucosal leiomyoma. A hypotonic glycine solution was instilled to distend the uterus. At one hour after the distending medium infusion started for hysteroscopic resection an electrolytic imbalance developed. One hour later myoclonus developed predominantly involving the bilateral sternocleidomastoidei and abdominal muscles. The patient was alert and cooperative; jerks were spontaneous and triggered by sensory stimuli. The electroencephalographic and brain computed tomography was normal. The clinical characteristics of her myoclonus resemble reticular reflex myoclonus, a form of subcortical myoclonus originating from the lower brainstem reticular formation. Given her severe hyponatremia we conjecture that she had symptomatic metabolic myoclonus caused by electrolytic disturbance. The case report we present underlines the need to detect in time and promptly treat neurological symptoms such as myoclonus suggesting resorption syndrome, an uncommon event complicating transcervical hysteroscopic surgery and urologic procedures.

Radiological findings in mammary autologous fat injections: a multi-technique evaluation.

AIM: To describe the radiological appearance of normal and pathological findings resulting from mammary autologous fat injections (lipofilling). MATERIALS AND METHODS: Informed consent and institutional review board approval were obtained. From January 2008 to December 2010, all patients that had undergone breast lipofilling at our institution (Catholic University) were consecutively enrolled. The site and amount of autologous fat injections were known. Mammography, ultrasonography, and magnetic resonance imaging (MRI) were prospectively obtained preoperatively, and 6 and 12 months after the procedure. Normal and pathological findings were described. RESULTS: Twenty-four patients (mean age 50.8 ± 10.5 years; range 26-70 years) were included. Fourteen patients underwent lipofilling after mastectomy, eight after wide local excision, one as a treatment for a congenital asymmetry, and one as a treatment for Poland syndrome. No severe complications were observed after treatment. Normal findings due to lipofilling ("oil cysts") were identified in 23 cases using ultrasound and in 16 using MRI. Liponecrosis, the most frequently observed complication, was detected in four cases using ultrasound and in eight by MRI. In one case mammography showed calcific fat necrosis. Mean amount of fat injected was 114.8 ± 55 ml. The average amount of fat grafted in patients who developed liponecrosis was 158.4 ± 42.7 versus 104.6 ± 52.3 ml (p = 0.0043, t-test). In one case breast cancer recurrence was diagnosed. CONCLUSION: Normal findings due to lipofilling are better identified by ultrasound, and pathological findings are best identified using MRI. Liponecrosis most frequently occurs when large amounts of fat are injected. In the authors' experience lipofilling does not interfere with breast cancer early diagnosis.

What is a multiple treatments meta-analysis?

Standard meta-analyses are an effective tool in evidence-based medicine, but one of their main drawbacks is that they can compare only two alternative treatments at a time. Moreover, if no trials exist which directly compare two interventions, it is not possible to estimate their relative efficacy. Multiple treatments meta-analyses use a meta-analytical technique that allows the incorporation of evidence from both direct and indirect comparisons from a network of trials of different interventions to estimate summary treatment effects as comprehensively and precisely as possible.