Background
Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of ...neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010.
Objectives
To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain.
Search methods
On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain.
Selection criteria
We selected all randomised or quasi‐randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration.
Main results
We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose‐dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare.
Authors' conclusions
There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.
Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.
Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.
Plasma exchange for Guillain‐Barré syndrome Chevret, Sylvie; Hughes, Richard AC; Annane, Djillali ...
Cochrane database of systematic reviews,
02/2017, Letnik:
2017, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Background
Guillain‐Barré syndrome (GBS) is an acute paralysing disease caused by peripheral nerve inflammation. This is an update of a review first published in 2001 and last updated in 2012.
...Objectives
To assess the effects of plasma exchange for treating GBS.
Search methods
On 18 January 2016 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched clinical trials registries.
Selection criteria
Randomised and quasi‐randomised trials of plasma exchange versus sham exchange or supportive treatment, or comparing different regimens or techniques of plasma exchange.
Data collection and analysis
We followed standard Cochrane methodology.
Main results
In the first version of this review there were six eligible trials concerning 649 participants comparing plasma exchange with supportive treatment. No new eligible trials have been identified in subsequent updates. Two other studies compared different numbers of plasma exchanges. Overall the included trials had a moderate risk of bias (in general, the studies were at low risk but all had a high risk of bias from lack of blinding).
In one trial with 220 severely affected participants, the median time to recover walking with aid was significantly shorter with plasma exchange (30 days) than without plasma exchange (44 days). In another trial with 91 mildly affected participants, the median time to onset of motor recovery was significantly shorter with plasma exchange (six days) than without plasma exchange (10 days). After four weeks, moderate‐quality evidence from the combined data of three trials accounting for a total of 349 patients showed that plasma exchange significantly increased the proportion of patients who recovered the ability to walk with assistance (risk ratio (RR) 1.60, 95% confidence interval (CI) 1.19 to 2.15).
In five trials with 623 participants in total, moderate‐quality evidence showed that the RR for improvement by one or more disability grades after four weeks was 1.64 (95% CI 1.37 to 1.96) times greater with plasma exchange. Participants treated with plasma exchange also fared better, according to moderate‐quality evidence, in time to recover walking without aid (three trials with 349 participants; RR 1.72, 95% CI 1.06 to 2.79) and requirement for artificial ventilation (five trials with 623 participants; RR 0.53, 95% CI 0.39 to 0.74). More participants had relapses by the end of follow‐up in the plasma exchange group than in the control group (six trials with 649 participants; RR 2.89, 95% CI 1.05 to 7.93; moderate‐quality evidence). Despite this, according to moderate‐quality evidence, the likelihood of full muscle strength recovery at one year was greater with plasma exchange than without plasma exchange (five trials with 404 participants; RR 1.24, 95% CI 1.07 to 1.45), and the likelihood of severe motor sequelae was less (six trials with 649 participants; RR 0.65, 95% CI 0.44 to 0.96). High‐quality evidence from six trials with 649 participants could not confirm or refute a lower risk of death following plasma exchange compared to control (RR 0.86, 95% CI 0.45 to 1.65).
Three trials (N = 556) provided details of serious adverse events during the hospital stay; combined analyses found no increase in serious infectious events compared to the control group (RR 0.91, 95% CI 0.73 to 1.13), nor were there clear differences in blood pressure instability, cardiac arrhythmias or pulmonary emboli.
Authors' conclusions
Moderate‐quality evidence shows significantly more improvement with plasma exchange than with supportive care alone in adults with Guillain‐Barré syndrome, without a significant increase in serious adverse events. According to moderate‐quality evidence, there was a small but significant increase in the risk of relapse during the first six to 12 months after onset in people treated with plasma exchange compared with those who were not treated. Despite this, after one year, full recovery of muscle strength was more likely and severe residual weakness less likely with plasma exchange.
Background
Guillain‐Barré syndrome (GBS) is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin (IVIg) is beneficial in other autoimmune diseases. This is an ...update of a review first published in 2001 and previously updated in 2003, 2005, 2007, 2010 and 2012. Other Cochrane systematic reviews have shown that plasma exchange (PE) significantly hastens recovery in GBS compared with supportive treatment alone, and that corticosteroids alone are ineffective.
Objectives
We had the following four objectives.
1. To examine the efficacy of intravenous immunoglobulin (IVIg) in hastening recovery and reducing the long‐term morbidity from Guillain‐Barré syndrome (GBS).
2. To determine the most efficacious dose of IVIg in hastening recovery and reducing the long‐term morbidity from GBS.
3. To compare the efficacy of IVIg and plasma exchange (PE) or immunoabsorption in hastening recovery and reducing the long‐term morbidity from GBS.
4. To compare the efficacy of IVIg added to PE with PE alone in hastening recovery and reducing the long‐term morbidity from GBS.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (2 December 2013), CENTRAL (2013, Issue 12 in The Cochrane Library), MEDLINE (January 1966 to November 2013) and EMBASE (January 1980 to November 2013). We checked the bibliographies in reports of the randomised trials and contacted the authors and other experts in the field to identify additional published or unpublished data.
Selection criteria
Randomised and quasi‐randomised trials of IVIg compared with no treatment, placebo treatment, PE, or other immunomodulatory treatments in children and adults with GBS of all degrees of severity. We also included trials in which IVIg was added to another treatment.
Data collection and analysis
Two authors independently selected papers, extracted data and assessed quality. We collected data about adverse events from the included trials.
Main results
Twelve trials were found to be eligible for inclusion in this review. Seven trials with a variable risk of bias compared IVIg with PE in 623 severely affected participants. In five trials with 536 participants for whom the outcome was available, the mean difference (MD) of change in a seven‐grade disability scale after four weeks was not significantly different between the two treatments: MD of 0.02 of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group; 95% confidence interval (CI) 0.25 to ‐0.20. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that IVIg significantly hastens recovery compared with supportive care. The primary outcome for this review, available for only one trial with 21 mildly affected children, showed significantly more improvement in disability grade after four weeks with IVIg than supportive treatment alone, MD 1.42, 95% CI 2.57 to 0.27.
In one trial involving 249 participants comparing PE followed by IVIg with PE alone, the mean grade improvement was 0.2 (95% CI ‐0.14 to 0.54) more in the combined treatment group than in the PE alone group; not clinically significantly different, but not excluding the possibility of significant extra benefit. Another trial with 34 participants comparing immunoabsorption followed by IVIg with immunoabsorption alone did not reveal significant extra benefit from the combined treatment.
Adverse events were not significantly more frequent with either treatment, but IVIg is significantly much more likely to be completed than PE.
One trial in altogether 51 children showed no significant difference when the standard dose was given over two days rather than five days.
Authors' conclusions
A previous Cochrane review has shown that PE hastens recovery compared with supportive treatment alone. There are no adequate comparisons of IVIg with placebo in adults, but this review provides moderate quality evidence that, in severe disease, IVIg started within two weeks from onset hastens recovery as much as PE. Adverse events were not significantly more frequent with either treatment but IVIg is significantly much more likely to be completed than PE. Also, according to moderate quality evidence, giving IVIg after PE did not confer significant extra benefit. In children, according to low quality evidence, IVIg probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose‐ranging studies are also needed and one is in progress.
Guillain-Barré syndrome Hughes, Richard AC; Cornblath, David R
Lancet,
11/2005, Letnik:
366, Številka:
9497
Journal Article, Book Review
Recenzirano
Guillain-Barré syndrome consists of at least four subtypes of acute peripheral neuropathy. Major advances have been made in understanding the mechanisms of some of the subtypes. The histological ...appearance of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain-Barré syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain-Barré syndrome have had a recent
Campylobacter jejuni infection, and axonal forms of the disease are especially common in these people. The lipo-oligosaccharide from the
C jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles acute motor axonal neuropathy. Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated in acute motor axonal neuropathy and, with the exception of GalNacGD1a, in acute motor and sensory axonal neuropathy. The Fisher's syndrome subtype is especially associated with antibodies to GQ1b, and similar cross-reactivity with ganglioside structures in the wall of
C jejuni has been discovered. Anti-GQ1b antibodies have been shown to damage the motor nerve terminal in vitro by a complement-mediated mechanism. Results of international randomised trials have shown equivalent efficacy of both plasma exchange and intravenous immunoglobulin, but not corticosteroids, in hastening recovery from Guillain-Barré syndrome. Further research is needed to discover treatments to prevent 20% of patients from being left with persistent and significant disability.
Summary Guillain-Barré syndrome (GBS) is an acute, acquired, monophasic autoimmune disorder of peripheral nerves that develops in susceptible individuals after infection and, in rare cases, after ...immunisation. Exposure to influenza via infection or vaccination has been associated with GBS. We review the relation between GBS and these routes of exposure. Epidemiological studies have shown that, except for the 1976 US national immunisation programme against swine-origin influenza A H1N1 subtype A/NJ/76, influenza vaccine has probably not caused GBS or, if it has, rates have been extremely low (less than one case per million vaccine recipients). By contrast, influenza-like illnesses seem to be relevant triggering events for GBS. The concerns about the risk of inducing GBS in mass immunisation programmes against H1N1 2009 do not, therefore, seem justified by the available epidemiological data. However, the experiences from the 1976 swine flu vaccination programme emphasise the importance for active and passive surveillance to monitor vaccine safety.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a progressive or relapsing and remitting paralysing illness probably due to an autoimmune response which should benefit from ...corticosteroids. Non-randomised studies suggest that corticosteroids are beneficial. Two commonly used corticosteroids are prednisone and prednisolone. Both are usually given as oral tablets. Prednisone is converted into prednisolone in the liver so that the effect of the two drugs is usually the same. Another corticosteroid, called dexamethasone, is more potent and is used in smaller doses.
To assess the effects of corticosteroid treatment compared to placebo or no treatment for CIDP and to compare the effects of different corticosteroid regimes.
On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE for randomised trials of corticosteroids for CIDP. We searched three other databases for information to include in the Discussion, and clinical trials registries for ongoing trials.
We included randomised or quasi-randomised trials of treatment with any form of corticosteroids or adrenocorticotrophic hormone for CIDP, diagnosed by an internationally accepted definition.
Two authors extracted the data and assessed risk of bias independently. The primary outcome was intended to be change in disability, with change in impairment after 12 weeks as a secondary outcome, and adverse events.
In one non-blinded randomised controlled trial (RCT) with 35 eligible participants, the primary outcome for this review was not available. The trial had a high risk of bias. Twelve of 19 participants treated with prednisone, compared with five of 16 participants randomised to no treatment, had improved neuropathy impairment scores after 12 weeks; the risk ratio (RR) for improvement was 2.02 (95% confidence interval (CI) 0.90 to 4.52). Adverse events were not reported in detail, but one prednisone-treated participant died.In a double-blind RCT comparing daily standard-dose oral prednisolone with monthly high-dose oral dexamethasone in 40 participants, none of the outcomes for this review were available. The trial had a low risk of bias. There were no significant differences in remission (RR 1.11; 95% CI 0.50 to 2.45 in favour of monthly dexamethasone) or change in disability or impairment after one year. Eight of 16 in the prednisolone, and seven of 24 in the dexamethasone group deteriorated. Adverse events were similar with each regimen, except that sleeplessness and moon facies (moon-shaped appearance of the face) were significantly less common with monthly dexamethasone.Experience from large non-randomised studies suggests that corticosteroids are beneficial, but long-term use causes serious side effects.
Very low quality evidence from one small, randomised trial did not show a statistically significant benefit from oral prednisone compared with no treatment. Nevertheless, corticosteroids are commonly used in practice. According to moderate quality evidence from one RCT, the efficacy of high-dose monthly oral dexamethasone was not statistically different from that of daily standard-dose oral prednisolone. Most adverse events occurred with similar frequencies in both groups, but sleeplessness and moon facies were significantly less common with monthly dexamethasone. Further research is needed to identify factors which predict response.
Plasma exchange for Guillain-Barré syndrome Raphaël, Jean Claude; Chevret, Sylvie; Hughes, Richard A C ...
Cochrane database of systematic reviews,
2012-Jul-11
7
Journal Article
Recenzirano
Guillain-Barré syndrome is an acute paralysing disease caused by peripheral nerve inflammation. This is an update of a review first published in 2001 and last updated in 2008.
To assess the effects ...of plasma exchange for treating Guillain-Barré syndrome.
We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 June 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (January 1966 to June 2011) and EMBASE (January 1980 to June 2011).
Randomised and quasi-randomised trials of plasma exchange versus sham exchange or supportive treatment.
Two review authors agreed the selection of eligible studies and independently assessed the risk of bias in included studies. Data were extracted by one review author and checked by a second review author. Likewise data for adverse events were extracted by one review author and checked by a second review author.
In the first version of this review there were six eligible trials concerning 649 participants comparing plasma exchange with supportive treatment. No new eligible trials have been identified in subsequent updates. Overall the included trials had a low risk of bias.Primary outcomes In one trial with 220 severely affected participants, the median time to recover walking with aid was significantly faster; with plasma exchange (30 days) than without (44 days). In another trial with 91 mildly affected participants, the median time to onset of motor recovery was significantly shorter with plasma exchange (six days) than without (10 days). After four weeks, combined data from three trials accounting for a total of 349 patients showed that plasma exchanged significantly increased the proportion of patients who recovered the ability to walk with assistance (risk ratio (RR) 1.60, 95% confidence interval (CI) 1.19 to 2.15).Secondary outcomes In five trials with 623 participants in total, the RR of being improved by one or more grades after four weeks was 1.64 (95% CI 1.37 to 1.96) in favour of plasma exchange. Participants treated with plasma exchange also fared significantly better in time to recover walking without aid (three trials with 349 participants, RR 1.72 (95% CI 1.06 to 2.79)) and requirement for artificial ventilation (five trials with 623 participants, RR 0.53 (95% CI 0.39 to 0.74)). There were significantly more participants with relapses by the end of follow-up in the plasma exchange than the control group (6 trials with 649 participants, RR 2.89 (95% CI 1.05 to 7.93)). Despite this, at one year the likelihood of full muscle strength recovery was significantly greater with plasma exchange than without (five trials with 404 participants, RR 1.24 (95% CI 1.07 to 1.45)) and the likelihood of severe motor sequelae was significantly less (six trials with 649 patients, RR 0.65 (95% CI 0.44 to 0.96)). There was no significant difference in deaths (six trials with 649 participants, RR 0.86 (95% CI 0.45 to 1.65)) or participants with adverse events (three trials with 556 participants), except fewer arrhythmias in plasma exchange treated participants (RR 0.75 (95% CI 0.56 to 1.00)).
Moderate-quality evidence shows significantly more improvement with plasma exchange than supportive care alone in adults with Guillain-Barré syndrome without a significant increase in serious adverse events. There was a small but significant increase in the risk of relapse during the first six to 12 months after onset in people treated with plasma exchange compared with those that were not treated. Despite this, after one year, full recovery was significantly more likely and severe residual weakness less likely with plasma exchange.
Plant NLRs are modular immune receptors that trigger rapid cell death in response to attempted infection by pathogens. A highly conserved nucleotide-binding domain shared with APAF-1, various ...R-proteins and CED-4 (NB-ARC domain) is proposed to act as a molecular switch, cycling between ADP (repressed) and ATP (active) bound forms. Studies of plant NLR NB-ARC domains have revealed functional similarities to mammalian homologues, and provided insight into potential mechanisms of regulation. However, further advances have been limited by difficulties in obtaining sufficient yields of protein suitable for structural and biochemical techniques. From protein expression screens in Escherichia coli and Sf9 insect cells, we defined suitable conditions to produce the NB-ARC domain from the tomato NLR NRC1. Biophysical analyses of this domain showed it is a folded, soluble protein. Structural studies revealed the NRC1 NB-ARC domain had co-purified with ADP, and confirmed predicted structural similarities between plant NLR NB-ARC domains and their mammalian homologues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
There are two types of diabetes. Type 1 diabetes affects younger people and needs treatment with insulin injections. Type 2 diabetes affects older people and can usually be treated by diet ...and oral drugs. Diabetic neuropathy affects 10% of patients with diabetes mellitus at diagnosis and 40% to 50% after 10 years. Enhanced glucose control is the best studied intervention for the prevention of this disabling condition but there have been no systematic reviews of the evidence.
Objectives
To examine the evidence for enhanced glucose control in the prevention of distal symmetric polyneuropathy in people with type 1 and type 2 diabetes.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (30 January 2012), CENTRAL (2012, Issue 1), MEDLINE (1966 to January 2012) and EMBASE (1980 to January 2012) for randomized controlled trials of enhanced glucose control in diabetes mellitus.
Selection criteria
We included all randomized, controlled studies investigating enhanced glycemic control that reported neuropathy outcomes after at least one year of intervention. Our primary outcome measure was annual development of clinical neuropathy defined by a clinical scale. Secondary outcomes included motor nerve conduction velocity and quantitative vibration testing.
Data collection and analysis
Two authors independently reviewed all titles and s identified by the database searches for inclusion. Two authors ed data from all included studies with a standardized form. A third author mediated conflicts. We analyzed the presence of clinical neuropathy with annualized risk differences (RDs), and conduction velocity and quantitative velocity measurements with mean differences per year.
Main results
This review identified 17 randomized studies that addressed whether enhanced glucose control prevents the development of neuropathy. Seven of these studies were conducted in people with type 1 diabetes, eight in type 2 diabetes, and two in both types. A meta‐analysis of the two studies that reported the primary outcome (incidence of clinical neuropathy) with a total of 1228 participants with type 1 diabetes revealed a significantly reduced risk of developing clinical neuropathy in those with enhanced glucose control, an annualized RD of ‐1.84% (95% confidence interval (CI) ‐1.11 to ‐2.56). In a similar analysis of four studies that reported the primary outcome, involving 6669 participants with type 2 diabetes, the annualized RD of developing clinical neuropathy was ‐0.58% (95% CI 0.01 to ‐1.17). Most secondary outcomes were significantly in favor of intensive treatment in both populations. However, both types of diabetic participants also had a significant increase in severe adverse events including hypoglycemic events.
Authors' conclusions
According to high‐quality evidence, enhanced glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio.
Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can ...therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.