Association of baseline physical activity participation with participant characteristics and outcomes following education and exercise-therapy in people with knee osteoarthritis: A GLA:D® Australia prospective cohort study.

OBJECTIVES: To investigate whether participants with knee osteoarthritis classified as 'more' or 'less' physically active at baseline differ in characteristics and/or outcomes at baseline and at 3 and 12 months following the commencement of an education and exercise-therapy program. METHODS: Prospective cohort study using the GLA:D® Australia registry. The University of California, Los Angeles Physical Activity Scale (UCLA) participant data dichotomised as 'more' (≥7) or 'less' active (≤6). Groups were compared using chi-square (obesity [baseline only], comorbidity prevalence, medication consumption, fear of damage from physical activity); and linear mixed model regression (12-item Injury Osteoarthritis Outcome Score [KOOS-12], pain [visual analogue scale], health-related quality of life [QoL] [EQ-5D-5L]) statistics, adjusted for age, sex and baseline physical activity at 3 and 12 months. RESULTS: We included 1059 participants (70% female). At baseline, 267 (25%) were classified as 'more' active, increasing to 29% and 30% at 3 and 12 months, respectively. At baseline, compared to the 'less' active group, the 'more' active group had a lower proportion of participants who were obese ('more' = 21% vs. 'less' = 44%), had comorbidities (58% vs. 74%) and consumed medications (71% vs. 85%); lower pain intensity (37 vs. 47); and higher KOOS-12 (59 vs. 50), and health-related QoL (0.738 vs. 0.665) scores. When accounting for age, sex and baseline physical activity, improvements seen in knee-related burden and health-related QoL were not different between groups at 3 or 12 months. Compared to the 'less' active group, the proportion of participants not consuming medication remained higher in the 'more' active group at 3 ('more' 45% vs. 'less' 28%) and 12 months (43% vs. 32%). CONCLUSION: 'More' active people with knee osteoarthritis were less likely to be obese, had fewer comorbidities, lower medication consumption, knee-related burden and pain intensity, and higher health-related QoL than 'less' active participants at all timepoints.

Knowledge, confidence and learning needs of physiotherapists treating persistent knee pain in Australia and Canada: a mixed-methods study.

AIM: To determine the knowledge and confidence of physiotherapists in managing knee osteoarthritis (OA) and patellofemoral pain (PFP); and explore their learning behaviors and preferences related to the management of these knee conditions. METHODS: One hundred and sixteen Australian and Canadian Physiotherapists were recruited via social media, e-mail, and an online course. Part 1: Quantitative involved an online survey evaluating knowledge of evidence and confidence in providing treatments for knee OA and PFP. Part 2: Qualitative involved semi-structured interviews with 13 participants exploring current practice and learning needs, that were analyzed using an initial framework structured on interview questions, followed by inductive approach to identify additional themes. RESULTS: Awareness regarding evidence supporting exercise for knee OA and PFP was good (89-96%), and qualitative themes indicated physiotherapists emphasized exercise-therapy and education. Perceived value of passive treatments and surgery varied. Preference for face-to-face workshops to address learning needs, alongside describing time and cost barriers to access them, emerged from qualitative findings. Online learning formats were viewed as convenient, but not as effective as face-to-face learning. CONCLUSION: Knowledge and confidence related to interventions for knee OA and PFP of Australian and Canadian physiotherapist participants broadly aligns with guidelines. Knowledge translation strategies focused on face-to-face workshops, supported by online education may help to bridge evidence-to-practice gaps.

Knee Osteoarthritis Education Interventions in Published Trials Are Typically Unclear, Not Comprehensive Enough, and Lack Robust Development: Ancillary Analysis of a Systematic Review.

OBJECTIVE: To summarize the content, development, and delivery of education interventions in clinical trials for people with knee osteoarthritis (OA). DESIGN: Ancillary analysis of a systematic review. LITERATURE SEARCH: MEDLINE, EMBASE, SPORTDiscus, CINAHL, and Web of Science were searched from inception to April 2020. STUDY SELECTION CRITERIA: Randomized controlled trials involving patient education for people with knee OA. DATA SYNTHESIS: Content of education interventions was matched against a predefined topic list (n = 14) and categorized as accurate and clear, partially accurate/lacks clarity, or not reported. We examined whether education interventions included skill development or stated learning objectives and if they were developed based on theory, previous research, or codesign principles. Delivery methods and mode(s) were also identified. Data were summarized descriptively. RESULTS: Thirty-eight education interventions (30 trials) were included. Interventions lacked comprehensiveness (median topics per intervention = 3/14, range = 0-11). Few topics were accurately and clearly described (10%, 13/136). Sixty-one percent (n = 23/38) of interventions targeted skill development, and 34% (n = 13/38) identified learning objectives. Forty-two percent (n = 16/38) were based on theory; 45% (n = 17/38) were based on research for chronic conditions, including 32% (n = 12/38) based on OA. Eleven percent of interventions (n = 4/38) were codesigned. Education was typically facilitated through face-to-face sessions (median = 9, range = 0-55), supplemented with telephone calls and/or written materials. CONCLUSION: Education interventions for people with knee OA lacked comprehensiveness plus accurate and clear descriptions of topics covered. Most interventions failed to identify learning objectives and were not based on theory, previous research, or codesign principles. J Orthop Sports Phys Ther 2022;52(5):276-286. Epub 14 Dec 2021. doi:10.2519/jospt.2022.10771.

The Validity, Reliability, and Responsiveness of the International Hip Outcome Tool-33 (iHOT-33) in Patients With Hip and Groin Pain Treated Without Surgery.

BACKGROUND: The International Hip Outcome Tool-33 (iHOT-33) was developed to evaluate patients seeking surgery for hip and/or groin (hip/groin) pain and may not be appropriate for those seeking nonsurgical treatment. PURPOSE: To evaluate the psychometric properties of the iHOT-33 total (iHOT-Total) score and all subscale scores in adults with hip/groin pain who were not seeking surgery. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Patients with hip/groin pain who were not seeking surgery were recruited from 2 ongoing studies in Australia. Semistructured one-on-one interviews assessed content validity. Construct validity was assessed by testing hypothesized correlations between iHOT-33 and Copenhagen Hip and Groin Outcome Score (HAGOS) subscale scores. Test-retest reliability was assessed in patients not undertaking treatment and who reported "no change" in their Global Rating of Change (GROC) score at 6-month follow-up. Scores were reliable at group and individual levels if intraclass correlation coefficients (ICCs) were ≥0.80 and ≥0.90, respectively. Scores were responsive if Spearman rank correlations (ρ) between the change in the iHOT-33 score and the GROC score were ≥0.40. RESULTS: In total, 278 patients with hip/groin pain (93 women; mean age, 31 years) and 55 pain-free control participants (14 women; mean age, 29 years) were recruited. The iHOT-33 demonstrated acceptable content validity. Construct validity was acceptable, with all hypothesized strong positive correlations between iHOT-33 and HAGOS subscale scores confirmed (r range, 0.60-0.76; P < .001), except for one correlation between the iHOT-Sport and HAGOS-Sport (r = .058; P < .001). All scores were reliable at the group level, except for the iHOT-33 job subscale (iHOT-Job) (ICC range, 0.78-0.88 [95% CI, 0.60-0.93]). None of the subscales met the criteria for adequate reliability for use at the individual level (all ICCs <0.90). Minimal detectable change values (group level) ranged from 2.3 to 3.7 (95% CI, 1.7-5.0). All iHOT-33 subscale scores were responsive (ρ range, 0.40-0.58; P≤ .001), except for the iHOT-Job in patients not undertaking treatment (ρ = 0.27; P = .001). CONCLUSION: All iHOT-33 subscale scores were valid for use in patients with hip/groin pain who were not seeking surgery. Acceptable test-retest reliability was found for all subscale scores at the group level, except the iHOT-Job. All subscale scores, excluding the iHOT-Job, were responsive, regardless of undertaking physical therapist-led treatment or no treatment.

Patient education improves pain and function in people with knee osteoarthritis with better effects when combined with exercise therapy: a systematic review.

QUESTION: Is patient education effective as a standalone intervention or combined with other interventions for people with knee osteoarthritis? DESIGN: Systematic review of randomised controlled trials. MEDLINE, EMBASE, SPORTDiscus, CINAHL and Web of Science were searched from inception to April 2020. The Cochrane Risk of Bias tool was used for included studies, and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to interpret certainty of results. PARTICIPANTS: People with knee osteoarthritis. INTERVENTION: Any patient education intervention compared with any non-pharmacological comparator. OUTCOME MEASURES: Primary outcomes were self-reported pain and function. RESULTS: Twenty-nine trials involving 4,107 participants were included, informing low to very-low certainty evidence. Nineteen of 28 (68%) pooled comparisons were not statistically significant. Patient education was superior to usual care for pain (SMD -0.35, 95% CI -0.56 to -0.14) and function in the short term (-0.31, 95% CI -0.62 to 0.00), but inferior to exercise therapy for pain in the short term (0.77, 95% CI 0.07 to 1.47). Combining patient education with exercise therapy produced superior outcomes compared with patient education alone for pain in the short term (0.44, 95% CI 0.19 to 0.69) and function in the short (0.81, 95% CI 0.54 to 1.08) and medium term (0.39, 95% CI 0.15 to 0.62). When using the Western Ontario and McMaster Universities Osteoarthritis Index for these comparisons, clinically important differences indicated that patient education was inferior to exercise therapy for pain in the short term (MD 1.56, 95% CI 0.14 to 2.98) and the combination of patient education and exercise therapy for function in the short term (8.94, 95% CI 6.05 to 11.82). CONCLUSION: Although patient education produced statistically superior short-term pain and function outcomes compared with usual care, differences were small and may not be clinically important. Patient education should not be provided as a standalone treatment and should be combined with exercise therapy to provide statistically superior and clinically important short-term improvements in function compared with education alone. REGISTRATION: PROSPERO CRD42019122004.

Oxygen therapy for interstitial lung disease: a systematic review.

This review aims to establish the impact of oxygen therapy on dyspnoea, health-related quality of life (HRQoL), exercise capacity and mortality in interstitial lung disease (ILD).We included studies that compared oxygen therapy to no oxygen therapy in adults with ILD. No limitations were placed on study design or intervention type. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. The primary outcome was dyspnoea.Eight studies evaluated the acute effects of oxygen (n=1509). There was no effect of oxygen therapy on modified Borg dyspnoea score at end exercise (mean difference (MD) -0.06 units, 95% CI -0.24-0.13; two studies, n=27). However, effects on exercise outcomes consistently favoured oxygen therapy. One study showed reduction in dyspnoea at rest with oxygen in patients who were acutely unwell (MD visual analogue scale 30 mm versus 48 mm, p<0.05; n=10). Four studies of long-term oxygen therapy (n=2670) had high risk of bias and no inferences could be drawn.This systematic review showed no effects of oxygen therapy on dyspnoea during exercise in ILD, although exercise capacity was increased. Future trials should evaluate whether acute improvements in exercise capacity with oxygen can be translated into improved physical activity and HRQoL.

Dyspnoea and comorbidity contribute to anxiety and depression in interstitial lung disease.

BACKGROUND AND OBJECTIVES: Little is known about the prevalence of anxiety in interstitial lung disease (ILD), and the contributors to depression are not clear. The aim of this study was to determine the prevalence and predictors of anxiety and depression in people with ILD. METHODS: One hundred and twenty-four individuals with ILD (age 64 years (standard deviation 12), 48 idiopathic pulmonary fibrosis) participated. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale to determine likely cases and borderline cases. Associations with demographic data, respiratory function, 6-min walk and Modified Medical Research Council Dyspnoea Scale (MMRC) were examined. RESULTS: The prevalence of anxiety was 31%, with clinically significant anxiety in 12%. Depression was present in 23% of individuals, with 7% having clinically significant depression. Independent predictors of anxiety were a higher MMRC score (P = 0.005, odds ratio (OR) for case 2.60, 95% confidence interval 1.37 to 4.92) and higher nadir SpO2 during walking (P = 0.003, OR for case 1.16, 1.04-1.30). Independent predictors of depression were a higher MMRC score (P = 0.006, case OR 3.84, 1.25-11.78, borderline case OR 2.44, 1.14-5.19) and a greater number of comorbidities (P = 0.003, case OR 2.02, 0.97-4.21, borderline case OR 2.26, 1.30-3.93). CONCLUSIONS: Anxiety and depression are present in a significant minority of individuals with ILD. Dyspnoea and comorbidities are important contributors that may be amenable to intervention.

Males and females differ in brain activation during cognitive tasks.

To examine the effect of gender on regional brain activity, we utilized functional magnetic resonance imaging (fMRI) during a motor task and three cognitive tasks; a word generation task, a spatial attention task, and a working memory task in healthy male (n = 23) and female (n = 10) volunteers. Functional data were examined for group differences both in the number of pixels activated, and the blood-oxygen-level-dependent (BOLD) magnitude during each task. Males had a significantly greater mean activation than females in the working memory task with a greater number of pixels being activated in the right superior parietal gyrus and right inferior occipital gyrus, and a greater BOLD magnitude occurring in the left inferior parietal lobe. However, despite these fMRI changes, there were no significant differences between males and females on cognitive performance of the task. In contrast, in the spatial attention task, men performed better at this task than women, but there were no significant functional differences between the two groups. In the word generation task, there were no external measures of performance, but in the functional measurements, males had a significantly greater mean activation than females, where males had a significantly greater BOLD signal magnitude in the left and right dorsolateral prefrontal cortex, the right inferior parietal lobe, and the cingulate. In neither of the motor tasks (right or left hand) did males and females perform differently. Our fMRI findings during the motor tasks were a greater mean BOLD signal magnitude in males in the right hand motor task, compared to females where males had an increased BOLD signal magnitude in the right inferior parietal gyrus and in the left inferior frontal gyrus. In conclusion, these results demonstrate differential patterns of activation in males and females during a variety of cognitive tasks, even though performance in these tasks may not vary, and also that variability in performance may not be reflected in differences in brain activation. These results suggest that in functional imaging studies in clinical populations it may be sensible to examine each sex independently until this effect is more fully understood.

Differential effects of chronic lithium and valproate on brain activation in healthy volunteers.

RATIONALE: Previous functional imaging studies have shown altered brain activity during cognitive task performance in bipolar patients. However, the fact that these patients are often on medication makes it unclear to what extent these changes reflect treatment effects. OBJECTIVES: This study aims to identify regional brain activity changes occurring following lithium and valproate treatment in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9), or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after 14 days of treatment with valproate, lithium or placebo. The changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after treatment were compared between the groups using a one-way ANOVA for each task followed by a post-hoc multiple comparisons correction. RESULTS: A significant group effect was noted in the change in BOLD signal magnitude from baseline to post-treatment, in all three tasks (working memory p< 0.000; spatial attention task p = 0.003; word generation paradigm p = 0.030). In the working memory task, the lithium group had a significant decrease in BOLD signal change, compared with the control group (p< 0.000). A decrease in BOLD signal change was also noted in the valproate group, in the spatial attention task (p = 0.004). Both lithium and valproate groups had a decreased BOLD signal in the verbal task, following treatment, compared with the placebo group (p = 0.061 (lithium approached significance); p = 0.050 (valproate)). CONCLUSIONS: These findings suggest that lithium and valproate have independent effects on brain activation that vary in a task and region-dependent manner.

Lithium alters brain activation in bipolar disorder in a task- and state-dependent manner: an fMRI study.

BACKGROUND: It is unknown if medications used to treat bipolar disorder have effects on brain activation, and whether or not any such changes are mood-independent. METHODS: Patients with bipolar disorder who were depressed (n = 5) or euthymic (n = 5) were examined using fMRI before, and 14 days after, being started on lithium (as monotherapy in 6 of these patients). Patients were examined using a word generation task and verbal memory task, both of which have been shown to be sensitive to change in previous fMRI studies. Differences in blood oxygenated level dependent (BOLD) magnitude between the pre- and post-lithium results were determined in previously defined regions of interest. Severity of mood was determined by the Hamilton Depression Scale for Depression (HAM-D) and the Young mania rating scale (YMRS). RESULTS: The mean HAM-D score at baseline in the depressed group was 15.4 +/- 0.7, and after 2 weeks of lithium it was 11.0 +/- 2.6. In the euthymic group it was 7.6 +/- 1.4 and 3.2 +/- 1.3 respectively. At baseline mean BOLD signal magnitude in the regions of interest for the euthymic and depressed patients were similar in both the word generation task (1.56 +/- 0.10 and 1.49 +/- 0.10 respectively) and working memory task (1.02 +/- 0.04 and 1.12 +/- 0.06 respectively). However, after lithium the mean BOLD signal decreased significantly in the euthymic group in the word generation task only (1.56 +/- 0.10 to 1.00 +/- 0.07, p < 0.001). Post-hoc analysis showed that these differences were statistically significant in Broca's area, the left pre-central gyrus, and the supplemental motor area. CONCLUSION: This is the first study to examine the effects of lithium on brain activation in bipolar patients. The results suggest that lithium has an effect on euthymic patients very similar to that seen in healthy volunteers. The same effects are not seen in depressed bipolar patients, although it is uncertain if this lack of change is linked to the lack of major improvements in mood in this group of patients. In conclusion, this study suggests that lithium may have effects on brain activation that are task- and state-dependent. Given the small study size and the mildness of the patient's depression these results require replication.

Valproate attenuates dextroamphetamine-induced subjective changes more than lithium.

Dextroamphetamine administration in healthy controls produces a range of subjective and physiological effects, which have been likened to those occurring during mania. However, it is uncertain if these can be attenuated by lithium since conflicting results have been reported. To date there have been no previous studies examining the effects of valproate on dextroamphetamine-induced mood and physiological changes. The current study was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n=12), 900 mg lithium (n=9), or placebo (n=12) pre-treatment for 14 days. Subjective and physiological measures were then obtained prior to administration of a 25 mg dose of dextroamphetamine, and at two time points after administration. Differences in the response to dextroamphetamine were assessed between the three treatment groups. The results of this study show that pre-treatment with lithium only significantly attenuated dextroamphetamine-induced change in happiness, while valproate pre-treatment significantly attenuated the effects of dextroamphetamine on happiness, energy, alertness and on the diastolic blood pressure. These results suggest that lithium and valproate do not have the same mechanism of action on dextroamphetamine-induced changes, and this finding may relate to differences in their mechanism of action in mood disorders.

Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation.

BACKGROUND: Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. RESULTS: In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. CONCLUSIONS: These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.

Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: a functional magnetic resonance imaging study of blood oxygen level-dependent response.

BACKGROUND: Dextroamphetamine is known to have profound effects on both subjective and physiologic measurements, but it is unclear to what extent these behavioral changes are a direct result of altered regional brain activation. One method to measure this is to use functional magnetic resonance imaging (fMRI). METHODS: In the present study, fMRI was used to measure both the spatial extent of changes (the number of pixels activated) and the magnitude of the blood oxygen level-dependent (BOLD) response. We examined the effects of motor, verbal, memory, and spatial attention task during fMRI in 18 healthy volunteers. Functional MRI measurements were obtained at baseline and again 75 min after an oral dose of 25 mg dextroamphetamine. RESULTS: Dextroamphetamine caused a decrease in the number of activated pixels and the magnitude of the BOLD response during the three cognitive tasks tested but not during the motor task. These changes were region and task specific. CONCLUSIONS: This is the first study to examine the effect of dextroamphetamine on the number of activated pixels and the BOLD response during the performance of a range of cognitive and motor tasks. Our results suggest that dextroamphetamine causes measurable decreases in brain activity in a variety of regions during cognitive tasks. These changes might be linked to behavioral changes observed after dextroamphetamine administration and could possibly be mediated by alterations in dopaminergic activation.

Response to flumazenil in the late luteal phase and follicular phase of the menstrual cycle in healthy control females.

RATIONALE: Animal studies of short-term progesterone administration and withdrawal model the natural increase and abrupt decrease in progesterone levels which occur in the late luteal phase (LP) of the human menstrual cycle (MC). Previously, studies in animals have shown that abrupt cessation of chronic or short-term progesterone administration results in pharmacological changes at the GABAA receptor, resulting in altered sensitivity to GABAA receptor neuromodulators such as benzodiazepines and flumazenil, a GABAA receptor antagonist. OBJECTIVES: This study's goal was to compare the response to flumazenil in the follicular phase (FP) and late LP in female healthy controls (HCs). We postulated that HC females would exhibit a greater psychological and somatic response to flumazenil in the late LP, a period of progesterone withdrawal, compared to the FP. METHODS: Twelve healthy females, without history of psychiatric disorder, were randomized to receive two injections of a 2 mg bolus injection of flumazenil (one in the late LP and one in the FP) and two injections of placebo (one in the late LP and one in the FP). Following injection, subjects were asked to rate the occurrence and intensity of panic symptoms on the panic symptom scale (PSS). RESULTS: A main treatment effect was detected for the PSS score response after flumazenil injection (P=0.008). However, there was no significant treatment-by-phase interaction observed (P=0.449). CONCLUSIONS: These findings indicate that MC phase did not affect the response to flumazenil in HC females. This result is contrary to our hypothesis of altered sensitivity to flumazenil in the late LP.

Neurobiological findings in bipolar II disorder compared with findings in bipolar I disorder.

OBJECTIVE: To determine whether there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II). METHOD: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C. RESULTS: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent. CONCLUSIONS: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.