Short- and long-term haemodynamic consequences of transcatheter closure of atrial septal defect and patent foramen ovale.

BACKGROUND: Transcatheter atrial septal defect (ASD) and patent foramen ovale (PFO) closure might have opposite short- and long-term haemodynamic consequences compared with restricted interatrial shunt creation, which recently emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF). Given the opposing approaches of ASD and PFO closure versus shunt creation, we investigated the early and sustained cardiac structural and functional changes following transcatheter ASD or PFO closure. METHODS: In this retrospective study, adult secundum-type ASD and PFO patients with complete echocardiography examinations at baseline and at 1­day and 1­year follow-up who also underwent transcatheter closure between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands were included. RESULTS: Thirty-nine patients (mean age 48 ± standard deviation 16 years, 61.5% women) were included. Transcatheter ASD/PFO closure resulted in an early and persistent decrease in right ventricular systolic and diastolic function. Additionally, transcatheter ASD/PFO closure resulted in an early and sustained favourable response of left ventricular (LV) systolic function, but also in deterioration of LV diastolic function with an increase in LV filling pressure (LVFP), as assessed by echocardiography. Age (ß = 0.31, p = 0.009) and atrial fibrillation (AF; ß = 0.24, p = 0.03) were associated with a sustained increase in LVFP after transcatheter ASD/PFO closure estimated by mean E/e' ratio (i.e. ratio of mitral peak velocity of early filling to diastolic mitral annular velocity). In subgroup analysis, this was similar for ASD and PFO closure. CONCLUSION: Older patients and patients with AF were predisposed to sustained increases in left-sided filling pressures resembling HFpEF following ASD or PFO closure. Consequently, these findings support the current concept that creating a restricted interatrial shunt might be beneficial, particularly in elderly HFpEF patients with AF.

Case series of children with steroid-Induced glaucoma.

Steroid-induced glaucoma is the most serious complication of the injudicious use of steroids, particularly among children affected by allergic conjunctivitis. This condition is steroid-dependent, and children are commonly being prescribed topical anti-inflammatories, including topical steroids, by general practitioners. Furthermore, topical steroids are also available over the counter, and this availability contributes to overuse without proper monitoring by an ophthalmologist. We present a series of five cases illustrating the devastating effect of unmonitored, long-term use of steroids among children for vernal keratoconjunctivitis. The medications were prescribed initially by general ophthalmologists and were continually bought over the counter by parents. At the presentation to our center, these patients were already compromised visually, exhibiting glaucomatous optic disc changes and high intraocular pressure. The series highlights the optic nerve damage resulting in irreversible visual compromises among children on long-term, topical steroids and the importance of regular monitoring with a low threshold for ophthalmologist referral.

Heart failure with preserved ejection fraction in women: the Dutch Queen of Hearts program.

Heart failure (HF) poses a heavy burden on patients, their families and society. The syndrome of HF comes in two types: with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The latter is on the increase and predominantly present in women, especially the older ones. There is an urgent need for mortality-reducing drugs in HFpEF, a disease affecting around 5 % of those aged 65 years and over. HFpEF develops in patients with risk factors and comorbidities such as obesity, hypertension, diabetes, COPD, but also preeclampsia. These conditions are likely to drive microvascular disease with involvement of the coronary microvasculature, which may eventually evolve into HFpEF. Currently, the diagnosis of HFPEF relies mainly on echocardiography. There are no biomarkers that can help diagnose female microvascular disease or facilitate the diagnosis of (early stages of) HFpEF. Recently a Dutch consortium was initiated, Queen of Hearts, with support from the Netherlands Heart Foundation, with the aim to discover and validate biomarkers for diastolic dysfunction and HFpEF in women. These biomarkers come from innovative blood-derived sources such as extracellular vesicles and circulating cells. Within the Queen of Hearts consortium, we will pursue female biomarkers that have the potential for further evolution in assays with point of care capabilities. As a spin-off, the consortium will gain knowledge on gender-specific pathology of HFpEF, possibly opening up novel treatment options.

Plasma extracellular vesicle protein content for diagnosis and prognosis of global cardiovascular disease.

Cardiovascular disease is a major public health problem worldwide. Its growing burden is particularly ominous in Asia, due to increasing rates of major risk factors such as diabetes, obesity and smoking. There is an urgent need for early identification and treatment of individuals at risk of adverse cardiovascular events. Plasma extracellular vesicle proteins are novel biomarkers that have been shown to be useful in the diagnosis, risk stratification and prognostication of patients with cardiovascular disease. Ongoing parallel biobank initiatives in European (the Netherlands) and Asian (Singapore) populations offer a unique opportunity to validate these biomarkers in diverse ethnic groups.

Diastolic heart failure: What we still don't know. Looking for new concepts, diagnostic approaches, and the role of comorbidities.

Heart failure with preserved ejection fraction (HFPEF) is responsible for half the disease burden of heart failure worldwide, yet there is still much we do not know about this syndrome. Its pathophysiology is classically attributed to diastolic dysfunction (thus "diastolic heart failure"), but accumulating evidence suggests that heterogeneous mechanisms contribute to HFPEF, including systolic abnormalities. Importantly, there remains no proven therapy for HFPEF. To date, clinical trials of neurohormonal blockade have failed to improve outcomes in HFPEF, despite their proven benefits in heart failure with reduced ejection fraction (HFREF). Therefore, it is still an urgent need to better understand the pathophysiology of HFPEF and identify new therapeutic targets. Such potential targets include the myocyte protein titin, intracellular calcium regulation, as well as modulation of the extracellular matrix. We also need to understand why the previous large trials have failed in HFPEF. Are we studying the right patients? How do we best diagnose this syndrome? Are we assessing the appropriate outcomes? Causes of mortality and morbidity differ between HFPEF and HFREF, and the high burden of comorbidities in HFPEF may contribute to noncardiovascular outcomes. Newer therapeutic approaches should be developed with these considerations in mind. In conclusion, HFPEF is still an enigma. New pathophysiological concepts, improved diagnostic strategies, and a better understanding of patient factors are needed to generate new therapeutic options in the future.

High rate of increased carotid intima-media thickness and atherosclerotic plaques in Chinese asymptomatic subjects with central obesity.

Both central obesity and increased carotid intima-media thickness (IMT) are markers of atherosclerosis and associated with cardiovascular diseases (CVD). Information of IMT in Chinese subjects with central obesity is limited. This study was performed to assess the rate of atherosclerosis and abnormal IMT in asymptomatic Chinese subjects with central obesity, and to investigate the association between IMT values and CVD risk factors including hypertension, hyperglycaemia and dyslipidaemia. We studied 122 centrally obese adults who had good past health. IMT measurements on carotid arteries were performed and fasting blood taken for plasma glucose and lipid profiles. Abnormal IMT was defined as > 0.9 mm. Atherosclerosis was defined as the presence of one or more visible plague. Of the 122 subjects, the mean (±SD) age was 59.4 ± 5.8 years (median [range]: 59.0 [45-75] years). The median IMT value was 0.70 mm (range: 0.53-1.19 mm) [men vs. women: 0.74 mm vs. 0.66 mm, P-value: < 0.001]. IMT values and the rate of atherosclerosis increased with age and the number of CVD risk factors (P-value for trend: < 0.05). Using binary logistic regression to predict the presence of atherosclerosis with the presence of abnormal IMT, age, gender, and other CVD risk factors as independent variables, age (OR [95% CI] = 1.13 [1.03, 1.23], P = 0.009) and abnormal IMT (OR [95% CI] = 4.05 [1.09, 15.03], P = 0.037) were independently associated with atherosclerosis. In conclusion, among Hong Kong Chinese asymptomatic subjects with central obesity, there was a high rate of CVD risk factors. We found that 19% of these subjects had carotid atherosclerotic plaques and 10% of them had abnormal IMT (>0.9 mm). Carotid IMT study may serve as an appropriate screening tool to diagnose atherosclerosis in the centrally obese middle-aged population.

Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus.

OBJECTIVES: To study the link between metabolic syndrome (MetS), endothelial injury, and atherosclerosis in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive SLE patients without a history of arterial thrombosis were screened for atherosclerosis at the carotid and coronary arteries by B-mode ultrasound [intima-media thickness (IMT)] and multidetector computed tomography (MDCT) scan (Agatston calcium scores), respectively. Plasma levels of homocysteine, high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule (sVCAM)-1, P-selectin, and soluble thrombomodulin (sTM) were assayed. Patients were stratified according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria for MetS, using the Asian criteria for abdominal obesity. Risk factors for atherosclerosis were studied. RESULTS: Of the 123 SLE patients (93% women; age 47.9+/-11 years; SLE duration 10.9+/-7.0 years) studied, 20 (16.3%) had MetS. The prevalence of MetS in the SLE patients was significantly higher than in 492 age- and sex-matched healthy controls (9.6%; p=0.03). Coronary calcification and abnormal carotid IMT were detected in 38 (31%) and 72 (59%) of SLE patients, respectively. Patients with MetS had a significantly higher Agatston score (69.5+/-95 vs. 16.4+/-57; p=0.03) and a numerically higher carotid IMT (p=0.43) than those without. In a logistic regression model, the MetS [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.01-9.59, p=0.049] was associated with coronary atherosclerosis after adjustment for age and other risk factors. In addition, patients with MetS had significantly higher levels of hsCRP (p=0.002), homocysteine (p=0.03), and sTM (p=0.01). CONCLUSIONS: The MetS is more prevalent in SLE patients than the general population and is associated with endothelial injury and coronary atherosclerosis. More aggressive control of risk factors is justified in these patients.

Rovibronically selected and resolved two-color laser photoionization and photoelectron study of the iron carbide cation.

By using a two-color laser excitation-photoionization scheme, we have obtained rovibronically selected and resolved state-to-state pulsed field ionization-photoelectron (PFI-PE) bands for FeC+(X2delta5/2; v+=0-2, J+), allowing unambiguous rotational assignments for the photoionization transitions. The finding of the J+ = 5/2 level as the lowest rotational state confirms that the ground FeC+ ion state is of 2delta5/2 symmetry. The observed changes in total angular momentum upon photoionization of FeC are |deltaJ+| = |J+ - J'|

Determining horizontal symmetry from neutrino mixing.

We argue that the best way to determine horizontal symmetry is from neutrino mixing and proceed to show that the only finite group capable of yielding the tribimaximal mixing for all Yukawa couplings is S4, or any group containing it. The method used is largely group theoretical, but it can be implemented by dynamical schemes in which the Higgs expectation values introduced to break S4 spontaneously are uniquely determined up to an unknown scale for each.

The effect of a job placement and support program for workers with musculoskeletal injuries: a randomized control trial (RCT) study.

BACKGROUND: This is a randomized clinical trial (RCT) to investigate the efficacy of a job placement and support program designed for workers with musculoskeletal injuries and having difficulties in resuming the work role. The program was planned to help injured workers to successfully return to work (RTW) by overcoming the difficulties and problems during the process of job seeking and sustaining a job using a case management approach. METHODOLOGY: A total of 66 injured workers were recruited and randomly assigned into the job placement and support group (PS group) or the self-placement group (SP group). A three-week job placement and support program was given to subjects in the PS group while subjects in the control group (SP group) were only given advice on job placement at a workers' health center. The PS program was comprised of an individual interview, vocational counseling, job preparation training, and assisted placement using the case management approach. The Chinese Lam Assessment of Stages of Employment Readiness (C-LASER), the Chinese State Trait and Anxiety Inventory (C-STAI), and the SF-36 were the outcome measures for the two groups before and after the training program to observe the changes in subjects' work readiness status, emotional status and their health related quality of life pre- and post-training program. The rate of return to work was measured for both groups of subjects after the training program. RESULTS: The results indicated that the rate of success in RTW (73%) was significantly higher in the job placement (PS) group than that of the self-placement (SP) group (51.6%) with P < 0.05. Significant differences were also found in C-STAI (P < 0.05), SF-36 (P < 0.05) and C-LASER scores on action (P < 0.05) between the two groups. CONCLUSION: The job placement (PS) program appeared to have enhanced the employability of injured workers. Workers who participated in the program also showed higher levels of work readiness and emotional status in coping with their work injuries.

Rovibrationally selected and resolved pulsed field ionization-photoelectron study of propyne: ionization energy and spin-orbit interaction in propyne cation.

By using a high-resolution infrared (IR) laser to prepare propyne (C(3)H(4)) in selected rotational levels of the excited nu(1) (acetylenic C-H stretching) vibration mode prior to vacuum ultraviolet (VUV) laser pulsed field ionization-photoelectron (PFI-PE) measurements, we have obtained rotationally resolved VUV-PFI-PE spectra for the C(3)H(4) (+)(X (2)E(32,12),nu(1) (+)=1) band. The analysis of these PFI-PE spectra leads to the determination of the spin-orbit constant of A=-13.0+/-0.2 cm(-1) for the C(3)H(4) (+)(X (2)E(32,12),nu(1) (+)=1) state. Using this A constant and the relative rotationally selected and resolved state-to-state photoionization cross sections thus measured, we have obtained an excellent simulation for the VUV-PFI-PE origin band of C(3)H(4) (+)(X (2)E(32,12)), yielding a value of 83 619.0+/-1.0 cm(-1) (10.367 44+/-0.000 12 eV) for the adiabatic ionization energy of C(3)H(4) [IE(C(3)H(4))]. The present two-color IR-VUV-PFI-PE study has also made possible the determination of the C-H stretching frequencies nu(1) (+)=3217.1+/-0.2 cm(-1) for C(3)H(4) (+)(X (2)E(32,12)). The spectral assignment and simulation were guided by high-level ab initio calculations on the IE(C(3)H(4)), Franck-Condon factors for photoionization transitions, and rotational constants and vibrational frequencies for C(3)H(4) (+).

An unusual case of both upper and lower gastrointestinal bleeding in a kidney transplant recipient.

BACKGROUND: Tuberculosis (TB) is an uncommon opportunistic infection in immunocompromised patients. Extrapulmonary infection involving the intestine is rare and poses diagnostic difficulties. CASE REPORT: A 49-year-old man with IgA nephropathy underwent a kidney transplantation in 1996 and was put on cyclosporine, azathioprine, and steroid. He suffered from a recurrence of his primary kidney disease and had a gradual deterioration of renal function since 1998. By 2005, he presented with an unusual gastrointestinal (GI) symptom with alternating signs of upper GI bleeding - melena - as well as lower GI bleeding with fresh rectal bleeding, resulting in severe anemia with hemoglobin level down to 5.0 g/dL. At the same time, his renal function further deteriorated and necessitated the initiation of dialysis while he was maintained on low-dose immunosuppressive drugs. Repeated upper and lower GI endoscopies were either unremarkable or revealed non-specific lesions. Symptoms persisted and exploratory laparotomy finally showed a 1 cm submucosal mass at the proximal jejunum and multiple inflammatory lesions at the terminal ileum. Segmental resection of the lesions was performed and confirmed TB infection. However, despite the initiation of anti-tuberculous treatment, the patient eventually died of complications. CONCLUSION: Diagnosing TB intestinal infection is a clinical challenge. A high index of suspicion in susceptible subjects is necessary, and early surgical intervention should always be considered when facing diagnostic uncertainties.

Psychosocial aspects of injured workers' returning to work (RTW) in Hong Kong.

INTRODUCTION: This study was designed to explore the psychosocial aspects of injured workers, their self-perceived capacity and how these factors influence their success in Return To Work (RTW). METHOD: Seventy-five subjects were recruited from the Hong Kong Workers' Health Centre and were assessed on three occasions consisting of interviews and four self-rated instruments including the Chinese Lam's Assessment of Employment Readiness (C-LASER), the SF-36 health survey, the Chinese State Trait and the Anxiety Inventory (C-STAI). RESULTS: Results showed that the contemplation and pre-contemplation sub-scores of C-LASER appeared to be the determining factors in predicting subjects' return-to-work status. Subjects who were more "ready for action" (the Actioners) were found to have significantly higher confidence and advocacy in job seeking than the Pre-Contemplators. Their employment readiness was shown to be affected by psychosocial factors such as perceived functioning and bodily pain, DISCUSSION: From this study, the injured workers' employment readiness appeared to associate with their RTW outcomes. Further studies would be needed to find out how the employment readiness of injured workers could be enhanced.

A 6-month follow-up of the effects of an information and communication technology (ICT) training programme on people with intellectual disabilities.

We investigated the long-term effects of an information and communication technology (ICT) training programme for people with intellectual disabilities (ID). A community-based ICT training programme was designed to enhance the computer skills of people with ID and prepare them to make use of ICT in their daily life. Of the 100 who had participated in the original ICT training programme, 59 of them and their caregivers agreed to participate in the follow-up interview. A computer skills checklist was used to assess the ICT competence of the participants before training, after training, and at the 6-month follow-up assessment. All caregivers were interviewed at the 6-month follow-up session to explore the use of ICT by people with ID and their needs for further training. Results from repeated measures ANOVA showed that participants maintained at the 6-month follow-up the basic ICT skills that they acquired during training [F=13.86, p<0.001]. Caregivers reported that participants spent more time in using the computers, but still needed occasional guidance. They also reported a need to advance their ICT skills beyond the basic computer training. We concluded that ICT training for people with ID would help them in maximizing the benefits of information technology via computers.

Very long-chain acyl-CoA dehydrogenase deficiency presenting as acute hypercapnic respiratory failure.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) is a key enzyme catalysing the dehydrogenation of long-chain fatty acids in mitochondrial beta-oxidation. VLCAD deficiency is a genetic disorder that commonly presents in infancy or childhood with episodes of hypoketotic hypoglycaemia, cardiomyopathy and liver dysfunction. The present study reports an 18-yr-old Chinese female who presented with acute hypercapnic respiratory failure and rhabdomyolysis after a period of prolonged fasting and exertion. VLCAD deficiency was confirmed with decreased VLCAD activity in cultured fibroblasts. The patient completely recovered with supportive care. Pulmonary function tests after the acute episode showed evidence of chronic subclinical respiratory muscle weakness. In conclusion, this rare metabolic disorder should be considered in patients presenting with unexplained acute respiratory paralysis and failure.

The effect of a "training on work readiness" program for workers with musculoskeletal injuries: a randomized control trial (RCT) study.

BACKGROUND: This is a clinical randomized trail (RCT) to investigate the effects of a three-week training program on work readiness designed for musculoskeletal injured workers with long-term sick leave who had difficulties resuming their work role. The program was planned to help injured workers overcome the psychological and psychosocial problems and to facilitate their Work Readiness on Return to Work (RTW) based on the Employment readiness model. METHODOLOGY: A total of 64 injured workers were recruited and randomly assigned into the training (T) and control (C) groups. Observations were blinded between service providers and evaluators. A three-week intensive training on work readiness program was given to the T group while subjects in the C group were given advice on job placement by social workers in a community work health center. The training program was comprised of individual vocational counseling and group therapy using cognitive behavioral approach to alleviate symptoms of stress, pain and anxiety. The Chinese Lam Assessment of Stages of Employment Readiness (C-LASER), the Chinese State Trait and Anxiety Inventory (C-STAI) and the Short form of Health Survey (SF-36) were used to evaluate all subjects' psychological health status and behavioral changes on job readiness before and after the intervention. RESULTS: Subjects in the T group showed significant improvement in their work readiness (p < 0.05), level of anxiety (p < 0.05) and their self perception of health status measured by SF-36 (p < 0.02) when compared with subjects in the C group. Control of chronic pain, negative motivation, and anxiety level were some of the key behavioral changes found from the study. CONCLUSION: The TWR program appeared to improve injured workers' motivation and employment readiness. Further study on the employment outcomes of subjects is recommended.

Disseminated strongyloidiasis: a retrospective study of clinical course and outcome.

A retrospective study was carried out to evaluate the clinical course and outcome of disseminated strongyloidiasis treated in a regional hospital in Hong Kong over a 10-year period. Seven cases were identified, and the case history of each patient was analysed. The most common presenting symptom was fever (100%). Five (71%) patients had gastrointestinal symptoms, the most common being abdominal pain and diarrhoea. Three (42%) patients had a significant drop in haemoglobin. Six (85%) patients had bronchoalveolar infiltrates on chest radiographs. Most patients were immunosuppressed by means of steroid treatment for their underlying primary disease. One patient was diabetic, and another had lymphoma and was receiving chemotherapy. Strongyloides larvae were identified in stool specimens in two patients, in sputum smears in two patients, and in gastric biopsies in three patients. Five (71%) of the patients with lung involvement progressed to respiratory failure and died. Two (29%) cases were complicated by gram-negative bacterial infection. No patient had eosinophilia on presentation. All patients received antihelminthic treatment of variable duration. The case fatality rate in the cohort was 71% despite aggressive supportive therapy. Pulmonary and bowel symptoms were prominent in our series. In conclusion, the diagnosis of disseminated strongyloidiasis is often delayed because of nonspecific presenting symptoms. Early diagnosis relies on a high index of clinical suspicion, especially in immunocompromised hosts. Screening for Strongyloides infection before the initiation of immunosuppressive therapy should be considered, especially in endemic areas.

Distribution of cannabinoid receptor 1 in the CNS of zebrafish.

The cannabinoid receptor 1 (Cb1) mediates the psychoactive effect of marijuana. In mammals, there is abundant evidence advocating the importance of cannabinoid signaling; activation of Cb1 exerts diverse functions, chiefly by its ability to modulate neurotransmission. Thus, much attention has been devoted to understand its role in health and disease and to evaluate its therapeutic potential. Here, we have cloned zebrafish cb1 and investigated its expression in developing and adult zebrafish brain. Sequence analysis showed that there is a high degree of conservation, especially in residues demonstrated to be critical for function in mammals. In situ hybridization revealed that zebrafish cb1 appears first in the preoptic area at 24 hours post-fertilization. Subsequently, transcripts are detected in the dorsal telencephalon, hypothalamus, pretectum and torus longitudinalis. A similar pattern of expression is recapitulated in the adult brain. While cb1 is intensively stained in the medial zone of the dorsal telencephalon, expression elsewhere is weak by comparison. In particular, localization of cb1 in the telencephalic periventricular matrix is suggestive of the involvement of Cb1 in neurogenesis, bearing strong resemblance in terms of expression and function to the proliferative mammalian hippocampal formation. In addition, a gradient-like expression of cb1 is detected in the torus longitudinalis, a teleost specific neural tissue. In relation to dopaminergic neurons in the diencephalic posterior tuberculum (considered to be the teleostean homologue of the mammalian midbrain dopaminergic system), both cb1 and tyrosine hydroxylase-expressing cells occupy non-overlapping domains. However there is evidence that they are co-localized in the caudal zone of the hypothalamus, implying a direct modulation of dopamine release in this particular region. Collectively, our data indicate the propensity of zebrafish cb1 to participate in multiple neurological processes.

Inter-relationships between DNA damage, ascorbic acid and glycaemic control in Type 2 diabetes mellitus.

AIMS: The onset of complications in Type 2 diabetes mellitus (DM) patients cannot be predicted in individuals. Evidence suggests a link between complications and hyperglycaemia, oxidative stress and antioxidants, but causality is unclear. This study investigated baseline (entry) fasting plasma ascorbic acid, lymphocytic DNA damage and glycaemic control in Type 2 DM as part of a long-term study, the aim of which is to explore a biomarker profiling approach to identify and improve outcome in high-risk subjects. METHODS: A cross-sectional study, in which DNA damage, glycated haemoglobin (HbA(1c)), fasting plasma glucose (FPG) and ascorbic acid (AA) were measured on fasting blood samples collected from 427 Type 2 DM subjects. RESULTS: DNA damage was significantly (P < 0.0001) and directly correlated to both FPG (r = 0.540) and HbA(1c) (r = 0.282), and was significantly (P < 0.0001), independently and inversely correlated to plasma AA (r = -0.449). In those subjects with both poor glycaemic control and low AA (< 48 microm, the overall mean value for the study group), DNA damage was significantly (P < 0.005) higher compared with those subjects with a similar degree of hyperglycaemia but with AA above the mean. CONCLUSIONS: The novel finding of a significant inverse relationship between plasma AA and DNA damage in Type 2 DM indicates that poorly controlled diabetic subjects might benefit from increased dietary vitamin C. The data also have important implications for biomarker profiling to identify those subjects who might benefit most from intensive therapy. Longer-term follow-up is underway.