Impact of contractures on daily functioning in adolescents with spinal muscular atrophy: a qualitative study.

PURPOSE: Exploring the impact of contractures in adolescents and young adults (AYA) with spinal muscular atrophy (SMA) on daily functioning and participation and the impact of received contracture management. METHODS: We included 14, non-ambulant AYA with SMA types 2/3 (10 females and 4 males), aged 16-30 years. Interviews focused on two topics: perceived impact of contractures on daily functioning and of previous contracture management. We used inductive thematic analysis for interview analysis. RESULTS: In general, participants experienced muscle weakness to be more of a hindrance than contractures; they had adapted to their contractures over time. Participants considered contracture treatment useful when goals were meaningful and realistic. Participants mentioned that their perspective on contracture management would change in light of a promise of improved motor function due to disease-modifying treatment. CONCLUSION: Despite the relatively low impact of contractures in comparison to the loss of muscle strength, non-ambulant AYA with SMA should be informed on the potential impact of contractures and benefits and potential adverse effects of their management. This information can support the shared decision-making process. While respecting individual choices, allows for incorporating interventions into daily life and the promotion of daily functioning and participation when children with SMA are growing up.

The variability of the perceived impact of contractures in non-ambulant adolescents and young adults with spinal muscular atrophy (SMA) underscores the need for individualized assessment and contracture management based on discussions about challenges, benefits and burden.In the treatment plan for contracture management in SMA it is important to take into account: 1) that adolescents often experienced physiotherapy as additional comfort, with less feeling of stiffness, and 2) that most perceived orthosis and standers as unnecessary and burdensome as contracture management.Clinicians should consider postural management in an early stage given the improved prognosis on motor development of children with SMA.Clinicians should monitor and revisit treatment goals, benefits and adverse effects on a regular basis as part of the shared goal-setting and decision-making in contracture management for children with SMA.

Bulbar Problems Self-Reported by Children and Adults with Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is hereditary motor neuron disorder, characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by the homozygous loss of function of the survival motor neuron (SMN) 1 gene. SMA shows a wide variability of disease severity. OBJECTIVE: To investigate self-reported bulbar problems in patients with SMA, and their relationship to age, functional motor scores and active maximum mouth opening. METHODS: We used the Diagnostic List of Dysphagia and Dysarthria in (pediatric) patients and relevant recent clinical data from the national SMA database. RESULTS: The 118 included patients with SMA frequently reported jaw problems (34%), fatigue associated with mastication (44%), choking (56%) and intelligibility problems (27%). Jaw, mastication and swallowing problems frequently occurred in combination with each other. There was an increase of reported bulbar problems in patients with SMA type 3a, older than 30 years of age, compared to younger patients of this SMA type.The Hammersmith Functional Motor Scale Expanded scores showed a negligible correlation with jaw and mastication problems, a low negative correlation with swallowing problems and a moderate negative correlation with intelligibility problems. Reduced mouth opening showed a significant, but low correlation with bulbar complaints in patients with SMA type 2. CONCLUSIONS: Fatigue associated with mastication and swallowing problems were frequently reported complaints. Patients 30 years and older with milder forms of SMA showed an increase of self-reported bulbar problems.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patient's opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4.

BACKGROUND AND PURPOSE: Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene-augmenting therapies. METHODS: We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type. RESULTS: We included 180 patients with SMA types 1-4 in the age range 1-77.5 years with median disease duration of 18 (range 0-65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross-sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously. CONCLUSIONS: Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages.

Using routine Haemophilia Joint Health Score for international comparisons of haemophilia outcome: standardization is needed.

INTRODUCTION: Haemophilia Joint Health Score (HJHS) is the most sensitive validated score for physical examination of joint health in haemophilia. HJHS performed at regular intervals can be used for clinical monitoring as well as for comparative outcomes research. AIM: To determine whether routinely collected HJHS could be used to compare outcome of three different prophylactic regimens in children with severe haemophilia A (primary) and which parameters caused variability in HJHS (secondary). METHODS: International retrospective observational multi-centre study comparing routine HJHS in 127 children with severe haemophilia A born from 1995 to 2009, from London, Stockholm and Utrecht centres. Patient and treatment data were collected from the European Paediatric Network for Haemophilia Management registry and patient files. The independent effects of regimens, physiotherapists, age and inhibitor status on HJHS were explored, using multivariable regression analysis. RESULTS: Prophylaxis varied across participating centres, with differences in initial frequency of infusions (1× per week vs. 3× per week), age at reaching infusions ≥3× per week, and dose kg(-1) week(-1) at HJHS assessment. Evaluation at median age of 11 years showed an illogical association of HJHS with treatment regimen: the least intensive regimen had the lowest HJHS. The HJHS increased with age and history of inhibitor, as expected (internal validity). But the comparison of prophylactic regimens was obscured by systematic differences in assessment between physiotherapists, both within and between centres. CONCLUSION: Inter-physiotherapist discrepancies in routine HJHS hamper comparison of scores between treatment regimens. For multi-centre research, additional inter-observer standardization for HJHS scoring is needed.

Peptide methyl ketones as reversible inhibitors of cysteine proteinases.

Peptide methyl ketones represent a new class of reversible, competitive cysteine proteinase inhibitor with little or no effect on serine proteinases. The affinity of the inhibitors to papain (EC 3.4.22.3), cathepsin B (EC 3.4.22.1) and cathepsin L (EC 3.4.22.15) depends on the peptide chain length and on side-chain effects. Variations in the P1 and P4 positions (terminology of Schechter and Berger) and their influence on the efficiency of the inhibitors have been investigated. The most effective inhibitors display inhibition constants in the micromolar range. In contrast to the endopeptidases papain and the cathepsins B and L, the aminoendopeptidase cathepsin H (EC 3.4.22.16) is not inhibited by N-acylated peptide methyl ketones but only by amino methyl ketones containing a free alpha-amino group. The endopeptidases are not affected by amino methyl ketones.

Quality criteria for medical staff admission: a beginning.

Pressures influencing the size and composition of medical staffs are increasing as hospitals and physicians respond to competition, market priorities, increasing numbers of physicians, and quality-of-care concerns. This article examines whether the quality of care provided by an applicant may be the primary criterion for admission to a hospital's medical staff. Methodological, legal, and organizational concerns that arise from this approach are reviewed. A quality criteria approach can assist in responding to increasing numbers of physicians, the transition to management care, and the marketing interests of a hospital.

Regulation of the in vitro monoclonal immunoglobulin production in cultures of peripheral blood mononuclear cells and bone marrow cells from myeloma patients mediated by T cell dependent mitogens.

In vitro monoclonal immunoglobulin (mIg) production of cultured tumour cells--prepared from the bone marrow (BM) or from the peripheral blood (PB) of 40 multiple myeloma (MM) patients, 16 patients with monoclonal gammopathy of undetermined significance and two patients with M. Waldenström--was measured with an enzyme-linked immunosorbent assay (ELISA) using anti-idiotype and anti-class specific antisera. After in vitro stimulation with pokeweed mitogen (PWM) or OKT3 antibody, mIg production was regularly suppressed in BM cell cultures, whereas enhanced, unaltered or suppressed production was observed in PB cell cultures. These observations show that the expanded clone in MM can still be regulated in vitro. Separation experiments demonstrated the involvement of T cells in this in vitro system. The results could be explained by the hypothesis that activated T cells can suppress mature cells of B cell differentiation, as found in BM of the patients, but stimulate earlier B cells from the peripheral blood towards differentiation into Ig secreting cells.

Cytostatic drug sensitivity test for human multiple myeloma, measuring monoclonal immunoglobulin produced by bone marrow cells in vitro.

An in vitro cytostatic drug sensitivity test for human multiple myeloma has been developed, predicting differences in sensitivity of the individual tumor to various anticancer drugs. Bone marrow preparations containing the tumor cells were incubated with cytostatic drugs and cultured for 10 days. Using an enzyme-linked immunosorbent assay we measured tumor products--monoclonal immunoglobulin and beta 2-microglobulin--in the culture supernatants. The reduction of these products in vitro due to the drugs administered was compared with the patients' further clinical course during treatment with different standard cytostatic drug regimens. We found a predictive value of more than 80% for this easily performed test.

State as a determinant of infants' heart rate response to stimulation.

With each infant serving as his own control, the data indicate that waking or sleeping states, independent of the prestimulation heart rate, can significantly affect the heart rate response to tactile stimulation.