Nonlinear regression models are applied in a broad variety of scientific fields. Various R functions are already dedicated to fitting such models, among which the function nls() has a prominent ...position. Unlike linear regression fitting of nonlinear models relies on non-trivial assumptions and therefore users are required to carefully ensure and validate the entire modeling. Parameter estimation is carried out using some variant of the least- squares criterion involving an iterative process that ideally leads to the determination of the optimal parameter estimates. Therefore, users need to have a clear understanding of the model and its parameterization in the context of the application and data considered, an a priori idea about plausible values for parameter estimates, knowledge of model diagnostics procedures available for checking crucial assumptions, and, finally, an under- standing of the limitations in the validity of the underlying hypotheses of the fitted model and its implication for the precision of parameter estimates. Current nonlinear regression modules lack dedicated diagnostic functionality. So there is a need to provide users with an extended toolbox of functions enabling a careful evaluation of nonlinear regression fits. To this end, we introduce a unified diagnostic framework with the R package nlstools. In this paper, the various features of the package are presented and exemplified using a worked example from pulmonary medicine.
To evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane.
We performed a ...randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin. In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale.
In part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters.
In this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.
Studies point to the persistence of symptoms in patients with non-critical COVID-19 after hospitalization, pointing to impairments in functionality, exercise capacity and effort desaturation, which ...characterize the need for continuity of management and treatment after acute illness.
To evaluate functional independence, exercise capacity, and effort desaturation after non-critical COVID-19 after hospital discharge.
A cross-sectional study included adult individuals with a noncritical COVID-19 diagnosis who were hospitalized for at least 24 hours between 30 and 180 days after hospital discharge. Participants were classified into 3 groups: G1M - one month after hospital discharge, G3M - three months after hospital discharge, and G6M - six months after charge. A digital form with clinical and sociodemographic questionnaire, modified MRC scale, Barthel Index, and London Chest Activity of Daily Living Scale was applied, in addition to the 6-minute Walk Test in G3M and G6M. The significance value was p<0.05.
We included 64 individuals (G1M=18, G3M=25, G6M=21). There was a significant difference in Barthel Index between G1M and G6M (p=0.007). G3M walked 420m vs 442m of G6M (p=0.25). 48% of participants in G3M and 52% in G6M walked a distance less than 80% of predicted; 28% of G3M participants had >=4% drop in SpO2, vs 19.05% in G6M (p=0.478). There was a high prevalence of persistent symptoms, with a significant association between dyspnea (p=0.001), cough (p=0.038) and angina (p=0.001) and decreased functional independence.
After non-critical COVID-19, decreased functional independence was observed, with significant improvement 6 months after hospital discharge, in addition to decreased exercise capacity, the occurrence of desaturation on exertion, and high prevalence of persistent symptoms with no improvement 6 months after hospitalization.
Patients with persistent symptoms after COVID-19 should be evaluated and treated in pulmonary rehabilitation clinics. The changes caused by non-critical COVID-19 remain in the short and medium term, as in critical COVID-19.
Hypophosphatasia (HPP) is a rare, heritable metabolic disorder caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Asfotase alfa (AA) is a human recombinant TNSALP that ...promotes bone mineralization and is approved to treat eligible patients with HPP.
This prospective single-center observational study evaluated AA in adults with pediatric-onset HPP over 2 years of treatment (ClinicalTrials.govNCT03418389). Primary outcomes evaluated physical function; secondary outcomes assessed quality of life (QoL) and pain.
The study included 17 females and 5 males (mean age: 48.7 years). Median distance walked in the 6-Minute Walk Test increased significantly from baseline to 12 months (P = 0.034) and results were sustained. Median Timed Up and Go test time significantly decreased from baseline at 12 (P = 0.003) and 24 months (P = 0.005), as did the median chair rise time test at 12 (P = 0.003) and 24 months (P < 0.002). The change from baseline in usual gait speed was significant at 12 (P = 0.003) and 24 months (P = 0.015). Mean dominant and nondominant hand grip strength improved at 24 months (P = 0.029 and P = 0.019, respectively). Median Short Form 36 Physical Component Summary scores significantly improved from baseline at 12 (P = 0.012) and 24 (P = 0.005) months, and median Lower Extremity Functional Scale scores improved from baseline at 12 (P = 0.001) and 24 (P = 0.002) months. No significant change was noted in pain level at these timepoints. While injection site reactions occurred in 86.4 % of the participants, there were no severe side effects or safety findings.
Adults with pediatric-onset HPP treated with AA experienced marked improvement in functional and QoL outcomes that were observed as early as within 3 months of initial treatment and were sustained over 24 months.
•Asfotase alfa in adults with hypophosphatasia was evaluated over 24 months.•Patients had marked improvement in functional and quality of life outcomes.•Response of bone turnover markers suggests onset of bone tissue remodeling.
Metformin, the classic anti-diabetic drug, improves motor symptoms in the DMSXL mouse model of myotonic dystrophy type 1. Bassez et al. now report a significant increase in patients' mobility ...following treatment with the maximal tolerated dose of metformin as compared to placebo in a double-blind randomized phase II clinical trial.
Abstract
Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.
Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore ...clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESMCSA) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6% ±15.8%. The average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.
•Dyspnoea persists in many patients following COVID-19 infection.•COVID-19 patients with persistent dyspnoea have impaired spirometry and gas exchange.•COVID-19 patients with persistent dyspnoea have ...reduced exercise performance.
The purpose of this study was to examine the physiological mechanisms of persistent dyspnoea in COVID-19 survivors. Non-critical patients (n = 186) with varying degrees of COVID-19 severity reported persistent symptoms using a standardized questionnaire and underwent pulmonary function and 6-minute walk testing between 30 and 90 days following the onset of acute COVID-19 symptoms. Patients were divided into those with (n = 70) and without (n = 116) persistent dyspnoea. Patients with persistent dyspnoea had significantly lower FVC (p = 0.03), FEV1 (p = 0.04), DLCO (p = 0.01), 6-minute walk distance (% predicted, p = 0.03), and end-exercise oxygen saturation (p < 0.001), and higher Borg 0-10 ratings of dyspnoea and fatigue (both p < 0.001) compared to patients without persistent dyspnoea. We have shown that dyspnoea is a common persistent symptom across varying degrees of initial COVID-19 severity. Patients with persistent dyspnoea had greater restriction on spirometry, lower DLCO, reduced functional capacity, and increased exertional desaturation and symptoms. This suggests that there is a true physiological mechanism that may explain persistent dyspnoea after COVID-19.
Objectives
To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations.
Design
A 24‐week, randomized, double‐blind, ...placebo‐controlled, parallel‐arm, proof‐of‐concept study.
Setting
Five centers in the United States.
Participants
Community‐dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women.
Intervention
Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21).
Measurements
Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6‐minute walk distance (6MWD).
Results
Thirty‐two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab‐treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 ± 2.19% vs −0.34 ± 2.59%, P < .001; Week 4: 6.12 ± 2.56% vs 0.16 ± 3.42%, P < .001; Week 8: 8.01 ± 3.70% vs 0.35 ± 3.32%, P < .001; Week 16: 7.72 ± 5.31% vs 0.42 ± 5.14%, P < .001; Week 24: 4.80 ± 5.81% vs −1.01 ± 4.43%, P = .002). Participants with slower walking speed at baseline receiving bimagrumab had clinically meaningful and statistically significantly greater improvements in gait speed (mean 0.15 m/s, P = .009) and 6MWD (mean 82 m, P = .022) than those receiving placebo at Week 16. Adverse events in the bimagrumab group included muscle‐related symptoms, acne, and diarrhea, most of which were mild in severity and resolved by the end of study.
Conclusion
Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed.
The study aimed to identify the factors associated with the 6-min walk distance (6MWD) and to provide reference values for the 6MWD in individuals with schizophrenia (SCZ) in Taiwan.
A proportional ...stratified sampling method was utilized based on distribution of gender, age and body mass index (BMI) at the study hospital. The 6-minute walk test was conducted according to the American Thoracic Society protocol.
A total of 237 patients with SCZ completed the 6-minute walk test. The 6MWD was significantly associated with age, height, weight, and length of the onset of SCZ. Stepwise linear regression revealed that height and age were significant determinants of 6MWD. The reference values for males and females at different age groups were determined. Notably, females over 60 walked substantially shorter than the age younger than 60.
Height and age were the main predictors for 6MWD among people with SCZ in Taiwan. The established reference values can be used to identify those at risk of poor cardiorespiratory fitness and as a target outcome during exercise programs in psychiatric rehabilitation. Our results highlight that older females with SCZ may be a priority group to target with exercise interventions to mitigate the faster decline in cardiorespiratory fitness.
IMPLICATIONS FOR REHABILITATION
Height and age were predictors of 6-min walk distance (6MWD) in schizophrenia (SCZ).
The established age- and gender reference values for the 6MWD can be used to identify those at risk of poor cardiorespiratory fitness.
Females with SCZ over age 60 may be a priority group to target with exercise interventions to mitigate the faster decline in cardiorespiratory fitness.
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