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.
RESUMEN: Las unidades de cuidados intensivos (UCI) y agudos han sido los contenedores del avance de la pandemia por COVID-19. Sin embargo, la estadía prolongada en esta unidad puede repercutir sobre ...la composición corporal (CC) y la capacidad derealizar ejercicio de los pacientes. El objetivo de esta investigación fue determinar si existe relación entre composición corporal (CC) y la prueba de caminata en 6 minutos (PC6m). Se reclutaron 17 personas (8 mujeres y 9 hombres). Se tomaron las siguientes medidas: PC6m, se consideró su distancia recorrida (DRPC6m) y su velocidad (VelPC6m). Las variables de CC medidas fueron índice de masa corporal (IMC), masa grasa (MG), masa libre de grasa (MLG) y masa magra (MM). La DRPC6m sólo mostró relación significativa con la MM corporal (MMC). Por otra parte, la VelPC6m tuvo una relación significativa con la MMC. Además de esto, la MLG del miembro inferior derecho y la MLG del miembro inferior izquierdo mostraron una relación con la VelPC6m (r=0,422; p=0,041 y r=0,417; p=0,025, respectivamente). También la MM del miembro inferior derecho y la MM del miembro inferior izquierdo se relacionaron significativamente con la VelPC6m (r=0,422; p=0,030 y r=0,420; p=0,042). En conclusión, existe relación entre composición corporal y VelPC6m. Esto permitiría aproximarse de manera rápida al nivel de funcionalidad con la que ingresa un paciente a un programa de rehabilitación.
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.
The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac ...amyloidosis (ATTR-CA).
This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA.
A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year.
The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P < 0.001). A 6MWT distance of <350 m was associated with a 2.2-fold higher risk of mortality (HR: 2.15; 95% CI: 1.85-2.50; P < 0.001), with a similar increased risk across National Amyloidosis Centre disease stages (P for interaction = 0.761) and genotypes (P for interaction = 0.172). An absolute (reduction of >35 m) and relative worsening (reduction of >5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P < 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P < 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro–B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P < 0.001).
The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality.
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•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.