Efficient testing of the biomarker positive and negative subgroups in a biomarker-stratified trial.

In many randomized placebo-controlled trials with a biomarker defined subgroup, it is believed that this subgroup has the same or higher treatment effect compared with its complement. These subgroups are often referred to as the biomarker positive and negative subgroups. Most biomarker-stratified pivotal trials are aimed at demonstrating a significant treatment effect either in the biomarker positive subgroup or in the overall population. A major shortcoming of this approach is that the treatment can be declared effective in the overall population even though it has no effect in the biomarker negative subgroup. We use the isotonic assumption about the treatment effects in the two subgroups to construct an efficient way to test for a treatment effect in both the biomarker positive and negative subgroups. A substantial reduction in the required sample size for such a trial compared with existing methods makes evaluating the treatment effect in both the biomarker positive and negative subgroups feasible in pivotal trials especially when the prevalence of the biomarker positive subgroup is less than 0.5.

Effects of Operating Mechanical Conditions and Polymer Networks of Nematic Elastomers on Photo-Induced Mechanical Performances.

Photoresponsive liquid-crystalline elastomers (LCEs) are promising candidates for light-controlled soft actuators. Photoinduced stress/strain originates from the changes in mechanical properties after light irradiation. However, the correlation between the photoinduced mechanical performance and in-use conditions such as stress/strain states and polymer network properties (such as effective crosslink density and dangling chain density) remains unexplored for practical applications. Here, isometric photo-induced stress or isotonic strain is investigated at different operating strains or stresses, respectively, on LCEs with polymer network variations, produced by different amounts of solvent during polymerization. As the solvent volume increases, the moduli and photoinduced stresses decrease. However, the photo-induced strain, fracture strain, fracture stress, and viscosity increase. The optical response performance initially increases with the operating strain/stress, peaks at a higher actuation strain/stress, and then, decreases depending on the polymer network. The maximum work densities, which also depend on the operating stress, are in the range of ≈200-300 kJm-3. These findings, highlighting the significant variations in the mechanical performance with the operating stress/strain ranges and amount of solvent used in the synthesis, are critical for designing LCE-based mechanical devices.

Rose geranium in sesame oil nasal spray to improve nasal vestibulitis symptoms: a randomized controlled trial.

PURPOSE: The purpose of this phase III randomized double-blinded controlled trial was to investigate the efficacy of a rose geranium in sesame oil (RG) nasal spray compared with an isotonic saline (IS) nasal spray for alleviating nasal vestibulitis symptoms among patients undergoing chemotherapy. METHODS: Patients undergoing active chemotherapy who reported associated nasal symptoms were randomized 1:1 to receive RG or IS, administered twice daily for 2 weeks. Consenting participants completed nasal symptom questionnaires at baseline and then weekly while on treatment. The proportion of patients experiencing improvements in their nasal symptoms 2 weeks after initiating the nasal spray, using a six-point global impression of change score, was estimated within and between each randomized arm, and compared between arms, using Fisher's exact test. The estimated odds ratio was determined (95% confidence interval). RESULTS: One hundred and six patients consented to this study; 43 participants in the RG arm and 41 in the IS arm were evaluable for the primary endpoint. Participants had a mean age of 57.8 years (SD 13.9). Demographic characteristics and baseline nasal symptoms were similar between arms. Of the evaluable participants who received RG, 67.4% reported improved nasal symptoms, compared with 36.6% of the participants who received IS (P = 0.009). Adverse events were sparse and did not differ between arms. CONCLUSION: Rose geranium in sesame oil significantly improves nasal vestibulitis symptoms among patients undergoing chemotherapy. TRIAL REGISTRATION: NCT04620369.

How to follow the guidelines, when the appropriate fluid is missing?

Intravenous maintenance fluid therapy (IV-MFT) is probably the most prescribed drug in paediatric hospital care. Recently paediatric societies have produced evidence-based practice guidelines that recommend the use of balanced isotonic fluid when prescribing IV-MFT in both acute and critical paediatric care. Unfortunately, the applicability of these guidelines could be called into question when a ready-to-use glucose-containing balanced isotonic fluid is not available. The main objective of this study was to describe the availability of glucose-containing balanced isotonic fluids in European and Middle Eastern paediatric acute and critical care settings. This work is an ancillary study of the survey dedicated to IV-MFT practices in the paediatric acute and critical care settings in Europe and Middle East, a cross-sectional electronic 27-item survey, emailed in April-May 2021 to paediatric critical care physicians across 34 European and Middle East countries. The survey was developed by an expert multi-professional panel within the European Society of Peadiatric and Neonatal Intensive Care (ESPNIC). Balanced isotonic fluid with glucose 5% was available for only 32/153 (21%) responders. Balanced isotonic fluid with glucose 5% was consistently available in the UK (90%) but not available in France, Greece, The Netherlands and Turkey.    Conclusion: Ready-to-use isotonic balanced IV solutions containing glucose in sufficient amount exist but are inconsistently available throughout Europe. National and European Medication Safety Incentives should guarantee the availability of the most appropriate and safest IV-MFT solution for all children. What is Known: • Intravenous maintenance fluid therapy (IV-MFT) is probably the most prescribed drug in paediatric hospital care. • Balanced isotonic fluid is recommended when prescribing IV-MFT in both acute and critical paediatric care. What is New: • Balanced isotonic fluid with glucose 5% is available for less than 25% of the prescribers in Europe and the Middle East. Availability of balanced isotonic fluid with glucose 5% varies from one country to another but can also be inconsistent within the same country. • Clinicians who have access to a ready-to-use balanced isotonic fluid with glucose 5% are more likely to consider its use than clinicians who do not have access to such an IV solution.

Isokinetic training of lower extremity during the early stage promote functional restoration in elder patients with disability after Total knee replacement (TKR) - a randomized control trial.

BACKGROUND: Transient progressive weakness and disability of lower limb during the early stage after TKR will increase the risk of fall, but the superior postoperative strength training mode have not been elucidated for functional restoration. This study aimed to compare whether the isokinetic lower limb training is superior to either isotonic or home isometric exercise during early stage after TKR in older people. METHODS: A total of 43 recruited old participants (mean age, 68.40 years old) receiving TKR were divided randomly based on the different four-week training modes into three groups including isokinetic, isotonic, and home isometric exercise (control group). The primary outcome was set as functional performance in terms of Timed Up and Go (TUG) test and the secondary outcomes include the peak torque of knee at 60 and 120 degree/ second, Short-Form 36 Health Survey (SF-36), and Western Ontario and McMaster Universities Arthritis index (WOMAC). RESULTS: All of the peak torque measurements of the knee improved significantly in both the isokinetic and the isotonic group, but not in the control group. Although isotonic training resulted in more strength gains, a significant enhancement in TUG test was observed in the isokinetic group only (p = 0.003). However, there were no significantly improvement of TUG test after training in other two groups. SF-36 and WOMAC improved after training in all three groups, with no significant difference in the degree of improvement between groups. CONCLUSION: Isokinetic training for 4 weeks following TKR effectively improved all the outcome parameters in this study, including the TUG test, lower limb strength, and functional scores. However, both isokinetic and isotonic training modes could be recommended after TKR because of no significant difference in the degree of improvement between these two groups. TRIAL REGISTRATION: Clinical trial registration number: NCT02938416. LEVEL OF EVIDENCE: I.

Isotonic balanced fluid versus 0.9% saline in patients with moderate to severe traumatic brain injury: A double-blinded randomised controlled trial.

BACKGROUND AND IMPORTANCE: Traumatic brain injury (TBI) is a global health concern with significant economic impact. Optimal fluid therapy aims to restore intravascular volume, maintain cerebral perfusion pressure and blood flow, thus preventing secondary brain injury. While 0.9% saline (NS) is commonly used, concerns about acid-base and electrolyte imbalance and development of acute kidney injury (AKI) lead to consideration of balanced fluids as an alternative. OBJECTIVES: This study aimed to compare the outcomes of patients with moderate to severe TBI treated with Sterofundin (SF) versus NS. DESIGN, SETTINGS AND PARTICIPANTS: A double-blinded randomised controlled trial of patients aged 18 to 65 years with TBI was conducted at the University Malaya Medical Centre from February 2017 to November 2019. INTERVENTION OR EXPOSURE: Patients were randomly assigned to receive either NS or SF. The study fluids were administered for 72 h as continuous infusions or boluses. Participants, investigators, and staff were blinded to the fluid type. OUTCOMES MEASURE AND ANALYSIS: The primary outcome was in-hospital mortality. Relative risk (RR) with 95% confidence interval (CI) was calculated. MAIN RESULTS: A total of 70 patients were included in the analysis, with 38 in the NS group and 32 in the SF group. The in-hospital mortality rate were 3 (7.9%) in the NS group vs. 4 (12.5%) in the SF group, RR = 1.29 (95% CI, 0.64 to 2.59; p = 0.695). No patients developed AKI and required renal replacement therapy. ICP on day 3 was significantly higher in the SF group (18.60 ± 9.26) compared to 12.77 ± 3.63 in the NS group, (95% CI, -11.46 to 0.20; p = 0.037). There were no significant differences in 3-day biochemical parameters and cerebral perfusion pressure, ventilator-free days, length of ICU stay, or Glasgow Outcome Scale-Extended (GOS-E) score at 6 months. CONCLUSIONS: In patients with moderate to severe TBI, the use of SF was not associated with reduced in-hospital mortality, development of AKI, or improved 6-month GOS-E when compared to NS.

The Contractile Machines of the Heart.

This chapter will describe basic structural and functional features of the contractile apparatus of muscle cells of the heart, namely, cardiomyocytes and smooth muscle cells. Cardiomyocytes form the contractile myocardium of the heart, while smooth muscle cells form the contractile coronary vessels. Both muscle types have distinct properties and will be considered with respect to their cellular appearance (brick-like cross-striated versus spindle-like smooth), arrangement of contractile proteins (sarcomeric versus non-sarcomeric organization), calcium activation mechanisms (thin-filament versus thick-filament regulation), contractile features (fast and phasic versus slow and tonic), energy metabolism (high oxygen versus low oxygen demand), molecular motors (type II myosin isoenzymes with high adenosine diphosphate [ADP]-release rate versus myosin isoenzymes with low ADP-release rates), chemomechanical energy conversion (high adenosine triphosphate [ATP] consumption and short duty ratio versus low ATP consumption and high duty ratio of myosin II cross-bridges [XBs]), and excitation-contraction coupling (calcium-induced calcium release versus pharmacomechanical coupling). Part of the work has been published (Neuroscience - From Molecules to Behavior", Chap. 22, Galizia and Lledo eds 2013, Springer-Verlag; with kind permission from Springer Science + Business Media).

An Isotonic Drink Containing Pacific Cod (Gadus macrocephalus) Processing Waste Collagen Hydrolysate for Bone and Cartilage Health.

Malnutrition is one of the major factors of bone and cartilage disorders. Pacific cod (Gadus macrocephalus) processing waste is a cheap and highly promising source of bioactive substances, including collagen-derived peptides and amino acids, for bone and cartilage structure stabilization. The addition of these substances to a functional drink is one of the ways to achieve their fast intestinal absorption. Collagen hydrolysate was obtained via enzymatic hydrolysis, ultrafiltration, freeze-drying, and grinding to powder. The lyophilized hydrolysate was a light gray powder with high protein content (>90%), including collagen (about 85% of total protein) and a complete set of essential and non-essential amino acids. The hydrolysate had no observed adverse effect on human mesenchymal stem cell morphology, viability, or proliferation. The hydrolysate was applicable as a protein food supply or a structure-forming food component due to the presence of collagen fiber fragments. An isotonic fitness drink (osmolality 298.1 ± 2.1 mOsm/L) containing hydrolysate and vitamin C as a cofactor in collagen biosynthesis was prepared. The addition of the hydrolysate did not adversely affect its organoleptic parameters. The production of such functional foods and drinks is one of the beneficial ways of fish processing waste utilization.

Smart Bioimpedance Device for the Assessment of Peripheral Muscles in Patients with COPD.

Muscle dysfunction and muscle atrophy are common complications resulting from Chronic Obstructive Pulmonary Disease (COPD). The evaluation of the peripheral muscles can be carried out through the assessment of their structural components from ultrasound images or their functional components through isometric and isotonic strength tests. This evaluation, performed mainly on the quadriceps muscle, is not only of great interest for diagnosis, prognosis and monitoring of COPD, but also for the evaluation of the benefits of therapeutic interventions. In this work, bioimpedance spectroscopy technology is proposed as a low-cost and easy-to-use alternative for the evaluation of peripheral muscles, becoming a feasible alternative to ultrasound images and strength tests for their application in routine clinical practice. For this purpose, a laboratory prototype of a bioimpedance device has been adapted to perform segmental measurements in the quadriceps region. The validation results obtained in a pseudo-randomized study in patients with COPD in a controlled clinical environment which involved 33 volunteers confirm the correlation and correspondence of the bioimpedance parameters with respect to the structural and functional parameters of the quadriceps muscle, making it possible to propose a set of prediction equations. The main contribution of this manuscript is the discovery of a linear relationship between quadriceps muscle properties and the bioimpedance Cole model parameters, reaching a correlation of 0.69 and an average error of less than 0.2 cm regarding the thickness of the quadriceps estimations from ultrasound images, and a correlation of 0.77 and an average error of 3.9 kg regarding the isometric strength of the quadriceps muscle.

Fully order restricted multi-arm multi-stage clinical trial design.

We consider a multi-arm trial with two or more active treatments plus a control where it is reasonable to assume an order for the treatment effects of the active arms compared to control. For example, the arms could be a high dose and low dose of a new drug and a placebo. The objective of the trial is to compare each active arm to control while maintaining strong control of the type 1 error rate. We show that when the study is powered to identify all promising treatments, a design that uses the order of the treatment effects to calculate the test statistic and to set the order of testing requires a smaller sample size than a design where each active arm is tested against the control arm independently. Under the considered settings, the sample size for a single-stage trial and a two-stage trial was reduced by at least 20%.

Torque and Discomfort During Electrically Evoked Muscle Contractions in Healthy Young Adults: Influence of Stimulation Current and Pulse Frequency.

OBJECTIVE: To investigate (1) how current and pulse frequency of electrical stimulation (ES) as well as contraction mode (isometric, concentric, and eccentric) influence torque output and discomfort and (2) how familiarization by repeated ES sessions influences ratings of perceived discomfort. DESIGN: An experimental study, 3 sessions. SETTING: A university laboratory. PARTICIPANTS: Eight healthy participants (5 men, 3 women; mean age 25.2 years; N=8). INTERVENTIONS: Participants completed 3 trial days, each including 17 electrically evoked thigh muscle contractions. On each trial day, the first 6 contractions consisted of 2 isometric, 2 concentric, and 2 eccentric muscle contractions randomly ordered with a fixed stimulation current and pulse frequency (200 mA, 20 Hz), while the remaining 11 muscle contractions were all isometric with randomly ordered combinations of current (100-250 mA) and pulse frequency (20-100 Hz). MAIN OUTCOME MEASURES: Torque and perceived discomfort were measured for each ES-evoked contraction. RESULTS: Overall, the findings revealed that a higher stimulation frequency was associated with an increased torque without increased discomfort, while higher currents were associated with increases of both torque and discomfort. Contraction type did not influence level of discomfort, despite eccentric contractions eliciting higher torque compared with concentric and isometric contractions (P<.001). Finally, a significant familiarization to ES (P<.001) was observed after just 1 of 3 identical stimulation sessions. CONCLUSIONS: The outlined data suggest that to elicit high torque levels while minimizing levels of discomfort in young subjects, eccentric muscle contractions evoked with a low stimulation current, and a high pulse frequency are preferable. Furthermore, a single familiarization session significantly lowers rating of perceived discomfort during ES.

Isotonic design for phase I cancer clinical trials with late-onset toxicities.

This article addresses the problem of identifying the maximum tolerated dose (MTD) in Phase I dose-finding clinical trials with late-onset toxicities. The main design challenge is how best to adaptively allocate study participants to tolerable doses when the evaluation window for the toxicity endpoint is long relative to the accrual rate of new participants. We propose a new design framework based on order-restricted statistical inference that addresses this challenge in sequential dose assignments. We illustrate the proposed method on real data from a Phase I trial of bortezomib in lymphoma patients and apply it to a Phase I trial of radiotherapy in prostate cancer patients. We conduct extensive simulation studies to compare our design's operating characteristics to existing published methods. Overall, our proposed design demonstrates good performance relative to existing methods in allocating participants at and around the MTD during the study and accurately recommending the MTD at the study conclusion.

Can a Therapeutic Strategy for Hypotension Improve Cerebral Perfusion and Oxygenation in an Experimental Model of Hemorrhagic Shock and Severe Traumatic Brain Injury?

BACKGROUND: Restoration of brain tissue perfusion is a determining factor in the neurological evolution of patients with traumatic brain injury (TBI) and hemorrhagic shock (HS). In a porcine model of HS without neurological damage, it was observed that the use of fluids or vasoactive drugs was effective in restoring brain perfusion; however, only terlipressin promoted restoration of cerebral oxygenation and lower expression of edema and apoptosis markers. It is unclear whether the use of vasopressor drugs is effective and beneficial during situations of TBI. The objective of this study is to compare the effects of resuscitation with saline solution and terlipressin on cerebral perfusion and oxygenation in a model of TBI and HS. METHODS: Thirty-two pigs weighing 20-30 kg were randomly allocated into four groups: control (no treatment), saline (60 ml/kg of 0.9% NaCl), terlipressin (2 mg of terlipressin), and saline plus terlipressin (20 ml/kg of 0.9% NaCl + 2 mg of terlipressin). Brain injury was induced by lateral fluid percussion, and HS was induced through pressure-controlled bleeding, aiming at a mean arterial pressure (MAP) of 40 mmHg. After 30 min of circulatory shock, resuscitation strategies were initiated according to the group. The systemic and cerebral hemodynamic and oxygenation parameters, lactate levels, and hemoglobin levels were evaluated. The data were subjected to analysis of variance for repeated measures. The significance level established for statistical analysis was p < 0.05. RESULTS: The terlipressin and saline plus terlipressin groups showed an increase in MAP that lasted until the end of the experiment (p < 0.05). There was a notable increase in intracranial pressure in all groups after starting treatment for shock. Cerebral perfusion pressure and cerebral oximetry showed no improvement after hemodynamic recovery in any group. The groups that received saline at resuscitation had the lowest hemoglobin concentrations after treatment. CONCLUSIONS: The treatment of hypotension in HS with saline and/or terlipressin cannot restore cerebral perfusion or oxygenation in experimental models of HS and severe TBI. Elevated MAP raises intracranial pressure owing to brain autoregulation dysfunction caused by TBI.

Eight-week neuromuscular electrical stimulation training produces muscle strength gains and hypertrophy, and partial muscle quality improvement in the knee extensors.

This study investigated the effect of an 8-week neuromuscular electrical stimulation (NMES) training programme (3 days/week) on muscle quantity and quality and single-joint performance in the knee extensors. Thirty-nine untrained young male participants were randomly assigned to NMES training (n = 21) and control (n = 18) groups. The 8-week NMES training induced significant increase in the isometric maximal voluntary contraction (MVC) torque of the knee extensors (≈9.3%), muscle volume of the individual and entire quadriceps muscles determined by magnetic resonance imaging (≈3.3%-6.4%), and a significant decrease in the ultrasound echo intensity of the vastus lateralis (≈-4.0%); however, hypertrophy of the vastus intermedius (i.e., the deep muscle) was limited (≈3.3%). In the NMES training group, the repeated measures correlations of the isometric MVC torque with the muscle volume of the entire quadriceps muscle and each quadriceps muscle were significant (rrm (20) = 0.551-0.776), whereas that of the isometric MVC torque with the ultrasound echo intensity of the vastus lateralis was not significant. These findings suggest that NMES training produces muscle strength gains, muscle hypertrophy, and partial muscle quality improvement and that the NMES training-induced muscle strength gains is caused by muscle hypertrophy in the knee extensors.

Hip Abductor and External Rotator Strengths Correlate With Hop Symmetry in Men Athletes 2 Years After Anterior Cruciate Ligament Reconstruction.

CONTEXT: Hip muscle strength and hop performance limb symmetries after anterior cruciate ligament reconstruction (ACLR) are not well studied. This study aimed to determine the differences in hip abductors' (ABD) and external rotators' (ER) muscle strength measures between limbs, and the relationship between hip ABD and ER muscle strengths and hop performance limb symmetry indices (LSIs) 2 years after ACLR. DESIGN: Cross-sectional study. METHODS: Forty (level I/II) men athletes 2 years after unilateral ACLR completed 4 single-legged hop tests and involved hip ABD and ER strength testing (maximum voluntary isometric contraction [MVIC]; isokinetic peak torque [PKTQ] at 60°, 180°, and 300°/s; and isotonic peak velocity at 75% of their MVICs). Muscle strength measures were normalized to body mass, and hop performances were reported as LSIs. Paired t test was used to determine strength differences between limbs, and the Pearson correlation coefficient was used to assess the relationship between involved hip muscle strength measures and hop performance LSIs. RESULTS: Hip ER-MVIC (involved: 60.26 [12.01], uninvolved: 63.68 [13.17] N·m/kg) and ER eccentric PKTQ at 60°/s (involved: 32.59 [9.28]; uninvolved: 35.73 [10.50] N·m/kg) were significantly different between limbs (P ≤ .018). Single-hop LSI correlated with hip ER-PKTQ at 180°/s (r = .354) and 300°/s (r = .324, P ≤ .041), while triple-hop LSI correlated with hip ER-MVIC (r = .320), concentric ER-PKTQ at 180°/s (r = .355), eccentric ER-PKTQ at 60°/s (r = .314), and hip ABD-PKTQ at 60°/s (r = .364) and 300°/s (r = .336, P ≤ .049). CONCLUSIONS: Men athletes demonstrated symmetrical hop performance and hip muscle strengths, except for ER hip's MVIC and isokinetic eccentric peak torque at 60°/s 2 years after ACLR. Hop performance LSIs had a few, yet positive moderate relationships with involved hip ABDs and ER strength measures. This may indicate that hip ABD and ER muscle strength measures contribute to athletes' hop performances 2 years after ACLR. Post-ACLR rehabilitation programs might incorporate hip muscle strengthening training to improve athletes' functional performances.

Muscle contraction exercise for low back pain.

Background: Low-back pain (LBP) continues to be one of the main problems for which sufferers seek treatment in primary care. It can be treated with different physiotherapy mechanisms. Objective: The purpose of the study is to compare the effect of isotonic and isometric exercise on the reported pain of patients with low back pain. Methods: Thirty participants, 16 males and 14 females aged between 22 and 50 years suffering from nonspecific low back pain were included. The sample was divided randomly into two groups, group A isometric exercises and group B isotonic exercises, both groups received conservative therapy of TENS and infrared (IR) therapy. The following outcome measures were used: Visual analogue scale, modified Oswestry disability index (MODI) and Endurance Test Measurement were administered pre-treatment and at the end of four weeks of treatment. Results: Both groups were comparable in terms of demographic data, except for weight. Inter group analysis was done using the Mann-Whitney test. When comparing pre- and post-treatments using VAS scores, there were no significant differences between group A and group B (pre-test: P=0.285; Post-test: P=0.838). Mann-Whitney test was used to calculate the P-value test between pre-treatment and post- treatment for MODI and there was no significant difference between group A and group B, where the pre-test P-value was 0.061, and post-treatment was 0.077. Comparing between groups, pre- and post-abdominal endurance scores were done using the Mann-Whitney test. The pre-treatment scores revealed P value of 0.345, and the post-treatment scores revealed P value of 0.305. Therefore, there is no statistically significant difference between group A and group B in endurance scores. Conclusion: There was no difference between the use isotonic and isometric exercises on LBP patients.

Efficacy of hypertonic saline versus isotonic saline among children with cystic fibrosis: A systematic review and meta-analysis.

Background: Inhaled hypertonic saline (HS) reduces pulmonary exacerbations in patients with cystic fibrosis (CF) aged 6 or more years. However, the effectiveness of HS in improving clinical outcomes in younger children aged 6 or less years is not established. This study examines the efficacy of HS in younger CF patients. Methods: Searches were conducted across three databases (Medline, Cochrane Central and EMBASE) from inception through July 2022. Randomized controlled trials assessing the impact of HS in younger CF patients were included. Trials involving only patients greater than 6 years or control group other than isotonic saline (IS) were excluded. Outcomes measured included lung clearance index (LCI), cystic fibrosis questionnaire (CFQ-R) score, spirometry measures, oxygen saturation, respiratory rate, height and weight. Outcomes were reported as mean differences (MDs) with 95% confidence intervals. Results: Seven studies (n = 390 patients) were included in this review. HS significantly reduced the LCI (MD: -0.67; 95%CI, -1.05 to 0.29, P = 0.0006) compared to IS. In addition, HS was associated with significant improvements in height (MD: 2.23; 95%CI, -0.00 to 4.46, P = 0.05) and CFQ-R (MD: 4.30; 95%CI, 0.65-7.95, P = 0.02), but not in oxygen saturation (MD: -0.15; 95%CI, -0.54 to 0.25, P = 0.47), respiratory rate (MD: -0.21; 95%CI, -2.19 to 1.77, P = 0.83) or weight (MD: 0.70; 95%CI, -0.47 to 1.87, P = 0.24). Furthermore, HS did not significantly improve spirometry measures, including FEV1 (MD: -0.11; 95%CI, -0.21 to 0.43, P = 0.51) and forced vital capacity (MD: 0.27; 95%CI, -0.49 to 1.04, P = 0.48), but significantly improved FEF25-75 (MD: 0.12; 95% CI, 0.05-0.20; P = 0.002). Discussion: Treatment with HS in younger children with CF improves lung clearance, symptoms and quality of life. FEF25-75 may prove a more sensitive measure for assessing intervention related improvements in pediatric CF trials. Conclusion: The findings support HS as a therapeutic method in CF-affected children.

A semiparametric isotonic regression model for skewed distributions with application to DNA-RNA-protein analysis.

In this paper, we propose a semiparametric regression model that is built upon an isotonic regression model with the assumption that the random error follows a skewed distribution. We develop an expectation-maximization algorithm for obtaining the maximum likelihood estimates of the model parameters, examine the asymptotic properties of the estimators, conduct simulation studies to explore the performance of the proposed model, and apply the method to evaluate the DNA-RNA-protein relationship and identify genes that are key factors in tumor progression.

Non-local muscle fatigue is mediated at spinal and supraspinal levels.

The objective was to measure the corticospinal excitability and motoneuron responsiveness of the right and left Biceps Brachii (BB), and left Abductor Digiti Minimi (ADM) muscles in response to submaximal isotonic fatiguing contractions performed by the right BB muscle. With the familiarization session, ten young moderately active male subjects came to the lab on seven occasions. Three sets of 3 min seated elbow curls at 25% of one-repetition maximum (1RM) separated by a 1-min rest performed by the right BB muscle were used as the fatiguing protocol. The motor evoked potential (MEP), cervicomedullary motor evoked potential (CMEP), and compound muscle action potential (Mmax) of the right BB muscle (baseline and after each set of the fatiguing task), the left BB and ADM muscles (baseline, post-fatigue, post-10, and post-20 min) were measured. MEP and CMEP were then normalized to Mmax for statistical analysis. The results showed that in the right BB muscle, there was a significant reduction in the MEP after performing the fatiguing task (p= 0.03), while no significant effect of time was seen in the CMEP (p= 0.07). In the left BB muscle, the MEP significantly decreased from pre-fatigue to post-fatigue (p= 0.01) and post-10 (p= 0.001), while there was a significant decline in the CMEP post-fatigue (p= 0.03). In the left ADM muscle, MEP significantly decreased post-fatigue (p= 0.03) and no changes were seen in the CMEP (p= 0.12). These results not only confirm the incidence of non-local muscle fatigue (NLMF) in response to performing submaximal isotonic fatiguing contractions but also as a new finding, imply that both spinal and supraspinal modulations account for the NLMF response.

Severe hospital-acquired hyponatremia in acutely ill children receiving moderately hypotonic fluids.

BACKGROUND: Hypotonic fluids have been associated with hospital-acquired hyponatremia. The incidence of life-threatening severe hyponatremia associated with hypotonic fluids has not been evaluated. METHODS: This was a population-based cohort study of 46,518 acutely ill children 15 years of age or under who visited the pediatric emergency department (ED) at Oulu University Hospital, Finland, between 2007 and 2017. We retrieved all electrolyte measurements from the comprehensive electronic laboratory system and reviewed medical records for all patients with severe hyponatremia. RESULTS: The overall occurrence of severe hyponatremia (serum sodium < 125 mmol/L) was found in 27 out of 46,518 acutely ill children (0.06%, 95% confidence interval 0.04-0.08%). After admission, severe hyponatremia developed in seven of 6,984 children receiving moderately hypotonic fluid therapy (0.1%, 95% confidence interval 0.04-0.2%), usually within 8 h of admission. All children who developed severe hyponatremia during hospitalization were severely ill. CONCLUSION: In this register-based cohort study of children presenting to the ED, severe hyponatremia developed in one of 998 acutely ill children receiving moderately hypotonic fluid therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.