Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency.

BACKGROUND: Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency. METHODS: DBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using 13C6-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing. RESULTS: From Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839-5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency. CONCLUSION: The screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.

High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan.

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the ABCD1 gene and can lead to Addison disease, childhood cerebral ALD, or adrenomyeloneuropathy. Presymptomatic hematopoietic stem cell transplantation is the only curative treatment for the disease and requires early detection through newborn screening (NBS) and close follow-up. Methods: An NBS program for ALD was performed by a two-tiered dried blood spot (DBS) lysophosphatidylcholine C26:0 (C26:0-LPC) concentration analysis. ABCD1 sequencing was eventually added as a third-tier test, and whole exome sequencing was used to confirm the diagnosis of all peroxisomal diseases. Affected newborns were followed-up for adrenal insufficiency and cerebral white matter abnormalities. Results: We identified 12 males and 10 females with ABCD1 variants, and 3 patients with Zellweger syndrome from 320,528 newborns. Eight (36.4%) ABCD1 variants identified in the current study were null variants, but there were no hotspots or founder effect. During a median follow-up period of 2.28 years, two (16.7%) male patients with ABCD1 variants developed Addison's disease. Extended family screening revealed one 28-year-old asymptomatic hemizygous father of a null variant (c.678delC). Among the three with Zellweger syndrome, one died at the age of 3 months, one showed developmental delay at the age of 1 year, and one was lost to follow-up. Conclusion: Screening for ALD has been added to the NBS program in Taiwan with a high degree of success. The screening algorithm revealed a high proportion of null variants in cases found by NBS in Taiwan, a subset of patients who may have earlier disease onset. We also demonstrate the feasibility of combining the diagnosis of ALD and other peroxisomal disorders into one screening algorithm.

Development of high-growth influenza H7N9 prepandemic candidate vaccine viruses in suspension MDCK cells.

BACKGROUND: Influenza vaccine manufacturers traditionally use egg-derived candidate vaccine viruses (CVVs) to produce high-yield influenza viruses for seasonal or pandemic vaccines; however, these egg-derived CVVs need an adaptation process for the virus to grow in mammalian cells. The low yields of cell-based manufacturing systems using egg-derived CVVs remain an unsolved issue. This study aimed to develop high-growth cell-derived CVVs for MDCK cell-based vaccine manufacturing platforms. METHODS: Four H7N9 CVVs were generated in characterized Vero and adherent MDCK (aMDCK) cells. Furthermore, reassortant viruses were amplified in adherent MDCK (aMDCK) cells with certification, and their growth characteristics were detected in aMDCK cells and new suspension MDCK (sMDCK) cells. Finally, the plaque-forming ability, biosafety, and immunogenicity of H7N9 reassortant viruses were evaluated. RESULTS: The HA titers of these CVVs produced in proprietary suspension MDCK (sMDCK) cells and chicken embryos were 2- to 8-fold higher than those in aMDCK cells. All H7N9 CVVs showed attenuated characteristics by trypsin-dependent plaque assay and chicken embryo lethality test. The alum-adjuvanted NHRI-RG5 (derived from the fifth wave H7N9 virus A/Guangdong/SP440/2017) vaccine had the highest immunogenicity and cross-reactivity among the four H7N9 CVVs. Finally, we found that AddaVax adjuvant improved the cross-reactivity of low pathogenic H7N9 virus against highly pathogenic H7N9 viruses. CONCLUSIONS: Our study indicates that cell-derived H7N9 CVVs possessed high growth rate in new sMDCK cells and low pathogenicity in chicken embryo, and that CVVs generated by this platform are also suitable for both cell- and egg-based prepandemic vaccine production.

Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.

BACKGROUND: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease. METHODS: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis. RESULTS: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively. CONCLUSIONS: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.

Process development for pandemic influenza VLP vaccine production using a baculovirus expression system.

BACKGROUND: Influenza viruses cause hundreds of thousands of respiratory diseases worldwide each year, and vaccination is considered the most effective approach for preventing influenza annual epidemics or pandemics. Since 1950, chicken embryonated eggs have been used as the main method for producing seasonal influenza vaccines. However, this platform has the main drawback of a lack of scale-up flexibility, and thus, egg-based vaccine manufacturers cannot supply sufficient doses within a short period for use for pandemic prevention. As a result, strategies for reducing the manufacturing time and increasing production capacity are urgently needed. Non-virion vaccine methods have been considered an alternative strategy against an influenza pandemic, and the purpose of maintaining an immunogenic capsule structure with infectious properties appears to be met by the virus-like particle (VLP) platform. RESULTS: An influenza H7N9-TW VLP production platform using insect cells, which included the expression of hemagglutinin (HA), NA, and M1 proteins, was established. To scale up H7N9-TW VLP production, several culture conditions were optimized to obtain a higher production yield. A high level of dissolved oxygen (DO) could be critical to H7N9-TW VLP production. If the DO was maintained at a high level, the HA titer obtained in the spinner flask system with ventilation was similar to that obtained in a shake flask. In this study, the HA titer in a 5-L bioreactor with a well-controlled DO level was substantially improved by 128-fold (from 4 HA units (HAU)/50 µL to 512 HAU/50 µL). CONCLUSIONS: In this study, a multigene expression platform and an effective upstream process were developed. Notably, a high H7N9-TW VLP yield was achieved using a two-step production strategy while a high DO level was maintained. The upstream process, which resulted in high VLP titers, could be further used for large-scale influenza VLP vaccine production.

Performance of the Four-Plex Tandem Mass Spectrometry Lysosomal Storage Disease Newborn Screening Test: The Necessity of Adding a 2nd Tier Test for Pompe Disease.

Early diagnosis of lysosomal storage diseases (LSDs) through newborn screening (NBS) has been adapted widely. The National Taiwan University Hospital Newborn Screening Center launched the four-plex tandem mass spectrometry LSD newborn screening test in 2015. The test determined activities of acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), acid ß-glucocerebrosidase (ABG; Gaucher), and acid α-l-iduronidase (IDUA; MPS-I) in dried blood spots (DBS). Through 2017, 64,148 newborns were screened for these four LSDs. The screening algorithm includes enzyme activity/ratio as the cutoffs for the first screening test and a second-tier test for Pompe disease screening. The second-tier Pompe disease screening test measured activity inhibition by acarbose. Twenty-nine newborns required a confirmatory test; six were confirmed to have Pompe disease, and nine were confirmed to have Fabry disease. The screen-positive rate for Pompe disease was 0.031%. Therefore, in Pompe disease newborn screening, a validated 2nd tier test is necessary to decrease false positives.

Mutation-adapted U1 snRNA corrects a splicing error of the dopa decarboxylase gene.

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine and norepinephrine deficiencies. The DDC gene founder mutation IVS6 + 4A > T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene. We found that only the modified U1 snRNA (IVS-AAA) that completely matched both the intronic and exonic U1 binding sequences of the mutated DDC gene could correct splicing errors of either the mutated human DDC minigene or the mouse artificial splicing construct in vitro. We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model. This treatment was well tolerated and improved both the survival and brain dopamine and serotonin levels of mice with AADC deficiency. Therefore, mutation-adapted U1 snRNA gene therapy can be a promising method to treat genetic diseases caused by splicing errors, but the efficiency of such a treatment still needs improvements.

3-O-methyldopa levels in newborns: Result of newborn screening for aromatic l-amino-acid decarboxylase deficiency.

BACKGROUND: The diagnosis of aromatic l-amino-acid decarboxylase (AADC) deficiency is often delayed because a cerebrospinal fluid analysis is required to detect a neurotransmitter deficiency. We here demonstrated that an elevated concentration of l-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into newborn screening program to precisely predict AADC deficiency. METHODS: After obtaining parental consent, an additional spot was punched from newborn filter paper, eluted, cleaned, and analyzed by tandem mass spectrometry. Newborns with a 3-OMD concentration exceeding 500ng/mL were referred for confirmatory testing. RESULTS: From September 2013 to December 2015, 127,987 newborns were screened for AADC deficiency. The mean 3-OMD concentration in these newborns was 88.08ng/mL (SD=27.74ng/mL). Four newborns exhibited an elevated 3-OMD concentration (range, 939-3241ng/mL). All four newborns were confirmed to carry two pathologic DDC mutations, indicating an incidence of AADC deficiency of 1:32,000. During the follow-up period, three patients developed typical symptoms of AADC deficiency. Among 16 newborns with mildly elevated 3-OMD levels, six were heterozygous for the DDC IVS6+4A>T mutation. CONCLUSION: Newborn screening of AADC deficiency was achieved with a 100% positive-predictive rate. An association for gestational age could be further elucidated.

Novel dual-function lens with microscopic and vari-focus capability incorporated with an aberration-suppression aspheric lens.

Substantial aberrations are ubiquitous in many conventional adaptive lenses due to the existence of deformable interface and thus inevitably compromise the optical performance. In this paper, we introduce a novel concept of dual-function fluidic lenses (DFFL) with a built-in aspheric polydimethylsiloxane lens (APL) to enable the design of a compact optical system with tunable imaging and aberration suppression properties. This is achieved by varying both hydrostatic pressures (i.e. adjusting the injected liquid volume change) such that a widely tunable focal length and the simultaneously integrated APL for aberrations correction. DFFL can transform to 4 modes: microscopic mode (APL only), APL/concave mode, APL/plano mode, and APL/convex mode. Focal tunability of DFFL from 12/8 mm to about 90/65 mm (DI water/ethanol) is demonstrated without any mechanical moving components. Aberration characterization is carried out systematically and the low cost, high performance microscopic mode can be easily achieved by actuating the contact between APL and PDMS membrane. In addition, DFFL turning to microscopic mode (focal length 7.32 mm and magnification 50X) can rival the images quality of commercial microscopes.

Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.

The synergistic effects for the co-cultivation of oleaginous yeast-Rhodotorula glutinis and microalgae-Scenedesmus obliquus on the biomass and total lipids accumulation.

In this co-culture of oleaginous yeast-Rhodotorula glutinis and microalgae-Scenedesmus obliquus, microalgae potentially acts as an oxygen generator for the growth of aerobic yeast while the yeast mutually provides CO2 to the microalgae as both carry out the production of lipids. To explore the synergistic effects of co-cultivation on the cells growth and total lipids accumulation, several co-culture process parameters including the carbon source concentration, temperature and dissolved oxygen level would be firstly investigated in the flask trials. The results of co-culture in a 5L photobioreactor revealed that about 40-50% of biomass increased and 60-70% of total lipid increased was observed as compared to the single culture batches. Besides the synergistic effects of gas utilization, the providing of trace elements to each other after the natural cells lysis was believed to be another benefit to the growth of the overall co-culture system.

Diagnosis of aromatic L-amino acid decarboxylase deficiency by measuring 3-O-methyldopa concentrations in dried blood spots.

BACKGROUND: Inherited defects that affect the synthesis or metabolism of neurotransmitters cause severe motor dysfunction. The diagnosis of these diseases, including aromatic L-amino-acid decarboxylase (AADC) deficiency, typically requires cerebrospinal fluid (CSF) neurotransmitter analysis. However, 3-O-methyldopa (3-OMD), which is a catabolic product of L-dopa that accumulates in individuals with AADC deficiency, can be detected in blood. METHODS: 3-OMD concentrations were measured in dried blood spots (DBSs). One 3.2-mm punch was eluted with 90% methanol containing a deuterated internal standard (3-OMD-d3), and then analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: 3-OMD in DBSs was shown to be stable for more than 28 days at 37°C. We measured DBS 3-OMD concentrations in controls and patients with AADC deficiency. 3-OMD concentrations in normal newborns and children decreased with age. Patients with AADC deficiency revealed >15-fold increase of DBS 3-OMD concentrations. Archive newborn screening DBS samples, obtained from 6 patients with AADC deficiency, revealed more than 19-fold increase of 3-OMD concentrations. CONCLUSIONS: We demonstrated that DBS 3-OMD concentrations were highly elevated in newborns and children with AADC deficiency. Because 3-OMD is stable in DBS, this method can be used for both high risk and newborn screening of AADC deficiency.

Treatment of congenital neurotransmitter deficiencies by intracerebral ventricular injection of an adeno-associated virus serotype 9 vector.

Dopamine and serotonin are produced by distinct groups of neurons in the brain, and gene therapies other than direct injection have not been attempted to correct congenital deficiencies in such neurotransmitters. In this study, we performed gene therapy to treat knock-in mice with dopamine and serotonin deficiencies caused by a mutation in the aromatic L-amino acid decarboxylase (AADC) gene (Ddc(KI) mice). Intracerebral ventricular injection of neonatal mice with an adeno-associated virus (AAV) serotype 9 (AAV9) vector expressing the human AADC gene (AAV9-hAADC) resulted in widespread AADC expression in the brain. Without treatment, 4-week-old Ddc(KI) mice exhibited whole-brain homogenate dopamine and serotonin levels of 25% and 15% of normal, respectively. After gene therapy, the levels rose to 100% and 40% of normal, respectively. The gene therapy improved the growth rate and survival of Ddc(KI) mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the Ddc(KI) mice were partially corrected, and the treated Ddc(KI) mice were slightly more active than normal mice. No immune reactions resulted from the treatment. Therefore, a congenital neurotransmitter deficiency can be treated safely through inducing widespread expression of the deficient gene in neonatal mice.

Chitosan/pectin/gum Arabic polyelectrolyte complex: process-dependent appearance, microstructure analysis and its application.

Novel chitosan/pectin/gum Arabic polyelectrolyte complex (PEC) solutions and membranes with various compositions were prepared for biomedical applications. The appearance of the PEC solutions, either clear or turbid, was process-dependent and depended on how the three components were dissolved and mixed. The addition of gum Arabic to the chitosan and pectin significantly decreased the viscosities of the resultant PEC solutions due to the formation of globe-like microstructures that was accompanied by network-like microstructures and other molecular entanglements. The mechanical strength and hydrophilicity of the PEC membranes manufactured from the PEC solutions, especially for a weight ratio of 84/8/8 (chitosan/pectin/gum Arabic), were enhanced compared to pure chitosan membranes. Moreover, the use of the 84/8/8 PEC membranes as a drug carrier exhibited steady and fairly complete release of a drug (insulin) for 6h. Based on these promising results, the chitosan/pectin/gum Arabic PEC membranes have great potential in controlled drug release applications.

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests.

BACKGROUND: Tandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate. METHODS: Three mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs). RESULTS: The results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate. CONCLUSIONS: Utilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.

Regulation of the dopaminergic system in a murine model of aromatic L-amino acid decarboxylase deficiency.

Aromatic l-amino acid decarboxylase (AADC) is responsible for the syntheses of dopamine and serotonin. Children with AADC deficiency exhibit compromised development, particularly with regard to their motor functions. Currently, no animal model of AADC deficiency exists. We inserted an AADC gene mutation (IVS6+4A>T) and a neomycin-resistance gene into intron 6 of the mouse AADC (Ddc) gene. In the brains of homozygous knock-in (KI) mice (Ddc(IVS6/IVS6)), AADC mRNA lacked exon 6, and AADC activity was <0.3% of that in wild-type mice. Half of the KI mice were born alive but grew poorly and exhibited severe dyskinesia and hindlimb clasping after birth. Two-thirds of the live-born KI mice survived the weaning period, with subsequent improvements in their growth and motor functions; however, these mice still displayed cardiovascular dysfunction and behavioral problems due to serotonin deficiencies. The brain dopamine levels in the KI mice increased from 9.39% of the levels in wild-type mice at 2weeks of age to 37.86% of the levels in wild-type mice at 8weeks of age. Adult KI mice also exhibited an exaggerated response to apomorphine and an elevation of striatal c-Fos expression, suggesting post-synaptic adaptations. Therefore, we generated an AADC deficient mouse model, in which compensatory regulation allowed the mice to survive to adulthood. This mouse model will be useful both for developing gene therapies for AADC deficiency and for designing treatments for diseases associated with neurotransmitter deficiency.

A randomized controlled trial of the effects of listening to non-commercial music on quality of nocturnal sleep and relaxation indices in patients in medical intensive care unit.

AIM: The purpose was to examine the effects of non-commercial music on quality of sleep and relaxation indices, including heart rate, mean arterial pressure, and respiratory rate in patients in intensive care units. BACKGROUND: There is currently insufficient scientific knowledge for the effects of music on quality of sleep in critically ill patients. DESIGN: A randomized controlled trial. METHODS: Between January-December 2010, 28 patients aged 39-78 years were randomly assigned to music and control groups. Participants in the music groups listened to non-commercial music for 45 minutes at nocturnal sleep time. In the control group, participants slept with no music. Participants were assessed using vital signs monitors, standardized questionnaire, and polysomnography. Polysomnography sleep was recorded for the first 2 hours of the nocturnal sleep. General estimating equation was applied to analyse data. FINDINGS: Participants in the music group had shorter stage N2 sleep and longer stage N3 sleep in the first 2 hours of the nocturnal sleep and improved self-reported sleep quality, compared with those in the control group. The music group patients also had significantly lower heart rates than those in the control group. The intensive care units patients experienced fragmented sleep with a high frequency of awakenings and severe reduction in random eye movement sleep during the first 2 hours of the nocturnal sleep. CONCLUSION: The findings provided evidence for nurses to use soothing music as a research-based nursing intervention for intensive care unit patients' sleep improvement.

Effects of music on immunity and physiological responses in healthcare workers: a randomized controlled trial.

Research-based evidence supports the effectiveness of soothing music in improving stress-related psycho-physiological indices in a clinical setting. However, there is currently insufficient scientific knowledge of the effects of music on immune markers of stress in humans. Therefore, the aims of the study were to compare the effects of music and quiet rest on the levels of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-10 (IL-10), heart rate and mean arterial pressure among healthcare workers. By using a randomized controlled trial design, 60 nurses were randomly assigned to the stimulating or sedating music or rest groups for 30 min. Participants' psychoneuroimmunological parameters were measured using enzyme-linked immunosorbent assays. General estimating equation was used to analyse data. Results revealed that IL-6, TNF-α and IL-10 were not detectable in this population. No significance differences in heart rate were found among the three groups. However, the stimulating music group had significantly higher mean arterial pressure levels than the sedating music group but no differences between the quiet rest group and the sedating music group. Music with different tempi had little effect on mean arterial pressure. Any effect of music on immune markers of stress requires further research.

The effects of music on the sleep quality of adults with chronic insomnia using evidence from polysomnographic and self-reported analysis: a randomized control trial.

BACKGROUND: Research-based evidence supports the therapeutic use of music to improve the sleep quality measured by self-reported questionnaires. However, scientific knowledge of the effects of music measured using standard polysomnography in chronic insomnia adults is currently insufficient. OBJECTIVES: The objective of this study was to evaluate the effect of soothing music on objective and subjective sleep quality in adults with chronic insomnia. METHODS: Fifty participants were enrolled in a randomized controlled trial conducted in the sleep laboratory of a hospital, with 25 participants allocated to the music group and 25 to the control group. For four days, the experimental group was exposed to soothing music selected by the participants or researchers for 45 min at nocturnal sleep time, whereas the control group was not exposed to music. Sleep was measured using polysomnography (PSG) and self-reported questionnaires. A general estimating equation was applied to analyze the data. RESULTS: After controlling for baseline data, the music group had significantly better scores for rested rating (p=0.01), shortened stage 2 sleep (p=0.03), and prolonged REM sleep (p=0.04) compared to the control group, shown by the generalized estimating equations. However, there was no evidence of the effectiveness of music on other sleep parameters as measured by PSG. Additional findings indicate no difference in sleep quality between those who listened to their own preferred music (n=10) and those who listened to music selected by the researchers (n=15). CONCLUSION: The results contribute to knowledge of the effectiveness of music as a therapy to improve sleep quality in adults experiencing insomnia. Listening to soothing music at nocturnal sleep time improved the rested rating scores, shortened stage 2 sleep, and prolonged REM sleep, but has little effect on sleep quality as measured by polysomnography and self-reported questionnaires.