The successful integration of an orthopedic implant into bone depends on the mechanisms at the tissue-implant interface and mostly on the osteoblast attachment phenomenon. Chitosan has emerged as an ...attractive biomacromolecule favoring osseointegration. In this study highly deacetylated chitosan coatings, with roughness of about 1 nm, were bonded to glass surfaces via silane-glutaraldehyde molecules. Human osteoblasts were used to study the development of attachment during the first 60 min. Chitosan favored the number of the attached cells compared to the uncoated surfaces for 30 min seeding time (t s). For t s up to 60 min the attached cell area was almost 210% significantly higher on the chitosan surfaces, indicating an enhanced spreading process. To determine the cell attachment strength, a micropipette aspiration method was used, where the value of the term I = ∫Fdt is representative of the single cell attachment-adhesion procedure and quantitatively reflects the strength evolution during attachment: F equals the detaching force applied on the cell. The results showed higher strength values on the chitosan surfaces. The findings reinforce the favorable environment of the biomacromolecule for the osteoblast and the new approach regarding the quantitatively evaluation of adhesion provides important contribution for the study of cell-material interaction, especially during the crucial first phase of cell attachment.
Abstract
Background
older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients.
Objective
to identify key ...barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people.
Methods
a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs.
Results
the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements.
Conclusion
recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population.
In complex mixtures, proton nuclear magnetic resonance (NMR) spectra are often very crowded, making spectral analysis complicated or even impossible, particularly when detailed structural information ...about the mixture components is needed. A new 1D NMR method (fluorine-edited selective TOCSY acquisition, FESTA) is introduced that facilitates the structural analysis of mixtures of species that contain fluorine. It allows simplified 1H spectra to be obtained that show only those protons that are in a spin system coupled to fluorine of interest. The new method is illustrated by factorizing a complex 1H spectrum into subspectra for individual spin systems involving different 19F sites.
Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all ...aspects of fatigue.
This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.
Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score n = 88 or ≥13 points for the mental score n = 41), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).
Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.
Abstract
Background
loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and ...has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass.
Methods
this is an ancillary study within two RCTs conducted among adults aged ≥65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60–19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass.
Results
we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1–97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation SD 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference MD 0.01 m/s, 95% confidence interval CI −0.06 to 0.09), similar handgrip strength at one year (MD −1.22 kg, 95% CI −2.60 to 0.15) and similar yearly change in muscle mass (MD −0.15 m2, 95% CI −0.49 to 0.18).
Conclusions
in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older.
Background
Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed ...whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4).
Objective
To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies.
Methods
We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1‐year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid‐Related Quality‐of‐Life Patient‐Reported Outcome Questionnaire.
Results
Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti‐TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between‐group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between‐group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti‐TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment.
Conclusions
Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.
Abstract
Importance
Subclinical hypothyroidism has been associated with heart failure, but no conclusive clinical trial assessed whether treating subclinical hypothyroidism with levothyroxine has an ...impact on cardiac function.
Objective
To assess the impact of levothyroxine treatment on cardiac function in subclinical hypothyroidism.
Design
This is a randomized, double-blind placebo-controlled, multicenter Swiss substudy within the TRUST trial.
Participants
Participants aged ≥65 years with subclinical hypothyroidism.
Intervention
Levothyroxine to achieve TSH normalization, or placebo including mock titrations.
Main outcome measures
Primary outcomes, assessed by echocardiography at the end of the trial were the left ventricular ejection fraction (LVEF, normal defined as >50%) for systolic function and the ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e' (E/e' ratio) for diastolic function. Secondary outcomes included transmitral E and A waves, e' lateral/septal, left atrial (LA) volume index and systolic pulmonary artery pressure.
Results
Of 217 randomized Swiss participants of the TRUST trial, 185 (mean age 74.1 years, 47% women, mean TSH at baseline 6.35 ± SD 1.95 mIU/L) underwent echocardiography. After a median treatment duration of 18.4 months, the mean TSH among participants randomized to levothyroxine (n=95) decreased to 3.55 mIU/L, whereas it remained elevated in the placebo group (n=89; 5.29 mIU/L). The mean LVEF was similar in both arms (adjusted between-group difference 0.4%, 95% CI −1.8% to 2.5%, P=0.72) and no significant differences were found for the E/e' ratio (adjusted between-group difference 0.4, 95% CI −0.7 to 1.4, P=0.47). In intention-to-treat and per-protocol analyses, no clinically significant differences were found for secondary diastolic function parameters: e' lateral 8 vs. 8 cm/s, P=0.54; e' septal 6 vs. 6 cm/s, P=0.75; LA volume index 34 vs. 33 ml/m2, P=0.57; E/A ratio 0.8 vs. 0.8, P=0.94; E deceleration time 225 vs. 216 ms, P=0.27, except for systolic pulmonary artery pressure (37 mm Hg in the levothyoxine group vs. 33 mm Hg in the placebo group, P=0.02 intention-to-treat and P=0.06 per protocol)
Conclusion
Treatment of subclinical hypothyroidism with levothyroxine was not associated with benefits regarding systolic and diastolic heart function in older adults with subclinical hypothyroidism.
Abstract
Background
Hypertension (HTN) is one of the most common cardiovascular risk factors in patients with atrial fibrillation (AF). As a potential risk factor for cerebral white matter lesions ...(WML), HTN might explain the increased risk of cognitive dysfunction in AF patients.
Methods
In a multicenter cohort study of patients with documented AF in Switzerland, systolic and diastolic blood pressure (SBP, DBP) was measured up to three times in a supine position and the mean was calculated. HTN was defined as controlled, when SBP was <140 and DBP <90 mmHg with treatment, and uncontrolled when SBP was ≥140 or DBP ≥90 mmHg with treatment. All patients underwent brain magnetic resonance imaging. Volumes of WML were assessed and graded using the Fazekas scale. A Fazekas score of ≥2 was defined as moderate or severe WML. Multivariable adjusted regression models were used to assess the association between BP and WML.
Results
Overall, 1738 patients were enrolled in this cross-sectional analysis (mean age 73 years, 73% males). Mean BP was 135/79 mmHg, 69% had a history of HTN. Any WMLs were found in 99% of the patients and 54% had at least moderate WMLs. The prevalence of Fazekas ≥2 was 47%, 50% and 61% among AF patients with SBP <120, 120–140 and ≥140mmHg (p<0.001), respectively. Volumes of WMLs significantly increased across the same SBP categories (2943, 3512 and 4988 mm3, p<0.001). Among patients with normotension, controlled and uncontrolled HTN, moderate or severe WMLs were present in 173 (42.5%), 345 (55%) and 307 (61%), respectively. SBP was associated with Fazekas ≥2 and WML volume after multivariable adjustment (Table). Compared to normotension, both controlled and uncontrolled HTN were significantly associated with higher WML volume (Table).
Association between blood pressure and white matter lesions
Blood pressure
Fazekas ≥2 OR (95% CI)
Volume WML β-coefficient (95% CI)
<120 mmHg
Ref
Ref
120–140 mmHg
1.17 (0.88; 1.55)
0.14 (−0.01; 0.30)
≥140 mmHg
1.49 (1.11; 2.00)
0.28 (0.12; 0.43)
Continuous, per SD
1.20 (1.09; 1.36), p<0.001
0.12 (0.06; 0.18), p<0.001
Normotension
Ref
Ref
Treated hypertension
1.26 (0.94; 1.68), p=0.12
0.22 (0.07; 0.38), p=0.005
Treated, uncontrolled hypertension
1.52 (1.13; 2.05), p=0.005
0.38 (0.21; 0.54), p<0.001
Regression analyses were adjusted for age, sex, BMI, smoking status, stroke, diabetes, coronary heart disease, AF type, and antihypertensive treatment. One standard Deviation (SD) of SBP = 18 mmHg. Volume of WML was log-transformed.
Conclusion
Moderate or severe cerebral WMLs are highly prevalent in AF patients and strongly associated with SBP. Our data suggests that optimal treatment of HTN might play an essential role in preventing WMLs.
Acknowledgement/Funding
Swiss National Science Foundation
Abstract
Background
Levothyroxine is one of the most commonly prescribed drugs. A common reason for levothyroxine treatment on patients with subclinical hypothyroidism are depressive symptoms. A ...meta-analysis of four RCTs (n = 278) found no benefit of levothyroxine therapy on depressive symptoms. However, the confidence interval does not exclude a small clinical benefit. We aim to assess the effect of levothyroxine therapy for depressive symptoms in patients with subclinical hypothyroidism using data from a RCT with more than 400 adults.
Methods
The TRUST trial was a double-blind, randomized, placebo-controlled trial involving adults aged ≥65y with subclinical hypothyroidism (elevated TSH levels (4.6-19.9 mU/L) and free thyroxine within the reference range). The outcome was depressive symptoms after 12 months based on the Geriatric Depression Scale (GDS-15), a 15-item questionnaire (range: 0 to 15, higher scores indicate more depressive symptoms, minimal clinical important difference: 2). The multivariable linear regression model was adjusted for levothyroxine starting dose, sex, site, and GDS-15 baseline score.
Results
425 Swiss and Dutch adults with subclinical hypothyroidism were randomised (mean age 75y, 56% female). The mean (SD) TSH was 6.6 (2.1) mU/L at baseline and after 12 months decreased to 3.8 (2.3) mU/L in the levothyroxine group vs 5.9 (2.7) mU/L in the placebo group. At baseline, the mean GDS-15 score was 1.3 (1.9) in the levothyroxine group and 1.0 (1.6) in the placebo group. The mean GDS-15 score at 12 months was 1.4 (2.1) in the levothyroxine and 1.1 (1.7) in the placebo group with an adjusted between-group difference of 0.2 for levothyroxine vs. placebo (95% CI:-0.1 to 0.5; p = 0.29).
Conclusions
In this by far largest RCT on the topic, levothyroxine therapy did not confer a benefit for depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine for depressive symptoms when they co-occur with subclinical hypothyroidism.
Key messages
Levothyroxine has no benefit on depressive symptoms in patients with subclinical hypothyroidism. Levothyroxine prescription to patients with subclinical hypothyroidism and depressive symptoms should be reconsidered.
IntroductionMultimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and ...underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy.Methods and analysisOPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People’s Prescriptions/Screening Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient’s admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient’s drug compliance, the number of significant drug–drug interactions, drug overuse and underuse and potentially inappropriate medication.Ethics and disseminationThe local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal.Main fundingEuropean Union’s Horizon 2020 programme.Trial registration number NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400.
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