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Neuropsychiatric Disease and Treatment 2023The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations....
INTRODUCTION
The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.
METHODS
We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.
RESULTS
We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.
DISCUSSION
We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.
PubMed: 37881807
DOI: 10.2147/NDT.S379703 -
Reproductive Biomedicine Online Jan 2023This commentary situates the recently published systematic review of empirical studies of surrogates' and intended parents' experiences of surrogacy by Kneebone, Beilby...
This commentary situates the recently published systematic review of empirical studies of surrogates' and intended parents' experiences of surrogacy by Kneebone, Beilby and Hammarberg within the context of increased international interest in legislative and regulatory reforms to surrogacy. The commentary evaluates the strengths of this systematic review, before turning to a discussion of how jurisdictions could introduce reforms aiming to facilitate domestic surrogacy arrangements, focusing on the UK and the Law Commission's recent proposals.
Topics: Pregnancy; Female; Humans; Surrogate Mothers; Parents
PubMed: 36319535
DOI: 10.1016/j.rbmo.2022.09.017 -
Journal of Clinical Medicine Oct 2022Obesity, and in particular extreme obesity, as a global health problem is an important risk factor for many diseases, including atherosclerotic cardiovascular disease... (Review)
Review
BACKGROUND
Obesity, and in particular extreme obesity, as a global health problem is an important risk factor for many diseases, including atherosclerotic cardiovascular disease (ACVD). Bariatric surgery might stop or slow atherogenesis by decreasing excessive weight in the early stages of atherogenesis, by suppressing low-grade systemic inflammation as well as by inhibiting oxidative stress and endothelial dysfunction. The aim of this meta-analysis was to provide an answer to whether bariatric surgery has a significant effect on intima-media thickness (IMT) which is a surrogate marker of early atherosclerosis and has a good correlation with atherosclerotic coronary heart disease.
METHODS
A systematic literature search in PubMed, Scopus, Embase, and Web of Science as well as grey literature was performed from inception to 1 July 2022. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V3 software. Overall, the estimate of effect size was measured by a random effects meta-analysis. To account for the heterogeneity of studies regarding study design, characteristics of the populations, and treatment duration, a random-effects model (using the DerSimonian-Laird method) and the generic inverse variance weighting approach were used. To assess the existence of publication bias in the meta-analysis, the funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used.
RESULTS
The meta-analysis of 30 trials, including 1488 subjects, demonstrated a significant decrease in IMT after bariatric surgery. The reduction in IMT was also robust in the leave-one-out sensitivity analysis. It must be stressed that the results of the random-effects meta-regression did not suggest any relationship between the changes in IMT and delta body mass index (BMI) or duration of follow-up after the bariatric surgery. However, the subgroup analyses showed a better IMT reduction after laparoscopic sleeve gastrectomy (LSG) when compared to Roux-en-Y gastric bypass (RYGB). Within a year, the IMT follow-up values showed a further improvement.
CONCLUSIONS
Bariatric surgery significantly reduced IMT. Significant associations were found between the surgery type and IMT changes, as well as a significant effect of follow-up duration on the changes of IMT after bariatric surgery.
PubMed: 36294377
DOI: 10.3390/jcm11206056 -
Reproductive Biomedicine Online Oct 2022This review reports on the experiences of surrogates and intended parents of surrogacy arrangements. The findings from 47 studies, conducted across 12 countries and... (Review)
Review
This review reports on the experiences of surrogates and intended parents of surrogacy arrangements. The findings from 47 studies, conducted across 12 countries and investigating predominately gestational surrogacy in a commercial setting, were analysed thematically, and are reported in a narrative summary. The findings reveal that the experiences of both parties of surrogacy arrangements are largely satisfactory and frequently involve positive relationships forming between one another, which they hope to maintain after birth. Some surrogacy participants experience challenges, particularly when the surrogate and intended parents reside in different countries. Intended parents face legal hurdles when returning home after an international arrangement. Concerningly, multiple reports of clinical practices in India have been published, in which commercial surrogacy was accessed by foreign intended parents, which infringed on surrogates' autonomy during the pregnancy. Intended parents turn to these international destinations when they face barriers to accessing surrogacy in their home country, such as the prohibition of commercial surrogacy. Looking beyond the altruistic and commercial dichotomy may alleviate some of the barriers to domestic surrogacy. Collaboration between professional fertility organizations to develop best practice guidelines can support clinics in providing international surrogacy services that minimize the risk of harm to those accessing care.
Topics: Altruism; Female; Humans; Pregnancy; Surrogate Mothers
PubMed: 35909052
DOI: 10.1016/j.rbmo.2022.06.006 -
Gastroenterology Aug 2021Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered...
BACKGROUND & AIMS
Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines.
METHODS
Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients.
RESULTS
Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient.
CONCLUSIONS
Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.
Topics: Canada; Consensus; Contraindications, Drug; Evidence-Based Medicine; Gastroenterology; Humans; Immunization; Immunocompromised Host; Immunosuppressive Agents; Inflammatory Bowel Diseases; Opportunistic Infections; Patient Safety; Risk Assessment; Risk Factors; Treatment Outcome; Vaccine Efficacy; Vaccines, Live, Unattenuated
PubMed: 33617891
DOI: 10.1053/j.gastro.2020.12.079 -
PLoS Medicine Nov 2020The first 1,000 days of life, i.e., from conception to age 2 years, could be a critical period for cardiovascular health. Increased carotid intima-media thickness (CIMT)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The first 1,000 days of life, i.e., from conception to age 2 years, could be a critical period for cardiovascular health. Increased carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis. We performed a systematic review with meta-analyses to assess (1) the relationship between exposures or interventions in the first 1,000 days of life and CIMT in infants, children, and adolescents; and (2) the CIMT measurement methods.
METHODS AND FINDINGS
Systematic searches of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), and Cochrane Central Register of Controlled Trials (CENTRAL) were performed from inception to March 2019. Observational and interventional studies evaluating factors at the individual, familial, or environmental levels, for instance, size at birth, gestational age, breastfeeding, mode of conception, gestational diabetes, or smoking, were included. Quality was evaluated based on study methodological validity (adjusted Newcastle-Ottawa Scale if observational; Cochrane collaboration risk of bias tool if interventional) and CIMT measurement reliability. Estimates from bivariate or partial associations that were least adjusted for sex were used for pooling data across studies, when appropriate, using random-effects meta-analyses. The research protocol was published and registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42017075169). Of 6,221 reports screened, 50 full-text articles from 36 studies (34 observational, 2 interventional) totaling 7,977 participants (0 to 18 years at CIMT assessment) were retained. Children born small for gestational age had increased CIMT (16 studies, 2,570 participants, pooled standardized mean difference (SMD): 0.40 (95% confidence interval (CI): 0.15 to 0.64, p: 0.001), I2: 83%). When restricted to studies of higher quality of CIMT measurement, this relationship was stronger (3 studies, 461 participants, pooled SMD: 0.64 (95% CI: 0.09 to 1.19, p: 0.024), I2: 86%). Only 1 study evaluating small size for gestational age was rated as high quality for all methodological domains. Children conceived through assisted reproductive technologies (ART) (3 studies, 323 participants, pooled SMD: 0.78 (95% CI: -0.20 to 1.75, p: 0.120), I2: 94%) or exposed to maternal smoking during pregnancy (3 studies, 909 participants, pooled SMD: 0.12 (95% CI: -0.06 to 0.30, p: 0.205), I2: 0%) had increased CIMT, but the imprecision around the estimates was high. None of the studies evaluating these 2 factors was rated as high quality for all methodological domains. Two studies evaluating the effect of nutritional interventions starting at birth did not show an effect on CIMT. Only 12 (33%) studies were at higher quality across all domains of CIMT reliability. The degree of confidence in results is limited by the low number of high-quality studies, the relatively small sample sizes, and the high between-study heterogeneity.
CONCLUSIONS
In our meta-analyses, we found several risk factors in the first 1,000 days of life that may be associated with increased CIMT during childhood. Small size for gestational age had the most consistent relationship with increased CIMT. The associations with conception through ART or with smoking during pregnancy were not statistically significant, with a high imprecision around the estimates. Due to the large uncertainty in effect sizes and the limited quality of CIMT measurements, further high-quality studies are needed to justify intervention for primordial prevention of cardiovascular disease (CVD).
Topics: Adolescent; Atherosclerosis; Breast Feeding; Cardiovascular Diseases; Carotid Intima-Media Thickness; Child; Female; Gestational Age; Humans; Infant; Pregnancy; Reproducibility of Results; Risk Factors
PubMed: 33226997
DOI: 10.1371/journal.pmed.1003414 -
BMJ Global Health Nov 2020Eighty percent of neonatal deaths occur among babies born preterm and/or small for gestational age (SGA). In sub-Saharan Africa and South Asia, approximately 40% of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Eighty percent of neonatal deaths occur among babies born preterm and/or small for gestational age (SGA). In sub-Saharan Africa and South Asia, approximately 40% of births occur outside of health facilities, and gestational age (GA) and birth weight are commonly unknown. Foot length (FL) has been proposed as a simple, surrogate measurement to identify and triage small babies born in the community. We conducted a systematic review and meta-analysis of the diagnostic accuracy of newborn FL to classify preterm and low birthweight infants.
METHODS
PubMed, EMBASE, Cochrane, Web of Science, POPLINE and WHO Global Health Library databases were searched. Studies of live-born infants that compared FL with GA and/or birth weight were included. Data on diagnostic accuracy were summarised, described, and pooled, as appropriate.
RESULTS
Six hundred and two studies were identified and 41 included. Techniques for measuring FL included use of a firm plastic ruler, callipers, footprint or a measuring board. Twelve studies assessed the diagnostic accuracy of FL to identify preterm births; however, data were not pooled given heterogeneity and low quality of GA. 19 studies used FL to identify low birthweight infants (<2500 g, <2000 g). Among studies in Asia (n=3), FL 7.7 cm had pooled sensitivity and specificity of 87.6% (95% CI 61.1% to 99.0%) and 70.9% (95% CI 23.5% to 95.1%), respectively, to identify <2500 g infants. FL 7.3 cm had 82.1% (95% CI 63.7% to 92.2%) sensitivity and 82.1% (95% CI 59.2% to 90.8%) specificity for identifying <2000 g infants (n=3). In the African studies (n=3), FL 7.9 cm had pooled sensitivity and specificity of 92.0% (95% CI 85.6% to 95.7%) and 71.9% (95% CI 44.5% to 89.1%), respectively, to identify <2500 g neonates.
CONCLUSIONS
FL is a simple proxy measure that can identify babies of low birthweight with high sensitivity, though somewhat lower specificity. Additional research is needed to determine the validity of FL to identify preterm infants, and understand the programmatic impact of screening on healthcare seeking and outcomes.
PROSPERO REGISTRATION NUMBER
CRD42015020499.
Topics: Africa South of the Sahara; Birth Weight; Global Health; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature
PubMed: 33208312
DOI: 10.1136/bmjgh-2020-002976