Long-term health-related and economic consequences of short-term outcomes in evaluation of perinatal interventions

<p>Abstract</p> <p>Background</p> <p>Many perinatal interventions are performed to improve long-term neonatal outcome. To evaluate the long-term effect of a perinatal intervention follow-up of the child after discharge from the hospital is necessary because serious sequelae from perinatal complications frequently manifest themselves only after several years. However, long-term follow-up is time-consuming, is not in the awareness of obstetricians, is expensive and falls outside the funding-period of most obstetric studies. Consequently, short-term outcomes are often reported instead of the primary long-term end-point. With this project, we will assess the current state of affairs concerning follow-up after obstetric RCTs and we will develop multivariable prediction models for different long-term health outcomes. Furthermore, we would like to encourage other researchers participating in follow-up studies after large obstetric trials (> 350 women) to inform us about their studies so that we can include their follow-up study in our systematic review. We would invite these researchers also to join our effort and to collaborate with us on the external validation of our prediction models.</p> <p>Methods/Design</p> <p>A systematic review of neonatal follow-up after obstetric studies will be performed. All reviews of the Cochrane Pregnancy and Childbirth group will be assessed for reviews on interventions that aimed to improve neonatal outcome. Reviews on interventions primary looking at other aspects than neonatal outcome such as labour progress will also be included when these interventions can change the outcome of the neonate on the short or long-term. Our review will be limited to RCTs with more than 350 women. Information that will be extracted from these RCTs will address whether, how and for how long follow-up has been performed. However, in many cases long-term follow-up of the infants will not be feasible. An alternative solution to limited follow-up could be to develop prediction models to estimate long-term health outcomes of the newborn based on specific perinatal outcomes and other covariates. For the development of multivariable prediction models for several health outcomes, we will use data available from a Dutch cohort study of preterm (< 32 weeks) and/or small for gestational age infants (< 1500 g). These infants were born in The Netherlands in 1983 and followed until they reached the age of 19.</p> <p>Discussion</p> <p>The systematic review will provide insight in the extent and methods used for follow-up assessments after obstetric RCTs in the past. The prediction models can be used by future studies to extrapolate short-term outcomes to a long-term horizon or to indicate for which neonates long-term follow-up is required, as their outcomes (either absence or presence of sequelae) cannot be adequately predicted from short-term outcomes and clinical background characteristics.</p

Utilizing Spatial Demographic and Life History Variation to Optimize Sustainable Yield of a Temperate Sex-Changing Fish

Fish populations vary geographically in demography and life history due to environmental and ecological processes and in response to exploitation. However, population dynamic models and stock assessments, used to manage fisheries, rarely explicitly incorporate spatial variation to inform management decisions. Here, we describe extensive geographic variation in several demographic and life history characteristics (e.g., size structure, growth, survivorship, maturation, and sex change) of California sheephead (Semicossyphus pulcher), a temperate rocky reef fish targeted by recreational and commercial fisheries. Fish were sampled from nine locations throughout southern California in 2007–2008. We developed a dynamic size and age-structured model, parameterized separately for each location, to assess the potential cost or benefit in terms of fisheries yield and conservation objectives of changing minimum size limits and/or fishing mortality rates (compared to the status quo). Results indicate that managing populations individually, with location-specific regulations, could increase yield by over 26% while maintaining conservative levels of spawning biomass. While this local management approach would be challenging to implement in practice, we found statistically similar increases in yield could be achieved by dividing southern California into two separate management regions, reflecting geographic similarities in demography. To maximize yield, size limits should be increased by 90 mm in the northern region and held at current levels in the south. We also found that managing the fishery as one single stock (the status quo), but with a size limit 50 mm greater than the current regulations, could increase overall fishery yield by 15%. Increases in size limits are predicted to enhance fishery yield and may also have important ecological consequences for the predatory role of sheephead in kelp forests. This framework for incorporating demographic variation into fisheries models can be exported generally to other species and may aid in identifying the appropriate spatial scales for fisheries management

Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences and Countermeasures.

Circadian (∼ 24 hour) timing systems pervade all kingdoms of life, and temporally optimize behaviour and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behaviour and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these too are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally-driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioural and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism

TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects

Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells

Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707