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Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed?

A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility.

Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret.

A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries).

Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods.

The core outcome set consists of viable intrauterine pregnancy confirmed by ultrasound (accouility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form.

Core Outcome Measures in Effectiveness Trials Initiative 1023.

Core Outcome Measures in Effectiveness Trials Initiative 1023.The extent that Pleistocene climate variability promoted speciation has been much debated. Here, we surveyed genetic markers in winged kelp Alaria in the Gulf of Alaska, Northeast Pacific Ocean to understand how paleoclimates may have influenced diversity in this kelp. The study included wide geographic sampling over 2800 km and large sample sizes compared to previous studies of this kelp. Mitochondrial 5'-COI (664 bp), plastid rbcL-3' (740 bp) and 8 microsatellite markers in 16 populations resolved 5 well-defined lineages. SEL120 nmr COI-rbcL haplotypes were distributed chaotically among populations around the Gulf of Alaska. Principal Coordinates Analysis of microsatellite genotypes grouped plants largely by organellar lineage instead of geography, indicating reproductive isolation among lineages. However, microsatellite markers detected hybrids at 3 sites where lineages co-occurred. Local adaptation on various time scales may be responsible for some genetic differences between populations located along wave-energy and salinity gradients, but the chaotic pattern of variability over hundreds of kilometers is likely due to isolations in northern refugia during Pleistocene ice ages. The range of divergences between populations indicates that episodic glaciations led to the creation of new lineages, but population turnover (local extinctions and recolonizations) limited the formation of new species in the Northeastern Pacific Ocean.A loss-of-function mutation in the melanocortin 1 receptor gene (MC1R), which switches off the eumelanin production, causes yellowish coat color variants in mammals. In a wild population of sables (Martes zibellina) in Hokkaido, Japan, the mutation responsible for a bright yellow coat color variant was inferred to be a cysteine replacement at codon 35 of the N-terminal extracellular domain of the Mc1r receptor. In the present study, we validated these findings by applying genome editing on Mc1r in mouse strains C3H/HeJ and C57BL/6N, altering the codon for cysteine (Cys33Phe). The resulting single amino acid substitution (Cys33Phe) and unintentionally generated frameshift mutations yielded a color variant exhibiting substantially brighter body color, indicating that the Cys35 replacement produced sufficient MC1R loss of function to confirm that this mutation is responsible for producing the Hokkaido sable yellow color variant. Notably, the yellowish mutant mouse phenotype exhibited brown coloration in subapical hair on the dorsal side in both the C3H/HeJ and C57BL/6N strains, despite the inability of the latter to produce the agouti signaling protein (Asip). This darker hair and body coloration was not apparent in the Hokkaido sable variant, implying the presence of an additional genetic system shaping yellowish hair variability.

The electronic Frailty Index (eFI) has been developed in primary care settings. The Hospital Frailty Risk Score (HFRS) was derived using secondary care data.

Compare the two different tools for identifying frailty in older people admitted to hospital.

Retrospective cohort study using the Secure Anonymised Information Linkage Databank, comprising 126,600 people aged 65+ who were admitted as an emergency to hospital in Wales from January 2013 up until December 2017.

Pearson's correlation coefficient and weighted kappa were used to assess the correlation between the tools. Cox and logistic regression were used to estimate hazard ratios (HRs) and odds ratios (ORs). The Concordance statistic and area under the receiver operating curves (AUROC) were estimated to determine discrimination.

Pearson's correlation coefficient was 0.26 and the weighted kappa was 0.23. Comparing the highest to the least frail categories in the two scores the HRs for 90-day mortality, 90-day emergency readmission and care home admissions within 1-year using the HFRS were 1.41, 1.69 and 4.15 for the eFI 1.16, 1.63 and 1.47. Similarly, the ORs for inpatient death, length of stay greater than 10days and readmission within 30-days were 1.44, 2.07 and 1.52 for the HFRS, and 1.21, 1.21 and 1.44 for the eFI. AUROC was determined as having no clinically relevant difference between the tools.

The eFI and HFRS have a low correlation between their scores. The HRs and ORs were higher for the increasing frailty categories for both the HFRS and eFI.

The eFI and HFRS have a low correlation between their scores. The HRs and ORs were higher for the increasing frailty categories for both the HFRS and eFI.Developers of SARS-CoV-2 vaccines should consider some of the lessons from a 'new' vaccine introduced in 1921, namely BCG.

Can the priorities for future research in infertility be identified?

The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified.

Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems.

Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. link2 A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research prioritit' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form.

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N/A.Detecting the signature of selection in coding sequences and associating it with shifts in phenotypic states can unveil genes underlying complex traits. Of the various signatures of selection exhibited at the molecular level, changes in the pattern of selection at protein-coding genes have been of main interest. To this end, phylogenetic branch-site codon models are routinely applied to detect changes in selective patterns along specific branches of the phylogeny. Many of these methods rely on a prespecified partition of the phylogeny to branch categories, thus treating the course of trait evolution as fully resolved and assuming that phenotypic transitions have occurred only at speciation events. Here, we present TraitRELAX, a new phylogenetic model that alleviates these strong assumptions by explicitly accounting for the uncertainty in the evolution of both trait and coding sequences. This joint statistical framework enables the detection of changes in selection intensity upon repeated trait transitions. We evaluated the performance of TraitRELAX using simulations and then applied it to two case studies. Using TraitRELAX, we found an intensification of selection in the primate SEMG2 gene in polygynandrous species compared to species of other mating forms, as well as changes in the intensity of purifying selection operating on sixteen bacterial genes upon transitioning from a free-living to an endosymbiotic lifestyle.[Evolutionary selection; intensification; $\gamma $-proteobacteria; genotype-phenotype; relaxation; SEMG2.].Hybrids between species often show extreme phenotypes, including some that take place at the molecular level. In this study, we investigated the phenotypes of an interspecies diploid hybrid in terms of protein-protein interactions inferred from protein correlation profiling. We used two yeast species, Saccharomyces cerevisiae and Saccharomyces uvarum, which are interfertile, but yet have proteins diverged enough to be differentiated using mass spectrometry. Most of the protein-protein interactions are similar between hybrid and parents, and are consistent with the assembly of chimeric complexes, which we validated using an orthogonal approach for the prefoldin complex. We also identified instances of altered protein-protein interactions in the hybrid, for instance, in complexes related to proteostasis and in mitochondrial protein complexes. Overall, this study uncovers the likely frequent occurrence of chimeric protein complexes with few exceptions, which may result from incompatibilities or imbalances between the parental proteomes.

Children with medical complexity (CMC) frequently experience fragmented care. We have demonstrated that outpatient comprehensive care (CC) reduces serious illnesses, hospitalizations, and costs for high-risk CMC. Yet continuity of care for CMC is often disrupted with emergency department (ED) visits and hospitalizations.

To evaluate a hospital consultation (HC) service for CMC from their outpatient CC clinicians.

Randomized quality improvement trial at the University of Texas Health Science Center at Houston with an outpatient CC clinic and tertiary pediatric hospital (Children's Memorial Hermann Hospital). Participants included high-risk CMC (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrolling in our clinic) receiving CC. Data were analyzed between January 11, 2018, and December 20, 2019.

The HC included serial discussions between CC clinicians, ED physicians, and hospitalists addressing need for admission, inpatient treatment, and transition back to alysis using a bayesian prior centered at RR of 0.78, reflecting the opinion of 7 experts knowledgeable about CMC, the probability that HC reduced hospital days was 96%.

Among CMC receiving comprehensive outpatient care, an HC service from outpatient clinicians likely reduced total hospital days, hospitalizations, PICU days, other outcomes, and health system costs. link3 Additional trials of an HC service from outpatient CC clinicians are needed for CMC in other centers.

ClinicalTrials.gov Identifier NCT02870387.

ClinicalTrials.gov Identifier NCT02870387.