Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.

A comparison of morphokinetic models and morphological selection for prioritizing euploid embryos: a multicentre cohort study.

STUDY QUESTION: Are morphokinetic models better at prioritizing a euploid embryo for transfer over morphological selection by an embryologist? SUMMARY ANSWER: Morphokinetic algorithms lead to an improved prioritization of euploid embryos when compared to embryologist selection. WHAT IS KNOWN ALREADY: PREFER (predicting euploidy for embryos in reproductive medicine) is a previously published morphokinetic model associated with live birth and miscarriage. The second model uses live birth as the target outcome (LB model). STUDY DESIGN, SIZE, DURATION: Data for this cohort study were obtained from 1958 biopsied blastocysts at nine IVF clinics across the UK from January 2021 to December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ability of the PREFER and LB models to prioritize a euploid embryo was compared against arbitrary selection and the prediction of four embryologists using the timelapse video, blinded to the morphokinetic time stamp. The comparisons were made using calculated percentages and normalized discounted cumulative gain (NDCG), whereby an NDCG score of 1 would equate to all euploid embryos being ranked first. In arbitrary selection, the ploidy status was randomly assigned within each cycle and the NDGC calculated, and this was then repeated 100 times and the mean obtained. MAIN RESULTS AND THE ROLE OF CHANCE: Arbitrary embryo selection would rank a euploid embryo first 37% of the time, embryologist selection 39%, and the LB and PREFER ploidy morphokinetic models 46% and 47% of the time, respectively. The AUC for LB and PREFER model was 0.62 and 0.63, respectively. Morphological selection did not significantly improve the performance of both morphokinetic models when used in combination. There was a significant difference between the NDGC metric of the PREFER model versus embryologist selection at 0.96 and 0.87, respectively (t = 14.1, P < 0.001). Similarly, there was a significant difference between the LB model and embryologist selection with an NDGC metric of 0.95 and 0.87, respectively (t = 12.0, P < 0.001). All four embryologists ranked embryos similarly, with an intraclass coefficient of 0.91 (95% CI 0.82-0.95, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Aside from the retrospective study design, limitations include allowing the embryologist to watch the time lapse video, potentially providing more information than a truly static morphological assessment. Furthermore, the embryologists at the participating centres were familiar with the significant variables in time lapse, which could bias the results. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the use of morphokinetic models, namely PREFER and LB, translates into improved euploid embryo selection. STUDY FUNDING/COMPETING INTEREST(S): This study received no specific grant funding from any funding agency in the public, commercial or not-for-profit sectors. Dr Alison Campbell is minor share holder of Care Fertility. All other authors have no conflicts of interest to declare. Time lapse is a technology for which patients are charged extra at participating centres. TRIAL REGISTRATION NUMBER: N/A.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

Performance of Contactless Respiratory Rate Monitoring by Albus HomeTM, an Automated System for Nocturnal Monitoring at Home: A Validation Study.

Respiratory rate (RR) is a clinically important predictor of cardio-respiratory deteriorations. The mainstay of clinical measurement comprises the manual counting of chest movements, which is variable between clinicians and limited to sporadic readings. Emerging solutions are limited by poor adherence and acceptability or are not clinically validated. Albus HomeTM is a contactless and automated bedside system for nocturnal respiratory monitoring that overcomes these limitations. This study aimed to validate the accuracy of Albus Home compared to gold standards in real-world sleeping environments. Participants undertook overnight monitoring simultaneously using Albus Home and gold-standard polygraphy with thoraco-abdominal respiratory effort belts (SomnomedicsEU). Reference RR readings were obtained by clinician-count of polygraphy data. For both the Albus system and reference, RRs were measured in 30-s segments, reported as breaths/minute, and compared. Accuracy was defined as the percentage of RRs from the Albus system within ±2 breaths/minute of reference counts. Across a diverse validation set of 32 participants, the mean accuracy exceeded 98% and was maintained across different participant characteristics. In a Bland-Altman analysis, Albus RRs had strong agreement with reference mean differences and the limits of agreement of -0.4 and ±1.2 breaths/minute, respectively. Albus Home is a contactless yet accurate system for automated respiratory monitoring. Validated against gold -standard methods, it enables long-term, reliable nocturnal monitoring without patient burden.

Telemedicine in Adult Rheumatology: In Practice and in Training.

Many rheumatology providers, including fellows-in-training, responded to the immediate need for maintaining patient access to care via telerheumatology during the COVID-19 pandemic. The rapidity of this transition did not permit an intentional approach to integrating fellow education and training into virtual patient care. Virtual patient care has since become an integrated, and perhaps, an embedded part of rheumatology practice that will likely endure beyond the COVID-19 pandemic. Thus, the development of best practices in telerheumatology, including those for fellow education and training as these new entrants prepare to enter our workforce, will benefit the entire specialty. In this work, we seek to describe current models for training learners in virtual patient care, characterize existing barriers to virtual care models, and offer strategies to integrate telerheumatology into curriculum development and training.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

Nonradiographic axial spondyloarthritis.

Non-radiographic axial spondyloarthritis (nr-axSpA) is a complex disease process that is part of the spectrum of axial spondyloarthritis (axSpA). This article reviews the current state of the literature as the understanding of this disease spectrum expands. The conceptual history and terminology, genetics, and epidemiology are reviewed. The clinical manifestations, diagnostic approach, and measures of disease activity are examined. Finally the current treatment modalities and recommendations and the research agenda for nr-axSpA are reviewed. With the advent of new criteria, the disease spectrum can be studied in a systematic manner. These data have enriched our knowledge that reflects an earlier or milder form of disease on a spectrum same as that of ankylosing spondylitis (or radiographic axSpA). We learned how patients present in this stage and that despite an unacceptable delay in diagnosis (regardless of the stage), the burden of disease is high and unremitting. nr-axSpA clinical trials have been somewhat heterogeneous (with variable inclusion criteria) but have nevertheless shown considerable efficacy with tumor necrosis factor inhibitors and flare on withdrawal of therapy.

Screening via CT angiogram after traumatic cervical spine fractures: narrowing imaging to improve cost effectiveness. Experience of a Level I trauma center.

OBJECT: Screening for vertebral artery injury (VAI) following cervical spine fractures is routinely performed across trauma centers in North America. From 2002 to 2007, the total number of neck CT angiography (CTA) studies performed in the Medicare population after trauma increased from 9796 to 115,021. In the era of cost-effective medical care, the authors aimed to evaluate the utility of CTA screening in detecting VAI and reduce chances of posterior circulation strokes after traumatic cervical spine fractures. METHODS: A retrospective review of all patients presenting with cervical spine fractures to Northeast Ohio's Level I trauma institution from 2002 to 2012 was performed. RESULTS: There was a total of 1717 cervical spine fractures in patients presenting to Northeast Ohio's Level I trauma institution between 2002 and 2012. CTA screening was performed in 732 patients, and 51 patients (0.7%) were found to have a VAI. Fracture patterns with increased odds of VAI were C-1 and C-2 combined fractures, transverse foramen fractures, and subluxation of adjacent vertebral levels. Ten posterior circulation strokes were identified in this patient population (0.6%) and found in only 4 of 51 cases of VAI (7.8%). High-risk fractures defined by Denver Criteria, VAI, and antiplatelet treatment of VAI were not independent predictors of stroke. CONCLUSIONS: Cost-effective screening must be reevaluated in the setting of blunt cervical spine fractures on a case-by-case basis. Further prospective studies must be performed to elucidate the utility of screening for VAI and posterior circulation stroke prevention, if identified.

The impact of preoperative depression on quality of life outcomes after posterior cervical fusion.

BACKGROUND CONTEXT: Posterior cervical fusion (PCF) has been shown to be an effective treatment for cervical spondylosis, but is associated with a 9% complication rate and high costs. To limit such complications and costs, it is imperative that proper selection of surgical candidates occur for those most likely to do well with the surgery. Affective disorders, such as depression, are associated with worsened outcomes after lumbar surgery; however, this effect has not been evaluated in patients undergoing cervical spine surgery. PURPOSE: To assess the predictive value of preoperative depression and the health state on 1-year quality of life (QOL) outcomes after PCF. STUDY DESIGN: A retrospective cohort analysis. PATIENT SAMPLE: Eighty-eight patients who underwent PCF for cervical spondylosis were reviewed. OUTCOME MEASURES: Preoperative and 1-year postoperative health outcomes were assessed based on the Pain Disability Questionnaire (PDQ), the Patient Health Questionnaire-9 (PHQ-9), and the EuroQol five-dimensions (EQ-5D) questionnaire. METHODS: Univariable and multivariable regression analyses were performed to assess for preoperative predictors of 1-year change in health status. RESULTS: Compared with preoperative health states, the PCF cohort showed statistically significant improved PDQ (87.8 vs. 73.6), PHQ-9 (7.7 vs. 6.6), and EQ-5D (0.50 vs. 0.60) scores at 1 year postoperatively. Only 10/88 (11%) patients achieved or surpassed the minimum clinically important difference for the PHQ-9 (5). Multiple linear and logistic regression analyses showed that increasing PHQ-9 and EQ-5D preoperative scores were associated with reduced 1-year postoperative improvement in health status (EQ-5D index). CONCLUSIONS: Of patients who undergo PCF, those with a greater degree of preoperative depression have lower improvements in postoperative QOL compared with those with less depression. Additionally, patients with better preoperative health states also attain lower 1-year QOL improvements.

Efficacy of N-acetyl cysteine in traumatic brain injury.

In this study, using two different injury models in two different species, we found that early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting, to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30-60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man.