Reconstituting human somitogenesis in vitro.

The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms; however, the details of this process in humans remain largely unknown owing to ethical and technical limitations. Despite recent advances with pluripotent stem cell-based approaches1-5, models that robustly recapitulate human somitogenesis in both space and time remain scarce. Here we introduce a pluripotent stem cell-derived mesoderm-based 3D model of human segmentation and somitogenesis-which we termed 'axioloid'-that captures accurately the oscillatory dynamics of the segmentation clock and the morphological and molecular characteristics of sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF-WNT signalling gradients and retinoic acid signalling components. We identify an unexpected critical role of retinoic acid signalling in the stabilization of forming segments, indicating distinct, but also synergistic effects of retinoic acid and extracellular matrix on the formation and epithelialization of somites. Comparative analysis demonstrates marked similarities of axioloids to the human embryo, further validated by the presence of a Hox code in axioloids. Finally, we demonstrate the utility of axioloids for studying the pathogenesis of human congenital spine diseases using induced pluripotent stem cells with mutations in HES7 and MESP2. Our results indicate that axioloids represent a promising platform for the study of axial development and disease in humans.

Transcriptional programs of Pitx2 and Tfap2a/Tfap2b controlling lineage specification of mandibular epithelium during tooth initiation.

How the dorsal-ventral axis of the vertebrate jaw, particularly the position of tooth initiation site, is established remains a critical and unresolved question. Tooth development starts with the formation of the dental lamina, a localized thickened strip within the maxillary and mandibular epithelium. To identify transcriptional regulatory networks (TRN) controlling the specification of dental lamina from the naïve mandibular epithelium, we utilized Laser Microdissection coupled low-input RNA-seq (LMD-RNA-seq) to profile gene expression of different domains of the mandibular epithelium along the dorsal-ventral axis. We comprehensively identified transcription factors (TFs) and signaling pathways that are differentially expressed along mandibular epithelial domains (including the dental lamina). Specifically, we found that the TFs Sox2 and Tfap2 (Tfap2a/Tfap2b) formed complimentary expression domains along the dorsal-ventral axis of the mandibular epithelium. Interestingly, both classic and novel dental lamina specific TFs-such as Pitx2, Ascl5 and Zfp536-were found to localize near the Sox2:Tfap2a/Tfap2b interface. To explore the functional significance of these domain specific TFs, we next examined loss-of-function mouse models of these domain specific TFs, including the dental lamina specific TF, Pitx2, and the ventral surface ectoderm specific TFs Tfap2a and Tfap2b. We found that disruption of domain specific TFs leads to an upregulation and expansion of the alternative domain's TRN. The importance of this cross-repression is evident by the ectopic expansion of Pitx2 and Sox2 positive dental lamina structure in Tfap2a/Tfap2b ectodermal double knockouts and the emergence of an ectopic tooth in the ventral surface ectoderm. Finally, we uncovered an unappreciated interface of mesenchymal SHH and WNT signaling pathways, at the site of tooth initiation, that were established by the epithelial domain specific TFs including Pitx2 and Tfap2a/Tfap2b. These results uncover a previously unknown molecular mechanism involving cross-repression of domain specific TFs including Pitx2 and Tfap2a/Tfap2b in patterning the dorsal-ventral axis of the mouse mandible, specifically the regulation of tooth initiation site.

Speciation across the Earth driven by global cooling in terrestrial orchids.

Although climate change has been implicated as a major catalyst of diversification, its effects are thought to be inconsistent and much less pervasive than localized climate or the accumulation of species with time. Focused analyses of highly speciose clades are needed in order to disentangle the consequences of climate change, geography, and time. Here, we show that global cooling shapes the biodiversity of terrestrial orchids. Using a phylogeny of 1,475 species of Orchidoideae, the largest terrestrial orchid subfamily, we find that speciation rate is dependent on historic global cooling, not time, tropical distributions, elevation, variation in chromosome number, or other types of historic climate change. Relative to the gradual accumulation of species with time, models specifying speciation driven by historic global cooling are over 700 times more likely. Evidence ratios estimated for 212 other plant and animal groups reveal that terrestrial orchids represent one of the best-supported cases of temperature-spurred speciation yet reported. Employing >2.5 million georeferenced records, we find that global cooling drove contemporaneous diversification in each of the seven major orchid bioregions of the Earth. With current emphasis on understanding and predicting the immediate impacts of global warming, our study provides a clear case study of the long-term impacts of global climate change on biodiversity.

Prophylactic muscle flaps in high-risk-for-poor-healing patients with prosthetic bypasses increases deep wound complications.

BACKGROUND: Incisional complications of groin after inflow or infrainguinal bypasses with prosthetic conduits can result in major morbidities that require reoperation, infected graft removal, and limb loss. Muscle flaps are typically performed to treat groin wound complications, but they are also done prophylactically at the time of index procedures in certain high-risk-for-poor-healing patients to mitigate anticipated groin wound complications. We used a nationwide multi-institutional database to investigate outcomes of prophylactic muscle flaps in high-risk patients who underwent prosthetic bypasses involving femoral anastomosis. METHODS: We utilized ACS-NSQIP database 2005-2021 to identify all elective inflow and infrainguinal bypasses that involve femoral anastomoses. Only high-risk patients for poor incisional healing who underwent prosthetic conduit bypasses were selected. A 1:3 propensity-matching was performed to obtain two comparable studied groups between those with (FLAP) and without prophylactic muscle flaps (NOFLAP) based on demographics and comorbidities. 30-day postoperative outcomes were compared. RESULTS: Among 35,011 NOFLAP, 990 of them were propensity-matched to 330 FLAP. There was no significant difference in 30-day mortality, MACE, pulmonary, or renal complications. FLAP was associated with higher bleeding requiring transfusion, longer operative time, and longer hospital stay. FLAP also had higher overall wound complications (15.2% vs. 10.6%; p = 0.03), especially deep incisional infection (4.9% vs. 2.4%; p = 0.04). CONCLUSION: Prophylactic muscle flap for prosthetic bypasses involving femoral anastomosis in high-risk-for-poor-healing patients does not appear to mitigate 30-day wound complications. Caution should be exercised with this practice and more long-term data should be obtained to determine whether prophylactic flaps decrease the incidence of graft infection.

Effects of cyanoacrylate on leakage pressures of cooled canine cadaveric jejunal enterotomies.

OBJECTIVE: To compare the intraluminal initial and maximal pressures of enterotomies closed using three different techniques (single-layer appositional continuous closure; closure with cyanoacrylate; a single-layer appositional closure augmented with cyanoacrylate) in a cooled canine cadaveric jejunal model and to report the initial leak location in all samples. STUDY DESIGN: Experimental, ex-vivo study. SAMPLE POPULATION: Grossly normal chilled small intestine segments from three canine cadavers. METHODS: A total of 45 chilled jejunal segments (n = 15 segments/group) were assigned to a handsewn group (HSE), a cyanoacrylate only group (CE) and a handsewn and cyanoacrylate group (HS + CE). A 2 cm antimesenteric enterotomy was performed and closure with one of the above techniques. Initial leakage pressures (ILP), maximal intraluminal pressures (MIP) and initial leakage location were recorded by a single observer. RESULTS: Handsewn enterotomies leaked at higher ILP when augmented with cyanoacrylate (83.3 ± 4.6 mmHg, p < .001) compared to both the HSE group (43.8 ± 5.3 mmHg) and the CE group (18.6 ± 3.5 mmHg). Those sealed with cyanoacrylate only leaked at a lower MIP compared with the other groups (p < .001). Maximal intraluminal pressures did not differ between handsewn enterotomies, whether augmented or not (p = .19). CONCLUSION: Reinforcement of a sutured enterotomy closure with cyanoacrylate was easy to perform and resulted in significantly increased initial leak pressures in cadaveric jejunum. CLINICAL SIGNIFICANCE: The increased leakage pressures achieved by reinforcing enterotomies with cyanoacrylate could consequently reduce the incidence of postoperative intestinal leakage following an enterotomy and may result in reduced patient morbidity or mortality.

No phylogenetic evidence for angiosperm mass extinction at the Cretaceous-Palaeogene (K-Pg) boundary.

The Cretaceous-Palaeogene mass extinction event (K-Pg) witnessed upwards of 75% of animal species going extinct, most notably among these are the non-avian dinosaurs. A major question in macroevolution is whether this extinction event influenced the rise of flowering plants (angiosperms). The fossil record suggests that the K-Pg event had a strong regional impact on angiosperms with up to 75% species extinctions, but only had a minor impact on the extinction rates of major lineages (families and orders). Phylogenetic evidence for angiosperm extinction dynamics through time remains unexplored. By analysing two angiosperm mega-phylogenies containing approximately 32 000-73 000 extant species, here we show relatively constant extinction rates throughout geological time and no evidence for a mass extinction at the K-Pg boundary. Despite high species-level extinction observed in the fossil record, our results support the macroevolutionary resilience of angiosperms to the K-Pg mass extinction event via survival of higher lineages.

Developing patient-refined colorectal cancer screening materials: application of a virtual community engagement approach.

INTRODUCTION: In partnership with a federally qualified health center (FQHC), an adapted virtual version of boot camp translation (BCT) was used to elicit input from Spanish-speaking Latino patients and staff to develop messaging and patient education materials for follow-up colonoscopy after abnormal fecal testing. We describe how we adapted an existing in-person BCT process to be delivered virtually and present evaluations from participants on the virtual format. METHODS: Three virtual BCT sessions were facilitated by bilingual staff and conducted via Zoom. These sessions included introductions and discussions on colorectal cancer (CRC), CRC screening, and gathered feedback from participants on draft materials. Ten adults were recruited from the FQHC. A research team member from the FQHC served as the point of contact (POC) for all participants and offered Zoom introductory sessions and/or technology support before and during the sessions. Following the third session, participants were invited to complete an evaluation form about their virtual BCT experience. Using a 5-point Likert Scale (where 5 = strongly agree), questions focused on session utility, group comfort level, session pacing, and overall sense of accomplishment. RESULTS: Average scores ranged from 4.3 to 5.0 indicating strong support towards the virtual BCT sessions. Additionally, our study emphasized the importance of a POC to provide technical support to participants throughout the process. Using this approach, we successfully incorporated feedback from participants to design culturally relevant materials to promote follow-up colonoscopy. CONCLUSION: We recommend ongoing public health emphasis on the use of virtual platforms for community engaged work.

Clinic Factors Associated With Mailed Fecal Immunochemical Test (FIT) Completion: The Difference-Making Role of Support Staff.

PURPOSE: Mailed fecal immunochemical test (FIT) programs can facilitate colorectal cancer (CRC) screening. We sought to identify modifiable, clinic-level factors that distinguish primary care clinics with higher vs lower FIT completion rates in response to a centralized mailed FIT program. METHODS: We used baseline observational data from 15 clinics within a single urban federally qualified health center participating in a pragmatic trial to optimize a mailed FIT program. Clinic-level data included interviews with leadership using a guide informed by the Consolidated Framework for Implementation Research (CFIR) and FIT completion rates. We used template analysis to identify explanatory factors and configurational comparative methods to identify specific combinations of clinic-level conditions that uniquely distinguished clinics with higher and lower FIT completion rates. RESULTS: We interviewed 39 clinic leaders and identified 58 potential explanatory factors representing clinic workflows and the CFIR inner setting domain. Clinic-level FIT completion rates ranged from 30% to 56%. The configurational model for clinics with higher rates (≥37%) featured any 1 of the following 3 factors related to support staff: (1) adding back- or front-office staff in past 12 months, (2) having staff help patients resolve barriers to CRC screening, and (3) having staff hand out FITs/educate patients. The model for clinics with lower rates involved the combined absence of these same 3 factors. CONCLUSIONS: Three factors related to support staff differentiated clinics with higher and lower FIT completion rates. Adding nonphysician support staff and having those staff provide enabling services might help clinics optimize mailed FIT screening programs.

The Shapes of Birds' Eggs: Evolutionary Constraints and Adaptations.

AbstractWe studied the shapes of eggs from 955 extant bird species across the avian phylogeny, including 39 of 40 orders and 78% of 249 families. We show that the elongation component of egg shape (length relative to width) is largely the result of constraints imposed by the female's anatomy during egg formation, whereas asymmetry (pointedness) is mainly an adaptation to conditions during the incubation period. Thus, egg elongation is associated with the size of the egg in relation to both the size of the female's oviduct and her general body conformation and mode of locomotion correlated with pelvis shape. Egg asymmetry is related mainly to clutch size and the structure of the incubation site, factors that influence thermal efficiency during incubation and the risk of breakage. Importantly, general patterns across the avian phylogeny do not always reflect the trends within lower taxonomic levels. We argue that the analysis of avian egg shape is most profitably conducted within taxa where all species share similar life histories and ecologies, as there is no single factor that influences egg shape in the same way in all bird species.

Randomized Controlled Trial of Advance Notification Phone Calls vs Text Messages Prior to Mailed Fecal Test Outreach.

BACKGROUND & AIMS: Mailing fecal immunochemical test (FITs) to individuals who are due for screening (mailed FIT outreach) increases colorectal cancer (CRC) screening. Little is known about how phone-based advance notifications (primers) affect the effectiveness of mailed FIT outreach programs. METHODS: We performed a prospective study of patients at a large urban health center, 50-75 years old and due for screening, with no record of a prior FIT. Participants were randomly assigned to groups that received a live phone call primer (n = 1203) or a text message primer (n = 1622), from June through December 2018. The participants were then mailed a FIT kit, followed by 2 automated calls, and live reminder calls delivered by the care team. The main outcome was completion of FIT within 3 months of assignment to the live phone call or text message group. RESULTS: Participants had a FIT completion rate of 16.8%, a mean age of 58 years, and 80% were Latino. In adjusted intention to treat analyses (n = 2825), FIT completion rates were higher in the patients assigned to receive a live phone call vs text message primer (percentage point difference, 3.3%; 95% CI, 0.4%-6.2%). Between-group differences increased to 7.3% points (95% CI, 3.6%-11.0%) in the per-protocol analysis of 2144 participants reached by the text message (1320/1622, 81%), live call (438/1203, 36%), or voice message (386/1203, 32%). This rate increased to 14.9% points (95% CI; 9.6%-20.1%) in the per-protocol analysis of 1758 participants reached by the text message or reached by the live call. CONCLUSIONS: In a randomized trial, advance notification live phone calls outperformed text messages in prompting health center patients who had not previously completed a FIT to complete a mailed FIT. Clinicaltrials.gov no: NCT03167125.

Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.

NEW FINDINGS: What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. ABSTRACT: Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non-overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. -6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

Follow-up colonoscopy after an abnormal stool-based colorectal cancer screening result: analysis of steps in the colonoscopy completion process.

BACKGROUND: Delays in receiving follow-up colonoscopy after an abnormal fecal immunochemical test (FIT) result are associated with increased colorectal cancer incidence and mortality. Little is known about patterns of follow-up colonoscopy completion in federally qualified health centers. METHODS: We abstracted the medical records of health center patients, aged 50-75 years, who had an abnormal FIT result between August 5, 2017 and August 4, 2018 (N = 711). We assessed one-year rates of colonoscopy referral, pre-procedure visit completion, colonoscopy completion, and time to colonoscopy; associations between these outcomes and patient characteristics; and reasons for non-completion found in the medical record. RESULTS: Of the 711 patients with an abnormal FIT result, 90% were referred to colonoscopy, but only 52% completed a pre-procedure visit, and 43% completed a colonoscopy within 1 year. Median time to colonoscopy was 83 days (interquartile range: 52-131 days). Pre-procedure visit and colonoscopy completion rates were relatively low in patients aged 65-75 (vs. 50-64), who were uninsured (vs. insured) or had no clinic visit in the prior year (vs. ≥ 1 clinic visit). Common reasons listed for non-completion were that the patient declined, or the provider could not reach the patient. DISCUSSION: Efforts to improve follow-up colonoscopy rates in health centers might focus on supporting the care transition from primary to specialty gastroenterology care and emphasize care for older uninsured patients and those having no recent clinic visits. Our findings can inform efforts to improve follow-up colonoscopy uptake, reduce time to colonoscopy receipt, and save lives from colorectal cancer. TRIAL REGISTRATION: National Clinical Trial (NCT) Identifier: NCT03925883.

Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

Congenital Urethrovaginal Fistula with Blind-Ending Vagina in a Female Pseudohermaphrodite Dog with Urinary Incontinence.

An 8 mo old male Doberman pinscher was referred for investigation of persistent urinary incontinence. Physical examination revealed urine leakage and abnormal external genitalia. A computed tomography scan identified a large fluid-filled cavity extending from the caudoventral abdomen displacing the colon and urinary bladder. No retained testicles were identified. A retrograde urethrogram study found a linear communication, cranial to the pubic brim between the urethra to the fluid-filled cavity (fistula). Exploratory celiotomy was performed, and an entire female reproductive tract with a blind-ending vagina and a urethrovaginal fistula was found. En bloc gonad hysterectomy was performed, the fistula was transected, and a careful urethral reconstruction was performed. The urinary incontinence resolved immediately after surgery, and no complications were reported. Mild urinary incontinence recurred 4 days following patient discharge, and a urine bacterial culture was positive for Klebsiella spp. An antibiotic course was prescribed, and the incontinence fully resolved. Congenital urogenital abnormalities should always be considered in young animals presenting with urinary incontinence. Here, a young female pseudohermaphrodite dog with a naturally occurring congenital urethrovaginal fistula is described. Exploratory surgery was required for definitive diagnosis and surgical intervention yielded a good medium-term outcome with resolution of clinical signs.

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells.

BACKGROUND: Hypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour. METHODS: We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression. RESULTS: We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population. CONCLUSIONS: These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

Common guillemot (Uria aalge) eggs are not self-cleaning.

Birds are arguably the most evolutionarily successful extant vertebrate taxon, in part because of their ability to reproduce in virtually all terrestrial habitats. Common guillemots, Uria aalge, incubate their single egg in an unusual and harsh environment; on exposed cliff ledges, without a nest, and in close proximity to conspecifics. As a consequence, the surface of guillemot eggshells is frequently contaminated with faeces, dirt, water and other detritus, which may impede gas exchange or facilitate microbial infection of the developing embryo. Despite this, guillemot chicks survive incubation and hatch from eggs heavily covered with debris. To establish how guillemot eggs cope with external debris, we tested three hypotheses: (1) contamination by debris does not reduce gas exchange efficacy of the eggshell to a degree that may impede normal embryo development; (2) the guillemot eggshell surface is self-cleaning; (3) shell accessory material (SAM) prevents debris from blocking pores, allowing relatively unrestricted gas diffusion across the eggshell. We showed that natural debris reduces the conductance of gases across the guillemot eggshell by blocking gas exchange pores. Despite this problem, we found no evidence that guillemot eggshells are self-cleaning, but instead showed that the presence of SAM on the eggshell surface largely prevents pore blockages from occurring. Our results demonstrate that SAM is a crucial feature of the eggshell surface in a species with eggs that are frequently in contact with debris, acting to minimise pore blockages and thus ensure a sufficient rate of gas diffusion for embryo development.

Non-invasive intravital imaging of head and neck squamous cell carcinomas in live mice.

Head and neck squamous cell carcinoma is one of the most common cancers with a 50% 5-year survival rate. Understanding the mechanisms that control development, progression, and spreading of the tumor to distal sites is of paramount importance to develop effective therapies. Here, we describe a minimally invasive procedure, which enables performing intravital microscopy of the mouse tongue in models for oral cancer and provides structural and dynamic information of the tumors at cellular and subcellular level.

Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force.

BACKGROUND: Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk. PURPOSE: To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015. STUDY SELECTION: Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts. DATA EXTRACTION: Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality. DATA SYNTHESIS: Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between "dense" and "nondense" at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes. LIMITATIONS: Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent. CONCLUSION: Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Development of a Self-Management Theory-Guided Discharge Intervention for Parents of Hospitalized Children.

BACKGROUND: Parents of hospitalized children, especially parents of children with complex and chronic health conditions, report not being adequately prepared for self-management of their child's care at home after discharge. PROBLEM: No theory-based discharge intervention exists to guide pediatric nurses' preparation of parents for discharge. PURPOSE: To develop a theory-based conversation guide to optimize nurses' preparation of parents for discharge and self-management of their child at home following hospitalization. METHODS: Two frameworks and one method influenced the development of the intervention: the Individual and Family Self-Management Theory, Tanner's Model of Clinical Judgment, and the Teach-Back method. A team of nurse scientists, nursing leaders, nurse administrators, and clinical nurses developed and field tested the electronic version of a nine-domain conversation guide for use in acute care pediatric hospitals. CONCLUSIONS: The theory-based intervention operationalized self-management concepts, added components of nursing clinical judgment, and integrated the Teach-Back method. CLINICAL RELEVANCE: Development of a theory-based intervention, the translation of theoretical knowledge to clinical innovation, is an important step toward testing the effectiveness of the theory in guiding clinical practice. Clinical nurses will establish the practice relevance through future use and refinement of the intervention.

Preeclampsia Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force.

IMPORTANCE: Preeclampsia is a complex disease of pregnancy with sometimes serious effects on maternal and infant morbidity and mortality. It is defined by hypertension after 20 weeks' gestation and proteinuria or other evidence of multisystem involvement. OBJECTIVE: To systematically review the benefits and harms of preeclampsia screening and risk assessment for the US Preventive Services Task Force. DATA SOURCES: MEDLINE, PubMed, and Cochrane Central Register of Controlled Trials databases from 1990 through September 1, 2015. Surveillance for new evidence in targeted publications was conducted through October 5, 2016. STUDY SELECTION: English-language trials and observational studies, including externally validated prediction models, of screening effectiveness, benefits, and harms from routine preeclampsia screening during pregnancy. DATA EXTRACTION AND SYNTHESIS: Independent dual review of article abstracts and full texts against a priori inclusion criteria. Meta-analysis was not performed because of clinical and statistical heterogeneity of included studies. MAIN OUTCOMES AND MEASURES: Maternal and infant health outcomes, including eclampsia, stroke, stillbirth, preterm birth, and low birth weight; screening and risk prediction test performance; harms of screening and risk assessment. RESULTS: Twenty-one studies (13 982 participants) were included. No studies directly compared the effectiveness of preeclampsia screening in a screened population vs an unscreened population; 1 US trial (n = 2764) found no difference in benefits or harms with fewer prenatal visits but was underpowered for rare, serious outcomes. For harms, a before-after comparison cohort noninferiority study of urine protein screening for specific indications compared with routine screening (n = 1952) did not identify harms with fewer urine screening tests. Four studies (n = 7123) reported external validation performance of 16 risk prediction models, 5 of which had good or better discrimination (c statistic >0.80) for prediction of preeclampsia, and positive predictive values of 4% in the largest, most applicable validation cohorts. Calibration was not reported despite being a key model performance measure. There were no studies of urine screening test performance conducted in asymptomatic primary care populations; 14 studies of protein urine test performance among women being evaluated for suspected preeclampsia (n = 1888) had wide-ranging test accuracy (sensitivity, 22%-100%; specificity, 36%-100%) and high statistical and clinical heterogeneity in tests used, eligibility criteria, and proteinuria prevalence (8.7%-93.8%). CONCLUSIONS AND RELEVANCE: Evidence to estimate benefits and harms of preeclampsia screening and the test performance of different screening approaches over the course of pregnancy was limited. Externally validated risk prediction models had limited applicability and lacked calibration and clinical implementation data needed to support routine use. Further research is needed to better inform risk-based screening approaches and improve screening strategies, given the complex pathophysiology and clinical unpredictability of preeclampsia.