SUMMARYDermal fibroblasts are required for structural integrity of the skin and for hair follicle development. Uniform Wnt signaling activity is present in dermal fibroblast precursors preceding hair follicle initiation, but the functional requirement of dermal Wnt signaling at early stages of skin differentiation and patterning remains largely uncharacterized. We show in mice that epidermal Wnt ligands are required for uniform dermal Wnt signaling/-catenin activity and regulate fibroblast cell proliferation and initiation of hair follicle placodes. In the absence of dermal Wnt signaling/-catenin activity, patterned upregulation of epidermal -catenin activity and Edar expression are absent. Conversely, forced activation of -catenin signaling leads to the formation of thickened dermis, enlarged epidermal placodes and dermal condensates that result in prematurely differentiated enlarged hair follicles. These data reveal functional roles for dermal Wnt signaling/-catenin in fibroblast proliferation and in the epidermal hair follicle initiation program.

SUMMARYCranial dermis develops from cephalic mesoderm and neural crest cells, but what signal(s) specifies the dermal lineage is unclear. Using genetic tools to fate map and manipulate a cranial mesenchymal progenitor population in the supraorbital region, we show that the dermal progenitor cells beneath the surface ectoderm process canonical Wnt signaling at the time of specification. We show that Wnt signaling/-catenin is absolutely required and sufficient for Dermo1 expression and dermal cell identity in the cranium. The absence of the Wnt signaling cue leads to formation of cartilage in craniofacial and ventral trunk regions at the expense of dermal and bone lineages. Dermo1 can be a direct transcription target and may mediate the functional role of Wnt signaling in dermal precursors. This study reveals a lineage-specific role of canonical Wnt signaling/-catenin in promoting dermal cell fate in distinct precursor populations.

Objectives: To determine the point prevalence of medication errors at the time of transition of care from an ICU to non-ICU location and assess error types and risk factors for medication errors during transition of care. Design: This was a multicenter, retrospective, 7-day point prevalence study. Setting: Fifty-eight ICUs within 34 institutions in the United States and two in the Netherlands. Patients: Nine-hundred eighty-five patients transferred from an ICU to non-ICU location. Interventions: None. Measurements and Main Results: Of 985 patients transferred, 450 (45.7%) had a medication error occur during transition of care. Among patients with a medication error, an average of 1.88 errors per patient (sd, 1.30; range, 1–9) occurred. The most common types of errors were continuation of medication with ICU-only indication (28.4%), untreated condition (19.4%), and pharmacotherapy without indication (11.9%). Seventy-five percent of errors reached the patient but did not cause harm. The occurrence of errors varied by type and size of institution and ICU. Renal replacement therapy during ICU stay and number of medications ordered following transfer were identified as factors associated with occurrence of error (odds ratio, 2.93; 95% CI, 1.42–6.05; odds ratio 1.08, 95% CI, 1.02–1.14, respectively). Orders for anti-infective (odds ratio, 1.66; 95% CI, 1.19–2.32), hematologic agents (1.75; 95% CI, 1.17–2.62), and IV fluids, electrolytes, or diuretics (odds ratio, 1.73; 95% CI, 1.21–2.48) at transition of care were associated with an increased odds of error. Factors associated with decreased odds of error included daily patient care rounds in the ICU (odds ratio, 0.15; 95% CI, 0.07–0.34) and orders discontinued and rewritten at the time of transfer from the ICU (odds ratio, 0.36; 95% CI, 0.17–0.73). Conclusions: Nearly half of patients experienced medication errors at the time of transition of care from an ICU to non-ICU location. Most errors reached the patient but did not cause harm. This study identified risk factors upon which risk mitigation strategies should be focused.

Wnt signaling is critical for proper development of the head and face in the mouse embryo, playing important roles in various aspects of craniofacial development ranging from axis formation to survival of cranial neural crest cells to patterning of the brain. The signaling requirements for the development of different cell lineages in the head and face are active areas of investigation. In this study, we use a recently developed TCF/Lef-LacZ transgenic reporter mouse to characterize the expression of canonical Wnt signaling activity during craniofacial development. We present an atlas of representative sections to show embryonic craniofacial development. Our results demonstrate a pattern of sustained Wnt signaling reporter activity in most tissues which suggests sequential roles in craniofacial development.

*Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2 -/-developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2 -/-embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1α) in Cited2 -/-lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters' anomaly and ocular hypervascularity.

Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. Despite its critical importance, gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase-seq and histone modification ChiP-seq data on various cell-types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell-types. We found a subset of the signature genes whose expression is dependent on Wnt/β-catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease.

Objectives Total pancreatectomy with islet autotransplantation can relieve pain associated with chronic pancreatitis while preserving islet function. Islet preparations are often contaminated by enteric flora. We assessed the impact of contaminated islet preparations on the prevalence of postoperative infection. Methods Electronic health records for patients who underwent total pancreatectomy with islet autotransplantation from August 1, 2011, to November 15, 2017 were retrospectively reviewed to compare the prevalence of postoperative infection in patients with a positive islet culture and islet culture negative patients. Results Sixty-one patients were included. Twenty-nine patients (47.5%) had a positive islet culture, and 23 (79.3%) of these patients received antimicrobial prophylaxis. The prevalence of postoperative infection did not differ between the islet culture positive and islet culture negative groups (41% vs 34%, P = 0.57). No infections occurred in the 6 islet culture positive patients who did not receive prophylaxis. No difference in intensive care unit or hospital length of stay or in 30-day or 90-day readmission rates were observed. Conclusions Despite the common use of postoperative systemic antimicrobials, we observed no difference in the prevalence of postoperative infection, length of stay, or hospital readmission in patients receiving a contaminated islet preparation. If prophylactic antimicrobials are used, the duration should be minimized.

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