Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. Much progress has been made to understand each of the two processes individually; however, it is not clear whether the two processes are coordinated and how they are deployed at the correct time and location. Here we show that an epithelial branching morphogenesis program antagonizes alveolar differentiation in the mouse lung. We find a negative correlation between branching morphogenesis and alveolar differentiation temporally, spatially, and evolutionarily. Gain-of-function experiments show that hyperactive small GTPase Kras expands the branching program and also suppresses molecular and cellular differentiation of alveolar cells. Loss-of-function experiments show that SRYbox containing gene 9 (Sox9) functions downstream of Fibroblast growth factor (Fgf)/Kras to promote branching and also suppresses premature initiation of alveolar differentiation. We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution.

The lung is a branched tubular network with two distinct compartments — the proximal conducting airways and the peripheral gas exchange region — separated by a discrete boundary termed the bronchoalveolar duct junction (BADJ). Here we image the developing mouse lung in three dimensions and show that two nested developmental waves demarcate the BADJ under the control of a global hormonal signal. A first wave of branching morphogenesis progresses throughout embryonic development, generating branches for both compartments. A second wave of conducting airway differentiation follows the first wave but terminates earlier, specifying the proximal compartment and setting the BADJ. The second wave is terminated by a glucocorticoid signaling: premature activation or loss of glucocorticoid signaling causes a proximal or distal shift, respectively, in BADJ location. The results demonstrate a novel mechanism of boundary formation in complex, three-dimensional organs and provide new insights into glucocorticoid therapies for lung defects in premature birth.

NA Laryngoscope, 127:781-786, 2017.

OBJECT Sagittal craniosynostosis has been treated using both cranial remodeling techniques and modification of the sagittal strip craniectomy. A more recent technique is to implant springs in conjunction with a suturectomy to transversely expand the parietal bones to accommodate the growing brain. In this paper the authors describe and evaluate several modifications to the spring-mediated cranioplasty (SMC) technique, most notably use of an ultrasonic scalpel to limit dural dissection and maximize opening of the stenosed suture by placement of multiple spring devices. In addition, the literature is reviewed comparing SMC to other surgical treatments of sagittal synostosis. METHODS The authors retrospectively reviewed patients who presented to the Children’s Hospital of Philadelphia with a diagnosis of sagittal synostosis from August 2011 to November 2014. A pooled data set was created to compare our institutional data to previously published work. A comprehensive literature review was performed of all previous studies describing the SMC technique, as well as other techniques for sagittal synostosis correction. RESULTS Twenty-two patients underwent SMC at our institution during the study period. Patients were 4.2 months of age on average, had a mean blood loss of 56.3 ml, and average intensive care unit and total hospital stays of 29.5 hours and 2.2 days, respectively. The cranial index was corrected to an average of 73.7 (SD 5.2) for patients who received long-term radiological follow-up. When comparing the authors’ institutional data to pooled SMC data, blood loss and length of stay were both significantly less (p = 0.005 and p < 0.001, respectively), but the preoperative cranial index was significantly larger (p = 0.01). A review of the SMC technique compared with other techniques to actively expand the skull of patients with sagittal synostosis demonstrated that SMC can be performed at a significantly earlier age compared with cranial vault reconstruction (CVR). CONCLUSIONS The authors found that their institutional modifications of the SMC technique were safe and effective in correcting the cranial index. In addition, this technique can be performed at a younger age than CVRs. SMC, therefore, has the potential to maximize the cognitive benefits of early intervention, with lower morbidity than the traditional CVR.

Objective: To evaluate differences in morbidity and mortality among mechanically ventilated patients with COVID-19 treated with therapeutic versus prophylactic anticoagulation. Methods: We performed a retrospective review of 245 COVID-19 positive patients admitted to the ICU requiring mechanical ventilation from March 1, 2020 through April 11, 2020 at Mount Sinai Hospital. Patients either received therapeutic anticoagulation for a minimum of 5 days or prophylactic dose anticoagulation. Morbidity and mortality data were analyzed. Results: Propensity score (PS) weighted Kaplan-Meier plot demonstrated a survival advantage (57% vs. 25%) at 35 days from admission to the ICU in patients who received therapeutic anticoagulation for a minimum of 5 days compared to those who received prophylactic anticoagulation during their hospital course. A multivariate Cox proportional hazard regression model with PS weights to adjust for baseline differences found a 79% reduction in death in patients who were therapeutically anticoagulated HR 0.209, [95% CI (0.10, 0.46), p <0.001]. Bleeding complications were similar between both groups. A 26.7% [95% CI (1.16, 1.39), p<0.001] excess mortality was found for each 1 mg/dL rise in serum creatinine over a 21-day period. Conclusions: Therapeutic anticoagulation is associated with a survival advantage among patients with COVID-19 who require mechanical ventilation in the ICU.