Comparing Neurodevelopmental Outcomes in Infants With Patent Ductus Arteriosus Stenting Versus Blalock-Taussig-Thomas Shunt: A Pilot Study.

Background: Patent ductus arteriosus stenting (PDAS) is a nonsurgical alternative to Blalock-Taussig-Thomas shunt (BTTS) for infants with ductal-dependent congenital heart disease. In this single-center study, we aimed to compare neurodevelopmental outcomes in children who underwent BTTS as initial palliation versus PDAS. Methods: Bayley Scales of Infant and Toddler Development Screening Test (Bayley-III) reports and mode of feeding data were collected for any patient who underwent PDAS or BTTS at Rady Children's Hospital from 2013 to 2021. We also prospectively administered the Parents' Evaluation of Development Status questionnaire (PEDS) to parents of children aged 2-8 years in this patient population. Results: Of the 99 patients, 64 received a Bayley-III assessment and/or PEDS screen. Of the 35 who had a Bayley-III, there was a higher proportion of patients with PDAS who scored as developmentally appropriate compared with BTTS. PEDS screen showed that a higher proportion of patients with PDAS had no parental concern for delay than that of patients with BTTS (63% vs 30%). Patients with BTTS were more likely to undergo gastrostomy tube placement than patients with PDAS. Conclusions: Our study suggests that neurodevelopmental measures are feasible, clinically relevant, and should be included in comparative effectiveness studies of infant congenital interventions. Whether PDAS offers neurodevelopmental benefit over BTTS should be confirmed in a prospective powered randomized controlled clinical trial.

Acute inorganic nitrate ingestion does not impact oral microbial composition, cognitive function, or high-intensity exercise performance in female team-sport athletes.

The purpose of this study was to investigate the effects of acute nitrate (NO3-)-rich beetroot juice ingestion on explosive and high-intensity exercise performance, oral microbiota composition, and cognitive flexibility (i.e., function), before and after maximal intermittent running exercise. Fifteen women team-sport athletes were assigned in a randomized, double-blind, crossover design to consume concentrated NO3--depleted beetroot juice (PL; 0.1 mmol NO3-) and NO3--rich beetroot juice (BR; 12.0 mmol NO3-) 2.5 h prior to performing a battery of exercise performance tasks and cognitive testing before and after the Yo-Yo intermittent recovery level 1 (YYIR1) running test. Resting plasma [NO3-] and plasma nitrite ([NO2-]) were elevated following BR (P < 0.001). BR did not impact global composition or relative abundance of taxa in the oral microbiome (P > 0.05) or cognitive flexibility before or after exercise (P > 0.05). There was no significant difference in performance during 20-m (PRE, PL: 4.38 ± 0.27 vs. BR: 4.38 ± 0.32 s; POST, PL: 4.45 ± 0.29 vs. BR: 4.43 ± 0.35 s) and 10-m sprints (PRE, PL 2.78 ± 0.15 vs. BR 2.79 ± 0.18 s; POST, PL: 2.82 ± 0.16 vs. BR: 2.81 ± 0.19 s), isokinetic handgrip dynamometry, medicine ball throw, horizontal countermovement jump, or YYIR1 (PL: 355 ± 163 m vs. BR: 368 ± 184 m) between BR and PL (P > 0.05). These findings indicate that acute dietary NO3- may not influence the oral microbiome, explosive and high-intensity exercise performance, or cognitive function in women team-sport athletes.

Stenting of the Patent Ductus Arteriosus.

Since PDA stenting was first attempted in the early 1990s, significant technical advancements have improved outcomes and some centers have even transitioned to exclusive PDA stenting for all infants with duct-dependent pulmonary circulation. In addition to its use in infants with duct-dependent pulmonary circulation, PDA stenting has also been adapted as a percutaneous palliative option for suprasystemic pulmonary arterial hypertension and as a component of the hybrid procedure. In this article, the authors aim to review indications and outcomes for PDA stenting, describe the procedure, and discuss future directions.

Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Dietary nitrate ingested with and without pomegranate supplementation does not improve resistance exercise performance.

This study tested the hypothesis that co-ingesting nitrate (NO3-)-rich beetroot juice (BR) and pomegranate powder (POM) would enhance neuromuscular performance during vertical countermovement jumps, explosive kneeling countermovement push-ups, and back squats compared to BR ingestion alone. Fifteen recreationally-active males were assigned in a double-blind, randomized, crossover design, to supplement in 3 conditions: (1) NO3--depleted beetroot juice (PL; 0.10 mmol NO3-) with two empty gelatin capsules; (2) NO3--rich beetroot juice (BR; 11.8 mmol NO3-) with two empty gelatin capsules, and (3) BR with 1,000 mg of POM powder in two capsules (BR + POM). Participants completed 5 countermovement jumps and 5 kneeling countermovement push-ups interspersed by 1 min of recovery. Subsequently, participants performed 2 sets of 2 × 70% one-repetition maximum back squats, interspersed by 2 min of recovery. Plasma [NO3-] and nitrite ([NO2-]) were elevated following BR and BR + POM compared with PL and POM (p < 0.001) with no differences between BR and BR + POM (p > 0.05) or PL and POM (p > 0.05). Peak power during countermovement jumps increased by 3% following BR compared to BR + POM (88.50 ± 11.46 vs. 85.80 ± 10.14 W/Kg0.67, p = 0.009) but not PL (88.50 ± 11.46 vs. 85.58 ± 10.05 W/Kg0.67, p = 0.07). Neuromuscular performance was not different between conditions during explosive kneeling push-ups and back squats (p > 0.05). These data provide insight into the efficacy of NO3- to modulate explosive resistance exercise performance and indicate that supplementing with BR alone or combined with POM has limited ergogenic potential on resistance exercise. Furthermore, caution is required when combining BR with POM, as this could compromise aspects of resistance exercise performance, at least when compared to BR ingested independently.

Erratum: Stenting of the Patent Ductus Arteriosus: A Meta-analysis and Literature Review.

[This corrects the article DOI: 10.1016/j.jscai.2022.100392.][This corrects the article DOI: 10.1016/j.jscai.2023.101051.].

Bronchial Remodeling Following Airway Stenting in Pediatric Patients With Tracheobronchial and Congenital Heart Disease.

Background: Treatment of tracheobronchial disease in medically complex infants with congenital heart disease (CHD) is often challenging. When conservative management or surgery fails or is contraindicated, airway stenting can allow for advancement of care or weaning of respiratory support. Methods: We identified 8 cases of airway stenting with balloon-expandable coronary bare-metal stents performed at our institution between February 2019 and September 2022 to relieve conservative treatment-refractory tracheobronchial disease in pediatric patients with CHD. All patients underwent rigid microlaryngoscopy, bronchoscopy, and flexible bronchoscopy as well as computed tomography angiography. Results: Eight patients underwent technically uncomplicated placement of balloon-expandable coronary bare-metal stents in the trachea or bronchus. Immediate improvement in respiratory parameters was noted following stent placement. Six patients were able to wean mechanical ventilation following stent placement, with a median of 2.5 days of mechanical ventilation following the procedure (range, 0-219). All stents were subsequently endoscopically removed at a median of 6.8 months (range, 0.4-16.3 months). In 6 patients, bronchoscopy after stent removal demonstrated a rounder configuration of the airway consistent with bronchial remodeling. Conclusions: In pediatric patients with tracheobronchial and CHD, airway stenting with balloon-expandable bare-metal coronary stents relieved respiratory symptoms with minimal complications and resulted in bronchial remodeling after stent removal.

Effects of Dietary Nitrate Supplementation on Performance and Muscle Oxygenation during Resistance Exercise in Men.

The purpose of the current study was to assess the effects of acute and short-term nitrate (NO3−)-rich beetroot juice (BR) supplementation on performance outcomes and muscle oxygenation during bench press and back squat exercise. Fourteen recreationally active males were assigned in a randomized, double-blind, crossover design to supplement for 4 days in two conditions: (1) NO3−-depleted beetroot juice (PL; 0.10 mmol NO3− per day) and (2) BR (11.8 mmol NO3− per day). On days 1 and 4 of the supplementation periods, participants completed 2 sets of 2 × 70%1RM interspersed by 2 min of recovery, followed by one set of repetitions-to-failure (RTF) at 60%1RM for the determination of muscular power, velocity, and endurance. Quadriceps and pectoralis major tissue saturation index (TSI) were measured throughout exercise. Plasma [NO3−] and nitrite ([NO2−]) were higher after 1 and 4 days of supplementation with BR compared to PL (p < 0.05). Quadriceps and pectoralis major TSI were not different between conditions (p > 0.05). The number of RTF in bench press was 5% greater after acute BR ingestion compared to PL (PL: 23 ± 4 vs. BR: 24 ± 5, p < 0.05). There were no differences between BR and PL for RTF for back squat or power and velocity for back squat or bench press (p > 0.05). These data improve understanding on the ergogenic potential of BR supplementation during resistance exercise.

Stenting of the Patent Ductus Arteriosus: A Meta-analysis and Literature Review.

Background: Patent ductus arteriosus (PDA) stent placement and systemic-pulmonary surgical shunt procedure can both be performed as palliation for infants with duct-dependent pulmonary circulation. The aim of this meta-analysis and literature review was to compare outcomes and study populations between the 2 methods as well as review the technical considerations and complications of PDA stenting. Methods: A systematic search was conducted using the PubMed database and meta-analysis was performed. Risk ratio and mean difference were used to compare the reported outcomes of studies across patients receiving PDA stent and surgical shunt. Results: In total, 1094 patients from 8 comparative observational studies were included. The PDA stent group had a lower mortality rate and a shorter hospital length of stay than the systemic-pulmonary surgical shunt group, although at the expense of increased reintervention rates. There were higher proportions of patients with single-ventricle physiology and single-source pulmonary blood flow in the surgical shunt group. Conclusions: PDA stenting appears to be a noninferior or possibly superior method of palliation for duct-dependent pulmonary circulation compared with systemic-pulmonary surgical shunt, recognizing, however, that patients receiving surgical shunt more often had single-ventricle physiology or single-source pulmonary blood flow in this meta-analysis.

Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx.

PURPOSE: De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273. METHODS AND MATERIALS: MC1273 is a prospective, phase 2 study evaluating adjuvant CRT to 30 to 36 Gy plus docetaxel for HPV+ OPSCC after surgery for high-risk patients. Matched standard-of-care control groups were retrospectively identified for patients treated with definitive CRT or adjuvant RT. Standardized costs were evaluated before radiation, during treatment (during RT), and at short-term (6 month) and long-term (7-24 month) follow-up periods. RESULTS: A total of 56 definitive CRT, 101 adjuvant RT, and 66 MC1273 patients were included. The CRT arm had more T3-4 disease (63% vs 17-21%) and higher N2c-N3 disease (52% vs 20-24%) vs both other groups. The total treatment costs in the CRT, adjuvant RT, and MC1273 groups were $47,763 (standard deviation [SD], $19,060], $57,845 (SD, $17,480), and $46,007 (SD, $9019), respectively, and the chemotherapy and/or RT costs were $39,936 (SD, $18,480), $26,603 (SD, $12,542), and $17,864 (SD, $3288), respectively. The per-patient, per-month, average short-term follow-up costs were $3860 (SD, $10,525), $1072 (SD, $996), and $972 (SD, $833), respectively, and the long-term costs were $978 (SD, $2294), $485 (SD, $1156), and $653 (SD, $1107), respectively. After adjustment for age, T-stage, and N-stage, treatment costs remained lower for CRT and MC1273 versus adjuvant RT ($45,450 and $47,114 vs $58,590, respectively; P < .001), whereas the total per-patient, per-month follow-up costs were lower in the MC1273 study group and adjuvant RT versus CRT ($853 and $866 vs $2030, respectively; P = .03). CONCLUSIONS: MC1273 resulted in 10% and 20% reductions in global costs compared with standard-of-care adjuvant RT and definitive CRT treatments. Substantial cost savings may be an added benefit to the already noted low toxicity and maintained quality of life of treatment per MC1273.

Immunity to Contact Scaling in MoS2 Transistors Using in Situ Edge Contacts.

Atomically thin two-dimensional (2D) materials are promising candidates for sub-10 nm transistor channels due to their ultrathin body thickness, which results in strong electrostatic gate control. Properly scaling a transistor technology requires reducing both the channel length (distance from source to drain) and the contact length (distance that source and drain interface with semiconducting channel). Contact length scaling remains an unresolved epidemic for transistor scaling, affecting devices from all semiconductors-silicon to 2D materials. Here, we show that clean edge contacts to 2D MoS2 can provide immunity to the contact-scaling problem, with performance that is independent of contact length down to the 20 nm regime. Using a directional ion beam, in situ edge contacts of various metal-MoS2 interfaces are studied. Characterization of the intricate edge interface using cross-sectional electron microscopy reveals distinct morphological effects on the MoS2 depending on its thickness-from monolayer to few-layer films. The in situ edge contacts also exhibit an order of magnitude higher performance compared to the best-reported ex situ metal edge contacts. Our work provides experimental evidence for a solution to contact scaling in transistors, using 2D materials with clean edge contact interfaces, opening a new way of designing devices with 2D materials.

Sustained Sub-60 mV/decade Switching via the Negative Capacitance Effect in MoS2 Transistors.

It has been shown that a ferroelectric material integrated into the gate stack of a transistor can create an effective negative capacitance (NC) that allows the device to overcome "Boltzmann tyranny". While this switching below the thermal limit has been observed with Si-based NC field-effect transistors (NC-FETs), the adaptation to 2D materials would enable a device that is scalable in operating voltage as well as size. In this work, we demonstrate sustained sub-60 mV/dec switching, with a minimum subthreshold swing (SS) of 6.07 mV/dec (average of 8.03 mV/dec over 4 orders of magnitude in drain current), by incorporating hafnium zirconium oxide (HfZrO2 or HZO) ferroelectric into the gate stack of a MoS2 2D-FET. By first fabricating and characterizing metal-ferroelectric-metal capacitors, the MoS2 is able to be transferred directly on top and characterized with both a standard and a negative capacitance gate stack. The 2D NC-FET exhibited marked enhancement in low-voltage switching behavior compared to the 2D-FET on the same MoS2 channel, reducing the SS by 2 orders of magnitude. A maximum internal voltage gain of ∼28× was realized with ∼12 nm thick HZO. Several unique dependencies were observed, including threshold voltage (Vth) shifts in the 2D NC-FET (compared to the 2D-FET) that correlate with source/drain overlap capacitance and changes in HZO (ferroelectric) and HfO2 (dielectric) thicknesses. Remarkable sub-60 mV/dec switching was obtained from 2D NC-FETs of various sizes and gate stack thicknesses, demonstrating great potential for enabling size- and voltage-scalable transistors.

Uniform Growth of Sub-5-Nanometer High-κ Dielectrics on MoS2 Using Plasma-Enhanced Atomic Layer Deposition.

Regardless of the application, MoS2 requires encapsulation or passivation with a high-quality dielectric, whether as an integral aspect of the device (as with top-gated field-effect transistors (FETs)) or for protection from ambient conditions. However, the chemically inert surface of MoS2 prevents uniform growth of a dielectric film using atomic layer deposition (ALD)-the most controlled synthesis technique. In this work, we show that a plasma-enhanced ALD (PEALD) process, compared to traditional thermal ALD, substantially improves nucleation on MoS2 without hampering its electrical performance, and enables uniform growth of high-κ dielectrics to sub-5 nm thicknesses. Substrate-gated MoS2 FETs were studied before/after ALD and PEALD of Al2O3 and HfO2, indicating the impact of various growth conditions on MoS2 properties, with PEALD of HfO2 proving to be most favorable. Top-gated FETs with high-κ films as thin as ∼3.5 nm yielded robust performance with low leakage current and strong gate control. Mechanisms for the dramatic nucleation improvement and impact of PEALD on the MoS2 crystal structure were explored by X-ray photoelectron spectroscopy (XPS). In addition to providing a detailed analysis of the benefits of PEALD versus ALD on MoS2, this work reveals a straightforward approach for realizing ultrathin films of device-quality high-κ dielectrics on 2D crystals without the use of additional nucleation layers or damage to the electrical performance.

Biomechanical Forces Promote Immune Regulatory Function of Bone Marrow Mesenchymal Stromal Cells.

Mesenchymal stromal cells (MSCs) are believed to mobilize from the bone marrow in response to inflammation and injury, yet the effects of egress into the vasculature on MSC function are largely unknown. Here we show that wall shear stress (WSS) typical of fluid frictional forces present on the vascular lumen stimulates antioxidant and anti-inflammatory mediators, as well as chemokines capable of immune cell recruitment. WSS specifically promotes signaling through NFκB-COX2-prostaglandin E2 (PGE2 ) to suppress tumor necrosis factor-α (TNF-α) production by activated immune cells. Ex vivo conditioning of MSCs by WSS improved therapeutic efficacy in a rat model of traumatic brain injury, as evidenced by decreased apoptotic and M1-type activated microglia in the hippocampus. These results demonstrate that force provides critical cues to MSCs residing at the vascular interface which influence immunomodulatory and paracrine activity, and suggest the potential therapeutic use of force for MSC functional enhancement. Stem Cells 2017;35:1259-1272.

Fluid shear stress activates YAP1 to promote cancer cell motility.

Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1-TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK-LIMK-cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis.

COST-EFFECTIVENESS OF STRUCTURED EDUCATION IN CHILDREN WITH TYPE-1 DIABETES MELLITUS.

OBJECTIVES: Kids in Control OF Food (KICk-OFF) is a 5-day structured education program for 11- to 16-year-olds with type 1 diabetes mellitus (T1DM) who are using multiple daily insulin injections. This study evaluates the cost-effectiveness of the KICk-OFF education program compared with the usual care using data from the KICk-OFF trial. METHODS: The short-term within-trial analysis covers the 2-year postintervention period. Data on glycated hemoglobin (HbA1c), severe hypoglycemia, and diabetic ketoacidosis (DKA) were collected over a 2-year follow-up period. Sub-group analyses have been defined on the basis of baseline HbA1c being below 7.5 percent (58.5 mmol/mol) (low group), between 7.5 percent and 9.5 percent (80.3 mmol/mol) (medium group), and over 9.5 percent (high group). The long-term cost-effectiveness evaluation has been conducted by using The Sheffield Type 1 Diabetes Policy Model, which is a patient-level simulation model on T1DM. It includes long-term microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (myocardial infarction, stroke, revascularization, and angina) diabetes-related complications and acute adverse events (severe hypoglycemia and DKA). RESULTS: The most favorable within-trial scenario for the KICk-OFF arm led to an incremental cost-effectiveness ratio (ICER) of £23,688 (base year 2009) with a cost-effectiveness probability of 41.3 percent. Simulating the long-term complications using the full cohort data, the mean ICER for the base case was £28,813 (base year 2011) and the probability of the KICk-OFF intervention being cost-effective at £20,000/QALY threshold was 42.6 percent, with considerable variation due to treatment effect duration. For the high HbA1c sub-group, the KICk-OFF arm was "dominant" (meaning it provided better health gains at lower costs than usual care) over the usual care arm in each scenario considered. CONCLUSIONS: For the whole study population, the cost-effectiveness of KICk-OFF depends on the assumption for treatment effect duration. For the high baseline HbA1c sub-group, KICk-OFF arm was estimated to be dominant over the usual care arm regardless of the assumption on the treatment effect duration.

Developing effective communication materials on the health effects of climate change for vulnerable groups: a mixed methods study.

BACKGROUND: Individuals with chronic health conditions or low socioeconomic status (SES) are more vulnerable to the health impacts of climate change. Health communication can provide information on the management of these impacts. This study tested, among vulnerable audiences, whether viewing targeted materials increases knowledge about the health impacts of climate change and strength of climate change beliefs, and whether each are associated with stronger intentions to practice recommended behaviors. METHODS: Low-SES respondents with chronic conditions were recruited for an online survey in six cities. Respondents were shown targeted materials illustrating the relationship between climate change and chronic conditions. Changes in knowledge and climate change beliefs (pre- and post-test) and behavioral intentions (post-test only) were tested using McNemar tests of marginal frequencies of two binary outcomes or paired t-tests, and multivariable linear regression. Qualitative interviews were conducted among target audiences to triangulate survey findings and make recommendations on the design of messages. RESULTS: Respondents (N = 122) reflected the target population regarding income, educational level and prevalence of household health conditions. (1) Knowledge. Significant increases in knowledge were found regarding: groups that are most vulnerable to heat (children [p < 0.001], individuals with heart disease [p < 0.001], or lung disease [p = 0.019]); and environmental conditions that increase allergy-producing pollen (increased heat [p = 0.003], increased carbon dioxide [p < 0.001]). (2) Strength of certainty that climate change is happening increased significantly between pre- and post-test (p < 0.001), as did belief that climate change affected respondents' health (p < 0.001). (3) Behavioral intention. At post-test, higher knowledge of heat vulnerabilities and environmental conditions that trigger pollen allergies were associated with greater behavioral intention scores (p = 0.001 and p = 0.002, respectively). In-depth interviews (N = 15) revealed that vulnerable audiences are interested in immediate-term advice on health management and protective behaviors related to their chronic conditions, but took less notice of messages about collective action to slow or stop climate change. Respondents identified both appealing and less favorable design elements in the materials. CONCLUSIONS: Individuals who are vulnerable to the health effects of climate change benefit from communication materials that explain, using graphics and concise language, how climate change affects health conditions and how to engage in protective adaptation behaviors.

Analysis of the Relationship Between Micrognathia and Cleft Palate: A Systematic Review.

Objective To gather data from relevant experimental and observational studies to determine the relationship between micrognathia and cleft palate. The goal is to raise awareness and motivate clinicians to consider the cause and effect relationship when confronted with patients with cleft palate, even if there is no clearly noticeable mandibular abnormality. Design Several electronic databases were systematically examined to find articles for this review, using search terms including "cleft palate," "micrognathia," "tongue," and "airway obstruction." PubMed was the source of all the articles chosen to be included. Exclusion criteria included case reports, articles focused on treatment options, and articles only tangentially related to cleft palate and/or micrognathia. Results A total of 930 articles were screened for relevance, and 82 articles were chosen for further analysis. Evidence gathered in this review includes a variety of etiological factors that are causative or associated with both micrognathia and cleft palate. Observational studies relating the two abnormalities are also included. Much of the included literature recognizes a cause-and-effect relationship between micrognathia and cleft palate. Conclusion On the basis of the published data, we suggest that micrognathia does induce cleft palate in humans and animals. With knowledge of this causative relationship, clinicians should consider the importance of gathering cephalometric data on the mandibles and tongues of patients presenting with isolated cleft palate to determine whether they have micrognathia as well. With more data, patterns may emerge that could give insight into the complex etiology of nonsyndromic cleft palate.

Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System.

UNLABELLED: Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. IMPORTANCE: Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin.