Feasibility of personalized circulating tumor DNA detection in stage II and III melanoma.

The objective of this study was to evaluate the feasibility of developing personalized, tumor-informed assays for patients with high-risk resectable melanoma and examine circulating tumor DNA (ctDNA) levels in relation to clinical status. Pilot prospective study of clinical stage IIB/C and resectable stage III melanoma patients. Tumor tissue was used to design bespoke somatic assays for interrogating ctDNA in patients' plasma using a multiplex PCR (mPCR) next-generation sequencing (NGS)-based approach. Plasma samples for ctDNA analysis were collected pre-/post-surgery and during surveillance. Out of 28 patients (mean 65 years, 50% male), 13 (46%) had detectable ctDNA prior to definitive surgery and 96% (27/28) tested ctDNA-negative within 4 weeks post-surgery. Pre-surgical detection of ctDNA was significantly associated with the later-stage ( P  = 0.02) and clinically evident stage III disease ( P  = 0.007). Twenty patients continue in surveillance with serial ctDNA testing every 3-6 months. With a median follow-up of 443 days, six out of 20 (30%) patients developed detectable ctDNA levels during surveillance. All six of these patients recurred with a mean time to recurrence of 280 days. Detection of ctDNA in surveillance preceded the diagnosis of clinical recurrence in three patients, was detected concurrent with clinical recurrence in two patients and followed clinical recurrence in one patient. One additional patient developed brain metastases without detection of ctDNA during surveillance but had positive pre-surgical ctDNA. Our results demonstrate the feasibility of obtaining a personalized, tumor-informed mPCR NGS-based ctDNA assay for patients with melanoma, particularly in resectable stage III disease.

High flow nasal cannula outside the ICU provides optimal care and maximizes hospital resources for patients with multiple rib fractures.

BACKGROUND: High flow nasal cannula (HFNC) use reduces work of breathing and improves oxygenation for patients with hypoxemic respiratory failure. Limited prior work has explored protocolized use of HFNC for trauma patients outside the Intensive Care Unit (ICU). The purpose of this study is to describe and evaluate use of HFNC for patients with rib fractures when therapy was standard of care on all floors of the hospital. METHODS: In 2018, the study hospital expanded use of HFNC (AIRVO; Fisher Paykel, Auckland, NZ) to all floors of the hospital, making it available in the ICU, Emergency Department (ED), and on general inpatient floors. The study group included adult patients with three or more rib fractures who received HFNC at any location in the hospital (Phase 2: January 2018-December 2019). The study group was compared to a historical control group when HFNC was available only in the ICU (Phase 1: March 2013-July 2015). Patients were excluded from the study if they received invasive mechanical ventilation prior to HFNC. Primary outcomes were mechanical ventilation rates, ICU days, length of hospitalization, and mortality. RESULTS: During the study period, 63 patients received HFNC, with 35% of patients (n = 22) receiving the duration of therapy outside the ICU. When compared to the control group (N = 63), there were no significant differences in total hospital days (9 vs. 9, p=.64), mechanical ventilation (19% vs. 13%, p=.47), or mortality (3% vs. 5%, p = 1.00). Twenty-seven percent of patients (n = 17) in the study group avoided the ICU during hospitalization. CONCLUSIONS: Findings suggest that HFNC therapy can be safely initiated and managed on all hospital floors for patients with multiple rib fractures. Making the therapy available outside the ICU may reduce healthcare resource use without adversely affecting patient outcomes.

Nasal high flow therapy use in wards in patients with chronic obstructive pulmonary disease may spare ICU resources.

Nasal high flow therapy has been previously studied for the management of acute hypoxic respiratory failure in patients with chronic obstructive pulmonary disease but the data regarding its use outside of the intensive care unit are sparse. We aimed to evaluate safety and efficacy of nasal high flow therapy outside of the intensive care unit in patients with acute hypoxic respiratory failure and known chronic obstructive pulmonary disease. We conducted a retrospective matched historic cohort study of adult patients with diagnosed chronic obstructive pulmonary disease presenting with acute hypoxic respiratory failure between December 2017 to June 2019, after the initiation of a new protocol, which allowed patients to be managed with nasal high flow therapy on the medical/surgical wards instead of transferring them to the ICU per prior standard of care. Nasal high flow therapy was initiated either in the emergency department or on the medical/surgical wards. Patients were matched with historical cohorts who were managed with prior standard of care based on age, body mass index, comorbidities, and home oxygen use. Primary outcome of interest was difference in rates of mechanical ventilation. Secondary outcomes included hospital length of stay, total number of days spent in the intensive care unit, and in-hospital mortality. A total of 90 patients met study inclusion criteria and were matched to 90 historical control patients. Among the study group, 8% required mechanical ventilation versus 9% in the control group (p = 0.79). Hospital length of stay was 7 days in study group versus 6 days in control group (p = 0.02), and in-hospital mortality was the same in both study and control groups at 12% (p = 0.99). Nineteen percent of study group patients required ICU level of care at any time during the admission compared with 49% of control group (p < 0.001). Nasal high flow therapy use in patients with acute hypoxic respiratory failure and underlying chronic obstructive pulmonary disease outside of the intensive care unit may spare ICU resources and cost without delay in definitive care such as mechanical ventilation.

Awake Prone Positioning in Non-Intubated Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19.

BACKGROUND: Awake prone positioning (APP) has been advocated to improve oxygenation and prevent intubation of patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). This paper aims to synthesize the available evidence on the efficacy of APP. METHODS: We performed a systematic review of proportional outcomes from observational studies to compare intubation rate in patients treated with APP or with standard care. RESULTS: A total of 46 published and 4 unpublished observational studies that included 2,994 subjects were included, of which 921 were managed with APP and 870 were managed with usual care. APP was associated with significant improvement of oxygenation parameters in 381 cases of 19 studies that reported this outcome. Among the 41 studies assessing intubation rates (870 subjects treated with APP and 852 subjects treated with usual care), the intubation rate was 27% (95% CI 19-37%) as compared to 30% (95% CI 20-42%) (P = .71), even when duration of application, use of adjunctive respiratory assist device (high-flow nasal cannula or noninvasive ventilation), and severity of oxygenation deficit were taken into account. There appeared to be a trend toward improved mortality when APP was compared with usual care (11% vs 22%), which was not statistically significant. CONCLUSIONS: APP was associated with improvement of oxygenation but did not reduce the intubation rate in subjects with acute respiratory failure due to COVID-19. This finding is limited by the high heterogeneity and the observational nature of included studies. Randomized controlled clinical studies are needed to definitively assess whether APP could improve key outcome such as intubation rate and mortality in these patients.

Early versus late awake prone positioning in non-intubated patients with COVID-19.

BACKGROUND: Awake prone positioning (APP) is widely used in the management of patients with coronavirus disease (COVID-19). The primary objective of this study was to compare the outcome of COVID-19 patients who received early versus late APP. METHODS: Post hoc analysis of data collected for a randomized controlled trial (ClinicalTrials.gov NCT04325906). Adult patients with acute hypoxemic respiratory failure secondary to COVID-19 who received APP for at least one hour were included. Early prone positioning was defined as APP initiated within 24 h of high-flow nasal cannula (HFNC) start. Primary outcomes were 28-day mortality and intubation rate. RESULTS: We included 125 patients (79 male) with a mean age of 62 years. Of them, 92 (73.6%) received early APP and 33 (26.4%) received late APP. Median time from HFNC initiation to APP was 2.25 (0.8-12.82) vs 36.35 (30.2-75.23) hours in the early and late APP group (p < 0.0001), respectively. Average APP duration was 5.07 (2.0-9.05) and 3.0 (1.09-5.64) hours per day in early and late APP group (p < 0.0001), respectively. The early APP group had lower mortality compared to the late APP group (26% vs 45%, p = 0.039), but no difference was found in intubation rate. Advanced age (OR 1.12 [95% CI 1.0-1.95], p = 0.001), intubation (OR 10.65 [95% CI 2.77-40.91], p = 0.001), longer time to initiate APP (OR 1.02 [95% CI 1.0-1.04], p = 0.047) and hydrocortisone use (OR 6.2 [95% CI 1.23-31.1], p = 0.027) were associated with increased mortality. CONCLUSIONS: Early initiation (< 24 h of HFNC use) of APP in acute hypoxemic respiratory failure secondary to COVID-19 improves 28-day survival. Trial registration ClinicalTrials.gov NCT04325906.

Implementation of High-Flow Nasal Cannula Therapy Outside the Intensive Care Setting.

BACKGROUND: High-flow nasal cannula (HFNC) is an option for respiratory support in patients with acute hypoxic respiratory failure. To improve patient outcomes, reduce ICU-associated costs, and ease ICU bed availability, a multi-phased, comprehensive strategy was implemented to make HFNC available outside the ICU under the supervision of pulmonology or trauma providers in cooperation with a dedicated respiratory therapy team. The purpose of this study was to describe the education and implementation process for initiating HFNC therapy outside the ICU and to convey key patient demographics and outcomes from the implementation period. METHODS: HFNC therapy was implemented at a tertiary hospital in the Midwest, with systematic roll-out to all in-patient floors over a 9-month period. Utilization of the therapy and patient outcomes were tracked to ensure safety and efficacy of the effort. RESULTS: During the implementation period, 346 unique subjects met study inclusion criteria. Median (interquartile range) hospital length of stay was 8 d (4-12), and median duration of HFNC therapy was 44 h (18-90). Two thirds of subjects (n = 238) received the entire course of HFNC therapy outside the ICU, and more than half of subjects (n = 184) avoided the ICU for their entire hospitalization. Moreover, 6% of subjects in the study group escalated from HFNC to noninvasive ventilation, and 5% of subjects escalated from HFNC to mechanical ventilation. CONCLUSIONS: A comprehensive implementation process and a robust therapy protocol were integral to initiating and managing HFNC in all hospital locations. Study findings indicate that patients with acute hypoxic respiratory failure can safely receive HFNC therapy outside the ICU with appropriate patient selection and staff education.

Stiff isotropic lattices beyond the Maxwell criterion.

Materials with a stochastic microstructure, like foams, typically exhibit low mechanical stiffness, whereas lattices with a designed microarchitecture often show notably improved stiffness. These periodic architected materials have previously been designed by rule, using the Maxwell criterion to ensure that their deformation is dominated by the stretching of their struts. Classical designs following this rule tend to be anisotropic, with stiffness depending on the load orientation, but recently, isotropic designs have been reported by superimposing complementary anisotropic lattices. We have designed stiff isotropic lattices de novo with topology optimization, an approach based on continuum finite element analysis. Here, we present results of experiments on these lattices, fabricated by additive manufacturing, that validate predictions of their performance and demonstrate that they are as efficient as those designed by rule, despite appearing to violate the Maxwell criterion. These findings highlight the enhanced potential of topology optimization to design materials with unprecedented properties.

Additively manufacturable micro-mechanical logic gates.

Early examples of computers were almost exclusively based on mechanical devices. Although electronic computers became dominant in the past 60 years, recent advancements in three-dimensional micro-additive manufacturing technology provide new fabrication techniques for complex microstructures which have rekindled research interest in mechanical computations. Here we propose a new digital mechanical computation approach based on additively-manufacturable micro-mechanical logic gates. The proposed mechanical logic gates (i.e., NOT, AND, OR, NAND, and NOR gates) utilize multi-stable micro-flexures that buckle to perform Boolean computations based purely on mechanical forces and displacements with no electronic components. A key benefit of the proposed approach is that such systems can be additively fabricated as embedded parts of microarchitected metamaterials that are capable of interacting mechanically with their surrounding environment while processing and storing digital data internally without requiring electric power.

Field responsive mechanical metamaterials.

Typically, mechanical metamaterial properties are programmed and set when the architecture is designed and constructed, and do not change in response to shifting environmental conditions or application requirements. We present a new class of architected materials called field responsive mechanical metamaterials (FRMMs) that exhibit dynamic control and on-the-fly tunability enabled by careful design and selection of both material composition and architecture. To demonstrate the FRMM concept, we print complex structures composed of polymeric tubes infilled with magnetorheological fluid suspensions. Modulating remotely applied magnetic fields results in rapid, reversible, and sizable changes of the effective stiffness of our metamaterial motifs.

A simple, highly efficient route to electroless gold plating on complex 3D printed polyacrylate plastics.

Compared to tedious, multi-step treatments for electroless gold plating of traditional thermoplastics, this communication describes a simpler three-step procedure for 3D printed crosslinked polyacrylate substrates. This allows for the synthesis of ultralight gold foam microlattice materials with great potential for architecture-sensitive applications in future energy, catalysis, and sensing.

Proactive Use of High-Flow Nasal Cannula With Critically Ill Subjects.

INTRODUCTION: It has been suggested that use of a high-flow nasal cannula (HFNC) could be a first-line therapy for patients with acute hypoxic respiratory failure. The purpose of this study was to determine if protocolized use of HFNC decreases unplanned intubation and adverse outcomes in an ICU population. METHODS: The study was a prospective evaluation of 2 cohorts who received HFNC per protocol. Control groups were retrospective selections of subjects who received HFNC in the pre-protocol period. Cohort 1 (n = 88) received mechanical ventilation for ≥ 24 h and was extubated directly to HFNC following strict protocol criteria. Cohort 2 (n = 83) were placed on HFNC when oxygen requirements escalated (>4 L/min). RESULTS: Cohort 1 did not differ from its control group in mortality, hospital stay, or ICU days, but there were significant decreases in incidence of Gram-negative pulmonary infection (30% vs 9%, P = .001) and use of bronchodilator therapy (81% vs 61%, P = .008). Failed extubation rates were nearly identical across groups, but time to re-intubation was shorter in the protocol group (24 vs 13 h, P = .19). Cohort 2 did not differ significantly from its control group in intubation rates or mortality, but subjects managed by protocol experienced significant decreases in ICU days (4 vs 3 d, P = .03) and hospital days (12 vs 8 d, P = .007). There was a trend toward fewer hours on HFNC (33 vs 24 h, P = .10) and faster time to intubation when HFNC failed (19 vs 9 h, P = .08). CONCLUSIONS: Extubation to HFNC led to a significant decrease in pulmonary infections and bronchodilator therapy in Cohort 1 but did not reduce length of stay or rates of failed extubation. When HFNC was used early and per protocol (Cohort 2), ICU and hospital lengths of stay were reduced and HFNC was initiated more quickly when the need for respiratory support escalated.

A Preventative Respiratory Protocol to Identify Trauma Subjects at Risk for Respiratory Compromise on a General In-Patient Ward.

BACKGROUND: Patients are at risk for respiratory complications after sustaining blunt chest trauma, yet contradictory evidence exists about the utility of prophylactic respiratory therapy to reduce respiratory complications in this population. This study assessed the effectiveness of a proactive respiratory protocol on an in-patient ward to identify trauma patients at risk for pulmonary complications, administer appropriate therapies, and prevent deterioration requiring transfer to the ICU. METHODS: Trauma patients received a respiratory therapy evaluation at the time of admission to a general in-patient ward at a Level 1 trauma center. If subjects met protocol inclusion criteria, they received prophylactic respiratory treatments, primarily MetaNeb therapy, Vest therapy, or EzPAP. Multiple phases were included to evaluate the effectiveness of the protocol, with 50 subjects in each phase: a pre-protocol phase before adoption of the protocol; phase 1, which was found to have low physician adherence and overly broad inclusion criteria; and phase 2, with improved adherence and narrower inclusion criteria. Study inclusion criteria mirror the protocol criteria from phase 2: ≥3 rib fractures; pulmonary contusion; exacerbation of COPD, asthma, or other lung disease; or age ≥65 y with expected immobility of ≥48 h. RESULTS: The respiratory protocol was associated with an elimination of unplanned admissions to the ICU. After controlling for injury severity and other important clinical factors, receiving the protocol significantly decreased hospital stay by approximately 1.5 d. More subjects were admitted from the emergency department directly to the ward, avoiding the ICU. Bronchodilator use also decreased, although the result did not reach statistical significance. CONCLUSIONS: Study results suggest that a preventive respiratory protocol had a beneficial effect on patient outcomes; receiving the protocol reduced hospital days and eliminated unplanned admission to the ICU.

Lightweight Mechanical Metamaterials with Tunable Negative Thermal Expansion.

Ice floating on water is a great manifestation of negative thermal expansion (NTE) in nature. The limited examples of natural materials possessing NTE have stimulated research on engineered structures. Previous studies on NTE structures were mostly focused on theoretical design with limited experimental demonstration in two-dimensional planar geometries. In this work, aided with multimaterial projection microstereolithography, we experimentally fabricate lightweight multimaterial lattices that exhibit significant negative thermal expansion in three directions and over a temperature range of 170 degrees. Such NTE is induced by the structural interaction of material components with distinct thermal expansion coefficients. The NTE can be tuned over a large range by varying the thermal expansion coefficient difference between constituent beams and geometrical arrangements. Our experimental results match qualitatively with a simple scaling law and quantitatively with computational models.

High-flow nasal cannula therapy for patients with blunt thoracic injury: A retrospective study.

OBJECTIVE: High-flow nasal cannula (HFNC) has been shown to reduce the need for mechanical ventilation (MV) and to decrease hospital and ICU days for patients with severe respiratory compromise. HFNC has not been evaluated in trauma patients, thus the goal of this study is to describe the use of HFNC in a chest-injured population. METHODS: A retrospective study examined trauma patients with moderate to severe thoracic injury admitted to the ICU at a tertiary hospital between March 2012 and August 2015. HFNC was delivered by the Fisher & Paykel Optiflow system. Primary outcomes were the need for intubation after HFNC for respiratory failure, length of hospitalization, and mortality. RESULTS: During the study period, 105 patients with blunt chest trauma were admitted to the ICU and received HFNC therapy. Eighteen percent received MV prior to HFNC. Overall, 69% of patients who received HFNC never received MV, and 92% of patients were discharged alive. The intubation rate for respiratory failure after HFNC was 18%. For patients who did not receive MV prior to HFNC, delay to first HFNC was correlated with increased hospital days (r s = 0.41, p = 0.001) and ICU days (r s = 0.41, p < 0.001). CONCLUSIONS: Study results suggest that HFNC is comparable with other methods of noninvasive ventilation and may be beneficial for patients with thoracic injury. Additional investigation is warranted to determine if early use of HFNC can deliver effective respiratory support and prevent intubation in this population.

High-Flow Nasal Cannula in a Mixed Adult ICU.

BACKGROUND: Humidified, high-flow nasal cannula (HFNC) enables mucociliary clearance, accurate oxygen measurement, precise control of flow, and low-level positive airway pressure. There is sparse information concerning the timing of HFNC on patient outcomes such as incidence of adverse events during hospitalization, ICU stay, and post-ICU stay. METHODS: This is a retrospective analysis of a heterogeneous population of medical and trauma ICU patients who received HFNC therapy in a critical care setting. The study sample included 145 subjects who were admitted to the ICU and received HFNC therapy between March 2012 and February 2014. HFNC was delivered by the Fisher & Paykel Optiflow system. RESULTS: Of the 145 subjects who received HFNC, 35 (24.1%) received mechanical ventilation before HFNC, 21 (14.5%) received mechanical ventilation after HFNC, and 89 (61.3%) never received mechanical ventilation. Delay to first HFNC was moderately associated with unplanned ICU admission and was strongly correlated with the development of ventilator-associated pneumonia. Subjects with a greater length of time between ICU admission and first use of HFNC experienced significantly longer stays in the ICU and post-ICU periods, even after controlling for adverse events and mechanical ventilation. CONCLUSIONS: Study results provide preliminary evidence that early use of HFNC is beneficial in a medical and trauma ICU population, as it was associated with decreased ICU and post-ICU lengths of stay and reduced incidence of adverse events. This suggests that HFNC should be considered early in the ICU as first-line oxygen therapy.

Ultralight, ultrastiff mechanical metamaterials.

The mechanical properties of ordinary materials degrade substantially with reduced density because their structural elements bend under applied load. We report a class of microarchitected materials that maintain a nearly constant stiffness per unit mass density, even at ultralow density. This performance derives from a network of nearly isotropic microscale unit cells with high structural connectivity and nanoscale features, whose structural members are designed to carry loads in tension or compression. Production of these microlattices, with polymers, metals, or ceramics as constituent materials, is made possible by projection microstereolithography (an additive micromanufacturing technique) combined with nanoscale coating and postprocessing. We found that these materials exhibit ultrastiff properties across more than three orders of magnitude in density, regardless of the constituent material.

Assessment of the implementation of a protocol to reduce ventilator-associated pneumonia in intensive care unit trauma patients.

Ventilator-associated pneumonia (VAP) is the primary hospital-acquired infection contracted by critically ill patients who receive mechanical ventilation. This retrospective study evaluated the efficacy of a multifaceted VAP prevention protocol in an adult trauma population. Ventilator-associated pneumonia was defined according to the National Healthcare Safety Network (2009) criteria. The number of days to onset of VAP in the postprotocol period was longer than the preprotocol period despite a concomitant increase in the number of mechanical ventilation days.

Utility of p16, Ki-67, and HPV test in diagnosis of cervical intraepithelial neoplasia and atrophy in women older than 50 years with 3- to 7-year follow-up.

BACKGROUND: Differentiating cervical intraepithelial neoplasia (CIN) from atrophy in postmenopausal women based on morphology alone is challenging. p16 and Ki-67 help distinguish CIN2/3 from atrophy. The goal of this study is to further characterize the utility of p16, Ki-67, and human papillomavirus (HPV) tests in women older than 50 years, particularly in CIN1. DESIGN: The authors retrospectively identified cervical specimens from three, 1-year time periods. Included were cases from women older than 50 years with benign diagnoses, atrophy, and CIN. Slides were stained with p16 and Ki-67 and graded as positive or negative. Medical records were reviewed for cytology, HPV test, and histopathologic diagnoses from the time of biopsy to 2010. RESULTS: A total of 97 cervical samples were included. In all, 34 (74%) CIN1 cases were negative for p16 and Ki-67. Of CIN1 cases with positive HPV tests, only 1/10 (10%) had positive p16 staining versus 2/2 (100%) of CIN2/3 cases. Of 39 women with CIN1 who had follow-up data available, 4 (10%) had subsequent histologic progression to CIN2/3 and none developed invasive disease. CONCLUSIONS: In our study, the majority of cases (74%) diagnosed as CIN1 in women ≥ 50 years are negative for p16 and Ki-67 and do not progress to high-grade dysplasia during 3- to 7-year follow-up. A combination of morphology, p16, and Ki-67 on cervical specimens in women older than 50 years, and furthermore, use of these stains on Pap tests in combination with HPV testing may help distinguish CIN from atrophy and reduce unnecessary invasive follow-up testing.

The diagnosis and characteristics of moderate dry eye in non-contact lens wearers.

PURPOSE: To identify and characterize moderate dry eye in non-contact lens wearers with a new scoring system-based dry eye questionnaire and to determine which objective tests better differentiate patients with moderate dry eye from healthy patients. METHODS: Fifty-two healthy subjects (21 women and 31 men with a mean age of 27.8 +/- 9.2 years) and 37 subjects with moderate dry eye (33 women and 4 men with a mean age of 36.4 +/- 12.9 years) completed a 42-item dry eye questionnaire. Seventeen healthy subjects (11 women and 6 men with a mean age of 30.5 +/- 9.7 years) and 28 subjects with moderate dry eye (24 women and 4 men with a mean age of 38.50 +/- 3.8 years) underwent additional objective assessment of ocular surface health, tear osmolality, tear stability, and tear volume. RESULTS: Subjects with moderate dry eye scored significantly higher (49.8 +/- 20.3, P<0.0001) on the dry eye questionnaire than did normal subjects (11.7 +/- 10.3). Ocular irritation symptoms worsened with progression of time of day in both groups of subjects. Internal reliability (0.95 Cronbach alpha) was excellent, and concurrent validity (Spearman rho 0.507) was acceptable when compared to the McMonnies and Ho dry eye questionnaire. Significant differences in tear osmolality (P<0.00001), invasive tear breakup time (P<0.034), and corneal vital dye staining (P<0.0001) were detected between the two groups of subjects. A stepwise linear regression on objective clinical tests, however, did not account for 77% of the total variance in the questionnaire scores. CONCLUSIONS: A unique scoring system-based dry eye questionnaire was validated to separate non-contact lens wearers with moderate dry eye from healthy subjects. Objective tests of tear osmolality and stability and ocular surface integrity were better than other clinical measures at identifying differences between the two subject groups. The results strongly support the evidence that the diagnosis and treatment of moderate dry eye requires a detailed assessment of self-perceived symptoms and that objective clinical testing alone may be insufficient.