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Abstract There is no current consensus on the follow up of kidney function in patients undergoing cardiopulmonary bypass (CPB). The main objectives of this pilot study is to collect preliminary data on kidney function decline encountered on the first postoperative visit of patients who have had CPB and to identify predictors of kidney function decline post hospital discharge. Design: Retrospective chart review. Adult patients undergoing open heart procedures utilizing CPB. Patient demographics, type of procedure, pre-, intra-, and postoperative clinical, hemodynamic echocardiographic, and laboratory data were abstracted from electronic medical records. Acute kidney disease (AKD), and chronic kidney disease (CKD) were diagnosed based on standardized criteria. Interval change in medications, hospital admissions, and exposure to contrast, from hospital discharge till first postoperative visit were collected. AKD, and CKD as defined by standardized criteria on first postoperative visit. 83 patients were available for analysis. AKD occurred in 27 (54%) of 50 patients and CKD developed in 12 (42%) out of 28 patients. Older age was associated with the development of both AKD and CKD. Reduction in right ventricular cardiac output at baseline was associated with AKD (OR: 0.5, 95% CI: 0.3, 0.79, P = 0.01). Prolongation of transmitral early diastolic filling wave deceleration time was associated with CKD (OR: 1.02, 95% CI: 1.01, 1.05, P = 0.03). In-hospital acute kidney injury (AKI) was a predictor of neither AKD nor CKD. AKD and CKD occur after CPB and may not be predicted by in-hospital AKI. Older age, right ventricular dysfunction and diastolic dysfunction are important disease predictors. An adequately powered longitudinal study is underway to study more sensitive predictors of delayed forms of kidney decline after CPB.

Heart failure occurs when the heart cannot pump adequate blood to the body, which afflicts over 60 million people worldwide. Its treatment options include physiotherapy, medication, mechanical heart support, heart surgery, or heart transplantation. Ventricular assist devices have direct blood contact while passive ventricular constraint devices have only modest therapeutic efficacy. Current direct cardiac compression devices are either bulky, require noisy driving pneumatic sources, or are unable to mimic the natural heart motion. This study introduces a robotic cardiac compression device made of soft artificial muscle filaments that can simultaneously produce radial, axial, and torsional movements, potentially augmenting the pumping function of a failing heart. An empirical model is developed to describe the device motion and an artificial pericardium is employed to enable uniform force distribution to the heart and real‐time pressure sensing. The proposed device could deliver a stroke volume of 70 mL at 15 beats per minute, or a cardiac output of 1.05 L min−1, and achieve a peak instantaneous flow rate of 2.8 L min−1 and an output pressure of 50 mmHg. The new devices are highly customizable and experimentally validated with fresh porcine heart. They are expected to inspire future development of nonblood‐contacting cardiac assist devices.

Abstract Haptic (touch) is important for effective interaction with the surroundings. In teleoperated surgical systems, its absence leads to reduced perception, making delicate tasks difficult and resulting in unexpected damage to surrounding tissues. To enhance safety, a force‐feedback system and haptic device are needed. However, existing haptic prototypes are associated with rigid, bulky, and heavy components, making effective communication with the skin problematic. This paper presents a teleoperated endoscopic surgical system with an integrated 3D force sensor and real‐time haptic feedback. A surgical robotic arm is remotely controlled by a soft haptic glove incorporated 3‐axis cutaneous device and a finger kinesthetic module. The 3D force sensor is constructed from hydraulic filament soft sensors that can induce pressure change under strain. To enable precise motion, the haptic glove is operated by a feedforward controller and a master‐slave architecture. Experiments with human subjects (n = 15) show that cutaneous and kinesthetic feedback significantly improves the user's performance (9.4 out of 10) compared to no haptic feedback (2.27 out of 10). Finally, subjects rank the new system as highly wearable, comfortable, and effective, which is expected to bridge a gap in the surgical field and support the future development of advanced teleoperated systems.

Abstract Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis.

Abstract In recent years, advances in modern technology have altered the practice of surgery from open to minimally invasive surgery (MIS) aided by robots. Teleoperated surgical robotic systems (TSRSs) provide numerous significant benefits for MIS over traditional approaches, including improved safety, more efficient and precise surgery, better cosmesis, shorter recovery time, and reduced postoperative pain. Existing TSRSs’ master consoles, with improvements in vision systems, designs, and control methods, have significantly enhanced human–robot interactions, resulting in safer and more accurate medical intervention operations. Despite advances, haptic technologies, including sensors, machine assistance, and intuitive devices for user interfaces, are still limited, resulting in less effective usage of TSRSs for surgical operations. This review presents a summary of the emerging TSRSs with a focus on their user interfaces. In addition, advanced sensing, haptic, smart garments, and medical image artificial intelligence (AI) assistance technologies are shown with their potential for use in master consoles of the TSRSs are shown. Finally, a discussion on the need for a smart human‐robot interface for TSRSs is given.

Abstract Three‐dimensional (3D) bioprinting technology offers great potential in the treatment of tissue and organ damage. Conventional approaches generally rely on a large form factor desktop bioprinter to create in vitro 3D living constructs before introducing them into the patient's body, which poses several drawbacks such as surface mismatches, structure damage, and high contamination along with tissue injury due to transport and large open‐field surgery. In situ bioprinting inside a living body is a potentially transformational solution as the body serves as an excellent bioreactor. This work introduces a multifunctional and flexible in situ 3D bioprinter (F3DB), which features a high degree of freedom soft printing head integrated into a flexible robotic arm to deliver multilayered biomaterials to internal organs/tissues. The device has a master‐slave architecture and is operated by a kinematic inversion model and learning‐based controllers. The 3D printing capabilities with different patterns, surfaces, and on a colon phantom are also tested with different composite hydrogels and biomaterials. The F3DB capability to perform endoscopic surgery is further demonstrated with fresh porcine tissue. The new system is expected to bridge a gap in the field of in situ bioprinting and support the future development of advanced endoscopic surgical robots.

Work-related musculoskeletal disorders (WMSDs) are often caused by repetitive lifting, making them a significant concern in occupational health. Although wearable assist devices have become the norm for mitigating the risk of back pain, most spinal assist devices still possess a partially rigid structure that impacts the user’s comfort and flexibility. This paper addresses this issue by presenting a smart textile-actuated spine assistance robotic exosuit (SARE), which can conform to the back seamlessly without impeding the user’s movement and is incredibly lightweight. To detect strain on the spine and to control the smart textile automatically, a soft knitting sensor that utilizes fluid pressure as a sensing element is used. Based on the soft knitting hydraulic sensor, the robotic exosuit can also feature the ability of monitoring and rectifying human posture. The SARE is validated experimentally with human subjects (N = 4). Through wearing the SARE in stoop lifting, the peak electromyography (EMG) signals of the lumbar erector spinae are reduced by 22.8% ± 12 for lifting 5 kg weights and 27.1% ± 14 in empty-handed conditions. Moreover, the integrated EMG decreased by 34.7% ± 11.8 for lifting 5 kg weights and 36% ± 13.3 in empty-handed conditions. In summary, the artificial muscle wearable device represents an anatomical solution to reduce the risk of muscle strain, metabolic energy cost and back pain associated with repetitive lifting tasks.

Abstract The marriage of textiles with artificial muscles to create smart textiles is attracting great attention from the scientific community and industry. Smart textiles offer many benefits including adaptive comfort and high conformity to objects while providing active actuation for desired motion and force. This paper introduces a new class of programmable smart textiles created from different methods of knitting, weaving, and sticking fluid-driven artificial muscle fibers. Mathematical models are developed to describe the elongation-force relationship of the knitting and weaving textile sheets, followed by experiments to validate the model effectiveness. The new smart textiles are highly flexible, conformable, and mechanically programmable, enabling multimodal motions and shape-shifting abilities for use in broader applications. Different prototypes of the smart textiles are created with experimental validations including various shape-changing instances such as elongation (up to 65%), area expansion (108%), radial expansion (25%), and bending motion. The concept of reconfiguring passive conventional fabrics into active structures for bio-inspired shape-morphing structures is also explored. The proposed smart textiles are expected to contribute to the progression of smart wearable devices, haptic systems, bio-inspired soft robotics, and wearable electronics.

BackgroundPublic Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development.MethodsWe identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis.ResultsThirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering.ConclusionWe found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice.

Background & Objectives Ultra-radical (UR) procedures, including splenectomy, are utilized to increase complete cytoreduction rates during Cytoreductive Surgery (CRS) performed with the aim of complete macroscopic clearance of disease. The purpose of this study was to investigate if splenectomy negatively impacts survival when undertaken during CRS for advanced ovarian cancer (AOC) and compare published splenectomy and cytoreduction rates. Methods A retrospective review of all consecutive patients who underwent cytoreductive surgery for AOC between 16/05/2013-28/01/2019. Survival, baseline patient characteristics, complications and surgical parameters were recorded. Propensity scored matching (PSM) was performed to reduce bias. Results 154 patients identified over 71 months. 97 underwent standard, 57 underwent UR surgery, 27 patients received splenectomy (17.5%) No difference was seen in overall survival (OS) between all patients (median OS 34 months (95%CI 25.9–41.1) and patients who underwent splenectomy (median OS not yet reached) (p = >0.05). After PSM for various baseline covariates, no significant difference in splenectomy versus non-splenectomy patients (3-year survival 54% compared to 56%) (P > 0.05). Three splenectomy specific complications occurred; one each of pancreatic tail injury, left pleural effusion and streptococcal pharyngitis during chemotherapy. We found wide variation in utilization of splenectomy in published case series; from 9% to 35%. Conclusions Splenectomy performed as part of CRS is not detrimental to survival in AOC. There is a wide variation in utilization of splenectomy in published case series with little correlation with cytoreduction rates.

Constrictive pericarditis is a rare cause of right-sided heart failure secondary to a stiff, non-compliant pericardium. Clinical presentation can vary considerably and requires a high suspicion for diagnosis. A 31-year-old male presented to the emergency department with complaints of abdominal distension. An abdominal ultrasound revealed large volume ascites; thus, it was initially suspected he had underlying cirrhosis. However, an echocardiogram revealed a diagnosis of constrictive pericarditis. It's important for clinicians to consider constrictive pericarditis in a patient presenting with unexplained right-sided heart failure.

Abstract Wound closure with surgical sutures is a critical challenge for flexible endoscopic surgeries. Substantial efforts have been introduced to develop functional and smart surgical sutures to either monitor wound conditions or ease the complexity of knot tying. Although research interests in smart sutures by soft robotic technologies have emerged for years, it is challenging to develop a soft robotic structure that possesses a similar physical structure as conventional sutures while offering a self-tightening knot or anchor to close the wound. This paper introduces a new concept of smart sutures that can be programmed to achieve desired and uniform tension distribution while offering self-tightening knots or automatically deploying secured anchors. The core technology is a soft hydraulic artificial muscle that can be elongated and contracted under applied fluid pressure. Each suture is equipped with a pressure locking mechanism to hold its temporary elongated state and to induce self-shrinking ability. The puncturing and holding force for the smart sutures with anchors are examined. Ex-vivo experiments on fresh porcine stomach and colon demonstrate the usefulness of the new smart sutures. The new approaches are expected to pave the way for the further development of smart sutures that will benefit research, training, and commercialization in the surgical field.

Stretchable composites comprising liquid metal (LM) inclusions and silicone elastomers (LME composites) are of great interest for soft electronics and wearable devices. LME composites consisting of highly deformable materials and low conductive filler ratios offer high stretchability and good strain‐tolerant conductance, while not compromising the functionality of their host systems. Despite advances, actively achieving electrical conductivity for LME composites with a low ratio of fillers is challenging, especially in highly deformable elastomers. Herein, a new fabrication strategy that turns nonconductive LME composites with highly deformable elastomers into conductive ones using a small amount of magnetic Ni‐doped LM is introduced. By actively manipulating conductive fillers with an external magnetic field, electrically conductive traces can sustainably be achieved at any desired location. Experimental results show that conductive traces have high conductivity of 2.55 × 105 S m−1, high stretchability (>450%), good strain‐tolerant conductance (R/R0 ≈ 1.56 at 250% strain), and especially a tensile modulus as low as 60.1 kPa at a very low loading ratio (9.7% by volume). The noncontacting magnetic fabrication also enables the creation of diverse configurations in 1D, 2D, and 3D, offering a broad range of potential applications from robotics, stretchable electronics, wearable devices, smart garments to biomedical systems.

We present a genome assembly from an individual female Anthocharis cardamines (the orange-tip; Arthropoda; Insecta; Lepidoptera; Pieridae). The genome sequence is 360 megabases in span. The majority (99.74%) of the assembly is scaffolded into 31 chromosomal pseudomolecules, with the W and Z sex chromosomes assembled. Gene annotation of this assembly on Ensembl has identified 12,477 protein coding genes.

Human epidermal Langerhans cells (LCs) maintain immune homeostasis in the skin. To examine transcriptional programming of human primary LCs during homeostasis, we performed scRNA-seq analysis of LCs before and after migration from the epidermis, coupled with functional assessment of their regulatory T cell priming capabilities. The analysis revealed that steady-state LCs exist in a continuum of maturation states and upregulate antigen presentation genes along with an immunoregulatory module including the genes IDO1, LGALS1, LAMTOR1, IL4I, upon their migration. The migration-induced transition in genomic state is accompanied by the ability of LCs to more efficiently prime regulatory T cell responses in co-culture assays. Computational analyses of the scRNAseq datasets using SCENIC and Partial Information Decomposition in Context identified a set of migration-induced transcription factors including IRF4, KLF6 and RelB as key nodes within a immunoregulatory gene regulatory network. These findings support a model in which efficient priming of immunoregulatory responses by LCs is dependent on coordinated upregulation of a migration-coupled maturation program with a immunoregulation-promoting genomic module.

Background: Implementation of an anesthesiology-led cardiac implantable electronic device (CIED) service can be viewed to have economic and efficiency challenges. This study evaluates the cost savings of an anesthesiology-led CIED service. Methods: A total of 830 patients presented in the pre-implementation period from 1 March 2016 to 31 December 2017, and 1981 patients presented in the post-implementation period from 1 January 2018 to 31 October 2021. Interrupted time-series analysis for single-group comparisons was used to evaluate the cost savings resulting from reduction in operating room (OR) start delays for patients with CIEDs. Results: OR start-time delay was reduced by 10.6 min (95%CI: −20.5 to −0.83), comparing pre- to post-implementation. For an OR cost of USD 45/min, we estimated the direct cost to the department to be USD 1.68/min. The intervention translated into a total cost reduction during the intervention period of USD 250,000 (USD 18,000 to USD 470,000) per year for the institution and USD 9800 (USD 730 to USD 17,000) per year for the department. The yearly cost of employing a full-time team of CIED specialists would have been USD 135,456. The service triggered electrophysiology consultation on 13 device malfunctions. Conclusions: An anesthesiology-led CIED service resulted in substantial cost savings, increased OR efficiency and patient safety.

Summary: T cell pathology in the skin leads to monocyte influx, but we have little understanding of the fate of recruited cells within the diseased niche, or the long-term impact on cutaneous immune homeostasis. By combining a murine model of acute graft-versus-host disease (aGVHD) with analysis of patient samples, we demonstrate that pathology initiates dermis-specific macrophage differentiation and show that aGVHD-primed macrophages continue to dominate the dermal compartment at the relative expense of quiescent MHCIIint cells. Exposure of the altered dermal niche to topical haptens after disease resolution results in hyper-activation of regulatory T cells (Treg), but local breakdown in tolerance. Disease-imprinted macrophages express increased IL-1β and are predicted to elicit altered TNF superfamily interactions with cutaneous Treg, and we demonstrate the direct loss of T cell regulation within the resolved skin. Thus, T cell pathology leaves an immunological scar in the skin marked by failure to re-set immune homeostasis.

Abstract Background After the success of PET/CT as a clinical diagnostic tool, the introduction of PET/MRI is a natural development aimed at further improving combined diagnostic imaging and reduced ionising radiation dose for half-body imaging. As with PET and CT, the combination of PET and MRI presents a series of issues that need to be addressed regarding workforce training and education. At present, there is a lack of agreement over the competencies, training requirements and educational pathways needed for PET/MRI operation. In the UK, following the establishment of the MR-PET imaging network, a task force was created to investigate the status of the workforce training, identify gaps and make recommendations regarding staff training. To do this, we ran a national survey on the status of the workforce training and the local practices across the UK’s seven PET/MRI sites, reviewed the literature, and convened a panel of experts, to assess all the evidence and make recommendations regarding PET/MRI competencies and training of nuclear medicine technologists and radiographers. Results There is limited literature available specifically on competencies and training for technologists and radiographers. The recommendations on the topic needed revisiting and adapting to the UK MR-PET network. The online survey confirmed the need for developing PET/MRI competencies and training pathways. Local organisational structures and practices were shared across the seven sites, based on models derived from experience outside the UK. The panel of experts agreed on the need for PET/MRI competencies and training strategies. Professional organisations started collaborative discussions with partners from both Nuclear Medicine and Radiography to set training priorities. Multidisciplinary collaboration and partnership were suggested as a key to a successful implementation of competencies and training. Conclusions The report identified the need for establishing competencies for the PET/MRI workforce, particularly for technologists and radiographers. It also helped defining these competencies as well as identifying the demand for bespoke training and the development of local and national courses to be implemented to fulfil this new training need.

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in the skin. Here the authors show, by transcriptomic, epigenetic and CRISPR editing analyses, that during LC migration and maturation the transcription factor IRF4 regulates expression of antigen presentation and co-stimulatory gene modules while attenuating inflammatory response genes.

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

Summary: Single-cell transcriptomics suffer from sensitivity limits that restrict low abundance transcript identification, affects clustering and can hamper downstream analyses. Here, we describe Constellation sequencing (Constellation-Seq), a molecular transcriptome filter that delivers two orders of magnitude sensitivity gains by maximizing read utility while reducing the data sparsity and sequencing costs. The technique reliably measures changes in gene expression and was demonstrated by resolving rare dendritic cell populations from a peripheral blood mononuclear cell sample sample and exploring their biology with extreme resolution. The simple and powerful method is fully compatible with standard scRNA-Seq library preparation protocols and can be used for hypothesis testing, marker validation or investigating pathways.

Soft actuators (SAs) have been used in many compliant robotic structure and wearable devices, due to their safe interaction with the wearers. Despite advances, the capability of current SAs is limited by scalability, high hysteresis, and slow responses. In this paper, a new class of soft, scalable, and high-aspect ratio fiber-reinforced hydraulic SAs is introduced. The new SA uses a simple fabrication process of insertion where a hollow elastic rubber tube is directly inserted into a constrained hollow coil, eliminating the need for the manual wrapping of an inextensible fiber around a long elastic structure. To provide high adaptation to the user skin for wearable applications, the new SAs are integrated into flexible fabrics to form a wearable fabric sleeve. To monitor the SA elongation, a soft liquid metal-based fabric piezoresistive sensor is also developed. To capture the nonlinear hysteresis of the SA, a novel asymmetric hysteresis model which only requires five model parameters in its structure is developed and experimentally validated. The new SAs-driven wearable robotic sleeve is scalable, highly flexible, and lightweight. It can also produce a large amount of force of around 23 N per muscle at around 30% elongation, to provide useful assistance to the human upper limbs. Experimental results show that the soft fabric sleeve can augment a user’s performance when working against a load, evidenced by a significant reduction on the muscular effort, as monitored by electromyogram (EMG) signals. The performance of the developed SAs, soft fabric sleeve, soft liquid metal fabric sensor, and nonlinear hysteresis model reveal that they can effectively modulate the level of assistance for the wearer. The new technologies obtained from this work can be potentially implemented in emerging assistive applications, such as rehabilitation, defense, and industry.

Incontinentia pigmenti (IP) is a rare genetic skin disorder with an X-linked dominant inheritance that is seen almost exclusively in females. Subungual keratoacanthoma (SUKA) is a rare benign neoplasm of the nail bed associated with IP. The recommended initial treatment of SUKA is conservative thereby sparing the digit in the form of excision and curettage. However, definitive treatment involves terminalisation of the affected digit. We report a case in a 54-year-old woman with IP who developed SUKA who was treated with local subungual excision and subsequent skin grafting who had previous terminalisation of other digits for the same condition. Subungual keratoacanthoma is a rare benign neoplasm that is typically treated with curettage and excision at the initial stages with terminalisation as the definitive treatment. Given the highly positive outcome in this case with minimal sacrifice to the dexterity of the patient and preservation of digit length, we feel that local subungual excision and skin grafting should be strongly considered as an alternative to amputation in moderate to severe cases of the condition.

ABSTRACT IMPACT: Current practice guidelines offer a variety of treatment options for sternal reconstruction but complications and infections remain a serious surgical problem. This work seeks to provide a comprehensive picture of the com-morbidities and reconstructive methods that lead to success and improve patient outcomes. OBJECTIVES/GOALS: Patients that undergo cardiac surgery via the median sternotomy approach are at risk of wound complications that require repair. We seek to evaluate how outcomes of sternal reconstruction are influenced by patient comorbidities, flap usage and internal mammary artery grafts and methods of sternal closure. METHODS/STUDY POPULATION: We identified patients between 2005 and 2020 who underwent sternotomy followed by debridement and flap coverage at our institution. Comorbidities, method of reconstruction, demographic data, surgical history, and other factors pertaining to mortality and morbidity were collected. The data will then be analyzed to identify population characteristics using logistic regression variables to determine univariate and adjusted multivariable measures of association with mortality. We present the pre-liminary data analyzed using chi-square and one-way anova in R. RESULTS/ANTICIPATED RESULTS: In this study we present a preliminary characterization of one institution’s sternal reconstruction patient outcomes with a variety of reconstruction methods including pectoralis advancement flaps, omental flaps and latissumus dorsi flaps. Notable preoperative comorbidities include 50% of patients > age 60, 18% with diabetes mellitus, 18 % with diagnosed hypertension, 18% with COPD, and 9% with a smoking history DISCUSSION/SIGNIFICANCE OF FINDINGS: In an evolving cardiothoracic landscape, clinical characteristics of patients being treated for sternal reconstructive surgery present a moving target. Understanding current risk factors, preoperative management and timing for aggressive surgical treatment offers an opportunity to update treatment protocol and maximize successful outcomes.

Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.

Chromosome conformation capture (3C) techniques are crucial to understanding tissue-specific regulation of gene expression, but current methods generally require large numbers of cells. This protocol describes two new low-input Capture-C approaches that can generate high-quality 3C interaction profiles from 10,000-20,000 cells, depending on the resolution used for analysis.

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, “non-dangerous” situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future “omics” investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology.

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.