Nature and human well-being: The olfactory pathway.

The world is undergoing massive atmospheric and ecological change, driving unprecedented challenges to human well-being. Olfaction is a key sensory system through which these impacts occur. The sense of smell influences quality of and satisfaction with life, emotion, emotion regulation, cognitive function, social interactions, dietary choices, stress, and depressive symptoms. Exposures via the olfactory pathway can also lead to (anti-)inflammatory outcomes. Increased understanding is needed regarding the ways in which odorants generated by nature (i.e., natural olfactory environments) affect human well-being. With perspectives from a range of health, social, and natural sciences, we provide an overview of this unique sensory system, four consensus statements regarding olfaction and the environment, and a conceptual framework that integrates the olfactory pathway into an understanding of the effects of natural environments on human well-being. We then discuss how this framework can contribute to better accounting of the impacts of policy and land-use decision-making on natural olfactory environments and, in turn, on planetary health.

Management of the Charcot Foot and Ankle: Nonreconstructive Surgery.

Diabetic neuroarthropathy is a complication of diabetes mellitus that results in instability of the foot, structural deformity, and soft-tissue breakdown. Commonly, midfoot collapse of the medial, lateral, or both longitudinal arches may result in increased plantar pressures and subsequent midfoot ulceration. Many of these wounds can be successfully managed with local wound care and off-loading; however, surgical intervention becomes necessary in cases of osteomyelitis or when the wound fails to heal despite conservative efforts. In cases where surgical reconstruction may not be indicated, nonreconstructive surgical efforts have shown effectiveness in resolving wounds and allowing patients to return to ambulatory lifestyles. This article serves as an update to current treatment recommendations for the nonreconstructive surgical management of Charcot neuroarthropathy.

Safety of Tibial Half Pins With Circular External Fixation for Foot and Ankle Reconstruction in Patients With Peripheral Neuropathy.

The primary aim of the study was to evaluate the rate of tibial fracture with half pin placement in conjunction with tensioned wires in Ilizarov static external fixator in patients with peripheral neuropathy. Concentric visualization through a rancho cube and careful identification of anterior, posterior, medial, and lateral borders of the tibia, the "perfect circle" technique was used to ensure avoidance of cortical breach. Bivariate analysis was performed comparing the rates of tibia fractures in those who did and did not employ the "perfect circle" technique for placement of tibial half pins; evaluating for demographics, rationale for external fixation use, and postoperative amputation and complication rates. Tibial stress fractures, and early removal of pin/wires from external fixator secondary to breakage both occurred at statistically significant higher rates in patients in which the "perfect circle" technique was not employed (p < .001 and p = .03 respectively). The overall rate of tibia stress fractures was 2.08% (2/96), 0% (0/85) when "perfect circle" technique was used, compared to 18.18% (2/11) when it was not used. This study demonstrates a substantially low rate of tibia stress fractures with half pin use, in contrast to prior literature and should provide foot and ankle surgeons confidence, particularly when appropriate placement is observed in this high-risk population.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice.

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

How to Create a Hot Foot Line to Prevent Diabetes-Related Amputations: Instant Triage for Emergency Department and Inpatient Consultations.

Emergency department visits for lower extremity complications of diabetes are extremely common throughout the world. Surprisingly, recent data suggest that such visits generate an 81.2% hospital admission rate with an annual bill of at least $1.2 billion in the United States alone. The likelihood of amputation and other subsequent adverse outcomes is strongly associated with three factors: 1) wound severity (degree of tissue loss), 2) ischemia, and 3) foot infection. Using these factors, this article outlines the basic principles needed to create an evidence-based, rapid foot assessment for diabetic foot ulcers presenting to the emergency department, and suggests the establishment of a "hot foot line" for an organized, expeditious response from limb salvage team members. We present a nearly immediate assessment and referral system for patients with atraumatic tissue loss below the knee that has the potential to vastly expedite lower extremity triage in the emergency room setting through greater collaboration and organization.

Image once, print thrice? Three-dimensional printing of replacement parts.

OBJECTIVE: The last 20 years has seen an exponential increase in 3D printing as it pertains to the medical industry and more specifically surgery. Previous reviews in this domain have chosen to focus on applications within a specific field. To our knowledge, none have evaluated the broad applications of patient-specific or digital imaging and communications in medicine (DICOM) derived applications of this technology. METHODS: We searched PUBMED and CINAHL from April 2012 to April 2017. RESULTS: 261 studies fulfilled the inclusion criteria. Proportions of articles reviewed: DICOM (5%), CT (38%), MRI (20%), Ultrasonography (28%), and Bio-printing (9%). CONCLUSION: There is level IV evidence to support the use of 3D printing for education, pre-operative planning, simulation and implantation. In order to make this technology widely applicable, it will require automation of DICOM to standard tessellation language to implant. Advances in knowledge: Recent lapses in intellectual property and greater familiarity with rapid prototyping in medicine has set the stage for the next generation of custom implants, simulators and autografts. Radiologists may be able to help establish reimbursable procedural terminology.

Illustration of Cost Saving Implications of Lower Extremity Nerve Decompression to Prevent Recurrence of Diabetic Foot Ulceration.

The US diabetic foot ulcer (DFU) incidence is 3-4% of 22.3 million diagnosed diabetes cases plus 6.3 million undiagnosed, 858 000 cases total. Risk of recurrence after healing is 30% annually. Lower extremity multiple nerve decompression (ND) surgery reduces neuropathic DFU (nDFU) recurrence risk by >80%. Cost effectiveness of hypothetical ND implementation to minimize nDFU recurrence is compared to the current $6.171 billion annual nDFU expense. A literature review identified best estimates of annual incidence, recurrence risk, medical management expense, and noneconomic costs for DFU. Illustrative cost/benefit calculations were performed assuming widespread application of bilateral ND after wound healing to the nDFU problem, using Center for Medicare Services mean expense data of $1143/case for unilateral lower extremity ND. Calculations use conservative, evidence-based cost figures, which are contemporary (2012) or adjusted for inflation. Widespread adoption of ND after nDFU healing could reduce annual DFU occurrences by at least 21% in the third year and 24% by year 5, representing calculated cost savings of $1.296 billion (year 3) to $1.481 billion (year 5). This scenario proffers significant expense reduction and societal benefit, and represents a minimum 1.9× return on the investment cost for surgical treatment. Further large cost savings would require reductions in initial DFU incidence, which ND might achieve by selective application to advanced diabetic sensorimotor polyneuropathy (DSPN). By minimizing the contribution of recurrences to yearly nDFU incidence, ND has potential to reduce by nearly $1 billion the annual cost of DFU treatment in the United States.

Reduction of pain via platelet-rich plasma in split-thickness skin graft donor sites: a series of matched pairs.

In the past decade, autologous platelet-rich plasma (PRP) therapy has seen increasingly widespread integration into medical specialties. PRP application is known to accelerate wound epithelialization rates, and may also reduce postoperative wound site pain. Recently, we observed an increase in patient satisfaction following PRP gel (Angel, Cytomedix, Rockville, MD) application to split-thickness skin graft (STSG) donor sites. We assessed all patients known to our university-based hospital service who underwent multiple STSGs up to the year 2014, with at least one treated with topical PRP. Based on these criteria, five patients aged 48.4±17.6 (80% male) were identified who could serve as their own control, with mean time of 4.4±5.1 years between operations. In both therapies, initial dressing changes occurred on postoperative day (POD) 7, with donor site pain measured by Likert visual pain scale. Paired t-tests compared the size and thickness of harvested skin graft and patient pain level, and STSG thickness and surface area were comparable between control and PRP interventions (p>0.05 for all). Donor site pain was reduced from an average of 7.2 (±2.6) to 3 (±3.7), an average reduction in pain of 4.2 (standard error 1.1, p=0.0098) following PRP use. Based on these results, the authors suggest PRP as a beneficial adjunct for reducing donor site pain following STSG harvest.

Use of collagenase ointment in conjunction with negative pressure wound therapy in the care of diabetic wounds: a case series of six patients.

BACKGROUND: Diabetic wounds with additional comorbidities are costly, time intensive, and difficult to heal. Often, multiple modalities may be necessary to achieve wound resolution, relying on the synergistic advantage of each therapy to affect wound healing. The selectivity of Clostridium collagenase is physiologically effective at degrading non-viable collagen fibers while preserving living collagen tissue. Additionally, negative pressure wound therapy (NPWT) has long been used to aid wound healing while concurrently depreciating biological wound burden time. METHODS: Six patients were selected from those appearing to our university based limb salvage service. Inclusion criteria included patients with a recurrent mixed fibrotic and granular wound base, in which NPWT was indicated, without exclusion criteria. Patients enrolled were administered clostridial collagenase ointment at each regularly scheduled NPWT dressing change. Patients were followed until healing, with visual representations of wound progression and time to full healing recorded. RESULTS: Tandem application of these therapies appeared to expedite wound healing by clearing degenerative fibrous tissue and expediting wound granulation without additional complication. Unfortunately, not all patients were able to reach full healing; with two patients experiencing ulcer recurrence, likely a result of their significant comorbid nature. CONCLUSION: In our experience, we have noticed a specific subgroup of patients who benefit greatly when collagenase enzymatic debridement therapy is combined with NPWT. It is our belief that this combination therapy combines the molecular clearing of non-viable collagen with the wound granulation necessary to advance complex wounds to the next step in healing despite the current paucity in literature discussing this specific pairing.

A passing glance? Differences in eye tracking and gaze patterns between trainees and experts reading plain film bunion radiographs.

Eye tracking and gaze pattern studies have been used to evaluate human behavior for decades. This is because of its ability to reveal conscious and subconscious behaviors when subjects are tasked with observation, decision making, and surgical performance. Many have popularized the use of this technology for radiographic assessment while evaluating radiologist behaviors, but little has been described for surgeon behavior patterns when evaluating preoperative deformities by radiograph. Because the radiographic assessment strongly influences surgical selection, the present study was designed to evaluate the differences between groups of novice and experienced surgeons' gaze patterns when tasked to describe hallux valgus deformities. The subjects were asked to rate the deformity as "none," "mild," "moderate," or "severe." Using an externally mounted eye tracking system, our study assessed saccades, fixations, overall time spent per radiograph, and the subjects' chosen bunion rating. Both the novice and advanced groups of foot and ankle surgeons were tasked to evaluate 25 total anteroposterior radiographs from patients who presented with a primary complaint of bunion pain. These patients were chosen at random, such that all participating surgeons had no previous patient familiarization. Statistically significant differences were observed with regard to the activity and rating of the moderate bunion films. The experience of surgeons does appear to modify gaze behavior with respect to time and attention, such that less overall time spent per image is needed by the advanced group, with improved efficiency. Future academic curriculum and training techniques could be developed to reflect these potential technical differences in search behavior, diagnostic technique, and surgical selection strategy.

How to do a 3-minute diabetic foot exam.

This brief exam will help you to quickly detect major risks and prompt you to refer patients to appropriate specialists.

How can I maintain my patient with diabetes and history of foot ulcer in remission?

Patients with diabetes and previous history of ulceration occupy the highest category of risk for reulceration and amputation. Annual recurrence rates of diabetic ulcerations have been reported as high as 34%, 61%, and 70% at 1, 3, and 5 years, respectively, with studies reporting 20% to 58% recurrence rate within 1 year. As the ever growing epidemic of diabetes expands globally, this sequelae of diabetic complication will continue to require increasing resources from the healthcare community to effectively manage. Recent data suggest that removal of preventative podiatric care from statewide reimbursement systems lead to significant and sustained increases in hospital admission (37%), charges (38%), length of stay (23%), and severe aggregate outcomes including amputation, sepsis and death (49%). The addition of comorbidities such as peripheral artery disease, poor nutrition, and non-adherence to preventive therapies not only increase a patient's likelihood for ulcer recurrence, but also cost of care and certainty of hospital admission. Currently, numerous efforts, guidelines, and industry generated products exist to prolong remission from ulceration; however, the clinical science for treating this patient population calls for much more effort. Despite this, data continue to suggest to demonstrate that appropriate follow-up care, shoe and insole modification, and patient education play a central role in reducing reulceration and amputation. Novel modalities for offloading and wearable sensor technologies offer the advantage of round-the-clock, patient specific and active response healthcare. These have the potential to detect, or even prevent, many wounds before they begin.

Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues.

Interleukin-2 (IL-2) is a multi-faceted cytokine, known for promoting proliferation, survival, and cell death depending on the cell type and state. For example, IL-2 facilitates cell death only in activated T cells when antigen and IL-2 are abundant. The availability of IL-2 clearly impacts this process. Our laboratory recently demonstrated that IL-2 is retained in blood vessels by heparan sulfate, and that biologically active IL-2 is released from vessel tissue by heparanase. We now demonstrate that heparanase digestion also releases a dimeric form of IL-2 that is highly cytotoxic to cells expressing the IL-2 receptor. These cells include "traditional" IL-2 receptor-bearing cells such as lymphocytes, as well as those less well known for IL-2 receptor expression, such as epithelial and smooth muscle cells. The morphologic changes and rapid cell death induced by dimeric IL-2 imply that cell death is mediated by disruption of membrane permeability and subsequent necrosis. These findings suggest that IL-2 has a direct and unexpectedly broad influence on cellular homeostatic mechanisms in both immune and non-immune systems.

Long-term survival analysis of the Canadian Lung Volume Reduction Surgery trial.

BACKGROUND: The Canadian Lung Volume Reduction Surgery (CLVRS) trial was a multicentered randomized controlled trial that concluded that lung volume reduction surgery improves functional status and health-related quality of life (for at least 2 years) in selected patients with advanced emphysema. METHODS: This retrospective observational study assessed the long-term survival of patients enrolled in the CLVRS at 8 to 10 years after randomization. Vital statistics were gathered through telephone contact, physician records, and municipal obituaries. Survival analysis was undertaken using Kaplan-Meier and the Cox proportional hazards models. RESULTS: Fifty-two patients (84% of the initial 62 patients randomized) had a median survival time of 4.11 years. A 16-month survival advantage and a 20% reduction in mortality was observed in the LVRS group as compared with the best medical care group. Although clinically meaningful, these differences were not statistically significant. CONCLUSIONS: These findings echo those of other published reports and demonstrate the potential long-term benefit of LVRS in the treatment of end-stage emphysema.

Interleukin-2 is present in human blood vessels and released in biologically active form by heparanase.

Interleukin-2 (IL-2) is a multifaceted cytokine with immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2-dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2-deficient mice were normal. The aortas of IL-2-deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.

Positron emission tomography in staging early lung cancer: a randomized trial.

BACKGROUND: Among patients with early-stage non-small cell lung cancer (NSCLC), preoperative imaging tests are important in defining surgical candidates. OBJECTIVE: To assess whether whole-body positron emission tomography and computed tomography (PET-CT) plus cranial imaging correctly upstages cancer in more patients with NSCLC than does conventional staging plus cranial imaging. DESIGN: Randomized clinical trial with recruitment from June 2004 to August 2007. The centralized, computer-generated, variable block size randomization scheme was stratified by treatment center and cancer stage. Participants, health care providers, and outcome assessors were not blinded to imaging modality assignment. SETTING: 8 hospitals and 5 PET-CT centers in academic institutions. PATIENTS: Eligible patients were older than 18 years; had histologic or cytologic proof of stage I, II, or IIIA NSCLC on the basis of chest radiography and thoracic CT; and had a tumor considered to be resectable. INTERVENTION: PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging. MEASUREMENTS: The primary outcome was correct upstaging, thereby avoiding stage-inappropriate surgery. Secondary outcomes were incorrect upstaging and incorrect understaging. RESULTS: 170 patients were assigned to PET-CT and 167 to conventional staging. Eight patients (3 who had PET-CT and 5 who had conventional staging) did not have planned surgery. Disease was correctly upstaged in 23 of 167 PET-CT recipients and 11 of 162 conventional staging recipients (13.8% vs. 6.8%; difference, 7.0 percentage points [95% CI, 0.3 to 13.7 percentage points]), thereby sparing these patients from surgery. Disease was incorrectly upstaged in 8 PET-CT recipients and 1 conventional staging recipient (4.8% vs. 0.6%; difference, 4.2 percentage points [CI, 0.5 to 8.6 percentage points]), and it was incorrectly understaged in 25 and 48 patients, respectively (14.9% vs. 29.6%; difference, 14.7 percentage points [CI, 5.7 to 23.4 percentage points]). At 3 years, 52 patients who had PET-CT and 57 patients who had conventional staging had died. LIMITATION: The relatively small sample and the fact that some patients did not have planned surgery limited the ability to determine precise differences in clinical outcomes that were attributable to testing strategies. CONCLUSION: Preoperative staging with PET-CT and cranial imaging identifies more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery, but the strategy also incorrectly upstaged disease in more patients.

Differentiation and transplantation of human embryonic stem cell-derived hepatocytes.

BACKGROUND & AIMS: The ability to obtain unlimited numbers of human hepatocytes would improve the development of cell-based therapies for liver diseases, facilitate the study of liver biology, and improve the early stages of drug discovery. Embryonic stem cells are pluripotent, potentially can differentiate into any cell type, and therefore could be developed as a source of human hepatocytes. METHODS: To generate human hepatocytes, human embryonic stem cells were differentiated by sequential culture in fibroblast growth factor 2 and human activin-A, hepatocyte growth factor, and dexamethasone. Functional hepatocytes were isolated by sorting for surface asialoglycoprotein-receptor expression. Characterization was performed by real-time polymerase chain reaction, immunohistochemistry, immunoblot, functional assays, and transplantation. RESULTS: Embryonic stem cell-derived hepatocytes expressed liver-specific genes, but not genes representing other lineages, secreted functional human liver-specific proteins similar to those of primary human hepatocytes, and showed human hepatocyte cytochrome P450 metabolic activity. Serum from rodents given injections of embryonic stem cell-derived hepatocytes contained significant amounts of human albumin and alpha1-antitrypsin. Colonies of cytokeratin-18 and human albumin-expressing cells were present in the livers of recipient animals. CONCLUSIONS: Human embryonic stem cells can be differentiated into cells with many characteristics of primary human hepatocytes. Hepatocyte-like cells can be enriched and recovered based on asialoglycoprotein-receptor expression and potentially could be used in drug discovery research and developed as therapeutics.

Perlecan: a major IL-2-binding proteoglycan in murine spleen.

Although interleukin-2 (IL-2) is typically considered a soluble cytokine, our laboratory has shown that the availability of IL-2 in lymphoid tissues is regulated, in part, by an association with heparan sulfate glycosaminoglycan. Heparan sulfate is usually found in proteoglycan form, in which the heparan sulfate chains are covalently linked to a specific core protein. We now show that perlecan is one of the major IL-2-binding heparan sulfate proteoglycans in murine spleen. IL-2 binds perlecan via heparan sulfate chains, as enzymatic removal of heparan sulfate from splenic perlecan abolishes its ability to bind IL-2. Furthermore, we demonstrate that perlecan-bound IL-2 supports the proliferation of an IL-2-dependent cell line. Identification of perlecan as a major heparan sulfate proteoglycan that binds IL-2 has implications for both the localization and regulation of IL-2 in vivo.

Influence of interleukin-2 deficiency on the generation of autoimmune B cells.

The production of auto-antibodies is one of the predominant characteristics of autoimmune disorders. Because IL-2 deficient mice develop autoimmunity, we asked how IL-2 deficiency might impair endogenous mechanisms of B cell tolerance. To this end, we mated BALB/c anti-dsDNA H chain knock-in mice, in which B cells producing anti-dsDNA antibodies are properly regulated, with IL-2 deficient mice and assessed the phenotype of their offspring. IL-2 deficient mice expressing the anti-dsDNA H chain knock-in allele developed anti-dsDNA antibodies of both IgM and IgG isotypes. Production of these antibodies occurred through the disruption of several mechanisms of endogenous tolerance, including deletion, maturational arrest, and follicular exclusion. In summary, our results suggest that IL-2 plays an important role in regulating B cell tolerance.