Treatment patterns in patients with newly diagnosed COPD in the USA.

BACKGROUND: Prompt and effective management with maintenance therapy (single or dual bronchodilator therapy) is recommended after the initial diagnosis of chronic obstructive pulmonary disease (COPD) to maintain lung function and prevent exacerbations. Contrary to guideline-based recommendations, most patients are not prescribed maintenance treatment at initial diagnosis. The current study assessed the pharmacologic treatment patterns and outcomes of newly diagnosed patients with COPD in the USA. METHODS: This retrospective, noninterventional study used de-identified data from the Inovalon Insights' database (Commercial, Medicaid Managed Care, and Medicare Advantage-insured individuals) between January 1, 2015, and December 31, 2021. The "patient journey" from initial diagnosis was followed over a 4-year period. The primary outcome measure was the number of moderate or severe exacerbations. Secondary outcome measures included the cumulative incidence of exacerbations, mean cumulative count of moderate and severe exacerbations, rates of moderate and severe exacerbations in patients who remained untreated after diagnosis in 12-month time periods for 4 years, sociodemographic and clinical characteristics, and pharmacologic treatment patterns. RESULTS: The cohort consisted of 238,158 newly diagnosed patients with COPD (female [52.9%]; mean age 63.8 years). The majority of patients with COPD had Medicaid as their primary insurance (46.2%). Overall, during the 4-year follow-up period, 32.9% of the patients had at least one moderate or severe exacerbation, and 25.8% and 13.8% experienced moderate and severe exacerbations, respectively. At diagnosis, 86.2% of the patients were untreated and most remained untreated by the end of the follow-up (63.8%). Most patients (62.0%) received long-acting beta-agonist (LABA)/inhaled corticosteroids (ICS) as their initial treatment at diagnosis, and LABA/ICS continued to be the most common initial treatment during the 4-year period (64.0% at year 1; 58.0% at year 4). CONCLUSIONS: Most patients with COPD were not treated at initial diagnosis and remained untreated during follow-up. Our data highlight a lack of adherence to recommendations for clinical practice.

Mice lacking ARV1 have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease.

Metabolic syndrome (MetS) is a term used to characterize individuals having at least three of the following diseases: obesity, dyslipidemia, hyperglycemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease (NAFLD). It is widespread, and the number of individuals with MetS is increasing. However, the events leading to the manifestation of MetS are not well-understood. Here, we show that loss of murine ARV1 (mARV1) results in resistance to acquiring diseases associated with MetS. Arv1-/- animals fed a high-fat diet were resistant to diet-induced obesity, had lower blood cholesterol and triglyceride levels, and retained glucose tolerance and insulin sensitivity. Livers showed no gross morphological changes, contained lower levels of cholesterol, triglycerides, and fatty acids, and showed fewer signs of NAFLD. Knockout animals had elevated levels of liver farnesol X receptor (FXR) protein and its target, small heterodimer protein (SHP). They also had decreased levels of CYP7α1, CYP8ß1, and mature SREBP1 protein, evidence suggesting that liver FXR signaling was activated. Strengthening this hypothesis was the fact that peroxisome proliferator-activating receptor α (PPARα) protein was elevated, along with its target, fibroblast growth factor 21 (FGF21). Arv1-/- animals excreted more fecal cholesterol, free fatty acids, and bile acids. Their small intestines had 1) changes in bile acid composition, 2) an increase in the level of the intestinal FXR antagonist, tauromuricholic acid, and 3) showed signs of attenuated FXR signaling. Overall, we believe that ARV1 function is deleterious when consuming a high-fat diet. We further hypothesize that ARV1 is critical for initiating events required for the progression of diseases associated with MetS and NAFLD.

Rapid virtual hematoxylin and eosin histology of breast tissue specimens using a compact fluorescence nonlinear microscope.

Up to 40% of patients undergoing breast conserving surgery for breast cancer require repeat surgeries due to close to or positive margins. The lengthy processing required for evaluating surgical margins by standard paraffin-embedded histology precludes its use during surgery and therefore, technologies for rapid evaluation of surgical pathology could improve the treatment of breast cancer by reducing the number of surgeries required. We demonstrate real-time histological evaluation of breast cancer surgical specimens by staining specimens with acridine orange (AO) and sulforhodamine 101 (SR101) analogously to hematoxylin and eosin (H&E) and then imaging the specimens with fluorescence nonlinear microscopy (NLM) using a compact femtosecond fiber laser. A video-rate computational light absorption model was used to produce realistic virtual H&E images of tissue in real time and in three dimensions. NLM imaging could be performed to depths of 100 µm below the tissue surface, which is important since many surgical specimens require subsurface evaluation due to contamination artifacts on the tissue surface from electrocautery, surgical ink, or debris from specimen handling. We validate this method by expert review of NLM images compared to formalin-fixed, paraffin-embedded (FFPE) H&E histology. Diagnostically important features such as normal terminal ductal lobular units, fibrous and adipose stromal parenchyma, inflammation, invasive carcinoma, and in situ lobular and ductal carcinoma were present in NLM images associated with pathologies identified on standard FFPE H&E histology. We demonstrate that AO and SR101 were extracted to undetectable levels after FFPE processing and fluorescence in situ hybridization (FISH) HER2 amplification status was unaffected by the NLM imaging protocol. This method potentially enables cost-effective, real-time histological guidance of surgical resections.

Systemic Loss of C-terminal Src Kinase Expression Elicits Spontaneous Suppurative Inflammation in Conditional Knockout Mice.

C-terminal Src kinase (Csk) is one of the critical negative regulators of the Src family of kinases. The Src family of kinases are nonreceptor tyrosine kinases that regulate inflammation, cell proliferation, motility, and adhesion. To investigate potential histologic lesions associated with systemic loss of Csk gene activity in adult mice, conditional Csk-knockout mice were examined. Cre-mediated systemic excision of Csk induced by tamoxifen treatment resulted in multiorgan inflammation. Specifically, induction of Csk gene excision with three days of tamoxifen treatment resulted in greater than 90% gene excision. Strikingly, these mice developed enteritis that ranged from minimal and suppurative to severe, fibrinonecrosuppurative and hemorrhagic. Other inflammatory lesions included suppurative pneumonia, gastritis, and myocarditis, and increased numbers of inflammatory cells within the hepatic parenchyma. When tamoxifen treatment was reduced from three days to one day in an effort to lower the level of Csk gene excision and limit lesion development, the mice developed severe suppurative to pyogranulomatous pneumonia and minimal to mild suppurative enteritis. Lesions observed secondary to Csk gene excision suggest important roles for Csk in downregulating the proinflammatory activity of the Src family of kinases and limiting neutrophil-mediated inflammation.

Tarsal tunnel syndrome secondary to schwannoma of the posterior tibial nerve.

Schwannoma is a benign tumor that arises from the peripheral nerve sheath. It presents as a discrete, often tender, and palpable nodule associated with neurogenic pain or paresthesia when compressed or traumatized. The growth rate is usually slow, and these lesions seldom exceed 2 cm in diameter. We report the case of a large schwannoma arising from the posterior tibial nerve located in the posterior medial ankle. The core needle biopsy findings were suggestive of a schwannoma, with spindle cells strongly and uniformly immunostaining for S-100 protein. The mass was marginally excised. The surgical specimen consisted of a grossly encapsulated white-yellow mass with irregular contours, measuring 3.7 × 3.5 × 2.7 cm. The cut surface showed areas of pin-point hemorrhage. The patient did not encounter any motor deficits; however, early results showed some subjective numbness. Few reports have been published of schwannomas arising from the tibial nerve. Marginal excision appears to be the recommended therapy for this tumor, without any evidence of recurrence at 9 months of follow-up.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.

Epidermal panfolliculoma: A report of 2 cases.

There are a variety of known lesions displaying differentiation toward various portions of the hair follicle. However, there is no established term given to an intraepidermal entity showing differentiation toward both upper and lower portions of the follicle. We report 2 cases of a histologically distinct variant of panfolliculoma that, unlike the traditionally described panfolliculoma, is located intraepidermally. The lesions were taken from the medial thigh of an 81-year-old man and the lateral thigh of a 61-year-old woman, clinically suspected to be an inflamed seborrheic keratosis and a squamous cell carcinoma, respectively. Each case appeared as a demarcated plaque-like lesion with mild epidermal hyperplasia and prominent differentiation toward the upper and lower segments of the hair follicle. The specific histologic features included focal differentiation toward the infundibulum and isthmus (infundibular cystic structures and pilar epithelium), inner root sheath (trichohyalin granules), the matrix/hair shaft (matrical cells, ghost cells and refractile keratinization), and follicular germ/papilla (papillary mesenchymal bodies). This varied histology is similar to that of the previously described panfolliculoma, differing in that it emanates largely from the epidermis rather than being predominantly dermally located. We propose the term "epidermal panfolliculoma" for these lesions.

Subtypes of mild cognitive impairment in older postmenopausal women: the Women's Health Initiative Memory Study.

Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. Four hundred forty-seven women 65 years of age and older from the Women's Health Initiative Memory Study were classified into the 4 MCI subgroups and a "no impairment" group and compared on clinical, sociodemographic, and health variables. A cognitive deficit in at least 1 domain was present in 82.1% of participants, with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, whereas 21.3% had an isolated nonmemory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multidomain MCI (42.8%), followed by nonamnestic multiple domain MCI (26.7%), nonamnestic single domain (24.1%), and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression, and prestudy and onstudy use of hormone therapy. Despite the attention it receives in the literature, amnestic MCI is the least common type highlighting the importance of identifying and characterizing other nonamnestic and multidomain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biologic differences between them, and rates for conversion to dementia.

Interactive histology of large-scale biomedical image stacks.

Histology is the study of the structure of biological tissue using microscopy techniques. As digital imaging technology advances, high resolution microscopy of large tissue volumes is becoming feasible; however, new interactive tools are needed to explore and analyze the enormous datasets. In this paper we present a visualization framework that specifically targets interactive examination of arbitrarily large image stacks. Our framework is built upon two core techniques: display-aware processing and GPU-accelerated texture compression. With display-aware processing, only the currently visible image tiles are fetched and aligned on-the-fly, reducing memory bandwidth and minimizing the need for time-consuming global pre-processing. Our novel texture compression scheme for GPUs is tailored for quick browsing of image stacks. We evaluate the usability of our viewer for two histology applications: digital pathology and visualization of neural structure at nanoscale-resolution in serial electron micrographs.

Comparison of nonlinear microscopy and frozen section histology for imaging of Mohs surgical margins.

Mohs surgery uses en face frozen section analysis (FSA) with complete margin examination for the excision of select basal cell carcinomas (BCC), obtaining excellent cosmetic outcomes and extremely low recurrence rates. However, Mohs with FSA is time-consuming because of the need to iteratively perform cryosectioning on sequential excisions. Fluorescent microscopies can image tissue specimens without requiring physical sectioning, potentially reducing the time to perform Mohs surgery. We demonstrate a protocol for nonlinear microscopy (NLM) imaging of surgical specimens that combines dual agent staining, virtual H&E rendering, and video rate imaging. We also introduce a novel protocol that enables micron-level co-registration of NLM images with FSA histology, and demonstrate that NLM can reproduce similar features similar to FSA in BCC specimens with both negative and positive surgical margins. We show that the fluorescent labels can be extracted with conventional vacuum infiltration processing, enabling subsequent immunohistochemistry on fluorescently labeled tissue. This protocol can also be applied to evaluate the performance of NLM compared with FSA in a wide range of pathologies for intraoperative consultation.

Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

IMPORTANCE: Extramammary Paget disease (EMPD), a rare intraepithelial adenocarcinoma, poses a therapeutic challenge with high postoperative recurrence rates and a limited number of effective local treatment options. OBJECTIVE: To describe the use and efficacy of a topical combination of fluorouracil and calcipotriene as a palliative therapy for refractory EMPD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series of 3 women with recurrent, refractory EMPD was conducted at Beth Israel Deaconess Medical Center, Boston, Massachusetts and Washington University School of Medicine, St Louis, Missouri. All patients were treated with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream or ointment. MAIN OUTCOMES AND MEASURES: Clinical and histopathological findings. RESULTS: All 3 women (1 in her 50s, 2 in their 70s) presented with recurrent EMPD (vulvar, perianal, and perioral) after surgery and/or irradiation, and their EMPD was refractory to treatment with imiquimod, 5%, cream. Owing to disease progression and/or intolerable adverse effects from imiquimod, the patients began treatment with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream. This treatment, which was well tolerated, was followed by clinical improvement in symptoms and appearance of the lesions in all 3 cases and histopathological signs of decreased tumor burden in 2 cases. Patients applied the combination topical therapy to affected areas with differing frequencies, ranging from 1 to 2 days per month to 4 consecutive days every 2 weeks. CONCLUSIONS AND RELEVANCE: Extramammary Paget disease frequently recurs even after aggressive surgical management and can be refractory to many topical and locoregional therapies. Palliative treatment with a combination of fluorouracil and calcipotriene may be a viable option for patients with recurrent, refractory EMPD.

Comparison of the effectiveness and tolerability of lidocaine patch 5% versus celecoxib for osteoarthritis-related knee pain: post hoc analysis of a 12 week, prospective, randomized, active-controlled, open-label, parallel-group trial in adults.

BACKGROUND: Cyclooxygenase-2 (COX-2) selective inhibitors and nonselective NSAIDs are commonly used to treat osteoarthritis (OA) of the knee. OBJECTIVE: The aim of this study was to compare the effectiveness of the lidocaine patch 5% with that of celecoxib 200 mg/d in the treatment of OA-related knee pain; however, the study was terminated prematurely by the sponsor because of tolerability concerns regarding the class of COX-2 selective inhibitors. A post hoc analysis of the available data is presented here. METHODS: This multicenter, randomized, open-label, active-controlled, parallel-group study included patients >or=18 years of age with unilateral or bilateral moderate to severe OA of the knee. Patients were randomized to receive treatment with either the lidocaine patch 5% or celecoxib 200 mg/d. The primary efficacy end point was change from baseline to 12 weeks in the Western Ontario and McMaster Universities (WOMAC) OA Index pain subscale. Secondary end points included additional WOMAC subscales and Brief Pain Inventory (BPI) measures. Because this trial was prematurely terminated, a post hoc analysis was performed using a random pattern-mixture model of all observed cases of the intent-to-treat population. RESULTS: A total of 143 patients were randomized to treatment (lidocaine patch 5%, 69 patients; mean [SD] age, 60.2 [11.4] years; 65.2% female; 66.7% white; weight, 94.1 [23.3] kg) or celecoxib 200 mg/d (74 patients; age, 58.2 [12.1] years; 63.5% female; 68.9% white; weight, 94.3 [22.5] kg). Baseline pain WOMAC OA subscale scores (lidocaine patch 5%, 12.087; celecoxib 200 mg/d, 12.514) and mean rates of change over time (baseline to week 2, -1.5916 vs -1.6513 per week; weeks 2-6, -0.0168 vs -0.119 per week; weeks 6-12, -0.1818 vs -0.1579 per week) were not significantly different between the 2 groups. Improvement in additional WOMAC subscales and in several BPI measures were not significantly different between the 2 groups. Treatment-related adverse events were reported in 8 patients in each treatment group (11.6% in the lidocaine patch 5% group and 10.8% in the celecoxib 200-mg/d group) and were considered mild or moderate in severity. CONCLUSION: Statistically significant differences in effectiveness and tolerability were not found between these 2 treatments in these patients with OA knee pain.

Iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders: Results from a phase 3, randomized open-label study.

OBJECTIVES: The recent availability of iron-based phosphate binders has raised some concerns about iron overload in patients with end-stage renal disease. This study evaluated iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders. METHODS: This analysis used 2-year follow-up data from an open-label, multicentre, randomized, active-controlled, parallel-group, phase 3 trial of lanthanum carbonate (SPD405-307). After a washout period, if patients' serum phosphate levels exceeded 5.9 mg/dL, they were randomized 1:1 to receive lanthanum carbonate (375-3000 mg/day) or non-iron-based standard therapy during a 6-week dose titration period. Patients achieving control of serum phosphate levels (⩽5.9 mg/dL) received maintenance therapy with lanthanum carbonate or standard therapy for up to 24 months. RESULTS: No clinically relevant changes in mean (standard deviation) iron parameters between the treatment groups (lanthanum carbonate, n = 682; standard therapy, n = 677) from baseline to month 24/final visit were observed: iron (µg/dL), -1.1 (41.8) versus 1.0 (38.7); ferritin (ng/mL), 208.4 (445.1) versus 262.4 (505.5); transferrin saturation (%), 2.8 (18.0) versus 2.8 (17.3); and haemoglobin (g/dL), 0.4 (1.9) versus 0.3 (1.7), respectively (all, p > 0.1). There were no clinically relevant changes in the percentage of patients receiving any anti-anaemic preparation in either treatment group (pre- vs post-randomization: lanthanum carbonate, 94.9% vs 97.8%; standard therapy, 95.1% vs 98.8%, respectively). This is in contrast to the study by Lewis and colleagues, which found significant increases in ferritin and transferrin saturation levels in patients receiving ferric citrate versus active control (calcium acetate and/or sevelamer carbonate) after 52 weeks of therapy. Although serum ferritin and transferrin saturation are the recommended iron indices by the Kidney Disease Outcome Quality Initiative, they are indirect indicators of iron status. Longer-term studies are required to understand fully the potential risks associated with iron overload. CONCLUSION: No evidence of iron accumulation was found in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based binders.

The Convergence of Vasculopathy and Vasculitis: Computer Mapping Analysis of 2 Renal Biopsies in a Patient with both Systemic Sclerosis and ANCA-Related Vasculitis.

Scleroderma vasculopathy and ANCA (antineutrophil cytoplasmic antibodies)-associated glomerulonephritis have rarely been reported to occur simultaneously in one patient. Herein, we report a patient who presented with a classic constellation of clinical and laboratory findings of systemic scleroderma and was subsequently found to be positive for p-ANCA. Two renal biopsies, performed 5 months apart, demonstrated typical changes of the two entities in both acute and "healed" phases, which were analyzed by computer mapping techniques. The two renal biopsies were serially sectioned and stained routinely, and with CD31 and CD34 as endothelial markers. The slides were digitized, aligned and analyzed. Each glomerular tuft was sequentially studied in terms of total area (µm2) and each biopsy was individually profiled. All arterial vessels were sequentially studied with whole vessel and luminal areas delineated and ratios calculated. The initial biopsy contained 32 glomeruli almost all with extensive fibrinoid necrosis and destruction of the capillary network. The arterial vessels (interlobular and arcuate) showed intimal edema with luminal occlusion. CD31/CD34 stains showed variable endothelial intactness but demonstrated the luminal size shifts. The second biopsy had 37 glomeruli that were either segmentally or globally sclerotic with no active changes. The vessels were now normally patent. Each glomerular tuft and arterial vessel in both biopsies was analyzed as a serial section histogram documenting these changes. These studies depict the rare occurrence of two entities together, the scleroderma kidney vasculopathy and the glomerulonephritis of ANCA-associated vasculitis syndrome both in an acute and healing phase, profiled by computer mapping techniques.

Rapid histopathological imaging of skin and breast cancer surgical specimens using immersion microscopy with ultraviolet surface excitation.

Rapid histopathological evaluation of fresh, unfixed human tissue using optical sectioning microscopy would have applications to intraoperative surgical margin assessment. Microscopy with ultraviolet surface excitation (MUSE) is a low-cost optical sectioning technique using ultraviolet illumination which limits fluorescence excitation to the specimen surface. In this paper, we characterize MUSE using high incident angle, water immersion illumination to improve sectioning. Propidium iodide is used as a nuclear stain and eosin yellow as a counterstain. Histologic features of specimens using MUSE, nonlinear microscopy (NLM) and conventional hematoxylin and eosin (H&E) histology were evaluated by pathologists to assess potential application in Mohs surgery for skin cancer and lumpectomy for breast cancer. MUSE images of basal cell carcinoma showed high correspondence with frozen section H&E histology, suggesting that MUSE may be applicable to Mohs surgery. However, correspondence in breast tissue between MUSE and paraffin embedded H&E histology was limited due to the thicker optical sectioning in MUSE, suggesting that further development is needed for breast surgical applications. We further demonstrate that the transverse image resolution of MUSE is limited by the optical sectioning thickness and use co-registered NLM to quantify the improvement in MUSE optical sectioning from high incident angle water immersion illumination.

Multiscale nonlinear microscopy and widefield white light imaging enables rapid histological imaging of surgical specimen margins.

The ability to histologically assess surgical specimens in real-time is a long-standing challenge in cancer surgery, including applications such as breast conserving therapy (BCT). Up to 40% of women treated with BCT for breast cancer require a repeat surgery due to postoperative histological findings of close or positive surgical margins using conventional formalin fixed paraffin embedded histology. Imaging technologies such as nonlinear microscopy (NLM), combined with exogenous fluorophores can rapidly provide virtual H&E imaging of surgical specimens without requiring microtome sectioning, facilitating intraoperative assessment of margin status. However, the large volume of typical surgical excisions combined with the need for rapid assessment, make comprehensive cellular resolution margin assessment during surgery challenging. To address this limitation, we developed a multiscale, real-time microscope with variable magnification NLM and real-time, co-registered position display using a widefield white light imaging system. Margin assessment can be performed rapidly under operator guidance to image specific regions of interest located using widefield imaging. Using simulated surgical margins dissected from human breast excisions, we demonstrate that multi-centimeter margins can be comprehensively imaged at cellular resolution, enabling intraoperative margin assessment. These methods are consistent with pathology assessment performed using frozen section analysis (FSA), however NLM enables faster and more comprehensive assessment of surgical specimens because imaging can be performed without freezing and cryo-sectioning. Therefore, NLM methods have the potential to be applied to a wide range of intra-operative applications.

An extensive phenotypic characterization of the hTNFalpha transgenic mice.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFalpha (hTNFalpha) have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFalpha transgenic mouse line. RESULTS: In addition to arthritis, these hTNFalpha transgenic mice demonstrated major alterations in body composition, metabolic rate, leptin levels, response to a high-fat diet, bone mineral density and content, impaired fertility and male sexual function. Many phenotypes displayed an earlier onset and a higher degree of severity in males, pointing towards a significant degree of sexual dimorphism in response to deregulated expression of TNFalpha. CONCLUSION: These results highlight the potential usefulness of this transgenic model as a resource for studying the progressive effects of constitutively expressed low levels of circulating TNFalpha, a condition mimicking that observed in a number of human pathological conditions.

Accurate Prediction of Tissue Viability at Postoperative Day 7 Using Only Two Intraoperative Subsecond Near-Infrared Fluorescence Images.

BACKGROUND: The ability to predict the future viability of tissue while still in the operating room and able to intervene would have a major impact on patient outcome. Although several objective methods to evaluate tissue perfusion have been reported, none to date has sufficient accuracy. METHODS: In eight Sprague-Dawley rats, reverse McFarlane dorsal skin flaps were created. Continuous near-infrared fluorescence angiography using indocyanine green was performed immediately after surgery, for a total of 30 minutes. These dynamic measurements were used to quantify indocyanine green biodistribution and clearance, and to develop a simple metric that accurately predicted tissue viability at postoperative day 7. The new metric was compared to previously described metrics. RESULTS: Reproducible patterns of indocyanine green biodistribution and clearance from the flap permitted quantitative metrics to be developed for predicting flap viability at postoperative day 7. Previously described metrics, which set the boundary between healthy and necrotic tissue as either 17 or 25 percent of peak near-infrared fluorescence at 2 minutes after indocyanine green injection, underestimated the area of necrosis by 75 and 48 percent, respectively. Our data suggest that both the shape and area of clinical necrosis occurring at postoperative day 7 can be predicted intraoperatively, with the boundary defined as near-infrared fluorescence intensities of 40 to 55 percent of peak fluorescence measured at 5 minutes. CONCLUSION: Two 750-msec intraoperative near-infrared fluorescence images obtained at time 0 and at 5 minutes after injection of indocyanine green accurately predicted skin flap viability 7 days after surgery.