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Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

Purpose Delirium leads to poor outcomes for patients and careers and has negative impacts on staff and service provision. Cancer rates in elderly populations are increasing and frequently, cancer diagnoses are a co-morbidity in the context of frailty. Data relating to the epidemiology of delirium in hospitalised cancer patients are limited. With the overarching purpose of improving delirium detection and reducing the morbidity and mortality of delirium in cancer patients, we reviewed the epidemiological data and approach to delirium detection in hospitalised, adult oncology patients. Methods MEDLINE, EMBASE, CINAHL, PsycINFO, and SCOPUS databases were searched from January 1996 to August 2017. Key concepts were delirium, cancer, inpatient oncology and delirium screening/detection. Results Of 896 unique studies identified; 91 met full-text review criteria. Of 12 eligible studies, four applied recommended case ascertainment methods to all patients, three used delirium screening tools alone or with case ascertainment tools sub-optimally applied, four used tools not recommended for delirium screening or case ascertainment, one used the Confusion Assessment Method with insufficient information to determine if it met case ascertainment status. Two studies presented delirium incidence rates: 7.8%, and 17% respectively. Prevalence rates ranged from 18–33% for general medical or oncology wards; 42–58% for Acute Palliative Care Units (APCU); and for older cancer patients: 22% and 57%. Three studies reported reversibility; 26% and 49% respectively (APCUs) and 30% (older patients with cancer). Six studies had a low risk of bias according to QUADAS-2 criteria; all studies in the APCU setting were rated at higher risk of bias. Tool selection, study flow and recruitment bias reduced study quality. Conclusion The knowledge base for improved interventions and clinical care for adults with cancer and delirium is limited by the low number of studies. A clear distinction between screening tools and diagnostic tools is required to provide an improved understanding of the rates of delirium and its reversibility in this population.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity. Four interlinked issues need to be addressed: 1) efficient clearing and labelling of heart tissue, 2) fast microscopic imaging of human-scale samples, 3) handling and processing of multi-terabyte 3D images, and 4) extraction of structural information in computationally tractable structure-based models of cardiac function. Preliminary studies show that each of these requirements can be achieved with the appropriate application and development of existing technologies.

Background Dispersion and gradients in repolarization have been associated with life‐threatening arrhythmias, but are difficult to quantify precisely from surface electrocardiography. The objective of this study was to evaluate electrocardiographic imaging (ECGI) to noninvasively detect repolarization‐based abnormalities. Methods and Results Ex vivo data were obtained from Langendorff‐perfused pig hearts (n=8) and a human donor heart. Unipolar electrograms were recorded simultaneously during sinus rhythm from an epicardial sock and the torso‐shaped tank within which the heart was suspended. Regional repolarization heterogeneities were introduced through perfusion of dofetilide and pinacidil into separate perfusion beds. In vivo data included torso and epicardial potentials recorded simultaneously in anesthetized, closed‐chest pigs (n=5), during sinus rhythm, and ventricular pacing. For both data sets, ECGI accurately reconstructed T‐wave electrogram morphologies when compared with those recorded by the sock (ex vivo: correlation coefficient, 0.85 [0.52–0.96], in vivo: correlation coefficient, 0.86 [0.52–0.96]) and repolarization time maps (ex‐vivo: correlation coefficient, 0.73 [0.63–0.83], in vivo: correlation coefficient, 0.76 [0.67–0.82]). ECGI‐reconstructed repolarization time distributions were strongly correlated to those measured by the sock (both data sets, R 2 ≥0.92). Although the position of the gradient was slightly shifted by 8.3 (0–13.9) mm, the mean, max, and SD between ECGI and recorded gradient values were highly correlated ( R 2 =0.87, 0.75, and 0.86 respectively). There was no significant difference in ECGI accuracy between ex vivo and in vivo data. Conclusions ECGI reliably and accurately maps potentially critical repolarization abnormalities. This noninvasive approach allows imaging and quantifying individual parameters of abnormal repolarization‐based substrates in patients with arrhythmogenesis, to improve diagnosis and risk stratification.

Background: Delirium is a distressing neuropsychiatric disorder affecting patients in palliative care. Although many delirium screening tools exist, their utility, and validation within palliative care settings has not undergone systematic review. Aim: To systematically review studies that validate delirium screening tools conducted in palliative care settings. Design: Systematic review with narrative synthesis (PROSPERO ID: CRD42019125481). A risk of bias assessment via Quality Assessment Tool for Diagnostic Accuracy Studies-2 was performed. Data sources: Five electronic databases were systematically searched (January 1, 1982–May 3, 2020). Quantitative studies validating a screening tool in adult palliative care patient populations were included. Studies involving alcohol withdrawal, critical or perioperative care were excluded. Results: Dual-reviewer screening of 3749 unique titles and abstracts identified 95 studies for full-text review and of these, 17 studies of 14 screening tools were included ( n = 3496 patients). Data analyses revealed substantial heterogeneity in patient demographics and variability in screening and diagnostic practices that limited generalizability between study populations and care settings. A risk of bias assessment revealed methodological and reporting deficits, with only 3/17 studies at low risk of bias. Conclusions: The processes of selecting a delirium screening tool and determining optimal screening practices in palliative care are complex. One tool is unlikely to fit the needs of the entire palliative care population across all palliative care settings. Further research should be directed at evaluating and/or adapting screening tools and practices to fit the needs of specific palliative care settings and populations.

Aim A serious syndrome for cancer in-patients, delirium risk increases with age and medical acuity. Screening tools exist but detection is frequently delayed or missed. We test the ‘Single Question in Delirium’ (SQiD), in comparison to psychiatrist clinical interview. Methods Inpatients in two comprehensive cancer centres were prospectively screened. Clinical staff asked informants to respond to the SQiD: “Do you feel that [patient’s name] has been more confused lately?”. The primary endpoint was negative predictive value (NPV) of the SQiD versus psychiatrist diagnosis (Diagnostic and Statistics Manual criteria). Secondary endpoints included: NPV of the Confusion Assessment Method (CAM), sensitivity, specificity and Cohen’s Kappa coefficient. Results Between May 2012 and July 2015, the SQiD plus CAM was applied to 122 patients; 73 had the SQiD and psychiatrist interview. Median age was 65 yrs. (interquartile range 54–74), 46% were female; median length of hospital stay was 12 days (5–18 days). Major cancer types were lung (19%), gastric or other upper GI (15%) and breast (14%). 70% of participants had stage 4 cancer. Diagnostic values were similar between the SQiD (NPV = 74, 95% CI 67–81; kappa = 0.32) and CAM (NPV = 72, 95% CI 67–77, kappa = 0.32), compared with psychiatrist interview. Overall the CAM identified only a small number of delirious cases but all were true positives. The specificity of the SQiD was 87% (74–95) The SQiD had higher sensitivity than CAM (44% [95% CI 41–80] vs 26% [10–48]). Conclusion The SQiD, administered by bedside clinical staff, was feasible and its psychometric properties are now better understood. The SQiD can contribute to delirium detection and clinical care for hospitalised cancer patients.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P, Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Building anatomically accurate models of the coronary vascular system enables potentially deeper understandings of coronary circulation. To achieve this, (a) images at different levels of vascular network-arteries, arterioles, capillaries, venules, and veins-need to be obtained through suitable imaging modalities; and (b) from images, morphological and topological information needs to be extracted using image processing techniques. While there are several modalities that enable the imaging of large vessels, microcirculation imaging-capturing vessels having diameter lesser than 100 μm-has to date been typically confined to small regions of the heart. This spatially limited microcirculatory information has often been used within cardiac models, with the potentially erroneous assumption that it is representative of the whole organ. However, with the recent advancements in imaging and image processing, it is rapidly becoming feasible to acquire, process, and quantify microcirculation data at the scale of whole organ. In this review, we summarize the progress toward this goal followed through a presentation of the current state-of-the-art imaging and image processing techniques in the context of coronary microcirculation extraction, prominently but not exclusively, from small animals.

Recognition of facial beauty is both inborn and learned through social discourses and exposures. Demographic shifts across the globe, in addition to cross-cultural interactions that typify 21st century globalization in virtually all industries, comprise major active evolutionary forces that reshape our individual notions of facial beauty. This article highlights the changing perceptions of beauty, while defining and distinguishing natural beauty and artificial beauty.

Transient post-thyroidectomy hypocalcemia is a common complication following thyroid surgery. Studies have identified risk factors and possible ways to help predict post-thyroidectomy hypocalcemia with the intent of ultimately limiting its incidence. This study evaluates the role of patient gender as a potential risk factor.A retrospective case series with chart review of 270 consecutive total thyroidectomy patients was conducted.Jewish General Hospital, a McGill University-affiliated hospital in Montreal, Canada.219 women and 51 men were included. Postoperative hypocalcemia was defined as any 1 of the following: total serum calcium 1.90 mmol/L or less, or signs and symptoms of hypocalcemia. The following were evaluated as potential confounding factors in the study: age, menopause, preoperative calcium, parathyroid hormone, magnesium and phosphate levels, presence of carcinoma in the surgical specimen, number of parathyroid glands preserved in situ, thyroid gland volume, and nodule size.Female patients experienced transient postoperative hypocalcemia in 24.7% (54/219) of cases, which was significantly greater than the 11.8% (6/51) incidence detected in men (P.05). This represents a female/male relative risk ratio of 2.1 (confidence interval, 1.0-4.6). There was no significant difference in rates of hypocalcemia between premenopausal and postmenopausal women (22.7% vs 26.6%).These findings suggest that being female is likely a risk factor for transient post-thyroidectomy hypocalcemia. Although this association is statistically significant, its magnitude and clinical relevance are uncertain and may be trivial. Additional research is needed to ascertain the physiologic mechanisms underlying this gender difference.

Objectives. The goal of the present study is to determine whether a decline in the 1-hour postoperative parathyroid hormone (PTH) level relative to the preoperative level is predictive of hypocalcemia. Methods. This is a retrospective study involving 142 consecutive patients who underwent total thyroidectomy. Changes in preoperative PTH levels were then compared with the 1-hour levels. Results. Thirty-four of 142 patients (23.9%) who underwent total thyroidectomy developed hypocalcemia. Thirty-one of the 34 patients who became hypocalcemic had a 1-hour postoperative PTH drop of 70% or more when compared with the preoperative value (sensitivity = 91%, specificity = 98%, positive predictive value = 94%, and negative predictive value = 97%). Conclusion. A decline in the preoperative PTH level of 70% or greater at 1 hour following total thyroidectomy appears to be a reliable predictor of patients at risk of developing hypocalcemia. By allowing thyroid surgeons to identify these patients in the early postoperative period, calcium supplementation can be initiated sooner.

Objectives A 1-hour post-thyroidectomy parathyroid hormone (PTH) level of ≤8 ng/L is predictive of patients who will develop hypocalcemia and guides early supplementation with calcium and vitamin D. However, most hypocalcemic patients fail to meet this criterion. The goal of this study was to determine whether PTH ≤ 15 ng/L could be used as a better predictor of hypocalcemia. Study Design, Subjects, and Methods This retrospective study involved 270 thyroidectomy patients (2004-2006). PTH and calcium levels, length of admission, supplementation, and rates of hypocalcemia were recorded. Results Forty-three percent (26/60) of patients developing hypocalcemia met the PTH ≤ 8 ng/L cut-off. In contrast, 80% (48/60) of patients developing hypocalcemia had a PTH ≤ 15 ng/L. Two point two percent of patients had a 1-hour PTH ≤ 15 ng/L and failed to develop hypocalcemia, for a specificity of 97%. Conclusions A 1-hour PTH cut-off of ≤15 ng/L for prophylactic supplementation should allow the prevention of the majority of cases of hypocalcemia, leading to significant cost savings by shortening hospital stays.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

The McGill Thyroid Nodule Score (MTNS) is a scoring system devised to help physicians to assess the preoperative risk that a thyroid nodule is malignant. It uses 22 different known risk factors for thyroid cancer (radiation exposure, microcalcifications on ultrasound, positive HBME-1 stain on biopsy, etc.) and attributes a percentage risk that the nodule is malignant. Recently, preoperative thyroglobulin (Tg) levels have been shown to correlate with the risk of malignancy. The aim of this study was to incorporate Tg levels into the already established MTNS.This is a retrospective analysis of 184 thyroidectomy patients at the McGill University Thyroid Cancer Center. Patients with preoperative Tg levels were included in the study, and patients with incidental papillary microcarcinoma without extrathyroidal extent on final pathology were excluded. MTNS scores were calculated for all patients. Preoperative Tg levels of 75 ng/mL added one point to the MTNS, and levels of 187.5 ng/mL added two points. The new system is named MTNS+.Malignancy rates were calculated for each MTNS+ score. Patients with a score of 0-1 were5% at risk of malignancy. The malignancy rate for scores of 2-3 was 14.29%, followed by 28.95% for scores of 4-6, 32.65% for scores of 7-8, 64.86% for scores of 9-11, 71.43% for scores of 12-14, 78.57% for scores of 15-18, and 92.31% for scores of 19-22. All patients (five of five) with an MTNS+ score of 23 or more had a malignant final pathology result. Patients with scores greater than eight had a relative risk of 2.5 [CI 1.79-3.49] of malignancy compared to patients with lower scores. MTNS+ showed good specificity at higher scores, with 89%, 96%, and 100% at scores above 11, 14, and 20 respectively. Compared to MTNS, adding Tg levels did not improve positive predictive values (PPV) or specificity, but improved sensitivity by 7.89% for scores greater than eight, and by up to 10.48% for scores greater than seven.This study shows that adding Tg to the MTNS increases the sensitivity of this scoring system. Moreover, it suggests that a combined scoring system such as the MTNS+ can accurately stratify the risk of well-differentiated malignancy in patients with thyroid nodules.

Fish bones are of particular interest to the otolaryngologist as accidental ingestion is one of the most common reasons for otolaryngology-related emergency department referrals. Furthermore, removal of fish bones deeply lodged in the oropharynx or hypopharynx can be both hazardous and technically difficult, and failure to accomplish safe removal could result in considerable morbidity and various critical complications.We present here a literature review on the topic of fish bones in otolaryngology with a focus on selection of patients for intervention and on removal techniques. We emphasize that retained fish bones should be approached with caution as their course can at times be unpredictable, as we describe here.

BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication.Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses.A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent's test result. Older offspring age (P ≤ .01), offspring gender (female, P = .05), parents' negative test result (P = .03), and parents' education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent's BRCA1/2 positive or variant of uncertain significance result.Many parents communicate their BRCA1/2 test results to young offspring. Parents' perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span.

There are presently a great number of publications pertaining to the clinical risk factors associated with thyroid cancer. These studies deal mostly with a single feature from either patient demographics, physical examination, laboratory values, imaging, or cytology. We sought to create a novel scoring system that integrates the diagnostic indices of each of these clinical features for carcinoma.A retrospective analysis of 1047 consecutive thyroidectomy patients was performed. Each patient was assigned a cancer risk score according to a newly devised 22-variable scoring scheme termed the McGill Thyroid Nodule Score (MTNS). The MTNS was developed by a multidisciplinary team of endocrinologists, thyroid surgeons, and pathologists using already established evidence-based risk factors for thyroid cancer.The exact incidence of malignancy was calculated for each MTNS score based on final pathology. The incidence for scores of 1 to 3 was 27%, of 4 to 7 was 32%, of 8 was 39%, of 9 to 11 was 63%, of 12 to 13 was 88%, and of 14 to 18 was 93%. All (130 of 130) patients with a score ≥ 19 had carcinoma. A score ≤ 8 correlated with a 32% (115 of 357) risk of thyroid cancer, whereas a score8 implied an 86% (417 of 487) risk.Our data suggest that a combined scoring system, the MTNS, can serve as an accurate predictor of the risk for thyroid cancer in a specific thyroid nodule. This will help physicians better formulate management decisions accordingly.

our group has previously demonstrated that serum calcium levels measured in conjunction with parathyroid hormone (PTH) levels early in the postoperative period can help identify and prophylactically treat patients at significant risk for postthyroidectomy hypocalcemia. This study evaluated whether preoperative serum calcium levels can similarly be used as a reliable indicator of a patient's risk for developing postoperative hypocalcemia.this was a retrospective review of 1000 consecutive total thyroidectomy patients (2004-2008), with multiple exclusion criteria considered. Postoperative hypocalcemia was defined as total serum calcium of ≤ 1.90 mmol/L up to 1 month following surgery, a PTH ≤ 8 ng/L, or signs and symptoms of hypocalcemia. Laboratory values were drawn at various intervals according to our institution's protocol.the pertinent data were analyzed for 247 of 1000 patients and indicated that patients with a preoperative corrected calcium level below 2.27 mmol/L had a postthyroidectomy hypocalcemia rate of 63%, whereas those with a calcium level above 2.27 mmol/L experienced hypocalcemia 24% of the time (p.0001*). This threshold calcium value yielded a specificity of 93% and a likelihood ratio of 4.2.our data suggest that preoperative serum calcium levels may correlate with the development of postoperative hypocalcemia. A serum calcium level of 2.27 mmol/L is an important threshold separating patients with an elevated risk of hypocalcemia from those who will likely remain normocalcemic. These data are relevant and useful clinically in identifying patients at risk for hypocalcemia. Current studies are investigating whether patients below our critical threshold of 2.27 mmol/L would benefit from early prophylactic supplementation.

when fine-needle aspiration biopsy (FNAB) of a thyroid nodule yields indeterminate pathology, management decisions become complex, and other preoperative predictors of thyroid cancer must be employed to assess the risk of malignancy. Although thyroglobulin (Tg) is currently accepted as the serum marker of choice in the detection of well-differentiated thyroid cancer (WDTC) recurrence, its preoperative role in the workup of a thyroid nodule remains controversial. The purpose of this study was to evaluate the potential role for Tg as a preoperative indicator of primary WDTC, specifically in patients with indeterminate FNAB.this was a retrospective review of 861 consecutive thyroidectomy patients; 297 patients had indeterminate FNAB, of which 68 had serum levels of Tg measured prior to surgery. The predictive value of various threshold levels of preoperative Tg for WDTC was evaluated. Patients with nonindeterminate FNAB or final pathology containing medullary carcinoma, anaplastic carcinoma, or lymphoma were excluded.eighty-one percent (25 of 31) of patients with both indeterminate FNAB and preoperative Tg ≥ 75 microg/L had well-differentiated cancer on final pathology compared to 58% (172 of 297) of patients with indeterminate cytology alone (p = .014, RR = 1.4). In addition, mean preoperative Tg levels were found to be significantly higher in patients with WDTC compared to those with benign pathology (223 vs 53 microg/L, p = .007).our results imply that elevated preoperative serum Tg levels may be predictive of WDTC. This marker may be useful as an aid when making management decisions in patients with indeterminate cytology.

In this study we address the research question; How sensitive is a single question in delirium case finding? Of 33 ‘target’ admissions, consent was obtained from 21 patients. The single question: ‘Do you think [name of patient] has been more confused lately?’ was put to friend or family. Results of the Single Question in Delirium (SQiD) were compared to psychiatrist interview (ΨI) which was the reference standard. The Confusion Assessment Method (CAM) and two other tools were also applied. Compared with ΨI, the SQiD achieved a sensitivity and specificity of 80% (95% CI 28.3—99.49%) and 71% (41.90—91.61%) respectively. The CAM demonstrated a negative predictive value (NPV) of 80% (51.91—95.67%) and the SQiD showed a NPV of 91% (58.72—99.77%). Kappa correlation of SQiD with the ΨI was 0.431 (p = 0.023). The CAM had a kappa value of 0.37 (p = 0.050). A further important finding in our study was that the CAM had only 40% sensitivity in the hands of minimally trained clinical users. Conclusion: The SQiD demonstrates potential as a simple clinical tool worthy or further investigation.

The aim of this study was to obtain detailed information regarding the threedimensional structure of the gastro-oesophageal region, and, in particular, the fiber orientation of the different muscle layers of the junction. This was achieved by a study of an en bloc resection of the gastro-oesophageal junction (GOJ) harvested from a human cadaver. The excised tissue block was suspended in a cage to preserve anatomical relationships, fixed in formalin and embedded in wax. The tissue block was then processed by a custom-built extended-volume imaging system to obtain the microstructural information using a digital camera which acquires images at a resolution of 8.2 lm/pixel. The top surface of the tissue block was sequentially stained and imaged. At each step, the imaged surface was milled off at a depth of 50 lm. The processing of the tissue block resulted in 650 images covering a length of 32.25 mm of the GOJ. Structures, including the different muscle and fascial layers, were then traced out from the cross-sectional images using color thresholding. The traced regions were then aligned and assembled to provide a three-dimensional representation of the GOJ. The result is the detailed three-dimensional microstructural anatomy of the GOJ represented in a new way. The next stage will be to integrate key physiological events, including peristalsis and relaxation, into this model using mathematical modeling to allow accurate visual tools for training health professionals and patients. Clin. Anat. 23:287–296, 2010. V V C 2010 Wiley-Liss, Inc.

The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.

Stridor is a relatively common symptom during the neonatal period. The most probable cause of inspiratory stridor and supralaryngeal airway obstruction in infancy is laryngomalacia. Laryngeal cysts are known to be found in association with supraglottic prolapse and are a rare yet potentially lethal cause of respiratory distress in the newborn. In the absence of more alarming presenting signs, the vallecular cyst, a form of laryngeal cyst, frequently defies diagnosis. We present a series of illustrative cases to raise awareness of vallecular cyst to help reduce the therapeutic delays that are currently encountered clinically.A retrospective case series of four patients was reviewed. Each patient presented initially with stridor and additional signs of upper airway obstruction shortly after birth and was later diagnosed with vallecular cyst.The predominant presenting signs were stridor (four cases), signs of respiratory distress (three cases), failure to thrive (three cases), poor feeding (two cases), and cyanotic spells (one case). Age at presentation ranged from 16 days to 8 months. A definitive diagnosis was achieved by flexible laryngoscopy in all four cases. Coexistent laryngomalacia was found in three of the four cases. Primary outcomes at 1 month following marsupialization were complete remission in all four cases.The challenge in making an early diagnosis of vallecular cyst, especially when laryngomalacia is comorbid, has been reaffirmed in our case series. Diagnosis requires a high index of clinical suspicion in combination with careful inspection of the tongue base with direct examination and/or appropriate imaging modalities.

Systemic diseases such as Wegener granulomatosis, Churg-Strauss syndrome, and sarcoidosis can present initially as severe rhinitis alone. One clinical entity that mimics severe rhinitis and thus poses a particular challenge in this regard is extranodal T-cell lymphoma of the sinonasal tract. Sinonasal lymphoma has a vague initial presentation that masquerades as more common, benign causes of rhinitis but progresses as a "midfacial progressive destructive lesion" and is uniformly fatal if untreated. In the absence of systemic involvement, the precise etiology frequently defies diagnosis. We present a series of illustrative cases to raise awareness of this rare yet lethal disease to help reduce the therapeutic delays that are currently encountered clinically.A retrospective case series of four patients was reviewed. Each patient presented initially with severe rhinitis but was later diagnosed with extranodal natural killer/T-cell non-Hodgkin lymphoma of the sinonasal tract.The predominant presenting symptoms were unilateral nasal obstruction (four patients), rhinitis (three patients), and facial pain (two patients). Only one patient reported systemic B symptoms. Initial management of all four patients included repeated biopsies revealing nonspecific inflammation, which resulted in extensive therapeutic delays (mean time until diagnosis 21.5 months). The primary outcomes were two deaths and two complete remissions.The challenge in making an early diagnosis of T-cell lymphoma of the sinonasal tract has been reaffirmed in our case series. We emphasize that diagnosis requires a high index of clinical suspicion in combination with multiple deep and appropriately processed biopsies that are submitted for immunohistochemistry and molecular studies.

The aim of this work is to establish a computational pipeline for the simulation of blood flow in vasculatures and apply this pipeline to endovascular interventional scenarios, e.g. angioplasty in vertebral arteries.A patient-specific supra-aortal vasculature is digitized from a 3D CT angiography image. By coupling a reduced formulation of the governing Navier-Stokes equations with a wall constitutive equation we are able to solve the transient flow in elastic vessels. By further incorporating a bifurcation model the blood flow across vascular branches can be evaluated, thus flow in a large vasculature can be modeled. Vascular diseases are simulated by modifying the arterial tree configurations, e.g. the effective diameters, schematic connectivity, etc. Occlusion in an artery is simulated by removing that artery from the arterial tree.It takes about 2 min per cardiac cycle to compute blood flow in an arterial tree consisting of 38 vessels and 18 bifurcations on a laptop PC. The simulation results show that blood supply in the posterior region is compensated from the contralateral vertebral artery and the anterior cerebral arteries if one of the vertebral arteries is occluded.The computational pipeline is computationally efficient and can capture main flow patterns at any point in the arterial tree. With further improvement it can serve as a powerful tool for the haemodynamic analysis in patient-specific vascular structures.

The response of the heart to electrical shock, electrical propagation in sinus rhythm, and the spatiotemporal dynamics of ventricular fibrillation all depend critically on the electrical anisotropy of cardiac tissue. A long-held view of cardiac electrical anisotropy is that electrical conductivity is greatest along the myocyte axis allowing most rapid propagation of electrical activation in this direction, and that conductivity is isotropic transverse to the myocyte axis supporting a slower uniform spread of activation in this plane. In this context, knowledge of conductivity in two directions, parallel and transverse to the myofiber axis, is sufficient to characterize the electrical action of the heart. Here we present new experimental data that challenge this view. We have used a novel combination of intramural electrical mapping, and experiment-specific computer modeling, to demonstrate that left ventricular myocardium has unique bulk conductivities associated with three microstructurally-defined axes. We show that voltage fields induced by intramural current injection are influenced by not only myofiber direction, but also the transmural arrangement of muscle layers or myolaminae. Computer models of these experiments, in which measured 3D tissue structure was reconstructed in-silico, best matched recorded voltages with conductivities in the myofiber direction, and parallel and normal to myolaminae, set in the ratio 4:2:1, respectively. These findings redefine cardiac tissue as an electrically orthotropic substrate and enhance our understanding of how external shocks may act to successfully reset the fibrillating heart into a uniform electrical state. More generally, the mechanisms governing the destabilization of coordinated electrical propagation into ventricular arrhythmia need to be evaluated in the light of this discovery.

BACKGROUND Operative notes can be generated electronically by manual input of the entire note, free-form oral dictation, or using either an electronic template or a template for dictation. There are few studies that have directly compared these modalities in terms of speed, accuracy, and completeness. OBJECTIVE The objective was to determine whether electronic templates are more efficient and reduce errors compared to free-form oral dictation for the completion of Mohs micrographic surgery operative notes. METHODS Operative notes for 110 consecutive Mohs micrographic surgery cases were completed either by oral dictation or by electronic template. The time to dictate or complete the template was recorded for each note. Notes were subsequently edited, recording the number and type of errors as well as the time required to edit each note. RESULTS Compared with dictation, operative notes completed with the electronic template had fewer errors (5.8% vs. 81%), took less time to complete (175.5 seconds vs. 240.0 seconds), took less time to review and edit (41.6 seconds vs. 201.1 seconds), and were completed and signed in a more timely fashion (0.115 days vs. 20.7 days). CONCLUSION Electronic templates are a more accurate and rapid method compared to free-form oral dictation for the completion of Mohs micrographic surgery operative notes and have the advantage of being immediately available to review and sign.

Significant tissue structures exist in cardiac ventricular tissue, which are of supracellular dimension. It is hypothesized that these tissue structures contribute to the discontinuous spread of electrical activation, may contribute to arrhythmogenesis, and also provide a substrate for effective cardioversion. However, the influences of these mesoscale tissue structures in intact ventricular tissue are difficult to understand solely on the basis of experimental measurement. Current measurement technology is able to record at both the macroscale tissue level and the microscale cellular or subcellular level, but to date it has not been possible to obtain large volume, direct measurements at the mesoscales. To bridge this scale gap in experimental measurements, we use tissue-specific structure and mathematical modeling. Our models, which can incorporate ion channel models at the cell level into the reaction-diffusion equations at the tissue level, have enabled us to consider key hypotheses regarding discontinuous activation.

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

Significant tissue structures exist in cardiac ventricular tissue that are of supracellular dimension. It is hypothesized that these tissue structures contribute to the discontinuous spread of electrical activation, may contribute to arrhymogenesis and also provide a substrate for effective cardioversion. However, the influences of these mesoscale tissue structures in intact ventricular tissue are difficult to understand solely on the basis of experimental measurement. Current measurement technology is able to record at both the macroscale tissue level and the microscale cellular or subcellular level, but to date it has not been possible to obtain large volume, direct measurements at the mesoscales. To bridge this scale gap in experimental measurements, we use tissue-specific structure and mathematical modelling. Our models have enabled us to consider key hypotheses regarding discontinuous activation. We also consider the future developments of our intact tissue experimental programme.

One of the main limitations in using inverse methods for non-invasively imaging cardiac electrical activity in a clinical setting is the difficulty in readily obtaining high-quality data sets to reconstruct accurately a patient-specific geometric model of the heart and torso. This issue was addressed by investigation into the feasibility of using a pseudo-3D ultrasound system and a hand-held laser scanner to reconstruct such a model. This information was collected in under 20 min prior to a catheter ablation or pacemaker study in the electrophysiology laboratory. Using the models created from these data, different activation field maps were computed using several different inverse methods. These were independently validated by comparison of the earliest site of activation with the physical location of the pacing electrodes, as determined from orthogonal fluoroscopy images. With an estimated average geometric error of approximately 8 mm, it was also possible to reconstruct the site of initial activation to within 17.3 mm and obtain a quantitatively realistic activation sequence. The study demonstrates that it is possible rapidly to construct a geometric model that can then be used non-invasively to reconstruct an activation field map of the heart.

We present a finite element (FE) derived finite difference (FD) technique for solving cardiac activation problems over deforming geometries using a bidomain framework. The geometry of the solution domain is defined by a FE mesh and over these FEs a high resolution FD mesh is generated. The difference points are located at regular intervals in the normalized material space within each of the FEs. The bidomain equations are then transformed to the embedded FD mesh which provides a solution space that is both regular and orthogonal. The solution points move in physical space with any deformation of the solution domain, but the equations are set up in such a way that the solution is invariant as it is constructed in material space. The derivation of this new solution technique is presented along with a series of examples that demonstrate the accuracy of this bidomain framework. © 2003 Biomedical Engineering Society.

Lymphangiomas of the tongue are relatively uncommon, and traditional treatment modalities carry a high failure rate. We present here a case report of effective treatment of lymphangioma circumscriptum of the oral tongue using radiofrequency coblation, while including a review of the current literature.

A variety of scorpion venoms and purified toxins were tested for effects on ion channels in human T lymphocytes, a human T leukemia cell line (Jurkat), and murine thymocytes, using the whole-cell patch-clamp method. Nanomolar concentrations of charbdotoxin (CTX), a purified peptide component of Leiurus quinquestriatus venom known to block Ca2+-activated K+ channels from muscle, blocked "type n" voltage-gated K+ channels in human T lymphoid cells. The Na+ channels occasionally expressed in these cells were unaffected by the toxin. From the time course of development and removal of K+ channel block we determined the rates of CTX binding and unbinding. CTX blocks K+ channels in Jurkat cells with a Kd value between 0.5 and 1.5 nM. Of the three types of voltage-gated K+ channels present in murine thymocytes, types n and n' are blocked by CTX at nanomolar concentrations. The third variety of K+ channels, "type l," is unaffected by CTX. Noxiustoxin (NTX), a purified toxin from Centruroides noxius known to block Ca2+-activated K+ channels, also blocked type n K+ channels with a high degree of potency (Kd = 0.2 nM). In addition, several types of crude scorpion venoms from the genera Androctonus, Buthus, Centruroides, and Pandinus blocked type n channels. We conclude that CTX and NTX are not specific for Ca2+ activated K+ channels and that purified scorpion toxins will provide useful probes of voltage-gated K+ channels in T lymphocytes. The existence of high-affinity sites for scorpion toxin binding may help to classify structurally related K+ channels and provide a useful tool for their biochemical purification.