Search

Context Ketogenic diets (KDs) and low-fat diets (LFD) result in similar weight loss, but have differential cardiometabolic effects on lipids and insulin. Generally, weight loss decreases renin–angiotensin–aldosterone system (RAAS) activity. Objective Investigate the effects of KDs with varying sodium content vs LFD on RAAS in overweight and obese adults. Methods Twenty-eight participants were randomized 1:1 to a KD + ketone salt supplement (KD + KS) or a KD + placebo (KD + PL) arm with prepared hypocaloric meals. Twelve participants were enrolled in a post hoc LFD arm. Serum renin, aldosterone, and anthropometric and metabolic biomarkers were assessed at 0, 2, 4, and 6 weeks. Linear mixed models with random intercepts were used to compare between group differences controlling for sex and body mass index. Results Participants had a median age of 33 years, 51% female, weighed 91.3 kg, with body mass index 30.6 kg/m2. At 6 weeks, weight decreased by 6, 8, and 7 kg on average in the KD + KS, KD + PL, and LFD groups, respectively (P < .05). Aldosterone increased by 88% and 144% in the KD + PL and KD + KS groups, respectively, but did not change in the LFD after 6 weeks while renin decreased across groups. Systolic and diastolic blood pressure did not change in the KD + PL and KD + KS groups. Log ketones were positively associated with aldosterone (P < .001). Aldosterone was not associated with cardiovascular measures including blood pressure and ejection fraction (P > .05). Conclusion KD reduced weight and increased aldosterone without worsening cardiometabolic risk factors. Future KD studies are needed to elucidate mechanistic connections between ketones and aldosterone.

Biblical Hebrew lexicons unanimously present the basic meaning of the verb שׁאף as “pant, snuff.” Absent etymological evidence, however, the lexical value of the verb hangs on the contextual interpretation of three attestations where the verb has not undergone semantic expansion: Isa 42:14; Jer 2:24; 14:6. Fresh analysis of the philological evidence garners support for an alternate interpretation of שׁאף רוח in Jer 2:24; 14:6 as “bray, cry out” and suggests that ואשׁאף in Isa 42:14 constitutes an elliptical form of the phrase with the same meaning. This new semantic understanding in turn allows for a reanalysis of derived meanings, furnishing a revised understanding of the verb שׁאף.

Lung volume reduction surgery (LVRS) patient selection guidelines are based on the National Emphysema Treatment Trial. Because of increased mortality and poor improvement in functional outcomes, patients with non-upper lobe emphysema and low baseline exercise capacity are determined as poor candidates for LVRS. In well-selected patients with heterogeneous emphysema, LVRS has a durable long-term outcome at up to 5-years of follow-up. Five-year survival rates in patients range between 63% and 78%. LVRS seems a durable alternative for end-stage heterogeneous emphysema in patients not eligible for lung transplantation. Future studies will help identify eligible patients with homogeneous emphysema for LVRS.

Ketosis has been reported to benefit healthspan and resilience, which has driven considerable interest in development of exogenous ketones to induce ketosis without dietary changes. Bis hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone di-ester that can be used as a food ingredient that increases hepatic ketogenesis and blood beta-hydroxybutyrate (BHB) concentrations.Here, we provide the first description of blood ketone and metabolite kinetics for up to five hours after consumption of a beverage containing BH-BD by healthy adults (Consumption of BH-BD effectively raised plasma r-BHB concentrations to 0.8-1.7 mM in all conditions, and both peak r-BHB concentration and r-BHB area under the curve were greater with 25 g versus 12.5 g of BH-BD. Urinary excretion of r-BHB was1 g. Plasma concentration of the non-physiological isoform s-BHB was increased to 20-60 µM in all conditions. BH-BD consumption decreased plasma glucose and free fatty acid concentrations; insulin was increased when BH-BD was consumed with a meal.These results demonstrate that consumption of BH-BD effectively induces exogenous ketosis in healthy adults at rest.

Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-wk supervised exercise program after self-selection into a ketogenic diet (KD, n = 15) group or maintenance of their habitual mixed diet (MD, n = 14). Measures of metabolic health and muscle biopsies (vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-l-carnitine), and ketone (β-hydroxybutyrate+acetoacetate) substrates. Compared with MD, the KD resulted in increased whole body resting fat oxidation ( P < 0.001) and decreased fasting insulin ( P = 0.019), insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), P = 0.022], and visceral fat ( P < 0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, P = 0.009), ATP production (36%, P = 0.028), and ATP/H2O2(36%, P = 0.033) with the fat-based substrate. ATP production with the ketone-based substrate was four to eight times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, P = 0.035) and an increase in muscle triglyceride (81%, P = 0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.

Background Historically, pulmonary hypertension (PH) has been considered as one of the contraindications for lung volume reduction surgery (LVRS). Newer studies have shown that LVRS is successful in select emphysema patients with PH. Methods In-hospital and 1-year functional and quality of life (QOL) outcomes were studied in patients with PH post-LVRS. PH was defined as pulmonary artery pressure (PAP) exceeding 35 mm Hg by right heart catheterization (RHC), where available, or else exceeding 35 mm Hg by echocardiogram. Results Of 124 patients who underwent LVRS, 56 (45%) had PH (mean PAP, 41 mm Hg) with 48 mild to moderate and 8 severe PH. In-hospital outcomes were similar between patients with and without PH: hours of artificial ventilation (1.8 vs 0.06, P = .882), days in intensive care (4 vs 6, P = .263), prolonged air leak (12% vs 19%, P = .402), and days of hospital stay (13 vs 16, P = .072). Lung function improved significantly at the 1-year follow-up in patients with PH: forced expiratory volume in 1 second % predicted (26 vs 38, P = .001), forced vital capacity % (62 vs 90, P = .001), residual volume % predicted (224 vs 174, P = .001), diffusion capacity of the lung for carbon monoxide % predicted (36 vs 43, P = .001), 6-minute walk distance test (1104 vs 1232 feet, P = .001), and QOL utility scores (0.67 vs 0.77, P = .001). There were no differences in in-hospital, baseline, and follow-up functional and QOL outcomes between patients with and without PH. Conclusions In this small, single-institution cohort, outcomes of patients undergoing LVRS for emphysema with PH were similar to those of patients without PH. LVRS may be a potential option for select emphysema patients with PH.

The prior behavioral theory of the firm research documents that a firm’s external environment impacts the risk-return relationship, suggesting that drivers outside the firm are part of the risk-return puzzle. This study examines whether firms’ misery scores impact the return relationship. Using a sample of firm-year observations from 2002 to 2011, we investigate the relationship between the external environment related to misery and firms’ risk-return relationships by regressing five factors that proxy for firms’ external environments (e.g. misery levels) on risk and return. Our results suggest that both economic and non-economic external environmental factors impact firms’ risk-return relationship. Specifically, low unemployment rates and taxes are associated with higher levels of risk-taking, whereas greater access to leisure amenities decreases risk-taking. A firm’s return is negatively impacted by risk-taking associated with low unemployment and taxes and greater access to education and healthcare. However, a firm’s return is positively impacted by risk-taking associated with better air quality and lower property crime. The results suggest that a firm’s external environment impacts its performance. Therefore, future research may consider including location fixed effects to control for the unobservable external environmental factors that impact firm performance. Second, the results are of interest to practitioners as businesses can utilize the findings to develop internal programs that neutralize the external environment’s effects on firm performance.

Rib fractures are the most common thoracic injury after minor blunt trauma. Although rib fractures can produce significant morbidity, the diagnosis of injuries to underlying organs is arguably more important as these complications are likely to have the most significant clinical impact. Isolated rib fractures have a relatively low morbidity and mortality and treatment is generally conservative. As such, evaluation with standard chest radiographs is usually sufficient for the diagnosis of rib fractures, and further imaging is generally not appropriate as there is little data that undiagnosed isolated rib fractures after minor blunt trauma affect management or outcomes. Cardiopulmonary resuscitation frequently results in anterior rib fractures and chest radiographs are usually appropriate (and sufficient) as the initial imaging modality in these patients. In patients with suspected pathologic fractures, chest CT or Tc-99m bone scans are usually appropriate and complementary modalities to chest radiography based on the clinical scenario. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

IntroductionKetogenic diets (KDs) that elevate ketones into a range referred to as nutritional ketosis represent a possible nutrition approach to address the emerging physical readiness and obesity challenge in the military. An emerging body of evidence demonstrates broad-spectrum health benefits attributed to being in nutritional ketosis, but no studies have specifically explored the use of a KD in a military population using daily ketone monitoring to personalize the diet prescription.Materials and MethodsTo evaluate the feasibility, metabolic, and performance responses of an extended duration KD, healthy adults (n = 29) from various military branches participated in a supervised 12-wk exercise training program. Fifteen participants self-selected to an ad libitum KD guided by daily measures of capillary blood ketones and 14 continued their normal mixed diet (MD). A battery of tests were performed before and after the intervention to assess changes in body mass, body composition, visceral fat, liver fat, insulin sensitivity, resting energy metabolism, and physical performance.ResultsAll KD subjects were in nutritional ketosis during the intervention as assessed by daily capillary beta-hydroxybutyrate (βHB) (mean βHB 1.2 mM reported 97% of all days) and showed higher rates of fat oxidation indicative of keto-adaptation. Despite no instruction regarding caloric intake, the KD group lost 7.7 kg body mass (range −3.5 to −13.6 kg), 5.1% whole-body percent fat (range −0.5 to −9.6%), 43.7% visceral fat (range 3.0 to −66.3%) (all p < 0.001), and had a 48% improvement in insulin sensitivity; there were no changes in the MD group. Adaptations in aerobic capacity, maximal strength, power, and military-specific obstacle course were similar between groups (p > 0.05).ConclusionsUS military personnel demonstrated high adherence to a KD and showed remarkable weight loss and improvements in body composition, including loss of visceral fat, without compromising physical performance adaptations to exercise training. Implementation of a KD represents a credible strategy to enhance overall health and readiness of military service members who could benefit from weight loss and improved body composition.

Brain-Derived Neurotropic Factor (BDNF) expression is decreased in conditions associated with cognitive decline as well as metabolic diseases. One potential strategy to improve metabolic health and elevate BDNF is by increasing circulating ketones. Beta-Hydroxybutyrate (BHB) stimulates BDNF expression, but the association of circulating BHB and plasma BDNF in humans has not been widely studied. Here, we present results from three studies that evaluated how various methods of inducing ketosis influenced plasma BDNF in humans. Study 1 determined BDNF responses to a single bout of high-intensity cycling after ingestion of a dose of ketone salts in a group of healthy adults who were habitually consuming either a mixed diet or a ketogenic diet. Study 2 compared how a ketogenic diet versus a mixed diet impacts BDNF levels during a 12-week resistance training program in healthy adults. Study 3 examined the effects of a controlled hypocaloric ketogenic diet, with and without daily use of a ketone-salt, on BDNF levels in overweight/obese adults. We found that (1) fasting plasma BDNF concentrations were lower in keto-adapted versus non keto-adapted individuals, (2) intense cycling exercise was a strong stimulus to rapidly increase plasma BDNF independent of ketosis, and (3) clinically significant weight loss was a strong stimulus to decrease fasting plasma BDNF independent of diet composition or level of ketosis. These results highlight the plasticity of plasma BDNF in response to lifestyle factors but does not support a strong association with temporally matched BHB concentrations.

Background. Foods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate. Objective. We aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition. Methods. We performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based ‘Run-In’ diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution. Results. Compared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group. Conclusions. These results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.

Liquid-like membraneless organelles form via multiple, weak interactions between biomolecules. The resulting condensed states constitute novel solvent environments inside eukaryotic cells that partition biomolecules and may favour particular biochemical reactions. Here we demonstrate that, in addition to attractive interactions, repulsive electrostatic interactions modulate condensate properties. We find that net charge modulates the formation, morphology and solvent properties of model Ddx4 condensates in cells and in vitro and that a net negative charge is conserved across germ cell-specific Ddx4 orthologues. This conserved net charge provides a sensitivity to multivalent cations that is not observed in somatic paralogues. The disfavouring effect of a net negative charge in Ddx4 orthologues appears to be offset by increased charge patterning, indicating that fine tuning of both attractive and repulsive interactions can create responsive solvent environments inside biomolecular condensates.

Background: Ketogenic diets (KDs) that elevate beta-hydroxybutyrate (BHB) promote weight and fat loss. Exogenous ketones, such as ketone salts (KS), also elevate BHB concentrations with the potential to protect against muscle loss during caloric restriction. Whether augmenting ketosis with KS impacts body composition responses to a well-formulated KD remains unknown.Purpose: To explore the effects of energy-matched, hypocaloric KD feeding (Methods: Overweight and obese adults were provided a precisely defined hypocaloric KD (~75% of energy expenditure) for 6 weeks. In a double-blind manner, subjects were randomly assigned to receive ~24 g/day of a racemic BHB-salt (KD + KS; n = 12) or placebo (KD + PL; n = 13). A matched comparison group (n = 12) was separately assigned to an isoenergetic/isonitrogenous low-fat diet (LFD). Body composition parameters were assessed by dual x-ray absorptiometry and magnetic resonance imaging.Results: The KD induced nutritional ketosis (>1.0 mM capillary BHB) throughout the study (p < 0.001), with higher fasting concentrations observed in KD + KS than KD + PL for the first 2 weeks (p < 0.05). There were decreases in body mass, whole body fat and lean mass, mid-thigh muscle cross-sectional area, and both visceral and subcutaneous adipose tissues (p < 0.001), but no group differences between the two KDs or with the LFD. Urine nitrogen excretion was significantly higher in KD + PL than LFD (p < 0.01) and trended higher in KD + PL compared to KD + KS (p = 0.076), whereas the nitrogen excretion during KD + KS was similar to LFD (p > 0.05).Conclusion: Energy-matched hypocaloric ketogenic diets favorably affected body composition but were not further impacted by administration of an exogenous BHB-salt that augmented ketosis. The trend for less nitrogen loss with the BHB-salt, if manifested over a longer period of time, may contribute to preserved lean mass.

Intracellular compartmentalization through liquid-liquid phase separation is an emerging organizing principle of cell biology. These compartments, such as the nucleolus and stress granules, are collectively known as membraneless organelles or biomolecular condensates. In vitro studies of many protein components of biomolecular condensates, such as the intrinsically disordered regions of Ddx4, FUS, and Laf-1 proteins, have revealed much about the driving forces of the phase separation process. A common approach is to investigate how the temperature at which a protein solution forms condensates-the transition temperature-responds to changes in the solution composition. We describe a method to measure the in vitro transition temperature of a sub-10 μL sample of a phase-separating solution using transmitted light microscopy. Through monitoring changes in transition temperature with solution conditions, this approach allows the impact of additional biomolecules and additives to be quantitatively assessed and permits the construction of phase diagrams.

The hypogeous, sequestrate ascomycete genus Elaphomyces is one of the oldest known truffle-like genera. Elaphomyces has a long history of consumption by animals in Europe and was formally described by Nees von Esenbeck in 1820 from Europe. Until recently most Elaphomyces specimens in North America were assigned names of European taxa due to lack of specialists working on this group and difficulty of using pre-modern species descriptions. It has recently been discovered that North America has a rich diversity of Elaphomyces species far beyond the four Elaphomyces species described from North America prior to 2012. We describe eight new Elaphomyces species (E. dalemurphyi, E. dunlapii, E. holtsii, E. lougehrigii, E. miketroutii, E. roodyi, E. stevemilleri and E. wazhazhensis) of eastern North America that were collected in habitats from Quebec, Canada south to Florida, USA, west to Texas and Iowa. The ranges of these species vary and with continued sampling may prove to be larger than we have established. Castellano has studied authentic material of all European Elaphomyces species published through 2016 and it is interesting to note that many Elaphomyces species from eastern North America have morphological similarities but with distinct morphological differences to a number of European Elaphomyces species. Citation: Castellano MA, Crabtree CD, Mitchell D, Healy RA (2020). Eight new Elaphomyces species (Elaphomycetaceae, Eurotiales, Ascomycota) from eastern North America. Fungal Systematics and Evolution 7: 113–131. doi: 10.3114/fuse.2021.07.06

A low field strength (B0) system could increase cardiac MRI availability for patients otherwise contraindicated at higher field. Lower equipment costs could also broaden cardiac MR accessibility. The current study investigated the feasibility of cardiac function with steady-state free precession and flow assessment with phase contrast (PC) cine images at 0.35 T, and evaluated differences in myocardial relaxation times using quantitative T1, T2 and T2* maps by comparison with 1.5 and 3 T results in a small cohort of six healthy volunteers. Signal-to-noise ratio (SNR) differences across systems were characterized with proton density-weighted spin echo phantom data. SNR at 0.35 T was lower by factors of 5.5 and 15.0 compared with the 1.5 and 3 T systems used in this study. All cine images at 0.35 T scored 3 or greater on a five-point image quality scale. Normalized blood-myocardium contrast in cine images, left ventricular volumes (end diastolic volume, end systolic volume) and function (ejection fraction and stroke volume) measures at 0.35 T matched 1.5 and 3 T results. Phase-to-noise ratio in 0.35 T PC images (11.7 ± 1.9) was lower than 1.5 T (18.7 ± 5.2) and 3 T (44.9 ± 16.5). Peak velocity and stroke volume determined from PC images were similar across systems. Myocardial T1 increased (564 ± 13 ms at 0.35 T, 955 ± 19 ms at 1.5 T and 1200 ± 35 ms at 3 T) while T2 (59 ± 4 ms at 0.35 T, 49 ± 3 ms at 1.5 T and 40 ± 2 ms at 3 T) and T2* (42 ± 8 ms at 0.35 T, 33 ± 6 ms at 1.5 T and 24 ± 3 ms at 3 T) decreased with increasing B0. Despite SNR deficits, cardiovascular function, flow assessment and myocardial relaxation parameter mapping is feasible at 0.35 T using standard cardiovascular imaging sequences.

Intracellular compartmentalization through liquid-liquid phase separation is an emerging organizing principle of cell biology. These compartments, such as the nucleolus and stress granules, are collectively known as membraneless organelles or biomolecular condensates. In vitro studies of many protein components of biomolecular condensates, such as the intrinsically disordered regions of Ddx4, FUS, and Laf-1 proteins, have revealed much about the driving forces of the phase separation process. A common approach is to investigate how the temperature at which a protein solution forms condensates-the transition temperature-responds to changes in the solution composition. We describe a method to measure the in vitro transition temperature of a sub-10 μL sample of a phase-separating solution using transmitted light microscopy. Through monitoring changes in transition temperature with solution conditions, this approach allows the impact of additional biomolecules and additives to be quantitatively assessed and permits the construction of phase diagrams.

Although a rare malignancy, mortality from esophageal cancer remains high. Lymphadenectomy during esophagectomy is an essential part of the staging process for esophageal cancer and has been independently shown to affect overall survival. The optimal lymphadenectomy has been studied and will be reviewed below, including the total number of lymph nodes that need to be sampled to provide survival benefit, the lymph node ratio as a prognostic indicator, and the different anatomic dissections performed. It is recommended that a lymphadenectomy should at least include 15 lymph nodes sampled via at least a two-field approach and should have a standardized technique for submitting lymph nodes to pathology.

Lung cancer remains the leading cause of cancer death in both men and women. Smoking is the single greatest risk factor for the development of lung cancer. For patients between the age of 55 and 80 with 30 or more pack years smoking history who currently smoke or who have quit within the last 15 years should undergo lung cancer screening with low-dose CT. In patients who do not meet these criteria but who have additional risk factors for lung cancer, lung cancer screening with low-dose CT is controversial but may be appropriate. Imaging is not recommended for lung cancer screening of patient younger than 50 years of age or patients older than 80 years of age or patients of any age with less than 20 packs per year history of smoking and no additional risk factor (ie, radon exposure, occupational exposure, cancer history, family history of lung cancer, history of COPD, or history of pulmonary fibrosis). The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Chronic dyspnea may result from a variety of disorders of cardiovascular, pulmonary, gastrointestinal, neuromuscular, systemic, and psychogenic etiology. This article discusses guidelines for the initial imaging of six variants for chronic dyspnea of noncardiovascular origin: (1) Chronic dyspnea of unclear etiology; (2) Chronic dyspnea with suspected chronic obstructive pulmonary disease; (3) Chronic dyspnea with suspected central airways disease; (4) Chronic dyspnea with suspected interstitial lung disease; (5) Chronic dyspnea with suspected disease of the pleura or chest wall; and (6) Chronic dyspnea with suspected diaphragm dysfunction. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Acute respiratory illness, defined as cough, sputum production, chest pain, and/or dyspnea (with or without fever), is a major public health issue, accounting for millions of doctor office and emergency department visits every year. While most cases are due to self-limited viral infections, a significant number of cases are due to more serious respiratory infections where delay in diagnosis can lead to morbidity and mortality. Imaging plays a key role in the initial diagnosis and management of acute respiratory illness. This study reviews the current literature concerning the appropriate role of imaging in the diagnosis and management of the immunocompetent adult patient initially presenting with acute respiratory illness. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Java is arguably today’s most popular and widely used object-oriented programming language. Learning Java is a daunting task for students, and teaching it is a challenging undertaking for instructo...

The realization of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer’s disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1H-benzimidazol-2-one), described previously as a potent M1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702, together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. Although they impart beneficial effects on learning and memory, we conclude that these properties are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data support the notion that “pure” positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses.

The outcomes research efforts based on The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database include two established research programs with dedicated task forces and with data analyses conducted at the STS data analytic center: (1) The STS-sponsored research by the Access and Publications program, and (2) grant and institutionally funded research by the Longitudinal Follow-Up and Linked Registries Task Force. Also, the STS recently introduced the research program enabling investigative teams to apply for access to deidentified patient-level General Thoracic Surgery Database data sets and conduct related analyses at their own institution. Last year's General Thoracic Surgery Database-based research publications and the new Participant User File research program are reviewed.

Objectives To identify the variability of short- and long-term survival outcomes among closed Phase III randomized controlled trials with small sample sizes comparing SBRT (stereotactic body radiation therapy) and surgical resection in operable clinical Stage I non-small cell lung cancer (NSCLC) patients. Patients and methods Clinical Stage I NSCLC patients who underwent surgery at our institution meeting the inclusion/exclusion criteria for STARS (Randomized Study to Compare CyberKnife to Surgical Resection in Stage I Non-small Cell Lung Cancer), ROSEL (Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage (IA) Lung Cancer), or both were identified. Bootstrapping analysis provided 10,000 iterations to depict 30-day mortality and three-year overall survival (OS) in cohorts of 16 patients (to simulate the STARS surgical arm), 27 patients (to simulate the pooled surgical arms of STARS and ROSEL), and 515 (to simulate the goal accrual for the surgical arm of STARS). Results From 2000 to 2012, 749/873 (86%) of clinical Stage I NSCLC patients who underwent resection were eligible for STARS only, ROSEL only, or both studies. When patients eligible for STARS only were repeatedly sampled with a cohort size of 16, the 3-year OS rates ranged from 27 to 100%, and 30-day mortality varied from 0 to 25%. When patients eligible for ROSEL or for both STARS and ROSEL underwent bootstrapping with n = 27, the 3-year OS ranged from 46 to 100%, while 30-day mortality varied from 0 to 15%. Finally, when patients eligible for STARS were repeatedly sampled in groups of 515, 3-year OS narrowed to 70–85%, with 30-day mortality varying from 0 to 4%. Conclusion Short- and long-term survival outcomes from trials with small sample sizes are extremely variable and unreliable for extrapolation.