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Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament reconstruction with lateral extra-articular tenodesis using a strip of the iliotibial band (ITB) has been shown to increase postoperative stability of the knee. This Technical Note describes a method of ITB tenodesis in which a central slip of the ITB is passed deep to the lateral collateral ligament and then rerouted anteriorly for fixation at a location anterior and proximal to the lateral femoral epicondyle. Five whipstitches are passed through the ITB, and a second distal suture is tied around the distal end. Of the 4 suture tails, 3 are passed through a tenodesis screwdriver, and the screw is placed in the previously reamed bone socket. A closed loop is formed around the tenodesis screw by tying off the suture tails. This technique creates a sling around the lateral collateral ligament, which serves as a checkrein to internal rotation in cases in which increased stability is warranted, such as revision anterior cruciate ligament reconstruction in an athlete. [ABSTRACT FROM AUTHOR]

Objectives To reduce the incidence of urinary tract infection, Surgical Care Improvement Project 9 mandates the removal of urinary catheters within 48 hours postoperatively. In patients with thoracic epidural anesthesia, we sought to determine the rate of catheter reinsertion, the complications of reinsertion, and the factors associated with reinsertion. Methods We conducted a prospective observational study of consecutive patients undergoing major pulmonary or esophageal resection with thoracic epidural analgesia over a 2-year period. As per Surgical Care Improvement Project 9, all urinary catheters were removed within 48 hours postoperatively. Excluded were patients with chronic indwelling catheter, patients with urostomy, and patients requiring continued strict urine output monitoring. Multivariable logistic regression analysis was used to identify independent risk factors for urinary catheter reinsertion. Results Thirteen patients met exclusion criteria. Of the 275 patients evaluated, 60 (21.8%) required reinsertion of urinary catheter. There was no difference in the urinary tract infection rate between patients requiring reinsertion (1/60 [1.7%]) versus patients not requiring reinsertion (1/215 [0.5%], P = .389). Urethral trauma during reinsertion was seen in 1 of 60 patients (1.7%). After reinsertion, discharge with urinary catheter was required in 4 of 60 patients (6.7%). Multivariable logistic regression analysis found esophagectomy, lower body mass index, and benign prostatic hypertrophy to be independent risk factors associated with catheter reinsertion after early removal in the presence of thoracic epidural analgesia. Conclusions When applying Surgical Care Improvement Project 9 to patients undergoing thoracic procedures with thoracic epidural analgesia, consideration to delayed removal of urinary catheter may be warranted in patients with multiple risk factors for reinsertion. [ABSTRACT FROM AUTHOR]

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [ABSTRACT FROM AUTHOR]

Background Retransplantation has emerged as a therapeutic option for patients experiencing respiratory failure after single lung transplantation. However, outcomes associated with the surgical option (ipsilateral, contralateral, or bilateral lung retransplantation) has not been well evaluated. Methods The Organ Procurement and Transplantation Network database (1994 to 2012) was queried for all lung transplant procedures performed after an initial single lung transplantation. Donor and recipient demographics, before and after transplant characteristics, and outcomes were stratified by retransplant procedural choice and by interval between transplants. Risk factors for mortality were evaluated by Cox proportional hazards regression analysis. Results Of 325 prior single lung transplant recipients, 50 underwent ipsilateral, 175 contralateral, and 100 bilateral lung retransplantation. The number of retransplant procedures performed per year increased from 3 in 1994 to 31 in 2012, with an increasing proportion of contralateral retransplantation and declining proportions of ipsilateral and bilateral retransplantation. Survival was significantly better in the contralateral and bilateral retransplant groups than in the ipsilateral retransplant group at 30 days (94% and 89% versus 80%), 1 year (72% and 67% versus 50%), and 5 years (41% and 42% versus 20%). Ipsilateral retransplantation (hazard ratio 1.48; p = 0.042), mechanical ventilation before retransplant (hazard ratio 2.39; p < 0.001), and retransplantation performed in the first half of the study period (hazard ratio 1.45; p = 0.027) were associated with increased mortality. Conclusions After an initial single lung transplant, both the incidence of retransplantation and postoperative survival have increased with time. Although ipsilateral lung retransplantation may be the best available alternative in particular circumstances, this analysis suggests that contralateral or bilateral lung retransplantation may be preferable in patients for whom those options are medically sensible. [ABSTRACT FROM AUTHOR]

Background Hospital and surgeon volume each have an association with postoperative outcomes. The volume of lung cancer surgery at our Veterans Administration Medical Center (VAMC) is lower than at our academic medical center (AMC). We compared the outcomes after lobectomy at VAMC versus AMC to identify specific areas of clinical care requiring quality improvement. Methods To keep surgeon experience constant, data were derived from a prospective database from a single surgeon. Included were all male patients undergoing lobectomy for non-small cell lung cancer. Postoperative morbidity, mortality, and overall survival were compared after propensity score matching. Results From 2004 to 2013, 419 patients were evaluated (338 AMC, 81 VAMC). Outcomes comparison after propensity score matching of 81 AMC patients with 81 VAMC patients found a higher rate of major complications (12% versus 27%, p = 0.02) and longer hospital stay (median 6.0 versus 7.5 days, p < 0.001) for VAMC, but no difference in 90-day mortality (AMC 5% versus VAMC 6%, p > 0.99). Pneumonia was the specific complication found to be higher at VAMC (11% versus AMC 1.2%, p = 0.01). There was no difference in 5-year overall survival for stage I disease (AMC 68% versus VAMC 69%, p = 0.95). Conclusions Keeping surgeon experience constant, and after adjusting for patient factors, the rate of major complication after lobectomy is higher at VAMC. The difference is largely attributable to a higher rate of postoperative pneumonia at VAMC. Complications after pulmonary resection at VAMC could be reduced by implementing quality improvement initiatives aimed at reducing the rate of postoperative pneumonia. [ABSTRACT FROM AUTHOR]

How does the developing brain respond to recent experience? Repetition suppression (RS) is a robust and well-characterized response of to recent experience found, predominantly, in the perceptual cortices of the adult brain. We use functional near-infrared spectroscopy (fNIRS) to investigate how perceptual (temporal and occipital) and frontal cortices in the infant brain respond to auditory and visual stimulus repetitions (spoken words and faces). In Experiment 1, we find strong evidence of repetition suppression in the frontal cortex but only for auditory stimuli. In perceptual cortices, we find only suggestive evidence of auditory RS in the temporal cortex and no evidence of visual RS in any ROI. In Experiments 2 and 3, we replicate and extend these findings. Overall, we provide the first evidence that infant and adult brains respond differently to stimulus repetition. We suggest that the frontal lobe may support the development of RS in perceptual cortices. [ABSTRACT FROM AUTHOR]

Summary Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity. [ABSTRACT FROM AUTHOR]

Objective Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. Methods Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. Results Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (S I ). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus. Conclusions The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study. [ABSTRACT FROM AUTHOR]

A microscale combustion calorimeter (MCC) was modified to study gas phase combustion of polymers and flame-retardant plastics by adding carbon monoxide (CO) and carbon dioxide (CO 2 ) analyzers to the standard oxygen (O 2 ) analyzer. Experiments were conducted on 22 hydrocarbon, heteroatom and halogen-containing polymers of known composition over a wide range of combustion temperatures and oxygen concentrations. At high temperatures and excess oxygen when combustion was complete, the oxygen consumed (ΔO 2 ) and CO 2 produced by combustion of the pyrolysis gases were in quantitative agreement with theoretical values for all of these charring and non-charring polymers. At lower combustor temperatures, halogen-containing polymers exhibited significantly reduced fuel oxidation rates, as evidenced by a shift in maximum ΔO 2 , CO and CO 2 yields to much higher temperatures. [ABSTRACT FROM AUTHOR]

Background: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. Objective: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20% E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. Methods: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. Results: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference ±SE:0 .4 7 ± 0.14 mmol/L; P= 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (p = -0.18, P= 0.03) and positively correlated with changes in the acute insulin response to glucose (p = 0.15, P= 0.05). Conclusions: These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937. [ABSTRACT FROM AUTHOR]

Prevalence of Type 2 diabetes has increased at an alarming rate, highlighting the need to correctly predict the development of this disease in order to allow intervention and thus, slow progression of the disease and resulting metabolic derangement. There have been many recent 'advances' geared toward the detection of pre-diabetes, including genome wide association studies and metabolomics. Although these approaches generate a large amount of data with a single blood sample, studies have indicated limited success using genetic and metabolomics information alone for identification of disease risk. Clinical assessment of the disposition index (DI), based on the hyperbolic law of glucose tolerance, is a powerful predictor of Type 2 diabetes, but is not easily assessed in the clinical setting. Thus, it is evident that combining genetic or metabolomic approaches for a more simple assessment of DI may provide a useful tool to identify those at highest risk for Type 2 diabetes, allowing for intervention and prevention. [ABSTRACT FROM AUTHOR]

Time-resolved multivariate pattern analysis (MVPA), a popular technique for analyzing magneto- and electro-encephalography (M/EEG) neuroimaging data, quantifies the extent and time-course by which neural representations support the discrimination of relevant stimuli dimensions. As EEG is widely used for infant neuroimaging, time-resolved MVPA of infant EEG data is a particularly promising tool for infant cognitive neuroscience. MVPA has recently been applied to common infant imaging methods such as EEG and fNIRS. In this tutorial, we provide and describe code to implement time-resolved, within-subject MVPA with infant EEG data. An example implementation of time-resolved MVPA based on linear SVM classification is described, with accompanying code in Matlab and Python. Results from a test dataset indicated that in both infants and adults this method reliably produced above-chance accuracy for classifying stimuli images. Extensions of the classification analysis are presented including both geometric- and accuracy-based representational similarity analysis, implemented in Python. Common choices of implementation are presented and discussed. As the amount of artifact-free EEG data contributed by each participant is lower in studies of infants than in studies of children and adults, we also explore and discuss the impact of varying participant-level inclusion thresholds on resulting MVPA findings in these datasets. [ABSTRACT FROM AUTHOR]

Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B , PQBP1 , PIM2 , SLC35A2 , OTUD5 , KCND1 , and GRIPAP1 , as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3 , the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus. [Display omitted] [ABSTRACT FROM AUTHOR]

There have been few high-quality studies of the costs, preference-based health-related quality of life (HRQoL) and cost effectiveness of treatments for primary biliary cholangitis (PBC). We aimed to estimate the marginal effects of PBC complications and symptoms, accounting for treatment, on HRQoL and the annual cost of health care in the United Kingdom (UK). These are essential components for evaluation of cost effectiveness and this information will aid in evaluation of new treatments. Questionnaires were mailed to 4583 participants in the UK-PBC research cohort and data were collected on HRQoL and use of the National Health Service (NHS) in the UK from 2015 through 2016. HRQoL was measured using the EQ-5D-5L instrument. The annual cost of resource use was calculated using unit costs obtained from NHS sources. We performed econometric analyses to determine the effects of treatment, symptoms, complications, liver transplantation status, and patient characteristics on HRQoL and annual costs. In an analysis of data from 2240 participants (over 10% of all UK PBC patients), we found that PBC symptoms have a considerable effect on HRQoL. Ursodeoxycholic acid therapy was associated with significantly higher HRQoL regardless of response status. Having had a liver transplant and ascites were also independently associated with reduced HRQoL. Having had a liver transplant (US$4294) and esophageal varices (US$3401) were the factors with the two greatest mean annual costs to the NHS. Symptoms were not independently associated with cost but were associated with reduction in HRQoL for patients, indicating the lack of effective treatments for PBC symptoms. In an analysis of data from 2240 participants in the UK PBC, we found that HRQoL and cost estimates provide greater insight into the relative importance of PBC-related symptoms and complications. These findings provide estimates for health technology assessments of new treatments for PBC. [ABSTRACT FROM AUTHOR]

• Access to infants' multivariate neural representations has remained limited. • Visual stimuli decoded from 12−15-month-olds' EEG data, within 500 ms of onset. • Infant multivariate representations didn't linearly separate animal and body images. • Proof-of-concept for time-resolved multivariate pattern analysis of infant EEG. Tools from computational neuroscience have facilitated the investigation of the neural correlates of mental representations. However, access to the representational content of neural activations early in life has remained limited. We asked whether patterns of neural activity elicited by complex visual stimuli (animals, human body) could be decoded from EEG data gathered from 12−15-month-old infants and adult controls. We assessed pairwise classification accuracy at each time-point after stimulus onset, for individual infants and adults. Classification accuracies rose above chance in both groups, within 500 ms. In contrast to adults, neural representations in infants were not linearly separable across visual domains. Representations were similar within, but not across, age groups. These findings suggest a developmental reorganization of visual representations between the second year of life and adulthood and provide a promising proof-of-concept for the feasibility of decoding EEG data within-subject to assess how the infant brain dynamically represents visual objects. [ABSTRACT FROM AUTHOR]

A key goal of human neurodevelopmental research is to map neural and behavioral trajectories across both health and disease. A growing number of developmental consortia have begun to address this gap by providing open access to cross-sectional and longitudinal 'big data' repositories. However, it remains challenging to develop models that enable prediction of both within-subject and between-subject neurodevelopmental variation. Here, we present a conceptual and analytical perspective of two essential ingredients for mapping neurodevelopmental trajectories: state and trait components of variance. We focus on mapping variation across a range of neural and behavioral measurements and consider concurrent alterations of state and trait variation across development. We present a quantitative framework for combining both state- and trait-specific sources of neurobehavioral variation across development. Specifically, we argue that non-linear mixed growth models that leverage state and trait components of variance and consider environmental factors are necessary to comprehensively map brain-behavior relationships. We discuss this framework in the context of mapping language neurodevelopmental changes in early childhood, with an emphasis on measures of functional connectivity and their reliability for establishing robust neurobehavioral relationships. The ultimate goal is to statistically unravel developmental trajectories of neurobehavioral relationships that involve a combination of individual differences and age-related changes. [ABSTRACT FROM AUTHOR]

Around former glass factories in south eastern Sweden, there are dozens of dumps whose radioactivity and physico-chemical properties were not investigated previously. Thus, radiometric and physico-chemical characteristics of waste at Madesjö glass dump were studied to evaluate pre-recycling storage requirements and potential radiological and environmental risks. The material was sieved, hand-sorted, leached and scanned with X-Ray Fluorescence (XRF). External dose rates and activity concentrations of Naturally Occurring Radioactive Materials from 238U, 232Th series and 40K were also measured coupled with a radiological risk assessment. Results showed that the waste was 95% glass and dominated by fine fractions (<11.3 mm) at 43.6%. The fine fraction had pH 7.8, 2.6% moisture content, 123 mg kg−1 Total Dissolved Solids, 37.2 mg kg−1 Dissolved Organic Carbon and 10.5 mg kg−1 fluorides. Compared with Swedish EPA guidelines, the elements As, Cd, Pb and Zn were in hazardous concentrations while Pb leached more than the limits for inert and non-hazardous wastes. With 40K activity concentration up to 3000 Bq kg−1, enhanced external dose rates of 40K were established (0.20 μSv h−1) although no radiological risk was found since both External Hazard Index (H ex) and Gamma Index (I γ) were <1. The glass dump needs remediation and storage of the waste materials under a safe hazardous waste class 'Bank Account' storage cell as a secondary resource for potential future recycling. • Radiometric and physico-chemical characteristics of glass waste were investigated. • As, Cd, Pb and Zn were in hazardous concentrations according to Swedish EPA limits. • Pb leached more than limits for inert and non-hazardous waste unlike As, Cd and Zn. • External dose rates and gamma measurements showed enhanced levels of 40K. • External Hazard index and Gamma Index indicated no radiological exposure risks. [ABSTRACT FROM AUTHOR]

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. • MYC induces SREBP1, thereby regulating fatty acid synthesis and lipogenesis • Induction of MYC expression upregulates lipogenesis genes across MYC cancers • Mass spectrometry imaging shows common lipid changes across different MYC cancers • Inhibition of lipogenesis reverts MYC tumors in both xenograft and mouse models Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition. [ABSTRACT FROM AUTHOR]

So far, Streptococcus devriesei , which belongs to the mutans streptococci group, has been incriminated in the formation of caries in Equidae . We report the first human infection due to this species in a 54-year-old man with gangrenous cholecystitis. The patient was treated successfully by cholecystectomy and ceftriaxone. [ABSTRACT FROM AUTHOR]

Antagonists of tumor necrosis factor (TNF) are effective for induction and maintenance of remission of Crohn's disease (CD) and are generally prescribed when patients do not respond to conventional, less-costly medical therapies. Early initiation of anti-TNF therapy reduced rates of surgery and dose escalation due to loss of response. However, these drugs are expensive, so studies are needed on the cost effectiveness of early initiation. We aimed to determine the cost effectiveness of initiating treatment early in the disease course (within 2 years of CD diagnosis) vs later in the disease course (more than 2 years after diagnosis). We constructed a Markov model of a hypothetical cohort of patients with CD in Canada to simulate disease progression after initiation of infliximab or adalimumab therapy. We used published loss-of-response rates to compare the lifetime cost effectiveness of early vs late initiation of anti-TNF therapies. Transition probabilities and utilities were obtained through a literature search, and costs were obtained from the Alberta Ministry of Health. Sensitivity analysis was used to characterize uncertainty. Early initiation of infliximab yielded an additional 0.72 quality-adjusted life-years (QALYs) and saved $50,418 compared with late initiation. Early initiation of adalimumab yielded an additional 0.54 QALYs and saved $43,969. At a willingness-to-pay threshold of $50,000, early initiations of infliximab or adalimumab therapy had a 74% chance of being cost effective compared with late initiation. In a Markov model analysis, we found initiation of either infliximab or adalimumab within 2 years of CD diagnosis to provide significant cost savings and QALYs compared with later initiation (more than 2 years after diagnosis). [ABSTRACT FROM AUTHOR]

Recent work provides evidence that the infant brain is able to make top-down predictions, but this has been explored only in limited contexts and domains. We build upon this evidence of predictive processing in infants using a new paradigm to examine auditory repetition suppression (RS). RS is a well-documented neural phenomenon in which repeated presentations of the same stimulus result in reduced neural activation compared to non-repeating stimuli. Many theories explain RS using bottom-up mechanisms, but recent work has posited that top-down expectation and predictive coding may bias, or even explain, RS. Here, we investigate whether RS in the infant brain is similarly sensitive to top-down mechanisms. We use fNIRS to measure infants' neural response in two experimental conditions, one in which variability in stimulus presentation is expected (occurs 75% of the time) and a control condition where variability and repetition are equally likely (50% of the time). We show that 6-month-old infants exhibit attenuated frontal lobe response to blocks of variable auditory stimuli during contexts when variability is expected as compared to the control condition. These findings suggest that young infants' neural responses are modulated by predictions gained from experience and not simply by bottom-up mechanisms. [ABSTRACT FROM AUTHOR]

Little is known about the prevalence or treatment of pruritus associated with primary biliary cholangitis (PBC). We analyzed data from patients with PBC recruited from all clinical centers in the United Kingdom (UK) to characterize the prevalence, severity, progression, and treatment of pruritus. We performed cross-sectional and longitudinal studies of patients in the UK-PBC cohort to assess trajectories of pruritus. Data on pruritus frequency, severity, and therapy were collected via paper questionnaires completed by 2194 patients at their initial assessment in 2011 and then again in 2014 and 2017. Self-reported treatment data were validated against the prescription record of PBC cohort in the Clinical Practice Research Datalink, a primary care database. We defined persistent pruritus as itch that occurs frequently or all the time and severe pruritus as PBC-40 pruritus domain scores of 12 or more, throughout their disease course. Latent class mixed models were used to study pruritus trajectories and identify factors associated with high pruritus. At initial assessment, 1613 (73.5%) patients had experienced pruritus at some point since their development of PBC—persistent pruritus was reported by 34.5% of the patients and severe pruritus by 11.7%. Only 37.4% of patients with persistent pruritus and 50% with severe pruritus reported ever receiving cholestyramine. Frequencies of rifampicin use were 11% in patients with persistent pruritus and 23% in patients with severe pruritus. Comparison of 2011 and 2014 surveys (comprising 1423 patients) showed consistent self-reported data on pruritus. Proportions of patients in the UK-PBC cohort treated with cholestyramine or naltrexone (37.4% and 4.4%) did not differ significantly from proportions treated in the Clinical Practice Research Datalink cohort (30.4% and 4.4%) (P =.07 for cholestyramine and P =.32 for naltrexone). Latent class mixed models (n = 1753) identified 3 different groups of pruritus. Multivariable analysis identified younger age at diagnosis and higher level of alkaline phosphatase at 12 months after diagnosis as factors significantly associated with persistent high pruritus. In a large national cohort study of patients with PBC, we found a high prevalence of pruritus and inadequate guideline-recommended therapy. Patient-reported data used to determine pruritus prevalence and treatment are reliable. Younger age and levels of higher alkaline phosphatase were associated with persistent pruritus. We need to increase awareness and management of pruritus in PBC in the UK. [ABSTRACT FROM AUTHOR]

Background & Aims Endpoints in randomized controlled trials (RCTs) of Crohn’s disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. Methods We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. Results Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts’ Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. Conclusions In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD. [ABSTRACT FROM AUTHOR]

Background & Aims Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled randomized controlled trials of patients with UC. Methods We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo-controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication. Results We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite-clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient-reported efficacy and quality-of-life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%). Conclusion In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials. [ABSTRACT FROM AUTHOR]

There are many methods for long head of the biceps tendon (LHBT) tenodesis, but a consensus on a superior method has yet to be met. In this article, we introduce a method for arthroscopic suprapectoral biceps tenodesis using a tenodesis screw in the bicipital tunnel. The intra-articular portion of the biceps tendon is transected. The subdeltoid space is then viewed via a lateral portal, and the tendon is mobilized from the bicipital tunnel. The tendon is retrieved through the anterior portal, and 5 whipstitch passes and a second distal stitch are placed. Three of the suture tails are passed through the tenodesis screwdriver, and the tendon is maneuvered to the previously reamed bone socket located 1.5 cm superior to the pec tendon, just inferior to the bicipital groove. Once the tenodesis screw is fixated in sufficient bone stock, 5 alternating half hitches reinforce the construct by creating a closed loop through the screw. This described technique allows full visualization of the LHBT dissection and tenodesis throughout the procedure. Additionally, this technique provides a method to incorporate whipstitching with an arthroscopic tenodesis screw to provide additional strength to tendon fixation. [ABSTRACT FROM AUTHOR]

Arthroscopic repair of an isolated subscapularis tendon rupture has been previously described in the adult population; however, the technique has yet to be described in a pediatric patient. In this Technical Note, we describe an arthroscopic repair of an isolated subscapularis tendon rupture with concomitant mini-open suprapectoral biceps tenodesis in an adolescent patient. Standard anterior and posterior portals are established with an accessory portal in the anterosuperior angle of the acromion. A 0-PDS suture is used to pass strands of suture tape through the inferolateral and superolateral aspects of the subscapularis tendon. Suture tape is passed through a suture anchor and the accessory portal and is fixated at the junction of the inferior one-third and superior two-thirds of the subscapularis tendon footprint and at the junction of the superior one-third and inferior two-thirds of the subscapularis tendon footprint. Following subscapularis tendon fixation, biceps tenodesis is performed through either a mini-open subpectoral or arthroscopic suprapectoral approach. This described technique allows for full visualization of the subscapularis tendon and lesser tuberosity. Additionally, this technique allows for accurate placement of suture anchors to maximize footprint coverage and appropriate graft tensioning. [ABSTRACT FROM AUTHOR]