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Yu-Wen Chiu,1 Yu-Hsiang Kao,1 Michael J Simoff,2 David E Ost,3 Oliver Wagner,4 James Lavin,4 Richard A Culbertson,1 Dean G Smith1 1Health Policy & Systems Management, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; 2Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, Michigan, USA; 3Department of Pulmonology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Intuitive Surgical, Sunnyvale, California, USACorrespondence: Dean G SmithLSU Health Sciences Center – New Orleans, School of Public Health, 2020 Gravier St., New Orleans, LA, 70112, USAEmail dgsmith@lsuhsc.eduPurpose: To describe the distribution of diagnostic procedures, rates of complications, and total cost of biopsies for patients with lung cancer.Patients and Methods: Observational study using data from IBM Marketscan® Databases for continuously insured adult patients with a primary lung cancer diagnosis and treatment between July 2013 and June 2017. Costs of lung cancer diagnosis covered 6 months prior to index biopsy through treatment. Costs of chest CT scans, biopsy, and post-procedural complications were estimated from total payments. Costs of biopsies incidental to inpatient admissions were estimated by comparable outpatient biopsies.Results: The database included 22,870 patients who had a total of 37,160 biopsies, of which 16,009 (43.1%) were percutaneous, 14,997 (40.4%) bronchoscopic, 4072 (11.0%) surgical and 2082 (5.6%) mediastinoscopic. Multiple biopsies were performed on 41.9% of patients. The most common complications among patients receiving only one type of biopsy were pneumothorax (1304 patients, 8.4%), bleeding (744 patients, 4.8%) and intubation (400 patients, 2.6%). However, most complications did not require interventions that would add to costs. Median total costs were highest for inpatient surgical biopsies ($29,988) and lowest for outpatient percutaneous biopsies ($1028). Repeat biopsies of the same type increased costs by 40– 80%. Complications account for 13% of total costs.Conclusion: Costs of biopsies to confirm lung cancer diagnosis vary substantially by type of biopsy and setting. Multiple biopsies, inpatient procedures and complications result in higher costs.Keywords: cancer, diagnosis, economics, frequency

Funder: GlaxoSmithKline; Id: http://dx.doi.org/10.13039/100004330, Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract‐based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group‐by‐age interaction effect was found showing greater reductions with age in the alcohol‐dependent group within corpus callosum, overlapping with the group difference. We found no evidence of recovery with abstinence. A comparison of alcohol‐only‐ and alcohol‐polydrug‐dependent groups found no differences in FA. Overall, our findings show that AD is associated with lower FA and suggest that these alterations are primarily driven by lifetime alcohol consumption and cigarette smoking, showing no relationship with exposure to other substances such as cocaine, opiates or cannabis. Reductions in FA across the adult lifespan are more pronounced in AD and offer further support for the notion of accelerated ageing in relation to alcohol dependence. These findings highlight there may be lasting structural differences in white matter in alcohol dependence, despite continued abstinence.

Escherichia coli is a very versatile species for which diversity has been explored from various perspectives highlighting, for example, phylogenetic groupings, pathovars as well as a wide range of O serotypes. The highly variable O-antigen, the most external part of the lipopolysaccharide component of the outer membrane of E. coli, is linked to the innermost lipid A through the core region of LPS of which 5 different structures, denominated K-12, R1, R2, R3 and R4, have been characterized so far. The aim of the present study was to analyze the prevalence of these LPS core types in the E. coli species and explore their distribution in the different E. coli phylogenetic groups and in relationship with the virulence gene repertoire. Results indicated an uneven distribution of core types between the different phylogroups, with phylogroup A strains being the most diverse in terms of LPS core types while phylogroups B1, D and E strains were dominated by the R3 type and phylogroups B2 and C strains being dominated by the R1 type. Strains carrying the LEE virulence operon were mostly of the R3 type whatever the phylogroup while, within phylogroup B2, strains carrying a K-12 core all belonged to the complex STc131, one of the major clone of extra-intestinal pathogenic E. coli (ExPEC) strains. The origin of this uneven distribution is discussed but remains to be explained, as well as the consequences of carrying a specific core type on the physiology of the bacteria.IMPACT STATEMENTThe diversity of the E. coli species in terms of type of infections is well known, and its surface O-antigen which shows some correspondence to pathogenicity. This study is the first one to report in detail the diversity and distribution of the LPS core types in the E. coli species using whole genome sequences. This distribution of the 5 know core types is analyzed in the different phylogroups along with their association with specific virulence gene repertoire. Results indicate a non-random distribution of LPS core types in the E. coli species and, most interestingly, preferential association of certain core types with either some phylogenetic clades or with particular virulence gene repertoires. This work is a first step towards the identification of the origin of this diversity as well as towards the exploration of the physiological properties associated with specific core types.DATA SUMMARYComplete list of strains with associated data is available in supplementary table S1.

© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey-matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed-based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala-SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala-SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala-SN/VTA RSFC and accelerated age-related grey-matter atrophy through potentially distinct mechanisms.

Introduction: Evidence suggests that abnormalities in reward processing and increased impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised. This study used fMRI to investigate the BOLD response during reward and inhibitory control tasks and how such responses were associated with subjective and behavioural measures of impulsivity in abstinent alcohol, cocaine and polydrug addiction. We hypothesized a negative correlation between non-drug related reward anticipation and impulsivity measures in polydrug and alcohol dependence compared with healthy controls owing to increased impulsivity and thus more inhibitory control effort needed to maintain successful abstinence. Methods: Abstinent alcohol dependent (AD, n=27), polydrug dependent (PD, n=57) and healthy control (HC, n=65) participants were recruited [1] (REC number 11/H0707/9). Participants completed a battery of impulsivity measures; the Barratt Impulsiveness Scale (BIS-11) and the Urgency, Premeditation, (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPS-P) to measure trait impulsivity, the Kirby Delay Discounting task to measure choice impulsivity and the Stop Signal Task (SST) to measure impulsive action. Participants also underwent fMRI scanning (3-T) using the monetary incentive delay (MID) and Go/No-go (GNG) tasks. An a-priori region of interest approach was used to image BOLD response during the following contrasts: reward anticipation>neutral anticipation and no-go/go in the rIFG, OFC and caudate. Data was analysed using ANOVA or Kruskal- Wallis tests (with Tukey or Mann-Whitney U post-hoc tests respectively) and Pearson's or Spearman's rank correlations, as appropriate. Holm-Bonferroni correction was applied. Results: There were significant group differences in the BIS-11 (pneutral anticipation and no-go>go contrasts. In the overall population, significant but weak positive correlations were observed between BOLD response for the reward anticipation>neutral anticipation and no-go>go contrast in the rIFG (r=0.208, p=0.001), OFC (r=0.219, p=0.008) and caudate (r=0.208, p=0.012). Interestingly, while these associations were observed in the HC group no such associations existed in the AD and PD groups. Finally, no significant associations were observed between subjective impulsivity measures and BOLD signal change during either task. Conclusion: The overall findings of this study suggest that there is a relationship between BOLD response during reward processing and inhibitory control. However, in contrast to our hypothesis this association was positive and was not observed in AD or PD individuals, suggesting that such an association is dysregulated in addiction. Further work is required to better understand the association between BOLD response during reward processing and impulse control. This study was funded by the MRC (G1000018) with support from GSK.

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone ($\textit{n}$=18, alcohol) and in combination with cocaine and/or opioid dependence ($\textit{n}$=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence ($\textit{n}$=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

The usefulness of measuring plasma digoxin concentrations in the diagnosis of digoxin toxicity has been assessed in 83 in-patients. The mean plasma digoxin concentration in clinically toxic patients was significantly higher than the mean concentration in non-toxic patients. The overlap between the groups, however, was extensive and could partly be accounted for by hypokalaemia in those toxic patients whose plasma digoxin concentration was less than 3 ng/ml. There was, in addition, a higher incidence of hyperkalaemia, without obvious cause, in toxic patients than in non-toxic patients. Consideration of the incidence of various non-cardiac factors, specifically plasma potassium concentration greater than 5.0 mmol/l, plasma creatinine concentration greater than 150 mumol/l, daily maintenance dose greater than 6 microgram/kg, and age greater than 60 years, led to the development of guidelines to aid in the diagnosis of digoxin toxicity. Patients with plasma digoxin concentration greater than 3 ng/ml or with hypokalaemia should be considered probably toxic and those with plasma digoxin concentration greater than or equal to 3 ng/ml in the absence of hypokalaemia should only be considered toxic if they have at least two of the non-cardiac factors outlined above. Plasma digoxin concentrations could not be predicted with more than 31 per cent certainty by considering the magnitude of those non-cardiac factors.

© 2014, Japan Monkey Centre and Springer Japan. The California National Primate Research Center maintains a small colony of titi monkeys (Callicebus cupreus) for behavioral studies. While short tandem repeat (STR) markers are critical for the genetic management of the center’s rhesus macaque (Macaca mulatta) breeding colony, STRs are not used for this purpose in the maintenance of the center’s titi monkey colony. Consequently, the genetic structure of this titi monkey population has not been characterized. A lack of highly informative genetic markers in titi monkeys has also resulted in scant knowledge of the species’ genetic variation in the wild. The purpose of this study was to develop a panel of highly polymorphic titi monkey STRs using a cross-species polymerase chain reaction (PCR) amplification protocol that could be used for the genetic management of the titi monkey colony. We screened 16 STR primer pairs and selected those that generated robust and reproducible polymorphic amplicons. Loci that were found to be highly polymorphic, very likely to be useful for parentage verification, pedigree assessment, and studying titi monkey population genetics, were validated using Hardy–Weinberg equilibrium and linkage disequilibrium analyses. The genetic data generated in this study were also used to assess directly the impact on the colony’s genetic diversity of a recent adenovirus outbreak. While the adenovirus epizootic disease caused significant mortality (19 deaths among the 65 colony animals), our results suggest that the disease exhibited little or no influence on the overall genetic diversity of the colony.

Genetic differences between Indian and Chinese rhesus macaques contribute to the phenotypic variance of clinical trials, including experimental infection with SIVmac. The completion of the rhesus genome has facilitated the discovery of several thousand markers. Although the marker density necessary for whole genome association mapping of phenotypes has not yet been achieved, a SNP map will help researchers investigate variation in candidate genes. We developed a genome-wide SNP map for rhesus macaques containing 3,869 validated markers with an average distance of 0.88 megabases. We used the program VarLD to identify genomic areas with significant differences in linkage disequilibrium (LD) between Indian-derived and Chinese rhesus macaques, assuming that these areas provide the greatest potential for differential selection in these regional populations. These genomic areas provide entry to more detailed study of gene function. This method is also applicable to the study of differences in biomarkers between regional populations of other species.

Nine patients with rigid equinocavovarus contractures of the foot and ankle after ischemic episodes of the leg were treated from 1986 to 1989. The ischemic contractures occurred after tibial and fibular fractures in six cases, and after a trimalleolar ankle fracture, an electrical burn, and cardiac bypass surgery in one case each. Previous tendon and nerve releases had failed. The scarred portion of the various involved muscles of the deep posterior compartment were widely excised along with the respective tendons. A variety of additional foot procedures were generally necessary to obtain a plantigrade foot. Night splinting to maintain a plantigrade foot was prescribed for all patients.

Serotonin (5-hydroxytryptamine; 5-HT) is a signalling molecule within the central nervous system. Overall, the impression gained from biochemical, pharmacological, and neuroendocrine studies is that 5-HT synthesis or function is reduced in the brains of depressed patients. There is more direct evidence from animal studies and indirect evidence in man that drugs (and electroconvulsive therapy--ECT) which are efficacious in various facets of affective disorders have clear effects on 5-HT function. 5-HT function is complex. There are at least seven different 5-HT receptor subtypes, several anatomically different 5-HT neuronal tracts emanating from the raphe nuclei in the pons/medulla and projecting widely throughout the brain and downwards into the spinal cord. There are fine mechanisms controlling almost every aspect of function in the 5-HT neurone and the action of 5-HT released from it. There is ample scope for 5-HT to influence many areas of the brain involved in psychological, cognitive, sensory, autonomic, neuroendocrine, and emotional function. Inhibition of reuptake by drugs selective for 5-HT, such as paroxetine, has important acute and chronic effects on 5-HT systems and function, and upon other neurotransmitter systems with which 5-HT interacts. It is of great interest that selective and non-selective monoamine uptake blocking agents, monoamine oxidase inhibitors, lithium and ECT, all affect 5-HT function, albeit slightly differently, and that they should be efficacious in various aspects of affective illness.

As in all walks of life, clinical academic medicine has many vested interests, some acting for the greater good, some not. Socrates has a penchant for sniffing out pretension and sectional interest. Hippocrates is a thoughtful, gentlemanly physician unaccustomed to ensnarement by Socratic wiles, and when he and Socrates meet one day in the marketplace in Athens the following conversation about the state of clinical academic medicine ensues. It is not a dialogue for the timid. SOCRATES : Hippocrates, you are looking rather down in the mouth. What's up? HIPPOCRATES : I am having a sabbatical from my clinical labours to spend time thinking about medical academic and scientific matters. SOCRATES : How interesting. I had always thought of you as a proper doctor, not an academic one. HIPPOCRATES : Sometimes, Socrates, you can be so wounding. How can I explain to you the difference between an everyday hardworking physician in service and one who, while active in clinical work, also has an obligation to teach and by original research to forward his subject? SOCRATES : Are not research and practice compatible? HIPPOCRATES : To some extent they are. Indeed, those who are not labelled “clinical academics,” if they are enthusiastic clinicians with a love of order, can and do study their patients and make important and useful contributions to practice. SOCRATES : How does that differ from the sort of research you do? HIPPOCRATES : I have always been interested in the molecular causes of disease. SOCRATES : What use is that? HIPPOCRATES : Without such understanding, there can be no rational progress towards treatments and cures as yet undiscovered. SOCRATES : Do you use the word molecular in the same way as the disciples of Watson and Crick? HIPPOCRATES : Not entirely. Although their special science of molecular …

The evidence indicating a specific abnormality of brain 5-HT function in depressed patients is reviewed. Biochemical studies have indicated that low plasma levels of tryptophan are unlikely to be the primary 'cause' of depression or of abnormal brain 5-HT function in depression. However, there may be a reduction of 5-HT synthesis or function in the brains of depressed patients and the uptake of 5-HT into platelets from depressed patients is consistently reduced. Neuroendocrine studies have suggested that various groups of depressed patients may exhibit different types of abnormal 5-HT-mediated responses. It is important to distinguish between the acute and chronic pharmacological effects of antidepressant treatment, which may account for the latency seen between onset of therapy and full clinical effect. Clinical studies have provided further evidence that 5-HT is implicated in the causation and treatment of depression, as both 5-HT precursors and selective inhibitors of 5-HT uptake are effective in the treatment of depression. Furthermore, inhibition of 5-HT synthesis can block the effect of antidepressant compounds. It is concluded that 5-HT function is decreased during depression, and that this carries important implications for the pharmacology of antidepressant drugs.

Investigation has been made into the processes regulating the function activity of rat brain 5-hydroxytryptamine (5-HT) and the way that drugs used to treat depression act on these processes. Use was made of both biochemical measurements and a behavioural model in which the hyperactivity which follows increased 5-HT synthesis and release was measured as an index of functional activity of the amine. The following mechanisms are suggested to be important in the control of 5-HT function. Presynaptic mechanisms; precursor availability and the transport of tryptophan across the neuronal membrane, intraneuronal metabolism by monoamine oxidase, compartmentation, release and re-uptake. Postsynaptic mechanisms; the sensitivity of the post-synaptic receptor, the role of peptides in altering the size of the post-synaptic response and the action of other neurotransmitters controlling the magnitude of the postsynaptic response. In this regard 5-HT function has been shown to be altered by both dopamine and GABA. The action of anti-depressant drugs on these mechanisms is discussed.

The relationship between plasma catecholamines and injury severity was investigated in order to determine: a) whether a correlation existed between the severity of injury as assessed by the Injury Severity Score (ISS), and circulating noradrenaline and adrenaline; and b) whether such measurements were of prognostic value. It was found that in the immediate postinjury period, both noradrenaline and adrenaline correlated positively with ISS over the range of injury studied (ISS = 0-54; r = 0.67, p less than 0.01). It appeared that part of the response might be attributed to psychological rather than physical factors; at lower levels of injury (ISS less than 9) these psychological factors were possibly responsible for the whole of the observed effect. In the subsequent recovery period (greater than 24 hr postinjury) no clear relationship between plasma catecholamines and injury severity was maintained. Studies on patients who died as a consequence of their injuries failed to confirm the previously suggested prognostic value of plasma catecholamine determinations in this later postinjury period. However, plasma noradrenaline levels in this group were significantly higher on admission than in the casualties who survived serious injury (p less than 0.05). It is concluded that plasma catecholamine concentrations, in combination with other indices of injury severity, may provide useful information on the response to injury in man, and aid in the assessment of its overall severity in physiologic terms. Language: en

Publisher Summary The enzyme tryptophan-5-hydroxylase is present in brain and several groups have been reported to be present in a crude mitochondrial fraction. Depending upon the mode of homogenization and the concentration of the original homogenate, about 40–50% of the tryptophan-5-hydroxylase activity can be obtained from the crude mitochondrial fraction. Equilibrium centrifugation of the crude mitochondrial fraction on a discontinuous sucrose gradient reveals that the tryptophan-5-hydroxylase activity is highest in the synaptosome fraction and lowest in the mitochondrial fraction. Therefore, it appears that the synaptosome contains tryptophan-5-hydroxylase, and the activity seen in the high speed supernatant fraction reflects the activity originally present in the cytoplasm of the nerve cell body where 5-HT is detected in low concentrations by fluorescence microscopy. The inhibitory effect of phenylalanine upon 5-HTP production from tryptophan in an isoosmotic homogenate of rabbit hindbrain is illustrated with a graph in this chapter. The chapter establishes that tryptophan is taken up by the synaptosome component of crude mitochondrial fractions. It then investigates the effect of phenylalanine upon this uptake. The physiological importance of tryptophan transport across the nerve cell membrane as a factor controlling the substrate concentration for tryptophan-5-hydroxylase is yet to be determined.

How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we find that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (KYA), and after no more than 8,000-year isolation period in Beringia. Following their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 KYA, one that is now dispersed across North and South America and the other is restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative ‘Paleoamerican’ relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.