[Using cancer case identification algorithms in medico-administrative databases: Literature review and first results from the REDSIAM Tumors group based on breast, colon, and lung cancer]. / Recherche d'algorithmes d'identification des cancers dans les bases médico-administratives : premiers résultats des travaux du groupe REDSIAM Tumeurs sur les cancers du sein, du côlon-rectum et du poumon.

BACKGROUND: The development and use of healthcare databases accentuates the need for dedicated tools, including validated selection algorithms of cancer diseased patients. As part of the development of the French National Health Insurance System data network REDSIAM, the tumor taskforce established an inventory of national and internal published algorithms in the field of cancer. This work aims to facilitate the choice of a best-suited algorithm. METHOD: A non-systematic literature search was conducted for various cancers. Results are presented for lung, breast, colon, and rectum. Medline, Scopus, the French Database in Public Health, Google Scholar, and the summaries of the main French journals in oncology and public health were searched for publications until August 2016. An extraction grid adapted to oncology was constructed and used for the extraction process. RESULTS: A total of 18 publications were selected for lung cancer, 18 for breast cancer, and 12 for colorectal cancer. Validation studies of algorithms are scarce. When information is available, the performance and choice of an algorithm are dependent on the context, purpose, and location of the planned study. Accounting for cancer disease specificity, the proposed extraction chart is more detailed than the generic chart developed for other REDSIAM taskforces, but remains easily usable in practice. CONCLUSIONS: This study illustrates the complexity of cancer detection through sole reliance on healthcare databases and the lack of validated algorithms specifically designed for this purpose. Studies that standardize and facilitate validation of these algorithms should be developed and promoted.

The double burden of severe mental illness and cancer: a population-based study on colorectal cancer care pathways from screening to end-of-life care.

AIMS: Cancer is one of the main causes of death in persons with severe mental illness (SMI). Although their cancer incidence is similar, or sometimes even potentially lower compared to the general population, their cancer mortality remains higher. The role of healthcare provision and care equity in this mortality is increasingly being addressed in research, but available studies are limited in their scope. In this context, our aim was to compare colorectal cancer (CRC) care pathways from screening to end-of-life care in patients with and without pre-existing SMI on a national scale. METHODS: This research leverages real-world data from the French national health claims database, covering the entire population, to assess cancer screening, diagnosis, treatment and post-treatment follow-up as well as quality of care (QOC) pathways among patients with incident CRC in 2015-2018, considering whether they had pre-existing SMI. We matched patients with SMI with three patients without - on age, sex, region of residence, year of cancer incidence and cancer type and location at presentation - as well as nationally established quality of CRC care indicators and regression models adjusting for relevant socio-economic, clinical and care provider-related covariates. RESULTS: Among patients with incident CRC, 1,532 individuals with pre-existing SMI were matched with individuals without SMI. After adjusting for covariates, both colon and rectal cancer patients with SMI were less likely to participate in the national CRC screening programme and to receive advanced diagnostic examinations (e.g., colonoscopies and several complementary diagnostic examinations). They also had lower odds of receiving combined treatments (e.g., neoadjuvant chemotherapy, radiotherapy and excision) and of having access to targeted therapy or capecitabine but higher odds for invasive care (e.g., stoma). Colon cancer patients with SMI were also more likely to have no treatment at all, and rectal cancer patients with SMI were less likely to receive post-treatment follow-up. Suboptimal QOC was observed for both groups of patients, but to a higher extent for patients with SMI, with statistically significant differences for indicators focusing on diagnosis and post-treatment follow-up. CONCLUSIONS: Our findings reveal discrepancies across the care continuum of CRC between individuals with and without SMI and provide initial avenues on where to focus future efforts to address them, notably at the entry and exit stages of cancer care pathways, while calling for further research on the mechanisms preventing equity of physical healthcare for individuals with SMI.

COVID-19: The forgotten cases of hidden exiles.

PURPOSE OF THE RESEARCH: We describe two interventions to screen for SARS-CoV-2 in two squats of exiled persons in France following the diagnosis of symptomatic COVID-19 cases. PRINCIPAL RESULTS: In squat A, 50 (25%) persons were screened; 19 were found positive, and three accepted a transfer. In squat B, 65 (54%) persons were screened at three different times, and only two were found positive. MAJOR CONCLUSIONS: Discrepant outcomes may reflect different levels of sanitation, prevention, and acceptance of interventions. Refusal to be transferred to specific COVID-19 homes if tested positive underscores the importance of local sanitary solutions for all. Cross-curricular strategies addressed to exiled persons are essential means of providing medical and public health solutions designed to deter COVID-19 outbreaks in these populations.

A common promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and fat mass in obese girls.

Mutations in the leptin gene lead to rare obese syndromes of Mendelian inheritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity. These obese patients tend to have an elevation of serum leptin proportional to their adiposity but with a rather wide dispersion of leptin levels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohorts of obese girls, shows that a frequent promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and body fatness. Girls of comparable adiposity have different circulating leptin levels, depending on their genotype at this locus. Girls with the -/- Lep -2,549 genotype have 25% lower mean leptin levels than the girls with other genotypes, as reflected by differences in the regression slopes of leptin-to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circulating leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic association with an individual single-nucleotide polymorphism is not sufficient to assign function to this particular nucleotide site.

Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients.

BACKGROUND: The long-term impact of hepatitis C virus (HCV) infection in renal transplant recipients remains controversial. We report here our experience, in a homogeneous single center, of 499 patients with a fairly long follow-up. METHODS: We retrospectively studied 499 hepatitis B virus-negative patients who received an initial cadaver donor kidney transplantation at Necker Hospital between January 1, 1979 and December 31, 1994, with a graft or patient survival of at least 6 months. Anti-HCV antibodies were detected at time of transplantation in 112 patients (22%). Patient survival and causes of death were compared among anti-HCV-positive and -negative patients RESULTS: Our results clearly indicate that first cadaver kidney transplant recipients with anti-HCV antibodies had a significantly shorter patient and graft long-term survival than recipients without anti-HCV antibodies (P<0.01 and P<0.0001 respectively). Mean follow-up time after transplantation was 79+/-2 months in the former group and 81+/-5 months in the latter (NS). Increased mortality was primarily caused by liver disease (P<0.001) and sepsis (P<0.01). In a multivariate analysis, HCV infection significantly affected the mortality rate (odds ratio: 2.8). CONCLUSIONS: These results suggest that HCV infection has a harmful long-term impact on the survival of kidney transplant recipients.

Cancers in relatives of children with non-Hodgkin's lymphoma.

We undertook a family study of children treated at the Institute Gustave-Roussy in France to investigate a familial aggregation of cancer in the families of children with non-Hodgkin's lymphoma (NHL). We obtained family dat for 284 children with NHL. Using the Standardized Incidence Ratio, we compared the observed and expected number of families with at least one proband relative affected by cancer at a young age (before 46 years). We found a small but non-significant excess of all tumors in first-degree relatives (SIR = 1.3, 95% CI = 0.7-2.3) explained by a small but non-significant excess of hematological malignancies (SIR = 1.5, 95% CI = 0.2-5.5), particularly Hodgkin's disease and leukemia, and of osteosarcoma (SIR = 7.5, 95% CI = 0.1-41.4). This is probably a lower bound of the SIR, because the expected number of families was estimated from cancer incidence in France between 1978 and 1982, whereas most cancers occurred before this period. Other tumors were not in excess in first-degree relatives.

Extracellular serotonin is enhanced in the striatum, but not in the dorsal hippocampus or prefrontal cortex, in rats subjected to an operant conflict procedure.

In rats trained in an operant fixed-interval-30-s schedule of food reward (FI-30s), acute exposure to contingent footshock resulted in a response suppression that was released by diazepam (DZP; 4 mg/kg ip) but not by buspirone (0.25 or 0.50 mg/kg ip). Compared with baseline, hippocampal and cortical extracellular levels of serotonin (5-HText) did not change, regardless of operant period (punished or nonpunished) and drug. In contrast, in the striatum, an increase of 5-HText levels (535%) occurred during the punished period, counteracted by DZP. This effect was observed only in rats that were low responders during both nonpunished and punished periods, that is, those that exerted an efficacious control over responding. Uncontrollable shocks or exposure to an unfamiliar open field did not modify striatal 5-HText. Together, these results suggest that an acute activation of 5-HT neurons afferent to the striatum allows the rats to efficiently block responses that are negatively reinforced.

Benzodiazepines reduce the tolerance to reward delay in rats.

This study investigated whether benzodiazepines reduce the capacity of animals to wait for food reward. Rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate, but small (two pellets) vs delayed, but large (eight pellets). The rats learned within ten sessions to select (80-100%) the arm leading to the largest reward. Separate groups of rats were then confined for 15, 30 or 60 s in the arm associated with the largest reward before gaining access to the spacially contiguous goal-box. The choice of the other arm was not followed by a period of waiting. Under these conditions, the frequency with which the small-reward arm was chosen increased linearly as a function of the duration of the waiting period. Diazepam (2-4 mg/kg IP) dose-dependently increased the number of times the small-reward arm was chosen during the sessions for which the waiting period was fixed at 15 or 30 s. Nitrazepam (2 mg/kg IP), chlordiazepoxide (16 mg/kg IP) and clobazam (16 mg/kg IP) had similar effects. The action of diazepam was counteracted by simultaneous administration of flumazepil (Ro 15-1788, 8 mg/kg PO). In the absence of confinement, these benzodiazepines, diazepam (4 mg/kg) excepted, did not modify selection of the large-reward arm. Conversely, the serotonin uptake blockers indalpine (2-4 mg/kg IP) and zimelidine (8-16 mg/kg IP) dose-dependently increased preference for the arm leading to the delayed (25 s) but large reward. These results suggest that benzodiazepines, perhaps by increasing impulsivity, render the animals less prone than controls to tolerate delayed access to reward.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin and tolerance to delay of reward in rats.

RATIONALE: Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes. OBJECTIVE: The present study further examined the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer. METHODS: Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65-70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s. RESULTS: In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABA(A) receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1-2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4-8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT(1A) receptor agonist, 8-OH-DPAT (0.015-0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1-4 mg/kg IP), ipsapirone (0.5-1 mg/kg IP) and MDL 73005EF (1-2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg). CONCLUSIONS: These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT(1A) receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.

Extracellular dopamine in the rat prefrontal cortex during reward-, punishment- and novelty-associated behaviour. Effects of diazepam.

Variations of extracellular dopamine (DA(ext)) levels in prefrontal cortex were assessed by in vivo microdialysis. In rats trained in an operant fixed interval (FI(30s)) schedule of food delivery, acute exposure to contingent foot shocks resulted in a suppression of responding that was reversed by diazepam (4 mg/kg, ip). No changes in cortical DA(ext) levels occurred during this period in both control and treated rats. By contrast, in control rats, cortical DA(ext) levels increased (+25-40%) during the nonpunished component of the operant session, and during noncontingent food delivery (+25%). Control rats placed into an unfamiliar brightly lit openfield exhibited a marked increase in cortical DA(ext) levels (+100%). This effect occurred neither in rats given diazepam at a dose (2 mg/kg) which stimulated motor activity, nor during a second exposure to the openfield. In conclusion, a benzodiazepine-sensitive activation of mesoprefrontal DA neurones is induced by exposure to novel stressful surroundings and by food availability and consumption. The fact that cortical DA(ext) levels remained unchanged in rats that exerted complete control upon negative stimuli indicates that an activation of the mesoprefrontal DA system is not required for punishment-induced behavioural blockade.

Effects of chronic antidepressants in an operant conflict procedure of anxiety in the rat.

The effects of chronic antidepressants were investigated in an animal procedure for the study of anxiety and anxiolytics, the conditioned suppression of operant behavior in rats. In daily 18-min sessions, three periods of nonpunished lever pressing for food alternated with two 4-min periods signaled by a light-on conditioned stimulus during which 50% of the responses were randomly punished by electric foot shocks. Antidepressants were administered once daily for 7-8 weeks to trained, food-restricted rats. Desipramine (dose regimen increase from 4 to 16 mg/kg/day) induced a gradual (4-5-week latency) release of response suppression during punished periods over the course of several weeks of testing. This anxiolytic-like effect was still present 3 weeks following drug discontinuation. In contrast, chronic imipramine (dose regimen increase from 4 to 16 mg/kg/day), maprotiline (4 to 16 mg/kg/day), phenelzine (2 to 4 mg/kg/day), and fluoxetine (1 or 8 mg/kg/day; constant dose), resulted in no change in punished responding, suggesting that no anxiolytic-like effect developed in the course of chronic treatment with these compounds. The largest dose of all antidepressants studied (except fluoxetine) induced a moderate to marked reduction of nonpunished performance that disappeared within 1 week after the last injection. A transient release of conditioned response suppression emerged during the week that followed discontinuation of imipramine, maprotiline, and fluoxetine (8 mg/kg/day). This apparent anxiolytic-like activity might be due to a reduction of some adverse effect induced by the high doses used, and/or might have resulted from a new dynamic equilibrium between monoamine release, reuptake processes, and sensitivity of postsynaptic receptors. In conclusion, operant conflict procedures in rats seem not particularly able to model human anxiety sensitive to chronic antidepressant treatments.

[Reduced waiting capacities as a possible mechanism of action of benzodiazepines. A hypothesis derived from their behavioral effects in animals]. / Réduction des capacités à différer une conduite comme mécanisme possible de l'action des benzodiazépines. Une hypothèse issue de leurs effets comportementaux chez l'animal.

In classical punishment procedures, suppression of responding which allows the animal to avoid electric foot-shock is attenuated by benzodiazepines (BZD). Such a release of responding is interpreted as a reflection of the anxiolytic activity of BZD. In these situations however, behavioral suppression also delays the obtention of the food-reward. Therefore, shock-mediated waiting could be as critical a target as shock-induced fear for BZD in punishment procedures. The present study was designed to investigate whether BZD are effective in reducing the capacity of animals to wait for an expected food reward. Fasted rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate but small (2 pellets) vs delayed but large (8 pellets). Diazepam (2-4 mg/kg), nitrazepam (2 mg/kg), chlordiazepoxide (16 mg/kg) or clobazam (16 mg/kg) decreased the number of times the large reward was chosen by rats subjected to a waiting period of 15 s before having access to the large reward. In conflict situations, rats trained to press a level for food reward were given both 1 pellet and 1 electric foot-shock for pressing during punished periods of fixed duration signalled by a warning stimulus. The diazepam (2 mg/kg)-induced increase in the number of punished presses (anti-punishment effect) was closely related to the percent punishment time within a session. The release of punished responding reached a statistically significant level only when the total punishment-time accounted for at least 40% of the total duration of the session.(ABSTRACT TRUNCATED AT 250 WORDS)

[Semiologic study of chronic perennial and permanent paranasal sinus dysfunction. Prevalence of symptoms]. / Etude de la sémiologie des dysfonctionnements rhino-sinusiens chroniques perannuels et permanents. Prévalence des symptômes.

Rhino-sinus dysfunction is associated with several symptoms: nasal obstruction, anterior and posterior rhinorrhea, episodes of sneezing, painful or heavy feeling in the face, taste and smell disorders. Certain manifestations have an impact on the pharynx, the larynx or the tracheobronchial tree. This prospective study was conducted in 449 consecutive patients who consulted over an 18-months period from November 1995 to May 1997. The objective was to determine the symptom pattern, main disease of the nasal cavities and paranasal sinuses which were involved: chronic rhinitis, anterior sinusitis, bilateral and symmetric pansinusitis with or without nasosinus polyps. In the first part of the study, the frequency of different symptoms were determined for the main nasosinus diseases. Statistical analysis of the correlations between symptoms and diseases provided a specific approach to symptoms.

[A clinical study of chronic perennial and permanent rhino-sinusal dysfunction. II. Clinical pattern of different pathologies]. / Etude de la sémiologie des dysfonctionnements rhino-sinusiens chroniques perannuels et permanents. II. Profil sémiologique des différentes pathologies.

Following a univariate analysis of the clinical features of chronic perannual and permanent rhinosinus dysfunction, the aim of this work was to complete the study by a multivariate analysis. The analysis was based on the three main pathologies retained (chronic sinusitis, bilateral symmetrical pansinusitis, anterior facial sinusitis). Each pathological situation was divided into subgroups, Phadiatop positive or negative chronic rhinitis, bilateral symmetrical chronic panethmoiditis or stage I, II or III naso-sinus polyposis, maxillary sinusitis or anterior facial pansinusitis. The clinical features of these different entities were detailed (number, quality and laterality of the symptoms, results of the physical examination). This clinical description was compared with paraclinical findings, particularly computed tomography of the face.

[The role of the national education physician in the management of child abuse]. / Le rôle du médecin de l'éducation nationale dans la prise en charge de la maltraitance.

The school physician is in a key position to detect and to report cases of child ill-treatment. He has opportunities to listen to the child himself, to collect information upon his life at school as well as on his brothers and sisters; therefore he can get an accurate knowledge of the situation of that child. Afterwards, he will meet the child's parents. Through his relationships with many partners, such as the family physician, the hospital, educators, social workers and even justice, the school physician can clear up some facts, in order to complete his view on the case. Due to his particular responsibility to cope with situations of child distress, the school physician, as an adviser inside school, shall take an active part in terms of prevention.

A method for estimating cancer risk in p53 mutation carriers.

Germline mutations of the tumor-suppressor gene p53 have been described in families with multiple neoplasms as Li-Fraumeni syndrome families, or in subjects with second malignant tumor. In order to evaluate the increase in risk of cancer due to these mutations, a family study is being carried out. In families with a proband who developed a cancer before age 16, we select those with at least one cancer before age 45 among first- and second-degree relatives of the proband. All family members are screened for p53 germline mutations if the proband is a carrier of a mutation. We present here a method to estimate the probability that a carrier of a p53 germline mutation develops a given malignant tumor at a given age. This method uses the principle of maximum likelihood estimation. It takes into account the fact that individuals are related within a family, that some of them are not genotyped for p53, and that families have been selected on the criterion of existence of cancer. Simulated data allowed us to validate the method.

Effects of imipramine-like drugs and serotonin uptake blockers on delay of reward in rats. Possible implication in the behavioral mechanism of action of antidepressants.

This study investigated in rats the action of a variety of antidepressants in two behavioral models. In model 1, animals trained in a T-maze were allowed to choose between 2 magnitudes of reward: immediate but small reward (2 pellets) vs. a 25-sec delayed but large reward (10 pellets). Under this alternative, vehicle-injected rats selected the large-but-delayed reward in less than 40% of the trials. Desipramine 8 mg/kg, clomipramine 8 mg/kg, maprotiline 8 mg/kg, indalpine 2 to 4 mg/kg, zimelidine 8 to 16 mg/kg, nialamide 16 to 32 mg/kg and clenbuterol 0.03 to 0.06 mg/kg significantly increased the number of choices of the large-but-delayed reward. In model 2, rats were subjected to a fixed ratio 48 schedule of food reinforcement; after completion of a series of exactly 48 presses a food pellet was delivered, and if no further press occurred, a sequence of free pellets was initiated according to fixed, increasing intervals (from 5-80 sec). Pressing during the sequence stopped it and required the rat to complete again the fixed ratio 48 to be reinforced and to reintiate the sequence. Waiting for free reward was significantly lengthened by desipramine 8, clomipramine 16, indalpine 8, zimelidine 8 to 16, nialamide 32 and clenbuterol 0.007 to 0.06 mg/kg. These results suggest that, possibly through noradrenergic and serotonergic mechanisms, antidepressants markedly enhanced rats' ability to wait for food reward, an affect which might reflect the ability of these drugs to improve impulse control. The relevance of such a property in the therapeutic action of antidepressants remains to be delineated.

Distinct effects of diazepam and NK1 receptor antagonists in two conflict procedures in rats.

Convergent data suggest that SP, through the activation of neurokinin1 receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25-8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3-30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.