The impact of marital status at diagnosis on cancer survival in patients with differentiated thyroid cancer

Abstract

Previous studies have revealed that marital status influences the prognosis of patients with various types of cancer. We evaluated the influence of marriage on the survival outcomes in differentiated thyroid cancer (DTC). The Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2012 was used to compare cancer-specific mortality in different marital status, and in each sex, age, and stage stratification by multivariate Cox regression model. In total, 61,077 eligible patients were identified. The widowed group had the highest proportion of women, elderly patients (≥45 years), and advanced stage III/IV tumor (P = 0.001), but the total thyroidectomy (TT) performed and radioisotopes therapy rates were lower than those in the married group. Married patients had a better cancer-specific survival (CSS) than the unmarried (P < 0.05). Further analysis showed that widowed patients always presented the lowest CSS compared with other groups. Widowed patients had a significant increased risk for CSS compared with married patients in males [hazard ratio (HR) 2.72, 95% confidence interval (CI): 1.59–4.65, P = 0.001], females (HR 2.02, 95% CI: 2.24–4.06, P = 0.001), young patients (<45, HR 28.12, 95% CI: 3.48–227.25, P = 0.002), elderly patients (≥45, HR 28.12, 95% CI: 2.97, 95% CI: 2.30–3.83, P = 0.001), stage I (HR 8.44, 95% CI: 4.05–17.59, P = 0.001), stage II (HR 3.64, 95% CI: 1.30–10.20, P = 0.014), stage III (HR 2.27, 95% CI: 1.08–4.78, P = 0.031), and stage IV (HR 2.63, 95% CI: 1.94–3.57, P = 0.001). These results showed that unmarried status, especially for widowhood, increased the risk of cancer mortality in DTC patients.

Our results confirmed that the unmarried status has an independent impact on cancer-specific mortality with a varied risk compared to marriage. Moreover, we indicated that the unmarried patients groups were heterogeneous, and the widowed patients were always at the highest risk of death of cancer than those in other groups.

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Genetic alterations of differentiated thyroid carcinoma in iodine-rich and iodine-deficient countries

Abstract

BRAF V600E mutation, RET rearrangements, and RAS mutations are the common genetic alterations in differentiated thyroid carcinomas derived from follicular thyroid cells. However, the relationship between these alterations and iodine intake is still controversial. To clarify the influence of iodine intake on the occurrence of differentiated thyroid carcinomas, we performed molecular analyses for two differentiated carcinomas, papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs), from an iodine-rich country (Japan) and an iodine-deficient country (Vietnam). We examined 120 PTCs (67 Japanese and 53 Vietnamese) and 74 FTCs (51 Japanese and 23 Vietnamese). We carried out allele-specific polymerase chain reaction (AS-PCR) for BRAF V600E, PCR and direct sequencing for RAS mutations (codon 12, 13, and 61 in NRAS, HRAS, and KRAS), and RT-PCR for RET/PTC1 and RET/PTC3. BRAF V600E was present in 55/67 (82.1%) Japanese PTCs and 44/53 (83%) Vietnamese PTCs. RET/PTC1 was identified in only one PTC from each country, and no samples had RET/PTC3. NRAS mutation was found in 17/51 (33.3%) Japanese FTCs and 4/23 (17.4%) Vietnamese FTCs. NRAS mutation was cited in codon 61 (20 cases) and codon 12 (one case). None of FTCs had KRAS or HRAS mutations. There were no significant differences in the prevalence of BRAF V600E, RET/PTC, or RAS mutations between the two countries. Our study showed no differences in genetic alterations of thyroid cancers from iodine-rich and iodine-deficient countries, possibly suggesting that iodine intake might not affect the genetic alterations of differentiated thyroid cancer.

Iodine consumed in food in the Japanese and Vietnamese populations is not associated with the genetic alterations seen in differentiated thyroid carcinomas. However, our findings contribute to the understanding of carcinogenesis of thyroid tumors.

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Sorafenib treatment in children with relapsed and refractory neuroblastoma: an experience of four cases

Abstract

Metastatic neuroblastoma is an aggressive malignancy with a poor prognosis. Recent findings have shown that sorafenib decreases cell viability and increases apoptosis in human neuroblastoma cell lines. We report an experience of compassionate use of sorafenib in children with treatment-refractory neuroblastoma. Sorafenib showed transient anti-tumor activity in all four patients without adverse effects. However, progression was observed after a short stabilization phase. While sorafenib showed minimal anti-tumor activity in our patients, it might still be effective in patients with neuroblastoma in an earlier stage.

We report an experience of compassionate use of sorafenib in children with treatment-refractory neuroblastoma. Sorafenib showed transient anti-tumor activity in all four patients without adverse effects. However, progression was observed after a short stabilization phase. To our knowledge, this is the first report about sorafenib in relapsed/refractory neuroblastoma.

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Incidence and long-term outcome of postradiotherapy moyamoya syndrome in pediatric patients with primary brain tumors: a single institute experience in Taiwan

Abstract

We aimed to investigate the incidence and long-term outcome of moyamoya syndrome in pediatric patients with primary brain tumors after receiving cranial radiotherapy (RT) in a single institute in Taiwan. The complete medical records, medical images, and RT notes of 391 pediatric patients with primary brain tumors treated with cranial RT between January 1975 and December 2005 in Taipei Veterans General Hospital (TVGH), Taiwan, were entered into an electronic registry and reviewed. Eight (2%) cases of post-RT moyamoya syndrome were identified in the sample of 391 patients. The median latency was 3 years post-RT. Among the eight patients, three had craniopharyngioma, two had optic glioma, two had medulloblastoma, and one had a suprasellar astrocytoma. The prescribed physical doses of RT were in the range of 40–54 Gy. The incidence was highest in those with optic glioma (0.039/person-year), followed by craniopharyngioma (0.013/person-year), astrocytoma (0.003/person-year), and medulloblastoma (0.002/person-year). No patients died of vasculopathy. No difference in crude incidence was found between our results and those of other series. The incidence of moyamoya syndrome was diagnosis dependent, with the highest incidence among patients with optic glioma. No regional difference in incidence was found. Long-term, stable neurological function may be achieved following timely surgical intervention.

The incidence of moyamoya syndrome in pediatric patients of primary brain tumors after receiving radiotherapy was diagnosis dependent, with the highest incidence among patients with optic glioma. No regional difference in incidence was found. Long-term, stable neurological function may be achieved following timely surgical intervention.

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Effects of propolis and gamma-cyclodextrin on intestinal neoplasia in normal weight and obese mice

Abstract

Obesity is associated with colorectal cancer (CRC). This effect might be attributed to adipokine-supported signaling. We have established that propolis suppresses survival signaling in CRC cells in vitro; therefore, we ascertained the ability of a propolis supplement to modulate intestinal neoplastic development in C57BL/6J-ApcMin/+/J mice in the lean and obese state. To induce obesity, mice were fed with a Western diet containing 40% fat. Since the propolis supplement includes gamma-cyclodextrin, the interventions included diets supplemented with or without gamma-cyclodextrin. The animals were administered the following diets: (1) control diet, (2) control diet/gamma-cyclodextrin, (3) control diet/propolis, (4) Western diet, (5) Western diet/gamma-cyclodextrin, and (6) Western diet/propolis. Western diet, resulting in obesity, accelerated neoplastic progression, as evidenced by the larger size and higher grade dysplasia of the neoplasms. In the context of normal weight, gamma-cyclodextrin and propolis affected neoplastic progression, as determined by the size of the lesions and their grade of dysplasia. A statistically significant decrease in the number of adenomas was detected in mice fed a control diet with the propolis supplement (61.8 ± 10.6 vs. 35.3 ± 7.6, P = 0.008). Although there was no significant difference in the polyp numbers between the six groups, the mice with the lowest number and size of adenomas were those fed a Western diet with gamma-cyclodextrin. This unexpected outcome might be explained by the increased levels of apoptosis detected in the intestinal tissues of these obese mice. We posit that butyrate derived from the metabolism of gamma-cyclodextrin may contribute to the decreased neoplastic burden in the context of obesity; however, future studies are required to address this possibility.

Our in vivo analyses revealed that a propolis supplement significantly inhibits the intestinal neoplastic burden in the context of normal weight, but not obesity. In contrast, gamma-cyclodextrin, a food additive with which propolis is formulated, suppresses in a statistically significant manner the intestinal neoplastic burden in the context of obesity. We have also established that early-stage neoplasms in obese mice exhibit a lower number of somatic mutations than these in normal weight mice.

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Study Skills Inventory among Medical Students of Private and Government Medical Colleges in South India

2016-06-05T20-22-43Z
Source: International Journal of Community Medicine and Public Health
praveen kulkarni, kavitha HS, Chinmaye Melur, Siddalingappa hugar, renuka manjunath.
Background: Study skills are discrete techniques that can be learned, usually in a short time, and applied to all or most fields of study. The approach students choose appears to be a central factor in determining both the quality and quantity of their learning. Learning styles influence the maintenance of information and the depth of understanding. Methods: A prospective interventional study was conducted among the medical students of phase-II, phase-III part-I and part II studying in government and private medical colleges. The data regarding socio-demographic characteristics like age, sex, religion, total family income, locality, phase of MBBS Course, state in India from which the student came and the learning skills were collected on a self-administered pre tested structured questionnaire, which will also include Study Skills Inventory tool. Paired t test for academic performance before and after intervention, Mann Whitney test for difference in mean ranks in study skill scores between Government and private colleges, spearman correlation for academic skills and study skill scores were applied. Results: The note-taking skills, memory skills and time management skills of private medical college students and their academic performance were correlated significantly. There was a significant improvement in the academic performance of private medical college students by 3.01 and government medical college students by 3.69 after the intervention. Conclusions: There was a significant improvement in the academic performance of both private and government medical college students after the intervention.


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Inappropriate statistical method in a parallel-group randomized controlled trial results in unsubstantiated conclusions

The conclusions of Cassani et al. in the January 2015 issue of Nutrition Journal (doi:10.1186/1475-2891-14-5) cannot be substantiated by the analysis reported nor by the data themselves. The authors ascribed the observed decrease in inflammatory markers to the components of flaxseed and based their conclusions on within-group comparisons made between the final and the baseline measurements separately in each arm of the randomized controlled trial. However, this is an improper approach and the conclusions of the paper are invalid. A correct analysis of the data shows no such effects.

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A feasibility study of implementing grip strength measurement into routine hospital practice (GRImP): study protocol

Background: Handgrip strength is a non-invasive marker of muscle strength, and low grip strength in hospital inpatients is associated with poor healthcare outcomes including longer length of stay, increased functional limitations, and mortality. Measuring grip strength is simple and inexpensive. However, grip strength measurement is not routinely used in clinical practice. The aim of this study is to evaluate the feasibility of implementing grip strength measurement into routine clinical practice.Methods/designThis feasibility study is a mixed methods design combining qualitative, quantitative, and economic elements and is based on the acute medical wards for older people in one hospital. The study consists of three phases: phase 1 will define current baseline practice for the identification of inpatients at high risk of poor healthcare outcomes, their nutrition, and mobility care through interviews and focus groups with staff as well as a review of patients' clinical records. Phase 2 will focus on the feasibility of developing and implementing a training programme using Normalisation Process Theory to enable nursing and medical staff to measure and interpret grip strength values. Following the training, grip strength will be measured routinely for older patients as part of admission procedures with the use of a care plan for those with low grip strength. Finally, phase 3 will evaluate the acceptability of grip strength measurement, its adoption, coverage, and basic costs using interviews and focus groups with staff and patients, and re-examination of clinical records.DiscussionThe results of this study will inform the translation of grip strength measurement from a research tool into clinical practice to improve the identification of older inpatients at risk of poor healthcare outcomes.Trial registrationClinicaltrials.gov NCTO2447445

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Effectiveness of management interventions for control of invasive Common ragweed Ambrosia artemisiifolia: a systematic review protocol

Background: Alien species are severely impacting the environment, public health and socioeconomy at a global scale. Their management is thus of crucial importance and the subject of intensive research efforts. Common ragweed Ambrosia artemisiifolia L. is an alien species with negative impacts on agriculture, human health and biodiversity. It is a highly allergenic, wind-pollinated herb native to North America that was first introduced to Europe during the seventeenth century. It has since become widespread and is currently in an ongoing phase of rapid spread and increasing abundance. Several management approaches are currently implemented and effective control of the species can have strong socioeconomic benefits. However, evidence for management effectiveness is scattered and has not yet been synthesised systematically. For these reasons, we here aim to systematically review the evidence to assess (a) what is the effectiveness of management options used for control of Common ragweed Ambrosia artemisiifolia and (b) what is the effect of confounding factors such as habitat, climate and frequency and timing of treatment? Methods: This protocol specifies the methods for conducting a systematic review to answer the specified questions. Search terms relating to the population and the intervention (type of management) will be combined and searched in a range of databases and other sources. Specific inclusion criteria are (i) any population of Ambrosia artemisiifolia at any habitat including populations in agricultural settings and such used for experimental research at any geographic location (including its native range), (ii) any physical, chemical, biological or combined management action; (iii) direct outcome measures including change in coverage, abundance, biomass, survival, reoccurrence, biology (e.g. growth, height, leaf area) or pollen production. The wide range of quality of primary literature will be evaluated with a tailored system for assessing susceptibility to bias and the reliability of the studies. If extracted data are suitable for quantitative synthesis, we aim to calculate effect sizes and conduct meta-analyses.

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Microenvironmental Control of Adipocyte Fate and Function

Publication date: Available online 4 June 2016
Source:Trends in Cell Biology
Author(s): Benjamin D. Pope, Curtis R. Warren, Kevin Kit Parker, Chad A. Cowan
The properties of tissue-specific microenvironments vary widely in the human body and demonstrably influence the structure and function of many cell types. Adipocytes are no exception, responding to cues in specialized niches to perform vital metabolic and endocrine functions. The adipose microenvironment is remodeled during tissue expansion to maintain the structural and functional integrity of the tissue and disrupted remodeling in obesity contributes to the progression of metabolic syndrome, breast cancer, and other malignancies. The increasing incidence of these obesity-related diseases and the recent focus on improved in vitro models of human tissue biology underscore growing interest in the regulatory role of adipocyte microenvironments in health and disease.



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Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

Publication date: Available online 4 June 2016
Source:Trends in Cell Biology
Author(s): Shuguo Sun, Kenneth D. Irvine
The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell–cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell–cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell–cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated and to define their respective contributions in vivo.



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Issue Cover (June 2016)

Cover image by Daniel J. Hegeman, Ellie S. Hong, Vivian M. Hernández and C. Savio Chan

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Tridimensional finite element analysis of teeth movement induced by different headgear forces

Background: This study aimed to simulate the actions of low-pull (LP), high-pull (HP), and combined pull (CP) headgears (HGs) and to analyze tooth movement tendencies through finite element analysis. Methods: Tomographic slices of a human maxilla with complete permanent dentition were processed by reconstruction software, and the triangular surface mesh was converted into non-uniform rational B-spline (NURBS) curves. An HG facial bow was also modulated in 3D. The teeth and bone were considered to have isotropic and linear behavior, whereas the periodontal ligament was considered to have non-linear and hyperelastic behavior. Data regarding the application points, directions and magnitudes of forces were obtained from the literature and from a dolichofacial patient with class II, division 1 malocclusion, who was treated with a CP HG. Results: The CP HG promoted 37.1 to 41.1 %, and the HP HG promoted 19.1 to 31.9 % of LP distalization. The HP HG presented the highest intrusion, and the LP HG presented the highest extrusion of the first molar. The LP HG contracted the distal side, and the HP and CP HGs contracted the lingual and distobuccal roots of the second molar to a lesser degree. Conclusions: The LP HG promotes the greatest distalization, followed by the CP and HP HGs; the LP HG causes greater extrusion of the first molar, and the HP HG causes greater intrusion of the first molar. The LP HG causes greater contraction of the second molar than the HP HG.

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Ovarian malignancy unmasked by venous gangrene in a patient on warfarin therapy: a case report

Background: Venous gangrene complicating deep vein thrombosis in the context of anticoagulation use in patients with gynecologic malignancy is rarely reported. We report an unusual presentation of venous gangrene of the lower limbs associated with warfarin therapy in a 53-year-old woman from the Cook Islands with an occult ovarian cancer.Case presentationA 53-year-old woman of Cook Islands origin presented with exertional dyspnea, rapid atrial fibrillation, bilateral lower limb edema, and painful digital ischemia of her hallux. She was on warfarin therapy for atrial fibrillation and had a stable therapeutic international normalized ratio. Bilateral proximal lower limb deep vein thrombosis and digital gangrene subsequently developed in the setting of a supratherapeutic international normalized ratio and platelet count depletion. Her warfarin was reversed and heparin therapy was commenced with resulting correction of her thrombocytopenia. Conclusions: We would like to attract the attention of the reader to the potential hazard of the use of warfarin in patients with malignancy. In our case, we also demonstrated a predictive value of supratherapeutic international normalized ratio and platelet count depletion that could herald massive thrombosis and gangrene in a patient who was previously stable on warfarin therapy. Early recognition and prompt reversal of warfarin in these circumstances is essential to correct the unbalanced prothrombotic process that leads to extensive thrombosis and gangrene. The outlook of such cases remains dismal and results in extensive morbidity and mortality.

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The Trans-Pacific Partnership Agreement and health: few gains, some losses, many risks

Background: In early October 2015, 12 nations signed the Trans-Pacific Partnership Agreement (TPPA), promoted as a model '21 st century' trade and investment agreement that other countries would eventually join. There are growing concerns amongst the public health community about the potential health implications of such WTO+ trade and investment agreements, but little existing knowledge on their potential health impacts.Methods and resultsWe conducted a health impact review which allows for a summary estimation of the most significant health impacts of a set of policies, in our case the TPPA. Our analysis shows that there are a number of potentially serious health risks, with the following key pathways linking trade to health: access to medicines, reduced regulatory space, investor-state dispute settlement (ISDS), and environmental protection and labor rights. We also note that economic gains that could translate into health benefits will likely be inequitably distributed. Conclusion: Our analysis demonstrates the need for the public health community to be knowledgeable about trade issues and more engaged in trade negotiations. In the context of the COP21 climate change Agreement, and the UN Sustainable Development Goals, this may be an opportune time for TPPA countries to reject it as drafted, and rethink what should be the purpose of such agreements in light of (still) escalating global wealth inequalities and fragile environmental resources—the two most foundational elements to global health equity.

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Retrospective cohort analysis of healthcare claims in the United States characterising asthma exacerbations in paediatric patients

Background: Asthma is the most common chronic disease in childhood and places a significant burden on public and private health systems. This retrospective cohort analysis utilised administrative healthcare claims data (US Clinformatics™ Multiplan database; compliant with the US Department of Health & Human Services Health Insurance Portability and Accountability Act) to characterise asthma exacerbations requiring intervention in a US paediatric patient population. Methods: Patients aged > 1–17 years with a recorded asthma diagnosis and receiving treatment were identified in the US Clinformatics™ Multiplan database over a 9-year period (2004–2012). Both incident and prevalent cases of asthma were included, with the most recently recorded asthma diagnosis designated as the index date. The 12-month period following the index date was analysed for asthma exacerbations, defined as an event requiring treatment with systemic corticosteroid or resulting in an asthma-related hospitalisation or emergency department visit. Results: Data from 734,114 children with asthma (41.5 % females, 58.5 % males) were analysed, of this cohort 34.4 % experienced ≥ 1 exacerbation during the follow-up period. The proportion who experienced ≥ 1 exacerbation increased from 28.9 % in 2004 to 36.3 % in 2012, based on the reported index date. Their mean annual exacerbation frequency was 1.4; 85.8 % of exacerbations were defined by systemic corticosteroids use. A consistent trend of increased exacerbation incidence in the fall and early winter was observed, in particular exacerbations defined by systemic corticosteroid use. A greater proportion of asthma-related hospitalisations were associated with younger age. Conclusions: Approximately one-third of children experienced ≥ 1 exacerbation in real-world clinical practice. A targeted treatment approach with a focus on those with a history of recurrent exacerbations is recommended to improve asthma control. This targeted approach could also minimise the frequent systemic corticosteroid exposure particularly at an early age when side effects of systemic corticosteroids are more pronounced.

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High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer’s disease

Background: Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-β 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. Methods: Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2–11 years (median 4.9 years). Results: Individuals with CSF t-tau in the highest quartile (≥900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24–3.80]; HR 2.37 [95 % CI 1.10–5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08–2.56), rapid decline in Mini Mental State Examination score (≥4-point drop/12 months), and dying in severe dementia as outcomes. Conclusions: To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.

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We need to optimize piperacillin-tazobactam dosing in critically ill patients—but how?

No description available

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Rapid assessment of knowledge, attitudes, practices, and risk perception related to the prevention and control of Ebola virus disease in three communities of Sierra Leone

Background: The recent outbreak of the Ebola virus disease (EVD) in Sierra Leone has been characterized by the World Health Organization as one of the most challenging EVD outbreaks to date. The first confirmed case in Sierra Leone was a young woman who was admitted to a government hospital in Kenema following a miscarriage on 24 May 2014. On 5 January 2015, intensified training for an EVD response project was initiated at the medical university of Sierra Leone in Jui. To understand the knowledge, attitudes, practices, and perceived risk of EVD among the public, especially after this training, a rapid assessment was conducted from 10 to 16 March 2015. Methods: Interviews were conducted with 466 participants based on questionnaires that were distributed from 10 to 16 March 2015 by cluster sampling in three adjacent communities, namely Jui, Grafton, and Kossoh Town, in the Western Area Rural District of Sierra Leone. Results: It was found that knowledge about EVD was comprehensive and high. Positive attitude towards prevention was found to be satisfactory. Nearly all participants knew the reporting phone number 117 and had reported some change in behavior since learning about Ebola. More than half (62 %) of the participants had a history of travelling to urban areas, which increases the risk of infection. The multivariable logistic regression analysis showed that community and occupation were variables associated with perceived risk of EVD. Conclusions: Our study showed that community level social mobilization and community engagement were an effective strategy in the special context.

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A prospective multicenter cohort study of frailty in younger critically ill patients

Background: Frailty is a multidimensional syndrome characterized by loss of physiologic and cognitive reserve that heightens vulnerability. Frailty has been well described among elderly patients (i.e., 65 years of age or older), but few studies have evaluated frailty in nonelderly patients with critical illness. We aimed to describe the prevalence, correlates, and outcomes associated with frailty among younger critically ill patients. Methods: We conducted a prospective cohort study of 197 consecutive critically ill patients aged 50–64.9 years admitted to intensive care units (ICUs) at six hospitals across Alberta, Canada. Frailty was defined as a score ≥5 on the Clinical Frailty Scale before hospitalization. Multivariable analyses were used to evaluate factors independently associated with frailty before ICU admission and the independent association between frailty and outcome. Results: In the 197 patients in the study, mean (SD) age was 58.5 (4.1) years, 37 % were female, 73 % had three or more comorbid illnesses, and 28 % (n = 55; 95 % CI 22–35) were frail. Factors independently associated with frailty included not being completely independent (adjusted OR [aOR] 4.4, 95 % CI 1.8–11.1), connective tissue disease (aOR 6.0, 95 % CI 2.1–17.0), and hospitalization within the preceding year (aOR 3.3, 95 % CI 1.3–8.1). There were no significant differences between frail and nonfrail patients in reason for admission, Acute Physiology and Chronic Health Evaluation II score, preference for life support, or treatment intensity. Younger frail patients did not have significantly longer (median [interquartile range]) hospital stay (26 [9–68] days vs. 19 [10–43] days; p = 0.4), but they had greater 1-year rehospitalization rates (61 % vs. 40 %; p = 0.02) and higher 1-year mortality (33 % vs. 20 %; adjusted HR 1.8, 95 % CI 1.0–3.3; p = 0.039). Conclusions: Prehospital frailty is common among younger critically ill patients, and in this study it was associated with higher rates of mortality at 1 year and with rehospitalization. Our data suggest that frailty should be considered in younger adults admitted to the ICU, not just in the elderly. Additional research is needed to further characterize frailty in younger critically ill patients, along with the ideal instruments for identification.

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Antiepileptic drug combinations not involving valproate and the risk of fetal malformations

Summary

Objective

To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined.

Methods

An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999–2014).

Results

Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14–3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23–5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025).

Significance

The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

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The Reliability of Oral and Pharyngeal Dimensions Captured with Acoustic Pharyngometry

Abstract

Acoustic Pharyngometry (APh) is a method for quantifying oropharyngeal tract configuration using sound wave reflection and is commonly used in diagnostics and research of sleep apnea. The standard preset output of APh (minimal cross-sectional area) has been established as reliable. However, by conducting post-processing measures on specific breathing tasks, APh data can also reveal oral length, oral volume, pharyngeal length, and pharyngeal volume. Given that these measures may have utility in dysphagia research, the reliability of these measures is unknown and is the focus of the current study. Ten young healthy female volunteers completed two sessions of APh data collection to obtain measures of oral length, oral volume, pharyngeal length, and pharyngeal volume 1 week apart. Two-way mixed intraclass correlation coefficients were calculated to establish intra-rater reliability, inter-rater reliability, and test–retest reliability. Results revealed excellent levels of agreement within and across raters for all oropharyngeal tract parameters. Levels of test–retest agreement for oral length and oral volume indicated these parameters are appropriate for monitoring change within an individual. All parameters were deemed to have acceptable test–retest values as outcome measures in group-level analysis.

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Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety…

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Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety…

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Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety…

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Changing Adjuvant Breast-Cancer Therapy with a Signal for Prevention

Five randomized, full-scale studies have reported that 10 years of adjuvant endocrine therapy is beneficial for postmenopausal women with hormone-receptor–positive breast cancer. However, no prior study has involved more than 5 years of aromatase-inhibitor use or assessed a duration of adjuvant…

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Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety…

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Changing Adjuvant Breast-Cancer Therapy with a Signal for Prevention

Five randomized, full-scale studies have reported that 10 years of adjuvant endocrine therapy is beneficial for postmenopausal women with hormone-receptor–positive breast cancer. However, no prior study has involved more than 5 years of aromatase-inhibitor use or assessed a duration of adjuvant…

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A Plea for Ecological Argument Technologies

Abstract

In spite of significant research efforts, argument technologies do not seem poised to scale up as much as most commentators would hope or even predict. In this paper, I discuss what obstacles bar the way to more widespread success of argument technologies and venture some suggestions on how to circumvent such difficulties: doing so will require a significant shift in how this research area is typically understood and practiced. I begin by exploring a much broader yet closely related question: To what extent are people natively good at arguing? This issue has always been central to philosophical reflection and it has become even more urgent nowadays, with the explosion of persuasive technologies and unprecedented opportunities for large-scale social influence. The answer hinges on what aspect of argumentation is taken under consideration: evidence suggests that people are relatively bad at analyzing the structure of arguments, especially when these are presented out of context and in abstract terms; in contrast, data show that even laymen tend to excel in the interactive practice of argumentation, in particular when motivation is high and something significant is at stake. Unfortunately, current argument technologies are more closely tailored to the former type of activity than to the latter, which is the main reason behind their relative lack of success with the general public. Changing this state of affair will require a commitment to ecological argument technologies: that is, technologies designed to support real-time, engaging and meaningful argumentative interactions performed by laypeople in their ordinary life, instead of catering to the highly specific needs of a minority of niche users (typically, argumentation scholars).

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Χρόνιος πόνος και υποδοχείς της κανναβινόλης

Τα τελευταία χρόνια παρατηρήσεις έχουν φέρει στο φως αποτελέσματα ιδιαίτερης σημασίας για τη θεραπεία του χρόνιου πόνου.

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Φάρμακα για το λουμπάγκο

Επειδή τα περιστατικά του χρόνιου λουμπάγκο, δηλαδή των επώδυνων συνδρόμων στη μέση, αυξάνονται συνεχώς, τα τελευταία χρόνια καινούργια θεραπευτικά σχήματα έχουν αναπτυχθεί.

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Πόνοι στη μέση

Οι πόνοι στη μέση αποτελούν ένα μεγάλο κεφάλαιο της ιατρικής και ένα από τα πιο απλά ταυτόχρονα.

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Πόνοι στη μέση και νευρογλοία

Η νευρογλοία είναι η δομή γύρω από του νευρώνες σε όλο το κεντρικό νευρικό σύστημα, δηλαδή τόσο στον εγκέφαλο όσο και στο νωτιαίο μυελό, η οποία προστατεύει και «τροφοδοτεί» αυτά.

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Οι κανναβινοειδείς υποδοχείς

Οι κανναβινοειδείς υποδοχείς είναι χημικές ουσίες οι οποίες κατανέμονται σε ολόκληρο το σώμα αλλά ιδιαίτερα στο κεντρικό νευρικό σύστημα.

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Ο ρόλος της γλυκίνης στο λουμπάγκο

Το λουμπάγκο είναι μία επώδυνη κατάσταση με χρόνιους πόνους στη μέση η οποία έχει μεγάλη «απήχηση» στους ασθενείς όλων των χωρών σε διάφορες καταστάσεις, αλλά κυρίως στον πληθυσμό που εργάζεται χειρωνακτικά.

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Ο ρόλος της γλουταμάτης στον πόνο

Η γλουταμάτη είναι ένας νευροδιαβιβαστής, ένα πρωτεϊνικό μόριο, το οποίο «κυκλοφορεί» εντός του νευρικού συστήματος με τρόπο έτσι ώστε να διεγείρει διάφορους υποδοχείς, να εκφορτίζουν ταυτόχρονα ευαισθητοποιώντας το κεντρικό νευρικό σύστημα στα διάφορα ερεθίσματα του πόνου.

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Health-related quality of life after maxillectomy: obturator rehabilitation compared with flap reconstruction

Publication date: Available online 5 June 2016
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): J. Breeze, A. Rennie, A. Morrison, D. Dawson, J. Tipper, K. Rehman, N. Grew, D. Snee, N. Pigadas
Health-related quality of life (QoL) reported by patients has the potential to improve care after ablative surgery of the midface, as existing treatment algorithms still generally revolve around outcomes assessed traditionally only by clinicians. Decisions in particular relate to reconstruction with a flap compared with rehabilitation with an obturator, the need for adjuvant treatment, and morbidity related to the size of the defect. We prospectively collected health-related QoL assessments for 39 consecutive patients treated by maxillectomy between 01 January 2010 and 31 December 2014 using the University of Washington Quality of Life Questionnaire, and who had a mean (SD) duration of follow-up of 14 (4). We made sub-group analyses using paired t tests and analysis of variance (ANOVA) to compare reconstruction with a flap with rehabilitation with obturators, size of the vertical defect, and whether adjuvant treatment with radiotherapy or chemoradiotherapy adversely affected it. Overall there was a significant decrease in health-related QoL after treatment compared with before (p<0.001), but there was no significant difference in the effects of any of the paired reconstructive and rehabilitation treatments on it. Obturators remain an important option for rehabilitation in selected patients in addition to reconstruction with a flap. We found that neither increasing the size of the vertical defect (in an attempt to ensure clear margins) nor the use of postoperative radiotherapy seemed to have any adverse effect on QoL. More patients are required before we can conclude that the potential survival benefits of such measures may outweigh any adverse effects.



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Cross-cover of oral and maxillofacial surgery out-of-hours: an audit of a new adult treatment clinic

Publication date: Available online 5 June 2016
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A.K. Abou-Foul, N.P. Shah, J. Mirza, P. Anand
We present our experience of launching the adult treatment clinic - a daytime clinic for semiurgent referrals to oral and maxillofacial surgery (OMFS). This has proved to be an effective way in which cross-covering junior doctors could refer patients for a safe and efficient review in a supervised environment.



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Outcomes of treatment of fractures of the frontal sinus: review from a tertiary multispecialty craniofacial trauma service

Publication date: Available online 5 June 2016
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): Soudeh Chegini, Niamh Gallighan, Niall Mcleod, Rufus Corkill, Stana Bojanic, Stewart Griffiths, Daljit Dhariwal
There are no agreed national guidelines for the treatment of fractures of the frontal sinus and the naso-orbitoethmoid complex. The Oxford University Hospitals Craniofacial Trauma unit was set up five years ago as a joint oral and maxillofacial, ENT, and neurosurgical service, and we present our experience to date in the treatment of patients with such fractures. The study includes 91 patients with data collected from a prospective database. Patients underwent cranialisation if they met the criteria of persistent leak of cerebrospinal fluid (CSF), displaced fracture of the posterior wall or obstruction of the nasofrontal outflow tract. The mean follow-up time was 42 months (range 1-10 years). Three groups of patients were analysed. Group 1 met the criteria for, and were treated by, cranialisation (n=50). Group 2 met the criteria for cranialisation, but were treated conservatively because of coexisting conditions (n=8). Group 3 did not match the criteria for treatment, and were managed conservatively (n=33).The numbers of patients with complications or who required further operation were: group 1 (4/50), group 2 (3/8), and group 3 (3/33). There were significantly fewer complications among those patients who met the operative criteria and were treated by cranialisation than among those treated conservatively (p=0.04). These outcomes from one dedicated multispecialist craniofacial trauma unit in the UK may help surgeons who care for patients with this specific group of injuries. Our morbidity was in keeping with published figures.



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Recording Mouse Ultrasonic Vocalizations to Evaluate Social Communication

Mouse ultrasonic vocalizations are used as proxies to model the genetic bases of vocal communication deficits in mouse models for neuropsychiatric disorders. The present protocol describes three experimental contexts that reliably elicit ultrasonic vocalizations from pups (throughout development) and adult mice (same-sex interactions, male-estrus female interactions).

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The concurrent and predictive validity of the Dutch version of the Communicative Development Inventory in children with Down Syndrome for the assessment of expressive vocabulary in verbal and signed modalities

Publication date: September 2016
Source:Research in Developmental Disabilities, Volume 56
Author(s): S.R.J.M. Deckers, Y. Van Zaalen, E.J.M. Mens, H. Van Balkom, L. Verhoeven
The expressive vocabulary of children with Down Syndrome (DS) is generally measured with parental reports, such as the Communicative Development Inventory (CDI), given that standardized tests for assessing vocabulary levels may be too difficult for most young children with DS. The CDI provides important insight into the parents' perception of their child's vocabulary development. The CDI has proven to be a valid measurement of expressive vocabulary, spoken and gestural, in typical and atypical populations. The validity in children with DS is not well established and signed vocabulary is often not included. This longitudinal study examined the concurrent and predictive validity of the Dutch version of the CDI (N-CDI) in children with DS between 2;0 and 7;6 years old to assess spoken and signed vocabulary. N-CDI scores were assessed on strength of association with mental age, an expressive vocabulary test and spontaneous language analyses in a play setting with parents at T1 and T2 (1.5 years later), and a therapy setting with speech language pathologists at T1. The results of the present study show that the N-CDI is a valuable and valid measurement of expressive vocabulary in children with DS. Strengths and weaknesses of several assessment methods for expressive vocabulary are discussed.



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The role of biofilm on orthopaedic implants: the “Holy Grail” of post-traumatic infection management?

Abstract

The development of post-traumatic infection is potentially a limb threatening condition. The orthopaedic trauma literature lags behind the research performed by our arthroplasty colleagues on the topic of implant-related infections. Surgical site infections in the setting of a recent ORIF are notoriously hard to eradicate due to biofilm formation around the implant. This bacteria-friendly, dynamic, living pluri-organism structure has the ability to morph and adapt to virtually any environment with the aim to maintain the causative organism alive. The challenges are twofold: establishing an accurate diagnosis with speciation/sensitivity and eradicating the infection. Multiple strategies have been researched to improve diagnostic accuracy, to prevent biofilm formation on orthopaedic implants, to mobilize/detach or weaken the biofilm or to target specifically bacteria embedded in the biofilm. The purpose of our paper is to review the patho-physiology of this mysterious pluri-cellular structure and to summarize some of the most pertinent research performed to improve diagnostic and treatment strategies in biofilm-related infections.

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Neural indices of phonemic discrimination and sentence-level speech intelligibility in quiet and noise: A mismatch negativity study

Publication date: Available online 4 June 2016
Source:Hearing Research
Author(s): Tess K. Koerner, Yang Zhang, Peggy Nelson, Boxiang Wang, Hui Zou
Successful speech communication requires the extraction of important acoustic cues from irrelevant background noise. In order to better understand this process, this study examined the effects of background noise on mismatch negativity (MMN) latency, amplitude, and spectral power measures as well as behavioral speech intelligibility tasks. Auditory event-related potentials (AERPs) were obtained from 15 normal-hearing participants to determine whether pre-attentive MMN measures recorded in response to a consonant and vowel change in a double-oddball paradigm can predict sentence-level speech perception. The results showed that background noise increased MMN latencies and decreased MMN amplitudes with a reduction in the theta frequency band power. Differential noise-induced effects were observed for the pre-attentive processing of consonant and vowel changes due to different degrees of signal degradation by noise. Linear mixed-effects models further revealed significant correlations between the MMN measures and speech intelligibility scores. These results confirm the utility of MMN as an objective neural marker for understanding noise-induced variations as well as individual differences in speech perception, which has important implications for potential clinical applications.



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Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Accelerates the Progression of Renal Fibrosis in Lupus Nephritis by Activating SMAD and p38 MAPK in TGF-β1 Signaling Pathway

This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used for in vivo experiments and human proximal tubular cells (HK2 cells) were used for in vitro experiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, and α-SMA proteins. In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway.

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Errors as a Means of Reducing Impulsive Food Choice

Giving in to temptation of tasty food may result in long-term overweight problems. This protocol describes how to reduce imprudent preference for edible commodities during hypothetical intertemporal choices in women by associating them with errors.

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Assessing stability in mild and moderate Parkinson’s disease: Can clinical measures provide insight?

Publication date: Available online 5 June 2016
Source:Gait & Posture
Author(s): Ryan P. Hubble, Peter A. Silburn, Geraldine A. Naughton, Michael H. Cole
This cross-sectional study aimed to investigate the relationship between accelerometer-derived measures of movement rhythmicity and clinical measures of mobility, balance confidence and gait difficulty in people with Parkinson's disease (PD). Twenty-nine independently-living PD patients (Hoehn & Yahr stages 1-3) with no history of significant injury or orthopaedic/deep brain stimulation surgery were recruited from a database of patients who had expressed an interest to participate in research. Participants completed clinical assessments of mobility, postural stability, balance confidence and symptom severity, while head and trunk rhythmicity was evaluated during gait using accelerometers. Following data collection, patients were stratified based on disease stage into either a Mild (Hoehn & Yahr Stage 1) or Moderate (Hoehn & Yahr Stages 2 to 3) PD group. The results highlighted that the Moderate PD group had poorer quality of life, reduced balance confidence and increased gait and falls difficulty. Furthermore, for these patients, gait disability and the number of previous falls were both negatively correlated with multiple components of head and trunk rhythmicity. For the Mild PD group, six-meter walk time was positively correlated with ML head rhythmicity and linear regression highlighted a significant predictive relationship between these outcomes. For the Mild and Moderate PD groups, balance confidence respectively predicted anterior-posterior trunk rhythmicity and vertical head rhythmicity. While these findings demonstrate that falls history and the Gait and Falls questionnaire provide moderate insight into head and trunk rhythmicity in Moderate PD patients, objective and clinically-feasible measures of postural instability would assist with the management of these symptoms.



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Is age an independent risk factor for medical complications following minimally invasive radical prostatectomy? An evaluation of contemporary American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) data

Abstract

While robotic-assisted laparoscopic radical prostatectomy (RALRP) is an effective treatment for localized prostate cancer, the risk of complications in older patients can be a deterrent to surgery. We evaluated the rate of medical complications following RALRP in a national dataset of safety events, and assessed whether age is an independent risk factor for these complications. Retrospective analysis of patients undergoing RALRP between 2009 and 2012 in the prospectively maintained American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database was performed. Demographic and comorbid data were collated, medical complications occurring during the 30-day post-operative period were identified. We identified age-related comorbidities, and complications associated with these comorbidities. A binary logistic regression model with age and age-related comorbidities as predictors and specific complication as outcome, was used to evaluate whether age is an independent risk factor for these complications. 12,123 patients underwent RALRP between 2009 and 2012, with a mean age of 62 (22–92). Post-operative medical complications included urinary tract infection (UTI) (1.77 %), deep venous thrombosis (DVT) (0.67 %), pulmonary embolism (PE) (0.45 %), pneumonia (PNA) (0.27 %), myocardial infarction (MI) (0.12 %), and cerebrovascular accident (CVA) (0.01 %). Nine comorbidities were positively correlated with age (p < 0.05). Four medical complications were associated with these age-related comorbidities: MI, CVA, PNA, and UTI. On multivariate analysis, age was an independent risk factor for post-operative PNA (p < 0.05), but not for MI (p = 0.09), UTI (p = 0.3) or CVA (p = 0.2). Patient age was independently associated with post-operative pneumonia only. These data suggest that RALRP can be considered as a treatment option in selected older patients with minimal increased risk for post-operative complications.

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Apoptosis-associated protein expression in human salivary gland morphogenesis

Publication date: September 2016
Source:Archives of Oral Biology, Volume 69
Author(s): Tathyane H.N. Teshima, Renata C.F. Ianez, Claudia M. Coutinho-Camillo, Abigail S. Tucker, Silvia V. Lourenço
ObjectiveSalivary gland (SG) development is based on branching morphogenesis, in which programmed cell death has been proposed to play a role in cell signalling and organ shaping. In the mouse salivary gland apoptosis has been suggested to play a key role in lumen formation, removing the central cells of the epithelial stalks. Here we analyse the expression of several anti- and pro-regulators of apoptosis during human SG development in a range of developmental stages.DesignFoetal SGs obtained from the University of São Paulo were analysed by immunohistochemistry to assess the expression of apoptosis-associated proteins: caspases (caspase-6, -7, -9 and cleaved caspase-3), Bcl-2 family members (Bax, Bak, Bad, Bid, Bcl-2, Bcl-x and Bcl-xL), Survivin (BIRC5), Cytochrome C and Apaf-1.ResultsNuclear expression of Bax and Bak was identified in presumptive luminal areas at initial stages, while Bcl-xL showed the most relevant anti-apoptotic activity. Caspase-6, -7 and -9 were expressed during all stages, while interestingly cleaved caspase-3 showed no prominent expression, indicating that caspase-7 is the main effector. Apoptosome complex components Apaf-1 and Cytochrome C, as well as survivin were all positive in developing glands.ConclusionsThe particular expression pattern of several apoptotic regulators in human SG development suggests the existence of a fundamental role for apoptosis during duct formation. The absence of Bad and Bid expressions indicates that the instrinsic pathway is more active then the extrinsic during human gland formation. The subcellular localisation of intrinsic-apoptosis proteins correlated with apoptotic activity, but also suggested additional non-apoptotic functions.



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TWiV 392: Zika virus!

Four virologists discuss our current understanding of Zika virus biology, pathogenesis, transmission, and prevention, in this special live episode recorded at the American Society for Microbiology in Washington, DC.

Host: 

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Pimavanserin: First Global Approval

Abstract

Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT_2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis.

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