Understanding the relationship between patient language and outcomes in internet-enabled cognitive behavioural therapy: A deep learning approach to automatic coding of session transcripts.

Objective: Understanding patient responses to psychotherapy is important in developing effective interventions. However, coding patient language is a resource-intensive exercise and difficult to perform at scale. Our aim was to develop a deep learning model to automatically identify patient utterances during text-based internet-enabled Cognitive Behavioural Therapy and to determine the association between utterances and clinical outcomes. Method: Using 340 manually annotated transcripts we trained a deep learning model to categorize patient utterances into one or more of five categories. The model was used to automatically code patient utterances from our entire data set of transcripts (∼34,000 patients), and logistic regression analyses used to determine the association between both reliable improvement and engagement, and patient responses. Results: Our model reached human-level agreement on three of the five patient categories. Regression analyses revealed that increased counter change-talk (movement away from change) was associated with lower odds of both reliable improvement and engagement, while increased change-talk (movement towards change or self-exploration) was associated with increased odds of improvement and engagement. Conclusions: Deep learning provides an effective means of automatically coding patient utterances at scale. This approach enables the development of a data-driven understanding of the relationship between therapist and patient during therapy.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.

Adaptive autobiographical memory in younger and older adults: the indirect association of integrative and instrumental reminiscence with depressive symptoms.

Despite the established effectiveness of reminiscence-based interventions for depression, little research exists into the pathways through which specific reminiscence functions are related to depressive symptoms. Drawing on theory of the mechanisms of change in cognitive-reminiscence therapy, the current study tests the hypothesised indirect associations of adaptive integrative and instrumental reminiscence functions with depressive symptoms and whether these relationships might differ among younger and older adults. Questionnaires were completed by a large community sample of the Australian population. Multiple mediation models were tested in two groups: younger adults (n = 730, M age = 52.24, SD=9.84) and older adults (n = 725, M age= 73.59, SD=6.29). Results were consistent across age groups, indicating that there was direct relationship between these reminiscence functions and depressive symptoms, but that integrative reminiscence is indirectly associated with depressive symptoms through meaning in life, self-esteem, and optimism, and that instrumental reminiscence is indirectly associated with depressive symptoms through primary control and self-efficacy. This study provides support for the relationships between constructs underlying the proposed mechanisms of change in cognitive-reminiscence therapy for the treatment of depression, and suggests these relationships are similar for younger and older adults.

Apoptosome-dependent caspase activation proteins as prognostic markers in Stage II and III colorectal cancer.

BACKGROUND: Critical to successful execution of mitochondrial-mediated apoptosis is apoptosome formation and subsequent activation of caspases. Defects in this pathway have an important role in colorectal carcinogenesis and chemoresistance; therefore, the expression of apoptosome-associated proteins may be associated with clinical outcome and response to chemotherapy. METHODS: Here we performed a systematic analysis of the immunohistochemical expression of the key proteins involved in apoptosome-dependent caspase activation (APAF1, Pro-caspases 9 and 3, SMAC, and XIAP) in a cohort of Stage II and III colorectal cancer patients from a Phase III trial of adjuvant 5-fluorouracil-based chemotherapy vs postoperative observation alone. RESULTS: Survival analysis indicated that of the apoptosome-associated proteins examined here, Pro-caspase 3 and APAF1 have potential clinical utility as predictive markers in Stage II and III colorectal cancer, respectively. Interestingly, we identified APAF1 staining to be associated with better recurrence-free and overall survival in patients receiving chemotherapy. CONCLUSION: These studies reveal the importance of the apoptosome-dependent caspase activation pathway, specifically Pro-caspase 3 and APAF1 proteins, for predicting both prognosis and response to therapy.

PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma.

BACKGROUND: Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells. METHODS: Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples. RESULTS: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late-stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates. CONCLUSIONS: This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis.

Human IgG antibody profiles differentiate between symptomatic patients with and without colorectal cancer.

OBJECTIVE: Patients with cancer have antibodies against tumour antigens. Characterising the antibody repertoire may provide insights into aberrant cellular mechanisms in cancer development, ultimately leading to novel diagnostic or therapeutic targets. The aim of this study was to characterise the antibody profiles in patients whose symptoms warranted colonoscopy, to see if there was a difference in patients with and without colorectal cancer. METHODS: Patients were recruited from a colonoscopy clinic. Individual serum samples from 43 patients with colorectal cancer and 40 patients with no cancer on colonoscopy were profiled on a 37 830 clone recombinant human protein array. Antigen expression was evaluated by quantitative reverse transcription-PCR and by immunohistochemistry on tissue microarrays. RESULTS: Using a sex- and age-matched training set, 18 antigens associated with cancer and 4 associated with the absence of cancer (p<0.05) were identified and confirmed. To investigate the mechanisms triggering antibody responses to these antigens, antigen expression was examined in normal colorectal mucosa and colorectal carcinoma of the same patients. The identified antigens showed cellular accumulation (p53), aberrant cellular expression (high mobility group B1 (HMGB1)) and overexpression (tripartite motif-containing 28 (TRIM28), p53, HMGB1, transcription factor 3 (TCF3), longevity assurance gene homologue 5 (LASS5) and zinc finger protein 346 (ZNF346)) in colorectal cancer tissue compared with normal colorectal mucosa. CONCLUSIONS: It is demonstrated for the first time that screening high-density protein arrays identifies unique antibody profiles that discriminate between symptomatic patients with and without colorectal cancer. The differential expression of identified antigens suggests their involvement in aberrant cellular mechanisms in cancer.

Aberrant DNA methylation associated with MTHFR C677T genetic polymorphism in cutaneous squamous cell carcinoma in renal transplant patients.

BACKGROUND: Changes in genomic DNA methylation associated with cancer include global DNA hypomethylation and gene-specific hyper- or hypomethylation. We have previously identified a genetic variant in the MTHFR gene involved in the methylation pathway which confers risk for the development of squamous cell carcinoma (SCC) in renal transplant patients. This genetic variant has also been discovered to confer SCC risk in nontransplant patients with low folate status. OBJECTIVES: To explore the methylation profile of SCC compared with adjacent non-neoplastic skin using pyrosequencing, and to elucidate whether the MTHFR polymorphism impacts upon the methylation patterns in SCC. METHODS: We used pyrosequencing to evaluate global (using long interspersed nuclear element 1) and gene-specific (p16 and MGMT) methylation status in 47 SCCs and 40 adjacent autologous non-neoplastic skin samples in those with (n = 16) and without (n = 17) the MTHFR polymorphism. RESULTS: Pyrosequencing methylation analysis revealed that SCC was hypomethylated compared with adjacent non-neoplastic skin (P < 0.04). Patients with the MTHFR polymorphism had higher levels of global methylation in tumours and non-neoplastic skin compared with those without the MTHFR polymorphism (P < 0.002). There was no association between levels of methylation in tumour and non-neoplastic skin for the genes MGMT and p16. CONCLUSIONS: Global hypomethylation appears to be a feature of SCC. Aberrant methylation of DNA appears related to polymorphisms of MTHFR. Such findings suggest that intervention in the form of demethylating agents or folate supplementation might be beneficial in the treatment or prevention of SCC.

A developmental theory of environmental enrichment.

The differential brain development induced by sensory enrichment or deprivation is most apparent in rats with low brain weights. These differences are hypothesized to represent the retarded development of environment-dependent neurons in the isolated animals.

Learned histamine release.

Most of the effort directed at understanding the problems of allergy has focused on the interacting components of the immune system. The possibility that histamine may be released as a learned response has now been tested. In a classical conditioning procedure in which an immunologic challenge was paired with the presentation of an odor, guinea pigs showed a plasma histamine increase when presented with the odor alone. This suggests that the immune response can be enhanced through activity of the central nervous system.

Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis.

The optimum teicoplanin loading dose and duration of therapy required for rapid attainment of a therapeutic trough plasma concentration (C(min)) (> or = 10mg/L for serious Gram-positive infections and > or = 20mg/L for deep-seated infections) are not known. In this open-label, multicentre, observational study, teicoplanin levels were determined following administration of loading doses of 6 mg/kg every 12h on Day 1 followed by 6 mg/kg once or twice daily to hospitalised patients with suspected or diagnosed Gram-positive infections. C(min) levels for the first 4 days of treatment were collected 15min prior to drug administration. Levels were determined with an Abbott TDx/FLx Analyzer and Seradyn Teicoplanin Innofluor Assay Kit. The two target trough values (> or = 10mg/L and > or = 20mg/L) were only achieved by Day 4 in the once-daily group (n=34; mean 9.55 mg/L, 95% confidence interval (CI) 8.17-10.94 mg/L) and in the twice-daily group (n=40; mean 21.8 mg/L, 95% CI 17.21-26.39 mg/L), respectively. However, the mean C(min) in the twice-daily group was > or = 10mg/L (11.03 mg/L) by Day 2. To achieve rapid therapeutic C(min) concentrations targeted for the majority of serious Gram-positive infections, we recommend teicoplanin loading doses of 6 mg/kg every 12h for 48h followed by once-daily for infections other than infective endocarditis, septic arthritis and osteomyelitis. Regarding the latter infections, higher loading doses might be warranted to reach rapid steady-state concentrations.

Meaning in Life in Earlier and Later Older-Adulthood: Confirmatory Factor Analysis and Correlates of the Meaning in Life Questionnaire.

OBJECTIVE: To validate the Meaning in Life Questionnaire (MLQ) in earlier and later older-adulthood, and examine its correlates. METHOD: Participants in earlier ( n = 341, M age = 68.5) and later older-adulthood ( n = 341, M age = 78.6) completed the MLQ and other measures. Confirmatory multigroup analysis, correlations, and regression models were conducted. RESULTS: A two-factor (presence and search), eight-item model of the MLQ had a good fit and was age-invariant. Presence and search for meaning were largely unrelated. Meaning was associated with life satisfaction, well-being across a range of domains, and psychological resources. Searching for meaning correlated negatively with these variables, but to a lesser degree in later older-adulthood. DISCUSSION: The MLQ is valid in older-adulthood. Meaning in life is psychologically adaptive in older-adulthood. Searching for meaning appears less important, especially in later older-adulthood. Findings are discussed in the context of aging and psychosocial development.

Activities of some enzymes of pyrimidine and DNA synthesis in a rat transplantable hepatoma and human primary hepatomas, in cell lines derived from these tissues, and in human fetal liver.

Activites of the enzymes DNA polymerase, thymidine kinase, thymidylate kinase, thymidylate synthase, and deoxycytidylate deaminase have been measured in rat and human normal and neoplastic liver, in human fetal liver, and in cell lines derived from human hepatomas and rat transplantable hepatomas. The activities of these enzymes were increased in rat transplantable hepatomas, relative to rat normal or host liver, to a degree corresponding to the rapid growth rate of these tumors. With the exception of thymidine kinase, which did not change, the activities of these enzymes increased in human hepatomas relative to the corresponding host liver (apparently normal liver tissue from the same patient) and to human normal liver. The increases in enzyme activity observed in human hepatomas were small in comparison with those found in the rapidly growing rat hepatomas. The activities of deoxycytidylate deaminase in both human and rat liver tissues were 2 to 3 orders of magnitude higher than those of the other enzymes assayed. Activities of the enzymes of DNA synthesis in a slow-growing cell line derived from a human hepatoma were similar to those in human hepatoma tissues. In the case of rapidly growing cell lines derived from rat and human hepatomas, enzyme activities were higher than those in the corresponding tissues.

Caregiver perceptions about the impact of caring for patients with wet age-related macular degeneration.

PURPOSE: Caregivers of older persons with eye disease, namely age-related macular degeneration (AMD), have been reported to have a higher than expected distress. Very few studies have explored caregiver perceptions as to what is important when providing care. The aim of this study was to explore the perceptions of caregivers of persons with neovascular AMD in relation to the most important aspects of caring, as described in extended answers to self-administered survey questions. METHODS: A cross-sectional, self-administered survey of 643 caregivers of people with neovascular AMD, comprising 27 closed-response questions and 2 open ended questions. The latter were analysed as part of this study utilising and 'inductive' Grounded Theory approach. RESULTS: Six-hundred and forty-three caregiver responses to 2 open ended questions were analysed using an inductive approach and sorted into thematic networks. Three discrete categories arose: The Impact of Caring; Injections and Information and Activities of Daily Living. CONCLUSIONS: Most caregivers were family caregivers and were found to be compassionate and self-sacrificing. They accepted additional responsibility whilst providing an encouraging environment for their care recipient. As a result, they experience distress and consider their own needs as secondary. Very few seek or receive respite and this added burden can have a negative impact upon the relationship between caregiver and care recipient.

A new rhythm library for testing automatic external defibrillators: performance of three devices.

A library of arrhythmias obtained from patients with cardiac arrest was developed. Such a data base will permit both in vitro testing of the rhythm analysis system of automatic external defibrillators before clinical field trials are conducted and comparison of devices. Defibrillators equipped with voice/electrocardiographic tape recorders and used in the prehospital defibrillation programs in Iowa and King County, Washington provided the rhythm source. From these recordings, segments of ventricular fibrillation with minimal artifact and a duration of greater than or equal to 6 s were selected. Segments of ventricular fibrillation (n = 102) were categorized by average peak amplitude as fine (1 to less than 3 mm), medium (3 to less than 7 mm), coarse (7 to less than 12 mm) and extra coarse (greater than or equal to 12 mm), and transcribed onto high fidelity videocassette tapes. Nonventricular fibrillation cardiac arrest rhythms (n = 144), which included wide complex idioventricular rhythms, ventricular and supraventricular tachycardias, asystole and artifact, were also transcribed. Automatic external defibrillators developed by three manufacturers reached a treat (shock) decision on 88 to 93% of the ventricular fibrillation rhythms and on 5 to 10% of the nonventricular fibrillation rhythms. The latter decisions were defined as false positive, though for many rapid nonventricular fibrillation rhythms, countershock may be the appropriate treatment response. There were no statistically significant differences among the three devices in the shock/no shock decisions. A variety of ventricular fibrillation arrhythmias and terminology to express the preclinical performance of automatic external defibrillators are defined. Three commercially available automatic external defibrillators appear to successfully identify ventricular fibrillation and nonventricular fibrillation rhythms.(ABSTRACT TRUNCATED AT 250 WORDS)

The menstrual cycle, personality, and academic performance.

Considerable research supports the widespread complaint of mood and behavioral changes during the menstrual cycle. However, there is little evidence of effects on intellectual performance, even though students commonly complain of it. We studied the results obtained by 244 female medical and paramedical students in all examinations taken during one year. In view of suspected correlations between personality characteristics and degree of dysmenorrhea, an Eysenck Personality Inventory, measuring extroversion and neuroticism, was administered. The examination results of high and low scorers on these personality scales and of those women with prolonged (greater than or equal to six days) menses were reanalyzed. Not one of these analyses revealed significant menstrual-cycle effects on examination performance. Thus, while some persons may suffer, it does not seem that menstrual cycle effects are sufficient to handicap significantly the examination performance of the majority of female students.

Disseminated Strongyloides stercoralis infection. Association with ectopic ACTH syndrome and depressed cell-mediated immunity.

A patient with disseminated Strongyloides stercoralis was evaluated to elucidate host factors that may have led to the development of this infection. The patient was found to have oat cell carcinoma with hypercortisolism produced by tumor adrenocorticotropic hormone. His serum contained a potent inhibitor of lymphocyte blastogenesis. This patient's high level of endogenous cortisol may have impaired lymphocyte function and thereby facilitated infection with S stercoralis.

Ovulating ovary in an inguinal hemia.

BACKGROUND: An ovary can, occasionally, be found in an inguinal hernia in the newborn female. This is extremely rare in premenopausal women. We report a case of an ovulating ovary in an incarcerated inguinal hernia. There is only one similar case of incarcerated ovulating ovary reported in the literature. METHOD AND FINDINGS: A 23-year-old Turkish woman, mother of three children, presented with a painful swelling over the upper part of left labia majora of 48 hours duration. She was diagnosed as having an obstructed left inguinal hernia. At operation the left ovary and fallopian tube were seen in the left inguinal canal. The ovary and fallopian tube were congested but viable and mature ovarian follicles could be seen on the ovary. A biopsy was taken from the ovary, the ovary and the fallopian tube were easily reduced back into the abdominal cavity and the hernia repaired. DISCUSSION: The presence of an ovary in the inguinal canal is very rare and should be a differential diagnosis in women presenting with an irreducible lump in the inguinal area. It should be treated as a surgical emergency.

Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes.

Epidermolysis bullosa simplex is a heterogeneous group of inherited bullous disorders due to mutations in keratins 5 and 14. We report two different mutations in keratin 14 at codon 119 of the helix initiation peptide, each with different phenotypic expression. One, a sporadic case that clinically resembles Dowling-Meara epidermolysis bullosa simplex, resulted from conversion of methionine to threonine (M119T). The other, a multigeneration family with the Koebner phenotype, resulted from a previously unreported methionine to valine substitution (M119V). We suggest that loss of hydrophobicity during conversion of methionine to threonine is responsible for the more severe presentation of the first family, whereas maintenance of the hydrophobic nature of the amino acid with conversion to valine resulted in a less severe variant of epidermolysis bullosa simplex. Although most prior mutations in the highly conserved boundary motif of the alpha-helix have resulted in the Dowling-Meara subtype, our findings confirm that it is not always possible to predict the epidermolysis bullosa simplex severity on the basis of the location of the mutation along the keratin polypeptide. The specific amino acid substitution may be more critical in some cases.

Use of the automatic external defibrillator in homes of survivors of out-of-hospital ventricular fibrillation.

This 57-month study evaluated the use of automatic external defibrillators (AEDs) in the homes of high risk cardiac patients (survivors of out-of-hospital ventricular fibrillation [VF]). The goal was to determine the utility of these devices by trained lay persons in actual cardiac arrest episodes. Ninety-seven survivors of out-of-hospital VF were enrolled in the study; 59 patients received AEDs, and 38 patients served as a control group. During the study period, 7 deaths occurred in the hospital without preceding out-of-hospital cardiac arrest or from noncardiac causes. There were 14 out-of-hospital cardiac arrests, 10 in the AED group and 4 in the control group. There was 1 long-term survivor in the control group. In the AED group, among the 10 cardiac arrests for which the device was available, it was used in 6. Only 2 patients were in VF; 1 was resuscitated with residual neurologic deficits and survived several months. This study observed a small potential for AEDs to save high risk patients.